IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is caused in part by a dysregulated immune response to the intestinal flora. The common interleukin (IL)-12/IL-23p40 subunit is thought to be critical for the pathogenesis of IBD. We have analyzed the role of IL-12 versus IL-23 in two models of Helicobacter hepaticus-triggered T cell-dependent colitis, one involving anti-IL-10R monoclonal antibody treatment of infected T cell-sufficient hosts, and the other involving CD4+ T cell transfer into infected Rag-/- recipients. Our data demonstrate that IL-23 and not IL-12 is essential for the development of maximal intestinal disease. Although IL-23 has been implicated in the differentiation of IL-17-producing CD4+ T cells that alone are sufficient to induce autoimmune tissue reactivity, our results instead support a model in which IL-23 drives both interferon gamma and IL-17 responses that together synergize to trigger severe intestinal inflammation.


Community-driven development for computational biology at Sprints, Hackathons and Codefests.
Computational biology comprises a wide range of technologies and approaches. Multiple technologies can be combined to create more powerful workflows if the individuals contributing the data or providing tools for its interpretation can find mutual understanding and consensus. Much conversation and joint investigation are required in order to identify and implement the best approaches. Traditionally, scientific conferences feature talks presenting novel technologies or insights, followed up by informal discussions during coffee breaks. In multi-institution collaborations, in order to reach agreement on implementation details or to transfer deeper insights in a technology and practical skills, a representative of one group typically visits the other. However, this does not scale well when the number of technologies or research groups is large. Conferences have responded to this issue by introducing Birds-of-a-Feather (BoF) sessions, which offer an opportunity for individuals with common interests to intensify their interaction. However, parallel BoF sessions often make it hard for participants to join multiple BoFs and find common ground between the different technologies, and BoFs are generally too short to allow time for participants to program together. This report summarises our experience with computational biology Codefests, Hackathons and Sprints, which are interactive developer meetings. They are structured to reduce the limitations of traditional scientific meetings described above by strengthening the interaction among peers and letting the participants determine the schedule and topics. These meetings are commonly run as loosely scheduled "unconferences" (self-organized identification of participants and topics for meetings) over at least two days, with early introductory talks to welcome and organize contributors, followed by intensive collaborative coding sessions. We summarise some prominent achievements of those meetings and describe differences in how these are organised, how their audience is addressed, and their outreach to their respective communities. Hackathons, Codefests and Sprints share a stimulating atmosphere that encourages participants to jointly brainstorm and tackle problems of shared interest in a self-driven proactive environment, as well as providing an opportunity for new participants to get involved in collaborative projects.


Asthma Across Age: Insights From Primary Care.
Asthma is a heterogeneous disease comprising of multiple phenotypes and affects patients from childhood up to old age. In this review, we summarize the current knowledge on the similarities and differences in asthma across different age-groups, with emphasis on the perspective from primary care. Despite the similar disease presentation, phenotyping studies showed that there are differences in the distribution of phenotypes of asthma presenting in childhood compared to that in adulthood. Whereas, asthma with early age of onset tends to be of the atopic phenotype, the disease shifts toward the non-atopic phenotypes at later ages. Studies within primary care patients aiming to elucidate risk factors for future asthma exacerbation have shown pediatric and elderly patients to be at higher risk for future asthma attacks compared to other adult patients. Regardless, both pediatric and adult studies demonstrated previous asthma episodes and severity, along with high blood eosinophil to predict subsequent asthma attacks. Differences in childhood and adult asthma are not limited to the underlying phenotypes but also extends to the challenges in the diagnosis, treatment, and management of the disease. Diagnosis of asthma is complicated by age-specific differential diagnoses such as infectious wheezing and nasal obstruction in children, and aging-related problems such as heart disease and obesity in the elderly. There are also age-related issues leading to decreased disease control such as non-adherence, tobacco use, difficulty in using inhalers and corticosteroid-related side effects which hinder asthma control at different patient age-groups. Several clinical guidelines are available to guide the diagnosis and drug prescription of asthma in pediatric patients. However, there are conflicting recommendations for the diagnostic tools and treatment for pediatric patients, posing additional challenges for primary care physicians in working with multiple guidelines. While tools such as spirometry and peak flow variability are often available in primary care, their usage in preschool patients is not consistently recommended. FeNO measurement may be a valuable non-invasive tool which can be adopted by primary physicians to assist asthma diagnosis in preschool-age patients.


Task- and resting-state functional connectivity of brain regions related to affection and susceptible to concurrent cognitive demand.
A recent fMRI-study revealed neural responses for affective processing of stimuli for which overt attention irrespective of stimulus valence was required in the orbitofrontal cortex (OFC) and bilateral amygdala (AMY): activation decreased with increasing cognitive demand. To further characterize the network putatively related to this attenuation, we here characterized these regions with respect to their functional properties and connectivity patterns in task-dependent and task-independent states. All experiments of the BrainMap database activating the seed regions OFC and bilateral AMY were identified. Their functional characteristics were quantitatively inferred using the behavioral meta-data of the retrieved experiments. Task-dependent functional connectivity was characterized by meta-analytic connectivity modeling (MACM) of significant co-activations with these seed regions. Task-independent resting-state functional connectivity analysis in a sample of 100 healthy subjects complemented these analyses. All three seed regions co-activated with subgenual cingulum (SGC), precuneus (PCu) and nucleus accumbens (NAcc) in the task-dependent MACM analysis. Task-independent resting-state connectivity revealed significant coupling of the seeds only with the SGC, but not the PCu and the NAcc. The former region (SGC) moreover was shown to feature significant resting-state connectivity with all other regions implicated in the network connected to regions where emotional processing may be modulated by a cognitive distractor. Based on its functional profile and connectivity pattern, we suggest that the SGC might serve as a key hub in the identified network, as such linking autobiographic information [PCu], reward [NAcc], (reinforce) values [OFC] and emotional significance [AMY]. Such a role, in turn, may allow the SGC to influence the OFC and AMY to modulate affective processing.


Physical demands of professional rugby league training and competition using microtechnology.
To investigate the physical demands of professional rugby league match-play using microtechnology, and to compare these demands with typical training activities used to prepare players for competition. Prospective cohort study. Thirty elite rugby league players participated in this study. Seven hundred and eighty-six. training data sets and 104 data sets from National Rugby League matches were collected over one playing season. Movement was recorded using a commercially available microtechnology unit (minimaxX, Catapult Innovations), which provided information on speeds, distances, accelerations, physical collisions and repeated high-intensity efforts. Mean distances covered during match-play by the hit-up forwards, wide-running forwards, adjustables, and outside backs were 3,569 m, 5,561 m, 6,411 m, and 6,819 m, respectively. Hit-up forwards and wide-running forwards were engaged in a greater number of moderate and heavy collisions than the adjustables and outside backs, and more repeated high-intensity effort bouts per minute of play (1 bout every 4.8-6.3 min). The physical demands of traditional conditioning, repeated high-intensity effort exercise, and skill training activities were all lower than the physical demands of competition. These results demonstrate that absolute distances covered during professional rugby league matches are greater for outside backs, while the collision and repeated high-intensity effort demands are higher for hit-up forwards and wide-running forwards. The specific physical demands of competitive play, especially those demands associated with collisions and repeated high-intensity efforts, were not well matched by those observed in traditional conditioning, repeated high-intensity effort exercise, and skills training activities. Further research is required to investigate whether modifications need to be made to these training activities to better prepare players for the demands of National Rugby League competition.


Characterization of lipid-protein interactions in acetylcholinesterase lipoprotein extracted from bovine erythrocytes.
Acetylcholinesterase was released from bovine erythrocytes in hypo-osmotic sodium phosphate buffer. Initially, about 30% of the enzyme was released in a soluble lipoprotein form, and further incubation resulted in the progressive release of the enzyme in a particulate form. Solubilization of the acetylcholinesterase in the particulate fraction with Lubrol WX (2 mg/ml) resulted in the loss of all lipids except a non-exchangeable fraction identified as cardiolipin. Addition of a mixture of erythrocyte phospholipids to the soluble forms and to the Lubrol WX-solubilized enzyme resulted in the formation of particulate forms of the enzyme with increased partial specific volume and Stokes radius, and a break in the Arrhenius plot of the enzyme activity around 20 degrees C. The break in the Arrhenius plot was abolished by treatment of a soluble enzyme preparation with 1.8 M salt (NaCl) in phosphate buffer, conditions that allowed the extraction of cardiolipin from the enzyme by chloroform/methanol. Failure of the high-salt treatment to decrease the Stokes radius made it unlikely that the bound cardiolipin formed a boundary layer or annulus around the protein. It is suggested that cardiolipin is bound to the core of the dimeric protein structure, thereby controlling the acetylcholinesterase activity.


Learning to Approximate Density Functionals.
Density functional theory (DFT) calculations are used in over 40,000 scientific papers each year, in chemistry, materials science, and far beyond. DFT is extremely useful because it is computationally much less expensive than ab initio electronic structure methods and allows systems of considerably larger size to be treated. However, the accuracy of any Kohn-Sham DFT calculation is limited by the approximation chosen for the exchange-correlation (XC) energy. For more than half a century, humans have developed the art of such approximations, using general principles, empirical data, or a combination of both, typically yielding useful results, but with errors well above the chemical accuracy limit (1 kcal/mol). Over the last 15 years, machine learning (ML) has made major breakthroughs in many applications and is now being applied to electronic structure calculations. This recent rise of ML begs the question: Can ML propose or improve density functional approximations? Success could greatly enhance the accuracy and usefulness of DFT calculations without increasing the cost.In this work, we detail efforts in this direction, beginning with an elementary proof of principle from 2012, namely, finding the kinetic energy of several Fermions in a box using kernel ridge regression. This is an example of orbital-free DFT, for which a successful general-purpose scheme could make even DFT calculations run much faster. We trace the development of that work to state-of-the-art molecular dynamics simulations of resorcinol with chemical accuracy. By training on ab initio examples, one bypasses the need to find the XC functional explicitly. We also discuss how the exchange-correlation energy itself can be modeled with such methods, especially for strongly correlated materials. Finally, we show how deep neural networks with differentiable programming can be used to construct accurate density functionals from very few data points by using the Kohn-Sham equations themselves as a regularizer. All these cases show that ML can create approximations of greater accuracy than humans, and is capable of finding approximations that can deal with difficult cases such as strong correlation. However, such ML-designed functionals have not been implemented in standard codes because of one last great challenge: generalization. We discuss how effortlessly human-designed functionals can be applied to a wide range of situations, and how difficult that is for ML.


Women's satisfaction with decision-making related to augmentation of labour.
to describe women's experiences of participating in decision-making related to augmentation of labour. a qualitative approach using modified grounded theory technique. Open-ended interviews were conducted 1-3 days after childbirth. the interviews were performed in the postnatal wards in five hospitals (tertiary level) in Stockholm, Sweden. 20 newly delivered women who had received oxytocin infusion for augmentation of labour during childbirth. FINDINGS AND KEY CONCLUSIONS: support and guidance from midwives in combination with knowledge and expectations about the intervention seemed to be important for women's satisfaction with decision-making concerning augmentation of labour. Four patterns of decision-making were found. One group of women participated in the decision-making regarding augmentation of labour while a second group was invited, but refrained from participation. These women were satisfied with the decisions made. A third group of women did not participate, but wanted to and they were dissatisfied with the decisions made. The fourth group did not participate in the decision-making-and did not want to. These women accepted the decisions made. The desire for information exceeded the desire for involvement in decision-making and the majority of women had confidence in the midwives' assessment.


Polar solvent dynamics and electron-transfer reactions.
Polar solvents often exert a dramatic influence on reactions in solution. Equilibrium aspects of this influence involve differential solvation of reactants compared to the transition state that lead to alteration of the free-energy barrier to reaction. Such effects are well known, and often give rise changes in reaction rates of many orders of magnitude. Less well understood are effects arising from non-equilibrium, dynamical aspects of solvation. During the course of reaction, charge is rapidly redistributed among reactants. How the reaction couples to its solvent environment depends critically on how fast the solvent can respond to these changes in reactant charge distribution. In this article the dynamics of solvation in polar liquids and the influence of this dynamics on electron-transfer reactions are discussed. A molecular picture suggests that polar solvation occurs on multiple time scales as a result of the involvement of different types of solvent motion. A hierarchy of models from a homogeneous continuum model to one incorporating molecular aspects of solvation, combined with computer simulations, gives insight into the underlying dynamics. Experimental measures of solvation dynamics from picosecond and subpicosecond time-dependent Stokes shift studies are compared with the predictions of theoretical models. The implication of these results for electron-transfer reactions in solution are then briefly considered.


Recent changes in cervical cancer screening guidelines: U.S. women's willingness for HPV testing instead of Pap testing.
Cervical cancer screening guidelines in the United States were revised in 2018 to include the option of primary human papillomavirus (HPV) testing. The transition to this screening method may face difficulties as Pap testing has been the primary screening modality in the United States. The objective of this study is to assess information, motivation, and behavioral skills associated with willingness to receive an HPV test instead of a Pap test among women. The sample included U.S. 812 women, ages 30 to 65 years. Participants completed an online survey in 2018. The Information, Motivation, and Behavioral Skills (IMB) model was used to measure predictors of willingness for HPV testing. The outcome variables were willingness to receive the HPV test instead of the Pap test, with and without time interval details. Logistic regression modeling was used with SAS 9.4. Over half of the sample (55%) were willing to receive the HPV test. For the information domain, HPV knowledge was significantly associated with willingness for HPV testing (OR = 1.08, 95%CI 1.04-1.13). Significant motivating factors included: positive attitudes, social norms, perceived benefits, worry about cervical cancer, and worry about abnormal HPV tests. For behavioral skills, women were significantly more willing to get the HPV test if a provider recommended it (OR = 2.43, 95%CI 1.53-3.87) and currently up-to-date on cervical cancer screening guidelines (OR = 1.52, 95%CI 1.52-2.26). Addressing barriers and facilitators to willingness to transition to primary HPV testing over Pap testing is needed as the United States has updated guidelines for cervical cancer screening.


Structural basis for the kinetic differences between flavocytochromes b2 from the yeasts Hansenula anomala and Saccharomyces cerevisiae.
To understand the structural basis for the different catalytic behaviour of the flavocytochromes b2 from Saccharomyces cerevisiae and Hansenula anomala we have cloned and sequenced the gene encoding the latter. We have compared the amino acid sequences of the mature proteins in the context of the known crystal structure of S. cerevisiae flavocytochrome b2. Overall there is 60% sequence identity, but two surface loops in particular are strikingly different in primary structure and net charge.


Tenotomy immobilization as a model to investigate skeletal muscle fibrosis (with emphasis on Secreted frizzled-related protein 2).
The pathological endpoint of congenital and senile myopathies is chronic muscle degeneration characterized by the atrophy of contractile elements, accompanied by fibrosis and fatty infiltration of the interstitium. Tenotomy is the release of preload that causes abrupt shortening of the muscle and models atrophy and fibrosis without prominent inflammatory response. Fibrosis in the skeletal muscle is known to be triggered by transforming growth factor (TGF)-β, which is activated by inflammatory events. As these were lacking, tenotomy provided an opportunity to investigate transcriptional events on a background without inflammation. An unbiased look at the transcriptome of tenotomy-immobilized soleus muscle revealed that the majority of the transcriptional changes took place in the first 4 wk. Regarding atrophy, proteasomal and lysosomal pathways were actively involved in accompanying cathepsins and calpains in the breakdown of the macromolecular contractile machinery. The transcriptome provided clear-cut evidence for the upregulation of collagens and several extracellular matrix components that define fibrotic remodeling of the skeletal muscle architecture as well as activation of the fibro-adipogenic precursors. Concomitantly, Sfrp2, a Wnt antagonist as well as a procollagen processor, accompanied fibrosis in skeletal muscle with an expression that was stringently confined to the slow-twitch fibers. An interpreted mechanistic scenario construed the kinetic events initiated through the abnormal shortening of the muscle fibers as enough to trigger the resident latent TGF-β in the extracellular matrix, leading to the activation of fibroadipogenic precursors. As in the heart, Sfrp2 shows itself to be a therapeutic target for the prevention of irreversible fibrosis in degenerative skeletal muscle conditions.


Abrogation of cyclin D1 expression predisposes lung cancer cells to serum deprivation-induced apoptosis.
Cyclin D1 antisense (D1AS)-transfected lung epithelial cell lines were serum deprived and then analyzed for three hallmarks of apoptosis: appearance of single-strand DNA breaks, alteration of apoptosis-related protein expression, and induction of chromatin condensation. Single-strand DNA breaks appeared at significant levels 24 h after serum deprivation, whereas induction of chromatin condensation was observed after 72 h. The antioxidants dimethyl sulfoxide, ascorbate, and glutathione, as well as insulin-like growth factor-I, inhibited induction of DNA damage in this assay. Additionally, proliferating cell nuclear antigen expression is completely suppressed in the D1AS cells, indicating a mechanism to explain the reduced capacity for DNA repair. Increased expression of cyclin D1, which is a common lesion in lung cancer, may thus prevent induction of apoptosis in an oxidizing and growth factor-poor environment. Reducing cyclin D1 expression in lung cancer cells by expression of D1AS RNA disrupted these protective pathways.


Gene family for an elicitor-induced sesquiterpene cyclase in tobacco.
The initial step in the conversion of the isoprenoid intermediate farnesyl diphosphate to the sesquiterpenoid phytoalexin capsidiol in elicitor-treated tobacco tissues is catalyzed by an inducible sesquiterpene cyclase [5-epi-aristolochene synthase (EAS)]. Two independent cDNA clones (cEAS1 and cEAS2) encoding EAS were isolated from an elicitor-induced tobacco cDNA library by differential hybridization and subsequently were characterized by hybrid selection--in vitro translation. Insertion of cEAS1, a partial cDNA clone encoding 175 C-terminal amino acids, into an Escherichia coli expression vector resulted in accumulation of a fusion protein immunodetectable with EAS-specific polyclonal antibodies. The cDNA clones were used to isolate two full-length EAS genes that mapped 5 kilobases (kb) apart on one 15-kb genomic clone. The nucleotide sequences of the structural gene components were identical from 388 base pairs (bp) upstream of the transcription initiation site to 40 bp downstream of the translation termination codon, suggesting a relatively recent duplication event. The genes consist of 1479-bp open reading frames, each containing five introns and specifying 56,828-Da proteins. The N-terminal amino acid sequence deduced from the genomic clones was identical to the first 16 amino acids of the EAS protein identifiable by Edman degradation. RNA blot hybridization with cEAS1 demonstrated a mRNA induction time course consistent with the induction of the EAS mRNA translational activity with maximum levels 4-6 h after elicitation. EAS mRNA was not detected in control cells. DNA blot-hybridization analysis of genomic DNA revealed a copy number of approximately 12-15 for EAS-like genes in the tetraploid tobacco genome. The conservation of a putative allelic prenyl diphosphate binding motif is also discussed.


Green production of cocrystals using a new solvent-free approach by spray congealing.
Pharmaceutical cocrystals are used as a strategy to overcome poor physicochemical properties of drugs. The use of cocrystals in the pharmaceutical industry remains to be fully exploited due, in part, to the scarcity of suitable large-scale production methods and lack of robust and cost-effective processes. To overcome these challenges, spray congealing was used for the first time in the preparation of cocrystals. The work considered a feasibility study, followed by a design of experiments to assess the impact of varying atomization and cooling-related process parameters on cocrystal formation, purity, particle size, shape and bulk powder flow properties. It was demonstrated that spray congealing could be used to produce cocrystals. The thermal analysis and X-ray results of the spray-congealed products were different from the pure components or physical mixtures and were aligned with those reported for the same cocrystals systems produced by other techniques. Cocrystal particles were compact and spherical consisting of aggregates of individual cocrystals entangled or adhered with each other. From the design of experiments, the results demonstrated that varying the process parameters did not influence cocrystal formation, but had an impact on cocrystal purity. Moreover, it was demonstrated that cocrystal particle properties can be adjusted, in situ, by varying atomization and cooling efficiency, in order to produce particles more suited for incorporation in final dosage forms such as tablets.


Assessment of biochemical parameters and characterization of TNFα -308G/A and PTPN22 +1858C/T gene polymorphisms in the risk of obesity in adolescents.
Obesity is currently considered an inflammatory condition associated with autoimmune diseases, suggesting a common origin. Among other factors, candidate genes may explain the development of this disease. Polymorphisms in the tumor necrosis factor α (TNFα) and lymphoid protein tyrosine phosphatase (PTPN22) genes lead to an increased risk to development of immune and inflammatory diseases. The aim of the present study was to analyze the biochemical parameters and the effect of the TNFα -308G/A and PTPN22 +1858C/T polymorphisms in the susceptibility of adolescents to obesity. A group of 253 adolescent subjects were recruited and classified as obese, overweight or normal weight according to their nutritional status. Anthropometric measurements, clinical and biochemical data were analyzed. DNA was extracted from peripheral blood samples by the phenol-chloroform method, and TNFα -308G/A and PTPN22 1858C/T polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism assays. Clinical, genetic and biochemical parameters were analyzed to determine the existence of a possible association with the development of obesity. Statistically significant differences in body mass index, insulin, triglyceride levels and homeostatic model assessment for insulin resistance (HOMA-IR) index were observed among the three groups analyzed (P≤0.05). The studied polymorphisms did not confer a risk for developing obesity in the analyzed population (P>0.05); however, significantly low levels of insulin and decreased rates of HOMA-IR were observed in the 1858 CT genotype carriers of the PTPN22 gene. In conclusion, no association between the TNFα -308G/A and PTPN22 +1858C/T polymorphisms and the risk to development of obesity in the adolescent population analyzed was observed. However, the 1858 CT genotype of the PTPN22 gene was associated with variations of certain biochemical parameters analyzed.


Essential genes as antimicrobial targets and cornerstones of synthetic biology.
Essential genes are absolutely required for the survival of any living entity. Investigation of essential genes is therefore expected to advance tremendously our understanding of the universal principles of life. Determination of a minimal set of essential genes needed to sustain life also plays an important role in the emerging field of synthetic biology, whose goals include creation of a stringently controlled minimal cell with predesigned phenotypic traits. In addition, due to their indispensability for survival of bacteria, genes encoding essential cellular functions have great potential in medicine as promising targets for the development of novel antimicrobials. Here, we review recent advances in the investigation of essential genes, with emphasis on the practical applications in medicine and synthetic biology.


Distortion-invariant pattern recognition with Fourier-plane nonlinear filters.
The use of nonlinear techniques in the Fourier plane of pattern-recognition correlators can improve the correlators' performance in terms of discrimination against objects similar to the target object, correlation-peak sharpness, and correlation noise robustness. Additionally, filter designs have been proposed that provide the linear correlator with invariance properties with respect to input-signal distortions and rotations. We propose simple modifications to presently known distortion-invariant correlator filters that enable these filter designs to be used in a nonlinear correlator architecture. These Fourier-plane nonlinear filters can be implemented electronically, or they may be implemented optically with a nonlinear joint transform correlator. Extensive simulation results are presented that illustrate the performance enhancements that are gained by the unification of nonlinear techniques with these filter designs.


Non-invasive imaging of carotid arterial restenosis using 3T cardiovascular magnetic resonance.
Restenosis of the carotid artery is common following carotid endarterectomy, but analysis of lesion composition has mostly been based on histological study of explanted restenotic lesions. This study investigated the ability of 3T cardiovascular magnetic resonance (CMR) to determine the components of recurrent carotid artery disease and examined whether these differed from primary atherosclerotic plaque. 50 patients underwent 3T CMR of both carotid arteries using a standard multicontrast protocol: time-of-flight (TOF), T1-weighted (T1W), T2-weighted (T2W), and PD-weighted (PDW) Turbo-Spin-Echo (TSE) sequences. 25 patients had previously undergone carotid endarterectomy (mean time since surgery 1580 days, range 45-6560 days), and 25 with primary asymptomatic atherosclerotic plaques served as controls. Two experienced reviewers analysed the multicontrast CMR images according to the presence or absence of major plaque features and assigned an overall classification type. In patients with recurrent carotid disease following endarterectomy, the mean degree of restenosis was 51% (range 30-90%). Three distinct types of restenosis were identified: 5 patients (20%) showed CMR characteristics of fibro-atheromatous tissue, 11 patients (44%) had plaque features consistent with possible myointimal (fibromuscular) hyperplasia, and 6 patients (24%) had recurrent plaque suggestive of further lipid accumulation. Three patients (12%) showed evidence of post-surgical dissection of the carotid intima. Compared to primary atherosclerotic plaques, restenotic plaques were more likely to contain fibro-atheromatous tissue (p = 0.05) and smooth muscle (p < 0.01), and less likely to contain lipid (p < 0.01). Composition did not differ significantly between patients with early and late restenosis. As defined by CMR, restenotic lesions of the carotid artery fall into three distinct types and differ in composition from primary atherosclerotic plaques. If validated by subsequent histological studies, these findings could suggest a role for CMR in detecting high-risk (i.e. lipid-rich) restenotic lesions.


Awake laminotomy and discectomy using Dexmedetomidine as anesthetic.
Lumbar discectomy is the most common surgical procedure performed in the United States for patients having back and leg symptoms. The vast majority of the procedures are elective and are performed under general anesthesia. This is a reported case of a 40 year old woman with worsening symptoms of L5-S1 disc herniation unresponsive to conventional therapies. The use of Dexmedetomidine was discussed with the patient, explaining the advantage of motor and sensory testing during the surgery and immediate patient feedback. Awake laminotomy and discectomy could be performed as an ambulatory procedure, since the use of Dexmedetomidine as the main anesthetic represents a safe and convenient alternative to general anesthesia in this patient with lumbar disc herniation.


Physical activity questionnaire comprehension: lessons from cognitive interviews.
To determine whether respondents share researchers' understandings of concepts and questions frequently used in the assessment of usual physical activity (PA) behavior. As part of On the Move, a study aimed at reducing measurement error in self-reported physical activity (PA), we conducted cognitive interviews with 19 men and 21 women, ages 45-65, regarding their responses to the PA questionnaires used in two large, population-based studies, Life After Cancer Epidemiology and California Men's Health study. One questionnaire asks about the frequency, the duration, and the perceived intensity of a range of specific activities in several different domains over the past 12 months. The second questionnaire asks about frequency and duration of specific, mostly recreational activities, grouped by intensity (i.e., moderate or vigorous) over the past 3 months. We used verbal probing techniques to allow respondents to describe their thought processes as they completed the questionnaires. All interviews were tape-recorded and transcribed, and the transcripts were then analyzed using standard qualitative methods. Cognitive interviews demonstrated that a sizable number of respondents understood "intensity" in terms of emotional or psychological intensity rather than physical effort. As a result, the perceived intensity with which a participant reported doing a specific activity often bore little relationship to the MET value of that activity. Additionally, participants often counted the same activity more than once, overestimated work-related PA, and understood activities that were grouped together in a single category to be definitive lists rather than examples. Cognitive interviews revealed significant gaps between respondents' interpretations of some PA questions and researchers' assumptions about what those questions were intended to measure. Some sources of measurement error in self-reported PA may be minimized by additional research that focuses on the cognitive processes required to respond to PA questionnaires.


Pharmacological treatment of depression in geriatric chronic pain patients: a biopsychosocial approach integrating functional restoration.
A recent literature review concluded that the comorbidity of chronic pain and depression in adults is approximately 50%-65%. Physical and cognitive declines, concurrent multiple health conditions, and complex medication regimens add to the unique and complex challenges of effectively treating pain in particularly geriatric populations. Interdisciplinary medical intervention and monitoring for psychiatric sequelae, such as depression, cognitive change, and synergistic physical side effects are necessary. Areas covered: This review covers an extensive multi-database wide search of the pharmacotherapy of pain and depression in older adults, including biopsychosocial approaches. One of these, on which this review focuses, is Functional Restoration, an interdisciplinary application of quantified physical rehabilitation, case management, and cognitive behavioral and educational therapies to achieve improved well- being and better physical functioning. The biopsychosocial model incorporates an overview of the overlapping and interactive dimensions of a patient's life and addresses them within a comprehensive plan of treatment. Expert commentary: A multifactorial, rather than a single factor approach to the treatment of complicated health care problems such as chronic pain in an elderly patient is emphasized as an important change in perspective for the health care provider.


Palladium-catalyzed direct C-H arylations of dioxythiophenes bearing reactive functional groups: a step-economical approach for functional π-conjugated oligoarenes.
A Pd-catalyzed single-step C-H arylation of dioxythiophene derivatives bearing unprotected reactive functional groups (-OH, -COOH, -N3) in a phosphine-free manner has been developed. Various dioxythiopene-based oligoarenes with extended π-conjugation are obtained with good yields (up to 90%). These oligoarenes display suitable optical properties (absorption and emission maxima, quantum yields) and contain reactive functional groups suitable for further conjugations with bioactive molecules. This new methodology is step economical (fewer synthetic steps) and environmentally friendly (no toxic metal-containing by-products) and the oligoarenes synthesized are potentially applicable for bio-labeling, bioimaging, and biosensing.


Lower Serologic Response to COVID-19 mRNA Vaccine in Patients With Inflammatory Bowel Diseases Treated With Anti-TNFα.
Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)α biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs). Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibody levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinally. Overall, 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFα drug levels and vaccine responses did not affect anti-spike levels. Infection rate (∼2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFα, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.


Comparative genomics of the Campylobacter lari group.
The Campylobacter lari group is a phylogenetic clade within the epsilon subdivision of the Proteobacteria and is part of the thermotolerant Campylobacter spp., a division within the genus that includes the human pathogen Campylobacter jejuni. The C. lari group is currently composed of five species (C. lari, Campylobacter insulaenigrae, Campylobacter volucris, Campylobacter subantarcticus, and Campylobacter peloridis), as well as a group of strains termed the urease-positive thermophilic Campylobacter (UPTC) and other C. lari-like strains. Here we present the complete genome sequences of 11 C. lari group strains, including the five C. lari group species, four UPTC strains, and a lari-like strain isolated in this study. The genome of C. lari subsp. lari strain RM2100 was described previously. Analysis of the C. lari group genomes indicates that this group is highly related at the genome level. Furthermore, these genomes are strongly syntenic with minor rearrangements occurring only in 4 of the 12 genomes studied. The C. lari group can be bifurcated, based on the flagella and flagellar modification genes. Genomic analysis of the UPTC strains indicated that these organisms are variable but highly similar, closely related to but distinct from C. lari. Additionally, the C. lari group contains multiple genes encoding hemagglutination domain proteins, which are either contingency genes or linked to conserved contingency genes. Many of the features identified in strain RM2100, such as major deficiencies in amino acid biosynthesis and energy metabolism, are conserved across all 12 genomes, suggesting that these common features may play a role in the association of the C. lari group with coastal environments and watersheds.


Analysis of Molecular Markers by Anatomic Tumor Site in Stage III Colon Carcinomas from Adjuvant Chemotherapy Trial NCCTG N0147 (Alliance).
To determine the frequency and prognostic association of molecular markers by anatomic tumor site in patients with stage III colon carcinomas. In a randomized trial of adjuvant FOLFOX ± cetuximab, BRAF(V600E) and KRAS (exon 2) mutations and DNA mismatch repair (MMR) proteins were analyzed in tumors (N = 3,018) in relationship to tumor location, including subsite. Cox models were used to assess clinical outcome, including overall survival (OS). KRAS codon 12 mutations were most frequent at the splenic flexure and cecum; codon 13 mutations were evenly distributed. BRAF mutation frequency sharply increased from transverse colon to cecum in parallel with deficient (d) MMR. Nonmutated BRAF and KRAS tumors progressively decreased from sigmoid to transverse (all P < 0.0001). Significantly, poorer OS was found for mutant KRAS in distal [HR, 1.98; 95% confidence interval (CI), 1.49-2.63; P < 0.0001] versus proximal (1.25; 95% CI, 0.97-1.60; P = 0.079) cancers. BRAF status and outcome were not significantly associated with tumor site. Proximal versus distal dMMR tumors had significantly better outcome. An interaction test was significant for tumor site by KRAS (P(adjusted) = 0.043) and MMR (P(adjusted) = 0.010) for OS. Significant prognostic differences for biomarkers by tumor site were maintained in the FOLFOX arm. Tumor site was independently prognostic with a stepwise improvement from cecum to sigmoid (OS: P(adjusted) = 0.001). Mutation in BRAF or KRAS codon 12 was enriched in proximal cancers whereas nonmutated BRAF/KRAS was increased in distal tumors. Significant differences in outcome for KRAS mutations and dMMR were found by tumor site, indicating that their interpretation should occur in the context of tumor location.


A hypersensitivity of glycogen phosphorylase activation in hearts of diabetic rats.
This study was initiated to determine whether glycogen phosphorylase activation was defective in hearts of alloxan diabetic rats. When hearts were perfused by gravity flow for 1 to 10 min with various concentrations of epinephrine, activation of glycogen phosphorylase in the diabetic was significantly greater at every time and epinephrine concentration than that seen in the normal. Cyclic AMP accumulation and protein kinase activation by epinephrine in the diabetic were not appreciably different or were lower than the normal responses to the hormone. The effects of epinephrine on cAMP and protein kinase were blocked in both normal and diabetic hearts by propranolol. While the beta blocker prevented phosphorylase activation in the normal hearts, it did not block phosphorylase activation by epinephrine in the diabetic hearts. Likewise, the alpha agonist phenylephrine activated phosphorylase in the diabetic but not in the normal hearts. While glucagon produced the same phosphorylase hypersensitivity in diabetic hearts, the cAMP and protein kinase responses were not altered by diabetes. Phosphorylase phosphatase activity was found to be unaltered by either epinephrine or diabetes, whereas phosphorylase kinase activation by epinephrine in the diabetic was double the normal response. These data are consistent with a diabetes-related unmasking of an alpha effect on cardiac phosphorylase activation and an unexplained increase in the sensitivity of phosphorylase kinase activation by protein kinase.


Blood Pressure Lowering Medication, Visit-to-Visit Blood Pressure Variability, and Cognitive Function in Old Age.
Visit-to-visit blood pressure (BP) variability is associated with cognitive impairment. We assessed to what extent the association between BP variability and cognitive impairment is mediated by the association of BP lowering medication (BPLM) with both BP variability and cognition. We studied 5,606 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). BP was measured every 3 months during 3.2 years; BP variability was defined as the SD of BP measurements during follow-up. Cognitive function was assessed at baseline and during follow-up using the Stroop test, Letter-Digit Coding test, and immediate and delayed Picture-Word Learning tests. Multivariate regression models were used with and without adjustments for BPLM to calculate the percentage to which BPLM mediated the association between BP variability and cognition. Participants taking calcium antagonists had a higher score in baseline Letter-Digit Coding test (mean difference (95% confidence interval (CI) 0.45 (0.06; 0.88). Participants taking beta-blockers had a steeper decline in Stroop test (additional change per year (95% CI) 0.40 (0.09; 0.70) and Letter-Digit Coding test (0.08 (-0.15; -0.02)). Furthermore, a steeper decline in Stroop test was found in participants taking renin-angiotensin system (RAS) inhibitors (0.50 (0.16; 0.85). Systolic BP variability was higher in participants taking beta-blockers and RAS inhibitors (mean difference in systolic BP variability in mm Hg (95% CI) 0.75 (0.45; 1.04) and 1.37 (1.04; 1.71) respectively). Participants taking diuretics, calcium antagonists, and RAS inhibitors had a higher diastolic BP variability (mean difference in diastolic BP variability in mm Hg (95% CI) 0.27 (0.04; 0.49), 0.37 (0.12; 0.62) and 0.65 (0.37; 0.93) SD, respectively). Beta estimates remained essentially the same when we adjusted for BPLM in the association of BP variability with cognitive function. The association between BP variability and cognitive impairment was not mediated by BPLM.


Application of a kinetic fractionation of trace elements (Cd, Cu and Pb) in unpolluted soil samples.
The hazard due to the presence of large amounts of trace metals in some soils is strongly related to the speciation of these metals. The aim of this work was to apply an operationally defined fractionation based on kinetics which could distinguish "labile" (quickly extracted) and "non labile or slowly labile i.e. slowly extracted) cations, using the extraction kinetics of trace metals by EDTA. This kinetic fractionation has been applied to ten soil samples from Burgundy (France), which are known to be unpolluted. Copper, lead and cadmium were determined using this fractionation procedure. According to this fractionation, cadmium was found to be more mobile than copper or lead, both in terms of the labile concentration and the kinetic constants.


Astrocyte roles in traumatic brain injury.
Astrocytes sense changes in neural activity and extracellular space composition. In response, they exert homeostatic mechanisms critical for maintaining neural circuit function, such as buffering neurotransmitters, modulating extracellular osmolarity and calibrating neurovascular coupling. In addition to upholding normal brain activities, astrocytes respond to diverse forms of brain injury with heterogeneous and progressive changes of gene expression, morphology, proliferative capacity and function that are collectively referred to as reactive astrogliosis. Traumatic brain injury (TBI) sets in motion complex events in which noxious mechanical forces cause tissue damage and disrupt central nervous system (CNS) homeostasis, which in turn trigger diverse multi-cellular responses that evolve over time and can lead either to neural repair or secondary cellular injury. In response to TBI, astrocytes in different cellular microenvironments tune their reactivity to varying degrees of axonal injury, vascular disruption, ischemia and inflammation. Here we review different forms of TBI-induced astrocyte reactivity and the functional consequences of these responses for TBI pathobiology. Evidence regarding astrocyte contribution to post-traumatic tissue repair and synaptic remodeling is examined, and the potential for targeting specific aspects of astrogliosis to ameliorate TBI sequelae is considered.


IκB Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD.
Patients with CKD requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality rate than the general population with sepsis. The severity of cardiac dysfunction predicts mortality in patients with sepsis. Here, we investigated the effect of preexisting CKD on cardiac function in mice with sepsis and whether inhibition of IκB kinase (IKK) reduces the cardiac dysfunction in CKD sepsis. Male C57BL/6 mice underwent 5/6 nephrectomy, and 8 weeks later, they were subjected to LPS (2 mg/kg) or sepsis by cecal ligation and puncture (CLP). Compared with sham operation, nephrectomy resulted in significant increases in urea and creatinine levels, a small (P<0.05) reduction in ejection fraction (echocardiography), and increases in the cardiac levels of phosphorylated IκBα, Akt, and extracellular signal-regulated kinase 1/2; nuclear translocation of the NF-κB subunit p65; and inducible nitric oxide synthase (iNOS) expression. When subjected to LPS or CLP, compared with sham-operated controls, CKD mice exhibited exacerbation of cardiac dysfunction and lung inflammation, greater increases in levels of plasma cytokines (TNF-α, IL-1β, IL-6, and IL-10), and greater increases in the cardiac levels of phosphorylated IKKα/β and IκBα, nuclear translocation of p65, and iNOS expression. Treatment of CKD mice with an IKK inhibitor (IKK 16; 1 mg/kg) 1 hour after CLP or LPS administration attenuated these effects. Thus, preexisting CKD aggravates the cardiac dysfunction caused by sepsis or endotoxemia in mice; this effect may be caused by increased cardiac NF-κB activation and iNOS expression.


The effects of dwarfing genes on seedling root growth of wheat.
Most modern wheat cultivars contain major dwarfing genes, but their effects on root growth are unclear. Near-isogenic lines (NILs) containing Rht-B1b, Rht-D1b, Rht-B1c, Rht8c, Rht-D1c, and Rht12 were used to characterize the effects of semi-dwarfing and dwarfing alleles on root growth of 'Mercia' and 'Maris Widgeon' wheat cultivars. Wheat seedlings were grown in gel chambers, soil-filled columns, and in the field. Roots were extracted and length and dry mass measured. No significant differences in root length were found between semi-dwarfing lines and the control lines in any experiment, nor was there a significant difference between the root lengths of the two cultivars grown in the field. Total root length of the dwarf lines (Rht-B1c, Rht-D1c, and Rht12) was significantly different from that of the control although the effect was dependent on the experimental methodology; in gel chambers root length of dwarfing lines was increased by approximately 40% while in both soil media it was decreased (by 24-33%). Root dry mass was 22-30% of the total dry mass in the soil-filled column and field experiments. Root length increased proportionally with grain mass, which varied between NILs, so grain mass was a covariate for the analysis of variance. Although total root length was altered by dwarf lines, root architecture (average root diameter, lateral root:total root ratio) was not affected by reduced height alleles. A direct effect of dwarfing alleles on root growth during seedling establishment, rather than a secondary partitioning effect, was suggested by the present experiments.


Functional analysis of the Helicobacter pylori cag pathogenicity island reveals both VirD4-CagA-dependent and VirD4-CagA-independent mechanisms.
The type IV secretion machinery encoded by the cag pathogenicity island (PAI) of Helicobacter pylori has been implicated in a series of host responses during infection. Here, we analyzed the function of 12 cag PAI genes from both cag I and cag II loci, including the complete virB/D complex (virB4, virB7, virB8, virB9, virB10, virB11, and virD4). We monitored interleukin-8 (IL-8) secretion, CagA translocation and tyrosine phosphorylation, and induction of a scattering ("hummingbird") phenotype upon H. pylori infection of AGS gastric epithelial cells. For the first time, we have complemented individual cag PAI gene knockout mutants with their intact genes expressed from a shuttle vector and showed that complemented CagA and VirD4 restored wild-type function. Our results demonstrate that phenotypic changes and phosphorylation of CagA depended on all virB/D genes and several other genes of the cag PAI. Induction of IL-8 secretion depended largely on the same set of genes but was independent of CagA and VirD4. Thus, CagA translocation and induction of IL-8 secretion are regulated by VirD4-CagA-dependent and VirD4-CagA-independent mechanisms, respectively. The function of VirD4 as a possible adapter protein which guides CagA into the type IV secretion channel is presented in a model.


Clonal diversity and turnover of Streptococcus mitis bv. 1 on shedding and nonshedding oral surfaces of human infants during the first year of life.
Streptococcus mitis bv. 1 is a pioneer colonizer of the human oral cavity. Studies of its population dynamics within parents and their infants and within neonates have shown extensive diversity within and between subjects. We examined the genetic diversity and clonal turnover of S. mitis bv. 1 isolated from the cheeks, tongue, and primary incisors of four infants from birth to 1 year of age. In addition, we compared the clonotypes of S. mitis bv. 1 isolated from their mothers' saliva collected in parallel to determine whether the mother was the origin of the clones colonizing her infant. Of 859 isolates obtained from the infants, 568 were unique clones. Each of the surfaces examined, whether shedding or nonshedding, displayed the same degree of diversity. Among the four infants it was rare to detect the same clone colonizing more than one surface at a given visit. There was little evidence for persistence of clones, but when clones were isolated on multiple visits they were not always found on the same surface. A similar degree of clonal diversity of S. mitis bv. 1 was observed in the mothers' saliva as in their infants' mouths. Clones common to both infant and mothers' saliva were found infrequently suggesting that this is not the origin of the infants' clones. It is unclear whether mucosal immunity exerts the environmental pressure driving the genetic diversity and clonal turnover of S. mitis bv. 1, which may be mechanisms employed by this bacterium to evade immune elimination.


Synthesis and properties of oligonucleotides containing 2'-deoxynebularine and 2'-deoxyxanthosine.
The preparation of synthetic oligonucleotides containing 2'-deoxynebularine (dN) and 2'-deoxyxanthosine (dX) is described. The thermal stabilities of duplexes containing dX, dN, and 2'-deoxyinosine (dI) base-paired with the four natural bases have been measured. Xanthine base pairs have stabilities at pH 5.5 that are similar to those of dI-containing duplexes at neutral pH. When xanthine is paired with adenine or cytosine an unusual stabilization of the duplex structure is observed at acid pH. Incorporation of base mispairs opposite template xanthine sites were measured using Drosophila DNA polymerase alpha. The relative nucleoside incorporation rates are in the order: T greater than C much greater than A approximately equal to G. These rates do not correlate with relative thermodynamic stabilities of base mispairs with xanthine obtained from Tm measurements: T greater than G greater than A approximately equal to C. We suggest that DNA polymerase misinsertion rates are greatest when the base mispair can be formed in accordance with Watson-Crick as opposed to other base pairing geometries even though other geometries, e.g. wobble, may result in a more stable final DNA product.


How a woman's sexual adjustment after sustaining a spinal cord injury impacts sexual health interventions.
This qualitative study describes the female experience of sexual adjustment after spinal cord injury (SCI) in relation to the need for sexual health intervention. Ten women with SCI were interviewed using a predetermined, semistructured set of questions. Audiotaping and field notes were utilized to gather data. The investigators used consensus validation to complete data analysis, and all research findings were reviewed by the study participants for validation. Clinical findings indicated that there were a series of phases that women go through in sexual adjustment that affect when and how interventions were effective in meeting their sexual health needs. Women also identified the use of peers and support groups as essential adjuncts to professional intervention.


Clinically isolated neurosarcoidosis: a recommended diagnostic path.
The involvement of the central nervous system in sarcoidosis can manifest with a variety of neurological symptoms, most of them nonspecific. We identified 13 patients with neurosarcoidosis diagnosed at our clinic. Six of 13 patients presented with clinically isolated neurosarcoidosis (CINS) without signs or symptoms of systemic disease. CINS patients were not different with respect to age, as well as imaging and spinal fluid findings, or disease course. However, we found spinal cord involvement in neurosarcoidosis patients much more common than previously described (in 8 out of 13 patients). Spinal cord affection was associated with older age at diagnosis and a less favorable response to therapy. Based on our findings, we propose a diagnostic path for neurosarcoidosis, including spinal magnetic resonance imaging (MRI) as a mandatory and early step during diagnostic workup.


P-side up AlGaInP-based light emitting diodes with dot-patterned GaAs contact layers.
High-brightness p-side up AlGaInP-based red light emitting diodes (LEDs) with dot-patterned GaAs contact layer and surface rough structure are presented in this article. Initial LED structure of p-GaP/AlGaInP/GaAs is epitaxially grown using metal organic chemical vapor deposition technique. Using novel twice transferring process, the p-GaP layer is remained at the top side as both the current spreading and-window layer. Dot patterned GaAs contact dots are formed between main structure and rear mirror to improve light reflection and current spreading. Moreover, the surface of p-GaP window is further textured by nano-sphere lithography technique for improving the light extraction. Significant improvement in output power is found for AlGaInP LEDs with GaAs contact dots and roughened p-GaP window as compared with those of LEDs with traditional n-side up and p-side up structures without roughened surfaces.


Supplementation with Selenium and Coenzyme Q10 Reduces Cardiovascular Mortality in Elderly with Low Selenium Status. A Secondary Analysis of a Randomised Clinical Trial.
Selenium is needed by all living cells in order to ensure the optimal function of several enzyme systems. However, the selenium content in the soil in Europe is generally low. Previous reports indicate that a dietary supplement of selenium could reduce cardiovascular disease but mainly in populations in low selenium areas. The objective of this secondary analysis of a previous randomised double-blind placebo-controlled trial from our group was to determine whether the effects on cardiovascular mortality of supplementation with a fixed dose of selenium and coenzyme Q10 combined during a four-year intervention were dependent on the basal level of selenium. In 668 healthy elderly individuals from a municipality in Sweden, serum selenium concentration was measured. Of these, 219 individuals received daily supplementation with selenium (200 μg Se as selenized yeast) and coenzyme Q10 (200 mg) combined for four years. The remaining participants (n = 449) received either placebo (n = 222) or no treatment (n = 227). All cardiovascular mortality was registered. No participant was lost during a median follow-up of 5.2 years. Based on death certificates and autopsy results, all mortality was registered. The mean serum selenium concentration among participants at baseline was low, 67.1 μg/L. Based on the distribution of selenium concentration at baseline, the supplemented group was divided into three groups; <65 μg/L, 65-85 μg/L, and >85 μg/L (45 and 90 percentiles) and the remaining participants were distributed accordingly. Among the non-treated participants, lower cardiovascular mortality was found in the high selenium group as compared with the low selenium group (13.0% vs. 24.1%; P = 0.04). In the group with the lowest selenium basal concentration, those receiving placebo or no supplementation had a mortality of 24.1%, while mortality was 12.1% in the group receiving the active substance, which was an absolute risk reduction of 12%. In the middle selenium concentration group a mortality of 14.0% in the non-treated group, and 6.0% in the actively treated group could be demonstrated; thus, there was an absolute risk reduction of 8.0%. In the group with a serum concentration of >85 μg/L, a cardiovascular mortality of 17.5% in the non-treated group, and 13.0% in the actively treated group was observed. No significant risk reduction by supplementation could thus be found in this group. In this evaluation of healthy elderly Swedish municipality members, two important results could be reported. Firstly, a low mean serum selenium concentration, 67 μg/L, was found among the participants, and the cardiovascular mortality was higher in the subgroup with the lower selenium concentrations <65 μg/L in comparison with those having a selenium concentration >85 μg/L. Secondly, supplementation was cardio-protective in those with a low selenium concentration, ≤85 at inclusion. In those with serum selenium>85 μg/L and no apparent deficiency, there was no effect of supplementation. This is a small study, but it presents interesting data, and more research on the impact of lower selenium intake than recommended is therefore warranted. Clinicaltrials.gov NCT01443780.


Osmoregulation in the parasitic nematode Pseudoterranova decipiens.
When subjected to hyper- or hypo-osmotic stress at 5 degrees C for 24 h, third-stage larvae of the parasitic nematode Pseudoterranova decipiens do not exhibit changes in mass or in the osmotic pressure of the pseudocoelomic fluid. Immersion in solutions containing 3H2O demonstrates that exchange with the water in the pseudocoelomic fluid is substantially complete within 24 h. Sacs composed of cylinders of body wall without the intestine and pseudocoelomic fluid do not gain weight when immersed for 24 h in hypotonic medium. Metabolic poisons abolish the ability of whole worms and sacs to maintain their weight when immersed in hypotonic media. These observations support the conclusion that the nematode is capable of at least short-term osmoregulation and that the site of osmoregulation is the body wall. The observations that more fluid is passed from the anus in some hypo-osmotically stressed worms and that worms ligatured at the tail exhibit a small increase in mass when exposed to hypo-osmotic conditions may indicate that the intestine plays a minor and subsidiary role in osmoregulation.


C. elegans TRP channels.
Transient receptor potential (TRP) channels represent a superfamily of cation channels found in all eukaryotes. The C. elegans genome encodes seventeen TRP channels covering all of the seven TRP subfamilies. Genetic analyses in C. elegans have implicated TRP channels in a wide spectrum of behavioral and physiological processes, ranging from sensory transduction (e.g. chemosensation, touch sensation, proprioception and osmosensation) to fertilization, drug dependence, organelle biogenesis, apoptosis, gene expression, and neurotransmitter/hormone release. Many C. elegans TRP channels share similar activation and regulatory mechanisms with their vertebrate counterparts. Studies in C. elegans have also revealed some previously unrecognized functions and regulatory mechanisms of TRP channels. C. elegans represents an excellent genetic model organism for the study of function and regulation of TRP channels in vivo.


The roles and controls of GATA factors in blood and cardiac development.
GATA factors play central roles in the programming of blood and cardiac cells during embryonic development. Using the experimentally accessible Xenopus and zebrafish models, we report observations regarding the roles of GATA-2 in the development of blood stem cells and GATA-4, -5, and -6 in cardiac development. We show that blood stem cells develop from the dorsal lateral plate mesoderm and GATA-2 is required at multiple stages. Firstly, GATA-2 is required to make the cells responsive to VEGF-A signalling by driving the synthesis of its receptor, FLK-1/KDR. This leads to differentiation into the endothelial cells that form the dorsal aorta. GATA-2 is again required for the endothelial-to-haematopoietic transition that takes place later in the floor of the dorsal aorta. GATA-2 expression is dependent on BMP signalling for each of these inputs into blood stem cell programming. GATA-4, -5, and -6 work together to ensure the specification of cardiac cells during development. We have demonstrated redundancy within the family and also some evolution of the functions of the different family members. Interestingly, one of the features that varies in evolution is the timing of expression relative to other key regulators such as Nkx2.5 and BMP. We show that the GATA factors, Nkx2.5 and BMP regulate each other and it would appear that what is critical is the mutually supportive network of expression rather than the order of expression of each of the component genes. In Xenopus and zebrafish, the cardiac mesoderm is adjacent to an anterior population of cells giving rise to blood and endothelium. This population is not present in mammals and we have shown that, like the cardiac population, the blood and endothelial precursors require GATA-4, -5, and -6 for their development. Later, blood-specific or cardiac-specific regulators determine the ultimate fate of the cells, and we show that these regulators act cross-antagonistically. Fibroblast growth factor (FGF) signalling drives the cardiac fate, and we propose that the anterior extension of the FGF signalling field during evolution led to the recruitment of the blood and endothelial precursors into the heart field ultimately resulting in a larger four chambered heart. Zebrafish are able to successfully regenerate their hearts after injury. To understand the pathways involved, with a view to determining why humans cannot do this, we profiled gene expression in the cardiomyocytes before and after injury, and compared those proximal to the injury with those more distal. We were able to identify an enhancement of the expression of regulators of the canonical Wnt pathway proximal to the injury, suggesting that changes in Wnt signalling are responsible for the repair response to injury.


Identification and partial characterization of an elastolytic protease in the amphibian pathogen Batrachochytrium dendrobatidis.
Batrachochytrium dendrobatidis (Bd) is a fungus that causes chytridiomycosis, a disease that has been implicated as a cause of amphibian population declines worldwide. Infected animals experience hyperkeratosis and sloughing of the epidermis due to penetration of the keratinized tissues by the fungus. These symptoms have led us to postulate that Bd produces proteases that play a role in the infection process. Here, we show that Bd is capable of degrading elastin in vitro, a protein found in the extracellular matrix of the host animal. Elastolytic enzyme activity was partially purified using ion exchange chromatography and size-exclusion filtration from cultures grown in inducing media. The elastolytic activity of the purified fraction had a pH optimum of 8, was strongly inhibited by EDTA and phenylmethylsulfonyl fluoride (PMSF), and was partially inhibited by an elastase-specific inhibitor. This activity was also enhanced by the presence of Mg2+ and Ca2+ but not Zn2+. An antiserum directed against Aspergillus fumigatus serine protease (Alp) was found to react with a polypeptide of approximately 110 kDa from the purified material. Using immunofluorescence, this antiserum was also observed to react with zoospores and sporangia grown on toad skin. These observations suggest that Bd may produce proteases similar to those produced by other pathogenic fungi that are capable of degrading proteins found in the extracellular matrix. The proteolytic activity exhibited in vitro might aid the organism in its ability to colonize and destroy the epidermis of its amphibian host.


Investigation of the effect of the water to powder ratio on hydraulic cement properties.
The use of rheological properties to determine the optimal water: powder ratio of tricalcium silicate-based prototype materials incorporating alternative radiopacifiers and fillers. Determination of how the proportion of water incorporated affected the physicochemical behaviour of the materials. Endodontic cements replaced with 30% radiopacifier, and additions of calcium phosphate and micro-silica were tested. The unmodified cements were mixed with a 0.35 water: powder ratio which served as control. At this water: powder ratio, unmodified Portland cement without any addition had an adequate consistency and furthermore it has been well characterized. Assessment of material rheological properties enabled adjustment of the water: powder ratio in each material to provide comparable viscosity values to those of the pure cement. The flowability, phase analysis and calcium release were measured for both viscosity-matched and the standard 0.35 water: powder ratio blends. The prototype materials with the adjusted water: powder ratios were also characterized by scanning electron microscopy, energy-dispersive spectroscopy and evaluated for radio-opacity. The use of the 0.35 water: powder ratio is not appropriate when changing the radiopacifier and incorporating additives. Zirconium oxide did not vary the water: powder ratio but tantalum oxide and calcium tungstate resulted in an increase and decrease in water demand respectively. Using the standard 0.35 ratio when the mixture had a low water demand resulted in higher flowability values and calcium release in solution. Micro-silica and calcium phosphate altered the hydration of the materials. All materials were adequately radiopaque. Rheological assessment is an easy reproducible way to determine the water: powder ratios of materials with varying amounts of additives and radiopacifiers during development. Modifications to the water: powder ratio affects material properties.


The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice.
US28 is a constitutively active chemokine receptor encoded by CMV (also referred to as human herpesvirus 5), a highly prevalent human virus that infects a broad spectrum of cells, including intestinal epithelial cells (IECs). To study the role of US28 in vivo, we created transgenic mice (VS28 mice) in which US28 expression was targeted to IECs. Expression of US28 was detected in all IECs of the small and large intestine, including in cells expressing leucine rich repeat containing GPCR5 (Lgr5), a marker gene of intestinal epithelial stem cells. US28 expression in IECs inhibited glycogen synthase 3β (GSK-3β) function, promoted accumulation of β-catenin protein, and increased expression of Wnt target genes involved in the control of the cell proliferation. VS28 mice showed a hyperplastic intestinal epithelium and, strikingly, developed adenomas and adenocarcinomas by 40 weeks of age. When exposed to an inflammation-driven tumor model (azoxymethane/dextran sodium sulfate), VS28 mice developed a significantly higher tumor burden than control littermates. Transgenic coexpression of the US28 ligand CCL2 (an inflammatory chemokine) increased IEC proliferation as well as tumor burden, suggesting that the oncogenic activity of US28 can be modulated by inflammatory factors. Together, these results indicate that expression of US28 promotes development of intestinal dysplasia and cancer in transgenic mice and suggest that CMV infection may facilitate development of intestinal neoplasia in humans.


Ziprasidone-induced galactorrhea: a case report.
Second-generation antipsychotics presumably lack the typical side effects of conventional antipsychotics. A 34 year old Caucasian woman with ICD-10 diagnosis of Recurrent depressive disorder with current moderate symptoms, and with a history of repeated self-injury was treated with lithium, clonazepam and ziprasidone. On the ninth day of ziprasidone administration, galactorrhea appeared. After 36 days of ziprasidone therapy, galactorrhea persisted. The prolactin plasma level was 28 ng/ml. Thyroid tests (TSH,T3,T4) and the lithium plasma level were within the normal range during ziprasidone treatment. Two weeks after the ziprasidone withdrawal, galactorrhea disappeared and the prolactin level decreased down to 18 ng/ml. Psychiatrists should be aware that even second-generation antipsychotics, including ziprasidone, have a propensity to cause side-effects associated with the dopamine D2 receptor blockade, such as galactorrhea.


Fearful foragers: honey bees tune colony and individual foraging to multi-predator presence and food quality.
Fear can have strong ecosystem effects by giving predators a role disproportionate to their actual kill rates. In bees, fear is shown through foragers avoiding dangerous food sites, thereby reducing the fitness of pollinated plants. However, it remains unclear how fear affects pollinators in a complex natural scenario involving multiple predator species and different patch qualities. We studied hornets, Vespa velutina (smaller) and V. tropica (bigger) preying upon the Asian honey bee, Apis cerana in China. Hornets hunted bees on flowers and were attacked by bee colonies. Bees treated the bigger hornet species (which is 4 fold more massive) as more dangerous. It received 4.5 fold more attackers than the smaller hornet species. We tested bee responses to a three-feeder array with different hornet species and varying resource qualities. When all feeders offered 30% sucrose solution (w/w), colony foraging allocation, individual visits, and individual patch residence times were reduced according to the degree of danger. Predator presence reduced foraging visits by 55-79% and residence times by 17-33%. When feeders offered different reward levels (15%, 30%, or 45% sucrose), colony and individual foraging favored higher sugar concentrations. However, when balancing food quality against multiple threats (sweeter food corresponding to higher danger), colonies exhibited greater fear than individuals. Colonies decreased foraging at low and high danger patches. Individuals exhibited less fear and only decreased visits to the high danger patch. Contrasting individual with emergent colony-level effects of fear can thus illuminate how predators shape pollination by social bees.


[The epidemiologic transition of the adolescents in Mexico].
To identify the health status of adolescents in Mexico in their demographic, social and economic context. A literature search and review of vital statistics, and opinion surveys were performed in order to asses the impact of the epidemiologic transition on the availability and priority of health services for adolescents. The Omran epidemiologic model was used to classify the demographic, social and economic characteristics of Mexican adolescents in efforts to define their impact on the epidemiologic transition of this age group. Demographic data are presented in the perspective of the epidemiologic transition which permit us to make inferences on the social conditions, growth patterns and health needs of this age group in Mexico. Data are presented regarding the demand and availability of health services, the impact of education and employment opportunities and the role of family and the economy on their well being. Other important aspects presented include the role of education on the sexual and reproductive health of adolescents and the threat of the AIDS pandemic in this age group. These findings reveal a sequence of variables that can no longer be addressed in the traditional problem oriented approach and strongly suggest a need to profile the health needs of adolescents in an integrated, holistic fashion with emphasis in health promotion and healthy life styles to favor their integral, just and equitable development, and also help focus the societal response in an integrated manner.


Prevalence of attention deficit disorder among preschool age children.
Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood onset psychiatric disorders. Although the onset of ADHD is prior to the age of seven years, there is a paucity of data on the prevalence of the disorder in preschool age children. This study was performed to determine the prevalence rate of ADHD in preschool age children in kindergartens of south west, Mumbai. One thousand two hundred fifty (599 males and 651 females) children aged between 4-6 years, were selected from 40 kindergartens in 6 localities in south west Mumbai. The Conner's index questionnaire was completed for each child by teachers and parents. Parents of children whose scores were positive for ADHD (>15) were interviewed by a psychiatrist and the ADHD was diagnosed based on DSM-IV criteria Schedule for affective disorders. One hundred fifty two (12.2%) children were diagnosed to have ADHD. The prevalence of ADHD in preschool age school in south west of Mumbai is consistent with previous studies in other countries. This study recommends the need for diagnosis and treatment of ADHD in preschool age children.


Effects of mutations in the adenoviral E1B 55-kilodalton protein coding sequence on viral late mRNA metabolism.
The human subgroup C adenoviral E1B 55-kDa protein cooperates with the viral E4 Orf6 protein to induce selective export of viral, late mRNAs from the nucleus to the cytoplasm. Previous studies have suggested that such preferential transport of viral mRNA and the concomitant inhibition of export of cellular mRNAs are the result of viral colonization of specialized microenvironments within the nucleus. However, neither the molecular basis of this phenomenon nor the mechanism by which the E1B 55-kDa protein acts has been elucidated. We therefore examined viral late mRNA metabolism in HeLa cells infected with a series of mutant viruses that carry insertions at various positions in the E1B protein coding sequence (P. R. Yew, C. C. Kao, and A. J. Berk, Virology 179:795-805, 1990). All the mutations examined impaired cytoplasmic accumulation of viral L2 mRNAs and reduced L2 mRNA export efficiency. However, in most cases these defects could be ascribed to reduced E1B 55-kDa protein concentration or the unexpected failure of the altered E1B proteins to enter the nucleus efficiently. The latter property, the pleiotropic defects associated with all the mutations that impaired nuclear entry of the E1B protein, and consideration of its primary sequence suggest that these insertions result in misfolding of the protein. Insertion of four amino acids at residue 143 also inhibited viral mRNA export but resulted in increased rather than decreased accumulation of the E1B 55-kDa protein in the nucleus. This mutation specifically impaired the previously described association of the E1B protein with intranuclear structures that correspond to sites of adenoviral DNA replication and transcription (D. Ornelles and T. Shenk, J. Virol. 65:424-439, 1991) and the colocalization of the E1B and E4 Orf6 proteins. As this insertion has been shown to inhibit the interaction of the E1B with the E4 Orf6 protein in infected cell extracts (S. Rubenwolf, H. Schütt, M. Nevels, H. Wolf, and T. Dobner, J. Virol. 71:1115-1123, 1997), these phenotypes provide direct support for the hypothesis that selective viral mRNA export is determined by the functional organization of the infected cell nucleus.


Aortic involvement in rheumatic diseases.
To review the prevalence, mechanisms, presentations and clinical significance of aortic involvement in rheumatic inflammatory diseases. The medical literature, available through a PUBMED search was reviewed and the relevant information was summarized. In addition, selected articles related to aortic involvement in rheumatic diseases were included in this review. Rheumatic disorders may be categorized by their propensity to involve the aorta: conditions with a prevalence of 10% and more (Takayasu's arteritis, temporal arteritis, long-standing ankylosing spondylitis, Cogan's syndrome and relapsing polychondritis), disorders with uncommon but well documented aortic involvement and rheumatic conditions with rare case reports of such involvement. Clinical presentation of aortic disease is dependent on the part of aorta involved and may manifest by aortic pain and/or other symptoms caused by aortic dilatation, narrowing or aneurysm. The histopathology of inflammatory aortitis is characterized by lymphoplasmacytic infiltration with or without giant cells or granulomas. On the other hand, non-inflammatory aortic damage in rheumatic diseases may include Marfan-like cystic disintegration of the aortic media as well as accelerated atherosclerosis. Awareness of rheumatic conditions with a high potential for clinically significant aortic involvement may promote referral of such patients for aortic imaging and sometimes surgery before fatal complications intervene. Early diagnosis of aortic involvement can be advanced by informed consideration of such a complication in a rheumatic patient.


Complex speciation of humans and chimpanzees.
Genetic data from two or more species provide information about the process of speciation. In their analysis of DNA from humans, chimpanzees, gorillas, orangutans and macaques (HCGOM), Patterson et al. suggest that the apparently short divergence time between humans and chimpanzees on the X chromosome is explained by a massive interspecific hybridization event in the ancestry of these two species. However, Patterson et al. do not statistically test their own null model of simple speciation before concluding that speciation was complex, and--even if the null model could be rejected--they do not consider other explanations of a short divergence time on the X chromosome. These include natural selection on the X chromosome in the common ancestor of humans and chimpanzees, changes in the ratio of male-to-female mutation rates over time, and less extreme versions of divergence with gene flow (see ref. 2, for example). I therefore believe that their claim of hybridization is unwarranted.


Coining the Pablo Picasso Syndrome.
The Alice in Wonderland Syndrome has been well described in the literature. Along with sensory disturbances, patients notably experience metamorphopsias, or distortions in size (micropsia/macropsia) and distance (teleopsia), particularly of body parts. Some migraineurs, however, report dislocation and disorientation of body parts, which are common features found in paintings of Pablo Picasso. A 60-year-old female with a 20-year history of chronic migraine presented for evaluation of frequent headaches and visual disturbances. In between her attacks of migraine, she would occasionally notice alterations which she describes as a "Picasso" painting. When looking at people, she would note their ear on top of their head, or their right arm would be short and attached to the face. This would occur 1-2 times per week and would last 5 to 10 minutes. Inanimate objects, however, would not appear distorted. The available literature, including published works and biographies, suggests Picasso did not suffer from migraine. Nonetheless, careful descriptions taken from migraineurs with visual disturbances may uncover features that resemble his paintings, be it dislocation of limbs with hints of cubism, as reported above, or illusory splitting as has been previously reported. Dislocation or disorientation of body parts as a migraine-related visual phenomenon is rare and only sparsely reported in the medical literature. Coining of a "Pablo Picasso Syndrome" may better describe this occurrence.


Strain dependence of the cell wall-damage induced stimulon in Staphylococcus aureus.
The vancomycin stress induced transcriptome of the methicillin susceptible Staphylococcus aureus (MSSA) strain Newman was determined by microarray analysis. Subsets of the induced ORFs corresponded to those previously reported to be induced by vancomycin in the methicillin resistant S. aureus (MRSA) strains N315 and JH1, and/or by other cell wall active antibiotics in RN450; while other ORFs appeared to be induced strain specifically in Newman. Northern analyses showed that the induction pathway for several of the ORFs appeared to be altered in a number of clinical NARSA isolates. Induction was found to be dependent on inhibitory concentrations of antibiotics.


NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction.
During gestation, low oxygen environment is a major determinant of early placentation process, while persistent placental hypoxia leads to pregnancy-related complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). PE affects 5%-8% of all pregnancies worldwide and is a cause of maternal and fetal morbidity and mortality. During placental development, persistent hypoxia due to poor trophoblast invasion and reduced uteroplacental perfusion leads to maternal endothelial dysfunction and clinical manifestation of PE. Here we hypothesized that nuclear factor of activated T cells-5 (NFAT5), a well-known osmosensitive renal factor and recently characterized hypoxia-inducible protein, is also activated in vivo in placentas of PE and IUGR complications as well as in the in vitro model of trophoblast hypoxia. In JAR cells, low oxygen tension (1% O2) induced NFAT5 mRNA and increased its nuclear abundance, peaking at 16 h. This increase did not occur in parallel with the earlier HIF1A induction. Real-time PCR and Western blot analysis confirmed up-regulation of NFAT5 mRNA and NFAT5 nuclear content in human preeclamptic placentas and in rabbit placentas of an experimentally induced IUGR model, as compared with the control groups. In vitro lambda protein phosphatase (lambda PPase) treatment revealed that increased abundance of NFAT5 protein in nuclei of either JAR cells (16 h of hypoxia) or PE and IUGR placentas is at least partially due to NFAT5 phosphorylation. NFAT5 downstream targets aldose reductase (AR) and sodium-myo-inositol cotransporter (SMIT; official symbol SLC5A3) were not significantly up-regulated either in JAR cells exposed to hypoxia or in placentas of PE- and IUGR-complicated pregnancies, suggesting that hypoxia-dependent activation of NFAT5 serves as a separate function to its tonicity-dependent stimulation. In conclusion, we propose that NFAT5 may serve as a novel marker of placental hypoxia and ischemia independently of HIF1A.


Nuclear Magnetic Resonance Structural Mapping Reveals Promiscuous Interactions between Clathrin-Box Motif Sequences and the N-Terminal Domain of the Clathrin Heavy Chain.
The recruitment and organization of clathrin at endocytic sites first to form coated pits and then clathrin-coated vesicles depend on interactions between the clathrin N-terminal domain (TD) and multiple clathrin binding sequences on the cargo adaptor and accessory proteins that are concentrated at such sites. Up to four distinct protein binding sites have been proposed to be present on the clathrin TD, with each site proposed to interact with a distinct clathrin binding motif. However, an understanding of how such interactions contribute to clathrin coat assembly must take into account observations that any three of these four sites on clathrin TD can be mutationally ablated without causing loss of clathrin-mediated endocytosis. To take an unbiased approach to mapping binding sites for clathrin-box motifs on clathrin TD, we used isothermal titration calorimetry (ITC) and nuclear magnetic resonance spectroscopy. Our ITC experiments revealed that a canonical clathrin-box motif peptide from the AP-2 adaptor binds to clathrin TD with a stoichiometry of 3:1. Assignment of 90% of the total visible amide resonances in the TROSY-HSQC spectrum of (13)C-, (2)H-, and (15)N-labeled TD40 allowed us to map these three binding sites by analyzing the chemical shift changes as clathrin-box motif peptides were titrated into clathrin TD. We found that three different clathrin-box motif peptides can each simultaneously bind not only to the previously characterized clathrin-box site but also to the W-box site and the β-arrestin splice loop site on a single TD. The promiscuity of these binding sites can help explain why their mutation does not lead to larger effects on clathrin function and suggests a mechanism by which clathrin may be transferred between different proteins during the course of an endocytic event.


Six countries, six individuals: resourceful patients navigating medical records in Australia, Canada, Chile, Japan, Sweden and the USA.
In the absence of international standards, widely differing attitudes and laws, medical and social cultures strongly influence whether and how patients may access their medical records in various settings of care. Reviewing records, including the notes clinicians write, can help shape how people participate in their own care. Aided at times by new technologies, individual patients and care partners are repurposing existing tools and designing innovative, often 'low-tech' ways to collect, sort and interpret their own health information. To illustrate diverse approaches that individuals may take, six individuals from six nations offer anecdotes demonstrating how they are learning to collect, assess and benefit from their personal health information.


Visual impairment and blindness in spanish adults: geographic inequalities are not explained by age or education.
The objectives of this study were to examine for the first time the prevalence of visual impairment and blindness among adults in Spain, to explore regional differences, and to assess whether they may vary as a function of sex or be explained by age and individual or regional socioeconomic position. Data were obtained from the 2008 Spanish Survey on Disability, Personal Autonomy, and Dependency Situations, a cross-sectional survey based on a representative sample of the noninstitutionalized population of Spain. The sample was composed of 213 626 participants aged ≥15 years (103 093 men and 110 533 women); 360 were blind (160 men and 200 women), 4048 had near visual impairment (1397 men and 2651 women), and 4034 had distance visual impairment (1445 men and 2589 women). The prevalence of near and distance visual impairment was calculated for each region. Multiple logistic regression models were fitted to calculate odds ratios and 95% confidence intervals. All analyses were stratified by sex. Visual impairment was based on 3 questions aimed at identifying blindness and near and distance visual impairment. The prevalence (percentage) of blindness was 0.17 (men, 0.16; women, 0.18): 1.89 for near visual impairment (men, 1.36; women, 2.40), 1.89 for distance visual impairment (men, 1.40; women, 2.34), and 2.43 for any visual impairment (men, 1.81; women, 3.02). Regional inequalities in the prevalence of visual impairment were observed, correlated with regional income, and the prevalence was consistently higher among women than men. The magnitude of the inequalities remained after adjusting for age and educational level, and a north-to-south pattern of increasing prevalence was observed. Regional and sex inequalities in the prevalence of visual impairment and blindness were observed in Spain, with a north-to-south gradient of increasing prevalence that was not explained by age or individual educational level but was correlated with regional level of economic development. Factors that could be prioritized for future policies and research include differential regional economic development, rural environment, quality of eye care services, diabetes, ultraviolet light exposure, or gender inequalities in diagnostic and therapeutic health care.


Gamma Knife surgery for benign meningioma.
Meningioma is the most frequent benign tumor treated with Gamma Knife surgery (GKS); however, the assessment of its efficacy and safety in slow-growing tumors is an ongoing process, requiring analysis of long-term results. Three hundred sixty-eight patients harboring 400 meningiomas treated between 1992 and 1999 at Na Homolce Hospital were evaluated. The median patient age was 57 years (range 18-84 years). The median tumor volume was 4.4 cm3 (range 0.11-44.9 cm3). The median tumor margin dose to the 50% isodose line was 12.55 Gy (range 6.5-24 Gy). Descriptive analysis was performed in 331 patients (90%); 325 patients had a follow-up longer than 24 months (median 60 months), and six patients were included because of posttreatment complications. The volume of treated tumors decreased in 248 cases (69.7%), remained the same in 99 (27.8%), and increased in nine (2.5%). The actuarial tumor control rate was 97.9% at 5 years post-GKS. Perilesional edema after radiosurgery was confirmed on neuroimaging in 51 patients (15.4%). The temporary and permanent morbidity rates after radiosurgery were 10.2 and 5.7%, respectively. A significantly higher incidence of tumor volume increase was observed in men compared with women and in tumors treated with a margin dose lower than 12 Gy. Significant risk factors for edema included an age greater than 60 years, no previous surgery, perilesional edema before radiosurgery, a tumor volume greater than 10 cm3, a tumor location in the anterior fossa, and a margin dose greater than 16 Gy. Stereotactic radiosurgery is a safe method of treatment for meningiomas. A minimum margin dose of 12 to 16 Gy seems to represent the therapeutic window for benign meningiomas with a high tumor control rate in a mid-term follow-up period.


Transient hyperopia with lens swelling at initial therapy in diabetes.
The clinical courses of 10 eyes of five diabetic patients who exhibited bilateral transient hyperopia (maximum: 1:1-4.9 dioptres, spherical equivalent) after initiation of strict control of diabetes with or without insulin are reported. The hyperopia occurred within a few days after abrupt decrease in plasma glucose, progressed to maximum at days 7-14, and regressed gradually over 1 month thereafter. Transient cycloplegia had no effect on refractive error. During hyperopia, there were no significant changes in axial length or corneal curvature. However, thickened lens, decreased anterior chamber depth, and transient cataract were observed to significant degrees. It is suggested that the transient hyperopia, with lens swelling and opacity, was caused by decreased lens refractive index following water influx.


Strong and specific associations between cardiovascular risk factors and white matter micro- and macrostructure in healthy aging.
Cardiovascular health declines with age, increasing the risk of hypertension and elevated heart rate in middle and old age. Here, we used multivariate techniques to investigate the associations between cardiovascular health (diastolic blood pressure, systolic blood pressure, and heart rate) and white matter macrostructure (lesion volume and number) and microstructure (as measured by diffusion-weighted imaging) in the cross-sectional, population-based Cam-CAN cohort (N = 667, aged 18-88). We found that cardiovascular health and age made approximately similar contributions to white matter health and explained up to 56% of variance therein. Lower diastolic blood pressure, higher systolic blood pressure, and higher heart rate were each strongly, and independently, associated with white matter abnormalities on all indices. Body mass and exercise were associated with white matter health, both directly and indirectly via cardiovascular health. These results highlight the importance of cardiovascular risk factors for white matter health across the adult lifespan and suggest that systolic blood pressure, diastolic blood pressure, and heart rate affect white matter health via separate mechanisms.


Circulating Levels of miR-574-5p Are Associated with Neurological Outcome after Cardiac Arrest in Women: A Target Temperature Management (TTM) Trial Substudy.
Postresuscitation neuroprognostication is guided by neurophysiological tests, biomarker measurement, and clinical examination. Recent investigations suggest that circulating microRNAs (miRNA) may help in outcome prediction after cardiac arrest. We assessed the ability of miR-574-5p to predict neurological outcome after cardiac arrest, in a sex-specific manner. In this substudy of the Target Temperature Management (TTM) Trial, we enrolled 590 cardiac arrest patients for which blood samples were available. Expression levels of miR-574-5p were measured by quantitative PCR in plasma samples collected 48 h after cardiac arrest. The endpoint of the study was poor neurological outcome at 6 months (cerebral performance category scores 3 to 5). Eighty-one percent of patients were men, and 49% had a poor neurological outcome. Circulating levels of miR-574-5p at 48 h were higher in patients with a poor neurological outcome at 6 months (p < 0.001), both in women and in men. Circulating levels of miR-574-5p were univariate predictors of neurological outcome (odds ratio (OR) [95% confidence interval (CI)]: 1.5 [1.26-1.78]). After adjustment with clinical variables and NSE, circulating levels of miR-574-5p predicted neurological outcome in women (OR [95% CI]: 1.9 [1.09-3.45]), but not in men (OR [95% CI]: 1.0 [0.74-1.28]). miR-574-5p is associated with neurological outcome after cardiac arrest in women.