People underestimate the value of persistence for creative performance.
Across 7 studies, we investigated the prediction that people underestimate the value of persistence for creative performance. Across a range of creative tasks, people consistently underestimated how productive they would be while persisting (Studies 1-3). Study 3 found that the subjectively experienced difficulty, or disfluency, of creative thought accounted for persistence undervaluation. Alternative explanations based on idea quality (Studies 1-2B) and goal setting (Study 4) were considered and ruled out and domain knowledge was explored as a boundary condition (Study 5). In Study 6, the disfluency of creative thought reduced people's willingness to invest in an opportunity to persist, resulting in lower financial performance. This research demonstrates that persistence is a critical determinant of creative performance and that people may undervalue and underutilize persistence in everyday creative problem solving.


Clinical presentation of urolithiasis in older and younger population.
We compared stone size, localization, complaint at the time of applying, comorbidity, treatment and complications between older (60 years of age and older) and younger patients with urolithiasis (59 years of age and younger). We retrospectively reviewed the records of 950 consecutive patients who presented to our clinic and underwent surgery for urolithiasis from January 2007 to March 2012. The patients were divided into two groups: patients ≥ 60 years an patients < 60 years. There were 174 men and 61 women in elderly group, 528 men and 187 women in younger group. Ureteral stones were found more often in the younger group compared to elderly patients (p < 0.05). Conversely, bladder stone was more frequent in the elderly group. In the elderly group comorbidities are more frequent (diabetes mellitus, hypertension, ischemic heart disease, congestive heart disease, osteoarthritis and chronic obstructive lung). Patients ≥ 60 years significantly had larger kidney and bladder stones compared the younger, but ureteral stone sizes were not statistically different between the two groups. Older patients had a higher postoperative complication rate than younger patients (16% versus 3%, p < 0.05) although postoperative complications (e.g. urinary retention, cardiac dysrythmia, fever, constipation) were not serious and resolved with medical treatment. The average length of stay in hospital was longer in the elderly group, but the difference was not statistically significant. Elderly patients with urolithiasis usually have larger and more complex stone disease, more comorbidities and atypical presentation.


Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice.
Apolipoprotein E-deficient mice provide a useful system for studying the role of apolipoprotein E (apoE) in the function of distinct neuronal systems. In the present study we focused on the cholinergic system of these mice. This was pursued by measurements of specific biochemical, physiological and cognitive parameters. Morris Water Maze tasks revealed impairments in working memory but not in reference memory of the apoE-deficient mice. Measurements of brain choline acetyltransferase activities revealed them to be markedly lower in the hippocampus and frontal cortex of the apoE-deficient mice than in the corresponding brain areas of the controls, but unaltered in other brain areas. In addition, hypothermia induced by the centrally acting muscarinic agonist, oxotremorine, was reduced in the apoE-deficient mice as compared to controls. These results show that apoE-deficient mice have cholinergic deficits and highlight the importance of this mouse model for studying the interactions between apoE and the cholinergic nervous system.


Visualization of disconnection syndromes in humans.
Knowledge of the relationship between structure and function is essential to the exploration of the architecture of cognition. Cognitive processes require the coordinated activity of large-scale brain networks consisting of distant cortical regions, connected by long-range white matter tracts. Despite decades of connectional tracing studies in monkeys, the backwardness of human anatomy makes it difficult to draw conclusions from lesion studies and functional neuroimaging when brain connectivity is at issue. We propose an approach to clinico-anatomical correlation, based on a standardized atlas of white matter tracts derived from diffusion tensor imaging tractography. Using OVER-TRACK, a method based on tracking and overlapping white matter tracts, we mapped the course of three rostro-caudal association pathways in the Montreal Neurological Institute space. For each voxel we defined the probability of finding fibers belonging to individual tracts. This method is defined to localize in the white matter the overlapping lesion derived from a group of patients with brain damage. Our study provides a general approach for establishing anatomo-functional correlations by estimating the cortical areas connected in normal subjects, or disconnected by white matter lesions. This method will help researchers and clinicians to identify the neural bases of cognitive abilities and the behavioral consequences of brain lesions.


[Dynamics of the indices of the immune system as affected by endobronchial laser therapy in patients with complicated tuberculosis of the lungs].
The results of study of the local and humoral immune defense during endobronchial laser therapy of nonspecific endobronchitis in patients with newly diagnosed pulmonary tuberculosis are presented. Laser therapy proved to have no negative action on the humoral immunity in pulmonary tuberculosis patients during treatment of catarrhal and purulent endobronchitis, while a marked increase in IgM levels, thus rapidly reacting and well opsonizing antibodies can be regarded as a positive or stimulating the impact on the whole immune system. Endobronchial laser therapy for catarrhal and especially purulent inflammatory bronchial process in the multimodality treatment of patients with newly diagnosed pulmonary tuberculosis normalized parameters of the local immune system, especially that of locally secreted immunoglobulins, i.e. helium-neon laser radiation has a favourable influence on local immune defense, which is essential in increasing the efficacy of therapy of this category of patients.


Effect of thiols on beta 2-adrenoceptors in human mononuclear leucocytes.
The effect of the disulfide reducing agent dithiothreitol (DTT) and other thiols on binding of the beta-adrenoceptor antagonist (-)-125iodocyanopindolol (125ICYP) to human mononuclear leucocytes (MNL) was investigated. Saturation experiments and dissociation kinetics revealed two classes of specific 125ICYP binding sites, one of high and the other of low affinity, respectively. In intact MNL DTT caused a decrease in specific binding. This was due almost selectively to a decrease in the affinity of high affinity binding sites, which decreased gradually in a concentration-dependent manner to the affinity of low affinity binding sites. In MNL membranes DTT decreased not only the affinity but also the number of high affinity binding sites. The DTT effect was completely reversible by simple reoxidation on air. The structural isomers (+/-)-DTT. (-)-DTT and dithioerythritol revealed identical effects on specific binding, whereas the monothiols mercaptoethanol and alpha-monothioglycerol, having a lower redox potential, were considerably less effective. In the same concentration range that influenced specific binding. DTT stimulated intracellular cAMP production. These results suggest functionally important disulfide bridges which regulate the affinity of beta-adrenoceptor binding sites in human MNL. They stabilize the receptor in a high affinity state; their reduction causes the conversion of the high affinity state into a low affinity state in a process associated with stimulation of adenylate cyclase. Available evidence indicates that a similar transformation is made by beta-adrenoceptor agonists. Consequently low affinity 125ICYP binding sites preexistent in untreated cells could represent a reduced receptor state resulting from agonist-receptor interaction in vivo.


Relationship between delay discounting, delay aversion and psychosocial domains of diabetes care.
Delay discounting and aversion are important areas for diabetes management; however, little has been done to understand the relationship with psychosocial outcomes among adults with type 2 diabetes. This study used data from 365 adults with type 2 diabetes to evaluate relationships between delay discounting and aversion and psychosocial outcomes. Delay discounting and aversion were measured with the validated Quick Delay Questionnaire. Psychosocial outcomes included depression, measured by the PHQ, anxiety by the GAD scale, perceived stress by the PSS, and social support by the Duke Social Support and Stress Scale. Multiple linear regression was used to assess the relationship between delay discounting and aversion on psychological health and social support controlling for relevant covariates. Mean age of the sample was 61.8 years, 54.5 % were NHB, 41.8 % NHW, and 3.7 % Hispanic/Other. After adjusting for covariates, delay aversion was significantly associated with depression (beta = 0.35; p < 0.001), anxiety (beta = 0.52; p < 0.001), perceived stress (beta = 0.22; p < 0.001), and lower family support (beta = -0.62; p < 0.05). Delay discounting was significantly associated with depression (beta = 0.32; p < 0.001), anxiety (beta = 0.46; p < 0.001), and perceived stress (beta = 0.26; p < 0.001). This data is cross-sectional, future work should examine the longitudinal relationship while also including additional psychosocial outcomes. Delay discounting and aversion are significantly associated with poor psychosocial outcomes, including lower social support. As the body of evidence grows, additional research is needed to better understand the construct, mechanisms, and the impact of choice settings to better inform intervention development.


Engineering Cellular Microenvironments with Photo- and Enzymatically Responsive Hydrogels: Toward Biomimetic 3D Cell Culture Models.
Conventional cell culture techniques using 2D polystyrene or glass have provided great insight into key biochemical mechanisms responsible for cellular events such as cell proliferation, differentiation, and cell-cell interactions. However, the physical and chemical properties of 2D culture in vitro are dramatically different than those found in the native cellular microenvironment in vivo. Cells grown on 2D substrates differ significantly from those grown in vivo, and this explains, in part, why many promising drug candidates discovered through in vitro drug screening assays fail when they are translated to in vivo animal or human models. To overcome this obstacle, 3D cell culture using biomimetic hydrogels has emerged as an alternative strategy to recapitulate native cell growth in vitro. Hydrogels, which are water-swollen polymers, can be synthetic or naturally derived. Many methods have been developed to control the physical and chemical properties of the hydrogels to match those found in specific tissues. Compared to 2D culture, cells cultured in 3D gels with the appropriate physicochemical cues can behave more like they naturally do in vivo. While conventional hydrogels involve modifications to the bulk material to mimic the static aspects of the cellular microenvironment, recent progress has focused on using more dynamic hydrogels, the chemical and physical properties of which can be altered with external stimuli to better mimic the dynamics of the native cellular microenvironment found in vivo. In this Account, we describe our progress in designing stimuli-responsive, optically transparent hydrogels that can be used as biomimetic extracellular matrices (ECMs) to study cell differentiation and migration in the context of modeling the nervous system and cancer. Specifically, we developed photosensitive agarose and hyaluronic acid hydrogels that are activated by single or two-photon irradiation for biomolecule immobilization at specific volumes within the 3D hydrogel. By controlling the spatial location of protein immobilization, we created 3D patterns and protein concentration gradients within these gels. We used the latter to study the effect of VEGF-165 concentration gradients on the interactions between endothelial cells and retinal stem cells. Hyaluronic acid (HA) is particularly compelling as it is naturally found in the ECM of many tissues and the tumor microenvironment. We used Diels-Alder click chemistry and cryogelation to alter the chemical and physical properties of these hydrogels. We also designed HA hydrogels to study the invasion of breast cancer cells. HA gels were chemically cross-linked with matrix metalloproteinase (MMP)-degradable peptides that degrade in the presence of cancer cell-secreted MMPs, thus allowing cells to remodel their local microenvironment and invade into HA/MMP-degradable gels.


Can diffusion weighted magnetic resonance imaging help differentiate stroke from stroke-like events in MELAS?
The precise mechanism of neurological symptoms in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is still controversial. The diffusion weighted MR findings at the acute phase of a neurological event in MELAS are described and the pathophysiology of stroke-like lesion in the light of diffusion changes is discussed. Brain MRI was performed 2 days after the sudden onset of cortical blindness in a 25 year old patient with MELAS. Fluid attenuated inversion recovery (FLAIR) images showed multifocal cortical and subcortical hyperintensities located bilaterally in the frontobasal and the temporo-occipital lobes. Diffusion weighted images showed normal to increased apparent diffusion coefficient values in the acute left temporooccipital lesion and increased values in the older stroke-like lesions. These diffusion weighted findings support the metabolic rather than the ischaemic pathophysiological hypothesis for stroke-like episodes occurring in MELAS. Normal or increased apparent diffusion coefficient values within 48 hours of a neurological deficit of abrupt onset should raise the possibility of MELAS, especially if conventional MR images show infarct-like lesions.


Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes.
The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.


Modulation of cognitive flexibility by reward and punishment in BALB/cJ and BALB/cByJ mice.
Learning from feedback is one of the key mechanisms within cognitive flexibility, which is needed to react swiftly to constantly changing environments. The motivation to change behavior is highly dependent on the expectancy of positive (reward) or negative (punishment) feedback. Individuals with conduct disorder (CD) with high callous unemotional traits show decreased sensitivity to negative feedback and increased reward seeking. Previous studies have modeled traits associated with CD (i.e. heightened aggression and anti-social behavior) in BALB/cJ mice (compared to the BALB/cByJ mouse as controls). Based on these findings, we hypothesized reduced negative feedback-related cognitive flexibility to be present in BALB/cJ mice. The effect of negative feedback and reward sensitivity on cognitive flexibility in BALB/cJ and BALB/cByJ mice was examined in a reversal learning paradigm. BALB/cJ mice were more flexible in the acquisition of new contingencies under rewarding conditions compared to BALB/cByJ mice, while the presence of an aversive punishing stimulus decreased their learning performance. Additionally, BALB/cJ mice needed more correction trials to reach the reversal learning criterion. This was accompanied by a higher rate of perseverance, which could represent impaired error detection. The addition of a second punishment enhanced punishment sensitivity in BALB/cJ mice. In contrast, the performance of the BALB/cByJ mice was not affected by additional negative feedback. Taken together, the BALB/cJ can be considered to be less sensitive to learn from negative feedback and therefore may be a useful model to further characterize molecular and neural underpinnings of callous unemotional traits in CD.


[Efferent therapy in the treatment of solid tumors].
Endogenous intoxication and immune insufficiency accompany neoplastic process. Complex therapy for cancer worsens these pathologic conditions by its adverse effects (AE) and thus complicates treatment. Efferent therapy can provide continuity of antineoplastic therapy with normalization of hemostasis and decreasing the rate of AE and their intensity. Efferent therapy meaningfully increases patient's quality of life and decreases the needed drug support when used as a part of complex therapy. Proper use of efferent therapy can markedly increase efficacy of surgical treatment, radiation therapy and drug therapy.


[Use of sodium hydroxybutyrate in the treatment of narcolepsy].
The action of sodium hydroxybutyrate, a GABA derivative, was examined in 11 patients with narcolepsy. A two-week course of therapy was evaluated using clinical and electrophysiological research methods including polygraphic examination of night sleep. The use of the drug was associated with improvement in the patients' nocturnal sleep attended by an increase in the IV stage of the slow sleep phase, synchronizing shifts on the EEG in the period of diurnal wakefulness and a decrease in the initial emotional tension. To correct night sleep disturbances, it is advisable to include sodium hydroxybutyrate into a multimodality treatment of narcolepsy.


Inferring copy number and genotype in tumour exome data.
Using whole exome sequencing to predict aberrations in tumours is a cost effective alternative to whole genome sequencing, however is predominantly used for variant detection and infrequently utilised for detection of somatic copy number variation. We propose a new method to infer copy number and genotypes using whole exome data from paired tumour/normal samples. Our algorithm uses two Hidden Markov Models to predict copy number and genotypes and computationally resolves polyploidy/aneuploidy, normal cell contamination and signal baseline shift. Our method makes explicit detection on chromosome arm level events, which are commonly found in tumour samples. The methods are combined into a package named ADTEx (Aberration Detection in Tumour Exome). We applied our algorithm to a cohort of 17 in-house generated and 18 TCGA paired ovarian cancer/normal exomes and evaluated the performance by comparing against the copy number variations and genotypes predicted using Affymetrix SNP 6.0 data of the same samples. Further, we carried out a comparison study to show that ADTEx outperformed its competitors in terms of precision and F-measure. Our proposed method, ADTEx, uses both depth of coverage ratios and B allele frequencies calculated from whole exome sequencing data, to predict copy number variations along with their genotypes. ADTEx is implemented as a user friendly software package using Python and R statistical language. Source code and sample data are freely available under GNU license (GPLv3) at http://adtex.sourceforge.net/.


Identifying the neural correlates of doorway freezing in Parkinson's disease.
Freezing of gait (FOG) in Parkinson's disease (PD) is frequently triggered upon passing through narrow spaces such as doorways. However, despite being common the neural mechanisms underlying this phenomenon are poorly understood. In our study, 19 patients who routinely experience FOG performed a previously validated virtual reality (VR) gait paradigm where they used foot-pedals to navigate a series of doorways. Patients underwent testing randomised between both their "ON" and "OFF" medication states. Task performance in conjunction with blood oxygenation level dependent (BOLD) signal changes between "ON" and "OFF" states were compared within each patient. Specifically, as they passed through a doorway in the VR environment patients demonstrated significantly longer "footstep" latencies in the OFF state compared to the ON state. As seen clinically in FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. Functional magnetic resonance imaging revealed that footstep prolongation on passing through doorways was associated with selective hypoactivation in the presupplementary motor area (pSMA) bilaterally. Task-based functional connectivity analyses revealed that increased latency in response to doorways was inversely correlated with the degree of functional connectivity between the pSMA and the subthalamic nucleus (STN) across both hemispheres. Furthermore, increased frequency of prolonged footstep latency was associated with increased connectivity between the bilateral STN. These findings suggest that the effect of environmental cues on triggering FOG reflects a degree of impaired processing within the pSMA and disrupted signalling between the pSMA and STN, thus implicating the "hyperdirect" pathway in the generation of this phenomenon.


Epstein-Barr virus small RNAs potentiate tumorigenicity of Burkitt lymphoma cells independently of an effect on apoptosis.
The tumorigenic potential of the Burkitt lymphoma (BL) cell line Akata is dependent on the restricted latency program of Epstein-Barr virus (EBV) that is characteristically maintained in BL tumors. Within these cells, EBV-mediated inhibition of apoptosis correlates with an up-regulation of BCL-2 levels in concert with a down-regulation in c-MYC expression that occurs under growth-limiting conditions. Here we addressed whether EBV's effects on apoptosis and tumorigenicity are mediated by the EBV small RNAs EBER-1 and EBER-2. Stable expression of the EBERs in EBV-negative Akata BL cells, at levels comparable to those in EBV-positive cells, significantly enhanced the tumorigenic potential of EBV-negative BL cells in SCID mice, but did not fully restore tumorigenicity relative to EBV-positive Akata cells. Furthermore, wild-type or greater levels of EBER expression in EBV-negative Akata cells did not promote BL cell survival. These data therefore suggest that EBV can contribute to BL through at least two avenues: an EBER-dependent mechanism that enhances tumorigenic potential independent of a direct effect on apoptosis, and a second mechanism, mediated by an as-yet-unidentified EBV gene(s), that offsets the proapoptotic consequences of deregulated c-MYC in BL.


Sibling history of asthma is a risk factor for pain in children with sickle cell anemia.
The basis of the association between asthma and an increased rate of pain among children with sickle cell anemia (SCA) is unclear. To provide evidence for a familial contribution to this observation, we tested the hypothesis that a family history of asthma is associated with an increased pain rate. Using data from the Cooperative Study for Sickle Cell Disease (CSSCD), we identified 211 children with SCA with asthma history of the parents and siblings. A sibling history of asthma was associated with a greater rate of pain (mean rate ratio = 2.48, 95% CI = 1.6-4.0; P < 0.001) when compared with children without a sibling history of asthma. Parental history of asthma was not associated an increase rate of pain (mean ratio = 1.51, 95% CI= 0.92-2.62; P = 0.12). Further studies are needed to examine genetic and/or environmental risks for asthma as potential contributors to pain in children with SCA.


A clinical decision support system optimising adjuvant chemotherapy for colorectal cancers by integrating deep learning and pathological staging markers: a development and validation study.
The DoMore-v1-CRC marker was recently developed using deep learning and conventional haematoxylin and eosin-stained tissue sections, and was observed to outperform established molecular and morphological markers of patient outcome after primary colorectal cancer resection. The aim of the present study was to develop a clinical decision support system based on DoMore-v1-CRC and pathological staging markers to facilitate individualised selection of adjuvant treatment. We estimated cancer-specific survival in subgroups formed by pathological tumour stage (pT<4 or pT4), pathological nodal stage (pN0, pN1, or pN2), number of lymph nodes sampled (≤12 or >12) if not pN2, and DoMore-v1-CRC classification (good, uncertain, or poor prognosis) in 997 patients with stage II or III colorectal cancer considered to have no residual tumour (R0) from two community-based cohorts in Norway and the UK, and used these data to define three risk groups. An external cohort of 1075 patients with stage II or III R0 colorectal cancer from the QUASAR 2 trial was used for validation; these patients were treated with single-agent capecitabine. The proposed risk stratification system was evaluated using Cox regression analysis. We similarly evaluated a risk stratification system intended to reflect current guidelines and clinical practice. The primary outcome was cancer-specific survival. The new risk stratification system provided a hazard ratio of 10·71 (95% CI 6·39-17·93; p<0·0001) for high-risk versus low-risk patients and 3·06 (1·73-5·42; p=0·0001) for intermediate versus low risk in the primary analysis of the validation cohort. Estimated 3-year cancer-specific survival was 97·2% (95% CI 95·1-98·4; n=445 [41%]) for the low-risk group, 94·8% (91·7-96·7; n=339 [32%]) for the intermediate-risk group, and 77·6% (72·1-82·1; n=291 [27%]) for the high-risk group. The guideline-based risk grouping was observed to be less prognostic and informative (the low-risk group comprised only 142 [13%] of the 1075 patients). Integrating DoMore-v1-CRC and pathological staging markers provided a clinical decision support system that risk stratifies more accurately than its constituent elements, and identifies substantially more patients with stage II and III colorectal cancer with similarly good prognosis as the low-risk group in current guidelines. Avoiding adjuvant chemotherapy in these patients might be safe, and could reduce morbidity, mortality, and treatment costs. The Research Council of Norway.


Redox mediated photocatalytic water-splitting in optofluidic microreactors.
While photocatalytic water-splitting is a promising alternative energy source, low photocatalytic efficiencies in the visible spectrum hinders its widespread deployment and commercialization. Although screening combinations of new materials and characterizing their reaction kinetics offers possible improvements to efficiency, current experiments are challenged by expensive bulky setups and slow recovery of particles downstream. Optofluidics is a good platform for screening Z-scheme catalysts cheaply and rapidly. By alleviating the problems of mass transport it can also potentially increase reaction rates and efficiencies. Here, we demonstrate a novel optofluidic device based on applying catalyst sol-gels on planar channels while measuring the reaction output by monitoring the depletion of the redox mediators. We use our setup to study the kinetics of the TiO(2)-Pt water-splitting reaction mediated by I(-)/IO(3)(-) redox pairs under different flow rates. In particular, for TiO(2)-Pt, we show ~2-fold improvements in reaction rates and efficiencies.


A computational model integrating brain electrophysiology and metabolism highlights the key role of extracellular potassium and oxygen.
The human brain is a small organ which uses a disproportionate amount of the total metabolic energy production in the body. While it is well understood that the most significant energy sink is the maintenance of the neuronal membrane potential during the brain signaling activity, the role of astrocytes in the energy balance continues to be the topic of a lot of research. A key function of astrocytes, besides clearing glutamate from the synaptic clefts, is the potassium clearing after neuronal activation. Extracellular potassium plays a significant role in triggering neuronal firing, and elevated concentration of potassium may lead to abnormal firing patterns, e.g., seizures, thus emphasizing the importance of the glial K+ buffering role. The predictive mathematical model proposed in this paper elucidates the role of glial potassium clearing in brain energy metabolism, integrating a detailed model of the ion dynamics which regulates neuronal firing with a four compartment metabolic model. Because of the very different characteristic time scales of electrophysiology and metabolism, care must be taken when coupling the two models to ensure that the predictions, e.g., neuronal firing frequencies and the oxygen-glucose index (OGI) of the brain during activation and rest, are in agreement with empirical observations. The temporal multi-scale nature of the problem requires the design of new computational tools to ensure a stable and accurate numerical treatment. The model predictions for different protocols, including combinations of elevated activation and ischemic episodes, are in good agreement with experimental observations reported in the literature.


[Traffic related air pollution and population health: a review about São Paulo (SP), Brazil].
Air pollution is an important problem for São Paulo city and vehicles are the main source. About 11 million people are exposed to this pollution. To examine studies realized about air pollution and its effects on health of the population of São Paulo (Brazil) and methods of assessing exposure to pollution related to traffic. We performed a literature review using the keywords "air pollution", "São Paulo", and traffic-related air pollution. As results were obtained several studies that found relation between air pollution in São Paulo and respiratory and cardiovascular problems, fetal growth, increased mortality and hospitalizations, particularly in children and elderly people. In order to estimate the exposure, most of these studies consider the isotropic distribution of pollutants throughout the area, what prevents the evaluation of and the influence of traffic. Several methods have been used to analyze the air traffic exposure, which can be used isolated or combined. It is believed that the combination of models used to calculate pollutant concentrations to methods of georeferencing is the most appropriate approach for similar studies in São Paulo. The advantages of these methods are the ability to identify priority areas and situations, obtaining detailed information for adoption of public policies or measures, and to simulate different scenarios. The application of these methods in studies at São Paulo depends on the improvement of input data, air quality meteorological monitoring net enhancement and data of traffic volume.


Role of nutrition in managing the premenstrual tension syndromes.
The clinical, biochemical and endocrine effects of a total dietary program were evaluated in patients with the premenstrual tension syndromes (PMTS). The program consisted of dietary guidelines and nutritional supplementation. Open trials suggested that an initial dosage of the supplement consisting of six tablets daily gave the best symptomatic relief during the first three to six months. Double-blind studies confirmed that a daily average of six tablets decreased PMTS symptom scores to significantly lower levels than did the placebo. A significantly higher percentage of PMTS patients reported feeling better on the dietary program than did those on the placebo. Although significant changes were observed in some liver function tests, the values were within the normal ranges. The dietary program, implemented for three to six months, decreased serum estradiol 17-beta and increased serum progesterone levels during the midluteal phase in PMTS patients. Nonresponders using the program should be reevaluated and treated according to the results of the reevaluation and the PMTS symptoms.


[Painful nodular and plantar erythema in children].
According to our knowledge, only twenty-three similar cases have been reported in the literature. Possible hypotheses for localised painful red nodules on the feet in children include erythema nodosum, neutrophilic eccrine hidradenitis, traumatic plantar urticaria, vasculitis and cold panniculitis. We report a typical case of painful erythematous plantar nodules of the child. A 13-yr-old boy was first seen by a paediatrician for intermittent fever. The fever was associated with red, painful nodules on the soles. He was unable to walk. Routine blood chemistry parameters were within normal limits. Histopathologic examination of lesional skin revealed an image of septal and lobular panniculitis with vasculitis. Direct immunofluorescence study was not contributive. With proper antibiotic therapy, pain resolved within one week while fever and nodules cleared within two weeks. Briefly, this observation concerns a child disease occurring as painful erythematous plantar nodules. The lesions are spontaneously resolutive and the children are in good health. Our observation should constitute a supplementary group with the same classical symptoms of nodular plantar painful erythema of the child but moreover accompanied by a septal and lobular panniculitis with vasculitis at the histological examination. Further studies are necessary to verify these hypotheses.


Recovery time course in contractile function of fast and slow skeletal muscle after hindlimb immobilization.
Contractile properties were evaluated in rats remobilized after 6 wk of hindlimb casting to evaluate the regenerative capacity of fast and slow skeletal muscles. Contractile parameters were determined in vitro (22 degrees C) in the type I soleus (SOL), type IIA and IIB extensor digitorum longus (EDL), and the type IIB superficial vastus lateralis (SVL). Immobilization (IM) shortened the SOL isometric twitch duration after which contraction time and half-relaxation time required 4 and 7 days to recover, respectively. In contrast, IM prolonged the twitch in the EDL and SVL and recovery required 14 and 7 days, respectively. Peak tetanic tension (g/cm2) fell in the SOL and EDL with IM and full recovery required 28 days. In this regard, the SVL remained unaltered. Rates of tension development and decline remained essentially unaltered in the fast muscles after IM but fell in the SOL, requiring 14 days to fully recover. Maximal shortening velocity, which had been elevated in all three muscles by IM, recovered rapidly. The present results demonstrate that both fast and slow muscle have the ability to completely recover from 6 weeks of IM.


New approaches to recovery after stroke.
After a stroke, several mechanisms of neural plasticity can be activated, which may lead to significant recovery. Rehabilitation therapies aim to restore surviving tissue over time and reorganize neural connections. With more patients surviving stroke with varying degrees of neurological impairment, new technologies have emerged as a promising option for better functional outcomes. This review explores restorative therapies based on brain-computer interfaces, robot-assisted and virtual reality, brain stimulation, and cell therapies. Brain-computer interfaces allow for the translation of brain signals into motor patterns. Robot-assisted and virtual reality therapies provide interactive interfaces that simulate real-life situations and physical support to compensate for lost motor function. Brain stimulation can modify the electrical activity of neurons in the affected cortex. Cell therapy may promote regeneration in damaged brain tissue. Taken together, these new approaches could substantially benefit specific deficits such as arm-motor control and cognitive impairment after stroke, and even the chronic phase of recovery, where traditional rehabilitation methods may be limited, and the window for repair is narrow.


Gastrodin attenuates lithium-pilocarpine-induced epilepsy by activating AMPK-mediated PPARα in a juvenile rat model.
Gastrodin has shown the potential as an anticonvulsant. Epilepsy is a neurological disease with significant effects in children. In the current study, the therapeutic potential of gastrodin in handling pediatric epilepsy was explored by focusing on the AMPK/PPARα pathway. Three-week-old Sprague-Dawley rats were subjected to lithium-pilocarpine method to induce epileptic symptoms and then administrated with gastrodin. The effects of gastrodin on rats were first assessed using electroencephalogram (EEG) recording, Racine classification, Morris water maze test, and histological staining. The levels of BDNF and NGF, and the activity of AMPK/PPARα were measured. Based on the results of EEG, behavior analyses, and histological staining, epileptic symptoms were significantly alleviated by gastrodin. Moreover, the administration of gastrodin also suppressed the levels of BDNF and NGF, and activated the AMPK/PPARα pathway. In conclusion, our results demonstrated that gastrodin contributed to the alleviation of pediatric epilepsy by activating AMPK/PPARα signaling transduction.


Reduced satellite cell numbers with spinal cord injury and aging in humans.
Both sarcopenia and spinal cord injury (SCI) are characterized by the loss of skeletal muscle mass and function. Despite obvious similarities in atrophy between both models, differences in muscle fiber size and satellite cell content may exist on a muscle fiber type-specific level. In the present study, we compared skeletal muscle fiber characteristics between wheelchair-dependent young males with SCI (n = 8, 32 ± 4 yr), healthy elderly males (n = 8, 75 ± 2 yr), and young controls (n = 8, 31 ± 3 yr). Muscle biopsies were collected to determine skeletal muscle fiber type composition, fiber size, and satellite cell content. Severe atrophy and a shift toward approximately 90% Type II muscle fibers were observed in muscle obtained from males with SCI. Muscle fiber size was substantially smaller in both the SCI (Types I and II fibers) and elderly subjects (Type II fibers) when compared with the controls. Satellite cell content was substantially lower in the wheelchair-dependent SCI subjects in both the Types I and II muscle fibers (0.049 ± 0.019 and 0.050 ± 0.005 satellite cells per fiber, respectively) when compared with the young controls (0.104 ± 0.011 and 0.117 ± 0.009 satellite cells per fiber, respectively). In the elderly, the number of satellite cells was lower in the Type II muscle fibers only (0.042 ± 0.005 vs 0.117 ± 0.009 satellite cells per fiber in the elderly vs young controls, respectively). This is the first study to show that muscle fiber atrophy as observed with SCI (Types I and II fibers) and aging (Type II fibers) is accompanied by a muscle fiber type-specific reduction in satellite cell content in humans.


5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.
Opiates are widely used analgesics in anesthesiology, but they have serious adverse effects such as depression of breathing. This is caused by direct inhibition of rhythm-generating respiratory neurons in the Pre-Boetzinger complex (PBC) of the brainstem. We report that serotonin 4(a) [5-HT4(a)] receptors are strongly expressed in respiratory PBC neurons and that their selective activation protects spontaneous respiratory activity. Treatment of rats with a 5-HT4 receptor-specific agonist overcame fentanyl-induced respiratory depression and reestablished stable respiratory rhythm without loss of fentanyl's analgesic effect. These findings imply the prospect of a fine-tuned recovery from opioid-induced respiratory depression, through adjustment of intracellular adenosine 3',5'-monophosphate levels through the convergent signaling pathways in neurons.


Quartz Dust Exposure Affects NLRP3 Inflammasome Activation and Plasma Levels of IL-18 and IL-1Ra in Iron Foundry Workers.
To study the association between inhalation of particulate matter or quartz in Swedish iron foundries and the effects on NLRP3 inflammasome activation. Particle exposure measurements were performed during an eight-hour work day for 85 foundry workers at three Swedish iron foundries. Personal sampling was used for measurement of respirable quartz and dust and stationary measurements to obtain exposure measurements for inhalable dust and PM10. The NLRP3 inflammasome markers, interleukin- (IL-) 1β and IL-18, and inhibitors IL-1 receptor antagonist (IL-1Ra) and IL-18 binding protein (IL-18BP) were measured in plasma. Inflammasome activation was measured by caspase-1 enzymatic activity in monocytes in whole blood by flow cytometry, and expression of inflammasome-related genes was quantified using real-time PCR. Multiple linear regression analysis was used to investigate associations between PM exposures and inflammatory markers. Sex, age, smoking, current infection, BMI, and single nucleotide polymorphism in the inflammasome regulating genes CARD8 (C10X) and NLRP3 (Q705K) were included as covariates. The average exposure levels of respirable dust and quartz were 0.85 and 0.052 mg/m3, respectively. A significant exposure-response was found for respirable dust and IL-18 and for inhalable dust and IL-1Ra. Whole blood, drawn from study participants, was stimulated ex vivo with inflammasome priming stimuli LPS or Pam3CSK4, resulting in a 47% and 49% increase in caspase-1 enzymatic activity in monocytes. This increase in caspase-1 activity was significantly attenuated in the higher exposure groups for most PM exposure measures. The results indicate that exposure levels of PM in the iron foundry environment can affect the NLRP3 inflammasome and systemic inflammation.


An exploration of factors that influence the regular consumption of water by Irish primary school children.
Inadequate hydration has been linked to many factors that may impact on children's education and health. Teachers play an important role in the education and behaviour of children. Previous research has demonstrated low water intake amongst children and negative teachers' attitudes to water in the classroom. The present study aimed to explore teachers' knowledge about water and the perceived barriers to allowing children access to water during lesson time. In-depth interviews were conducted with 12 teachers from primary schools in the Midlands of Ireland. Interviews were continued until there was saturation of the data. Thematic analysis of the data was conducted. Participants had a poor knowledge of hydration requirements and the associated health benefits and effect on concentration. Low water intake amongst teachers and pupils, and barriers such as disruption to class and increased need to urinate, were reported. Teachers identified the hydration effect on learning as the education message most likely to influence the decision to allow water in the classroom. The issues, opinions and perceived barriers raised by teachers as part of this qualitative research provide a basis for future health promotion around water.


Evaluation and management of chronic work-related musculoskeletal disorders of the distal upper extremity.
This clinical review will describe the epidemiology, clinical presentation, and management of the following work-related musculoskeletal disorders (WMSDs) of the distal upper extremity: deQuervain's disease, extensor and flexor forearm tendinitis/tendinosis, lateral and medial epicondylitis, cubital tunnel syndrome, and hand-arm vibration syndrome (HAVS). These conditions were selected for review either because they were among the most common WMSDs among patients attending the New York State Occupational Health Clinics (NYSOHC) network, or because there is strong evidence for work-relatedness in the clinical literature. Work-related carpal tunnel syndrome is discussed in an accompanying paper. In an attempt to provide evidence-based treatment recommendations, literature searches on the treatment of each condition were conducted via Medline for the years 1985-1999. There was a dearth of studies evaluating the efficacy of specific clinical treatments and ergonomic interventions for WMSDs. Therefore, many of the treatment recommendations presented here are based on a consensus of experienced public health-oriented occupational medicine physicians from the NYSOHC network after review of the pertinent literature. A summary table of the clinical features of the disorders is presented as a reference resource.


The evolution of surgery at the New York Hospital.
Surgery evolved from colonial times through many innovations and developments. During this time it was transformed from a dangerous practice to a delicate and scientific art. Many of these early developments continue to be a part of modern surgical therapy. Although European discoveries have had a profound effect on this evolution, American advances solidified the link between the laboratory and the operating room. The New York Hospital-Cornell Medical Center, like other medical centers around the country, made important contributions to this evolution. Because the hospital has spanned American history, it also has paralleled surgical development in the United States.


Role of Pharmacy Residency Training in Career Planning: A Student's Perspective.
Pharmacy students typically become more focused on career planning and assessment in the final year of their PharmD training. Weighing career options in the advanced pharmacy practice experience year can be both exciting and stressful. The goal of this article is to provide a primer on how pharmacy students can assess how a residency can fit into career planning. This article will describe the various career paths available to graduating students, highlight ways in which a residency can complement career choices, review the current state of the job market for pharmacists, discuss the current and future plans for residency programs, and present thoughts from some current and former residents on why they chose to complete a residency. Most career paths require some additional training, and a residency provides appropriate experience very quickly compared to on-the-job training. Alternative plans to residency training must also be considered, as there are not enough residency positions for candidates. Directors of pharmacy must consider several factors when giving career advice on pharmacy residency training to pharmacy students; they should provide the students with an honest assessment of their work skills and their abilities to successfully complete a residency. This assessment will help the students to set a plan for improvement and give them a better chance at being matched to a pharmacy residency.


A Human Conditionally Immortalized Proximal Tubule Epithelial Cell Line as a Novel Model for Studying Senescence and Response to Senolytics.
Accumulating evidence suggests that senescence of kidney tubule epithelial cells leads to fibrosis. These cells secrete senescence-associated secretory phenotype (SASP) factors that are involved in diverse signaling pathways, influencing kidney fibrosis. Here, we investigated whether our previously established conditionally immortalized proximal tubule epithelial cell line overexpressing the organic anion transporter 1 (ciPTEC-OAT1) can be used as a valid in vitro model to study kidney senescence and senolytics response. CiPTEC-OAT1 proliferates rapidly at 33°C and exhibits a "senescence-like" arrest at 37°C, most likely due to suppression of SV40T expression and subsequent reactivation of the p53 and Rb pathways. To understand how permissive (33°C) and non-permissive (37°C) temperatures of the cell culture affect the senescence phenotype, we cultured ciPTEC-OAT1 for up to 12 days and evaluated the apoptosis and SASP markers. Day 0 in both groups is considered as the non-senescence group (control). Further, the potential of navitoclax, dasatinib, quercetin, and the combination of the latter two to clear senescent cells was evaluated. Maturation of ciPTEC-OAT1 at non-permissive temperature affected mRNA and protein levels of senescence markers. A remarkable upregulation in p21 gene expression was found in the non-permissive temperature group, whereas expression of Lamin B1 decreased significantly. SASP factors, including PAI-1A, IL-1β, CTGF, and IL-6 were upregulated, but no significant difference in Bcl-2 and Bcl-xl were found in the non-permissive temperature group. After culturing ciPTEC-OAT1 up to 12 days, cells in the non-permissive temperature group showed an upregulation in the apoptosis-associated proteins Bcl-2, BID, and Bax, and a downregulation in Mcl-1, Bad, Bak, and Bim at various time points. Further, Bcl-xl, Puma, Caspase 3, Caspase 7, and Caspase 9 showed initial upregulations followed by downregulations at later time points. The loss of Lamin B1, upregulation of SA-β-gal expression and increase in its activity, upregulation of p21 levels and downregulation of p53, along with the upregulation of SASP factors, confirmed that maturation at 37°C promotes senescence features. Finally, the senolytics response was evaluated by testing cell viability following exposure to senolytics, to which cells appeared dose-dependently sensitive. Navitoclax was most effective in eliminating senescent cells. In conclusion, culturing ciPTEC-OAT1 at 37°C induces a senescence phenotype characterized by increased expression of cell cycle arrest and anti-apoptosis markers, SASP factors, and responsiveness to senolytics treatment. Therefore, ciPTEC-OAT1 represents a valid model for studying kidney senescence by simply adjusting culture conditions.


EFFECTS OF SYNBIOTIC SUPPLEMENTATION ON GUT FUNCTIONING AND SYSTEMIC INFLAMMATION OF COMMUNITY-DWELLING ELDERS - SECONDARY ANALYSES FROM A RANDOMIZED CLINICAL TRIAL.
Aging is a complex process marked by alterations on gut functioning and physiology, accompanied by an increase on the inflammatory status, leading to a scenario called "inflammaging". To evaluate the effects of a synbiotic substance on systemic inflammation, gut functioning of community-dwelling elders. This is a secondary analysis from a randomized clinical trial, lasting 24 weeks, including 49 elders, distributed into two groups: SYN (n=25), which received a synbiotic substance (Frutooligossacaride 6g, Lactobacillus paracasei LPC-31 109 to 108 UFC, Lactobacillus rhamnosus HN001 109 to 108 UFC, Lactobacillus acidophilus NCFM 109 to 108 UFC e Bifidobacterium lactis HN019 109 to 108 UFC), or PLA (n=24), receiving placebo. The evaluations consisted of serum IL-10 e TNF-α (after overnight fasting), evaluation of chronic constipation (by Rome III Criteria) and faeces types (by Bristol Stool Form Scale). Data were compared before and after the supplementation time, and between groups. No significant differences were found between baseline and final values of serum inflammatory markers. Some subtle beneficial changes were observed in SYN, concerning both gut functioning and faeces types. From our data, synbiotic supplementation showed a subtle benefit in gut functioning in apparently healthy community-dwelling elders. Our findings can suggest that the benefits in healthy individuals were less expressive than the ones presented in studies with individuals previously diagnosed as dysbiosis. Future studies, comparing elders with and without gut dysbiosis can confirm our findings.


[Chikungunya fever--expanded distribution of a re-emerging tropical infectious disease].
Chikungunya fever has been originally distributed in several parts of Africa, South Asia and Southeast Asia. The disease is caused by Chikungunya virus, an enveloped, single-stranded ribonucleic acid virus of the alphavirus genus (family Togaviridae). In Asia, virus transmission to humans occurs predominantly by the bite of the female Aedes aegypti or Aedes albopictus mosquito. In rural Africa, other mosquito species are also implicated in virus transmission. Chikungunya fever is characterized by fever with sudden onset, headache, backache, myalgia, and rash as well as painful and long-lasting arthralgia, affecting primarily the peripheral joints. Joint pain frequently persists for two or more months. Treatment strategies are primarily supportive and symptomatic and comprise the continuous application of certain analgetics, i.e., paracetamol (acetaminophen) and several non-steroidal anti-inflammatory agents. Although there is no generally recommended specific antiviral therapy, the use of chloroquine, ribavirin and interferon-alpha might be useful. In 2005 and 2006, the largest epidemic of Chikungunya fever ever recorded has been occurred in the islands of the southwest Indian Ocean and in India. The epidemic affected at least 1.3 million cases in India alone. The most affected island was the French territory La Réunion, where approximately one third of the total population (266,000 of 770,000) suffered from the disease. Based on the extent of the epidemic and the busy tourism between India/the islands of the Indian Ocean and Europe, numerous cases have been reported in several European countries since 2005. In 2007, one of these travellers served as "index patient" for the first outbreak of Chikungunya fever in a temperate region. Between July and September 2007, more than 200 cases of infection with Chikungunya virus have been notified in a region of north eastern Italy. The first autochthonic outbreak in Europe has been associated with the presence of A. albopictus, which is found with a high population density in Italy. During the last decades, A. albopictus mosquitos have been spread into several temperate regions and are now widely distributed in several areas of South and Central Europe and North America.


[Intestine dysbacteriosis meaning in pathogenesis of chronic diarrhea of celiac disease and syndrome of the short small intestine].
To study the mechanisms of chronic diarrhea in patients with celiac disease and the syndrome of short small intestine. The study included 24 patients: 9 with celiac disease with malabsorption syndrome of II and III degree, 15 patients with the syndrome of short small intestine and 9 healthy volunteers. Study of microflora in the small and large intestine was performed by seeding serial dilutions of the contents of upper small intestine and feces, followed by qualitative and quantitative view of selected microorganisms. Value of free and conjugated bile acids were determined by electrophoresis followed by densitometry. 2/3 of the examined patients revealed bacterial colonization of the small intestine. Were inoculated staphylococci, E. coli, enterococci. Was found a significant change in the ratio of bile acids: a significant increase in free, damaging the mucous, and a decrease in conjugated involved in the digestion of lipids. Unabsorbed lipids were one of the causes of diarrhea in the examined groups of patients. Sequential antibiotic drugs and probiotic promoted the normalization of the stool, microflora of the small and large intestine.


[Guideline 'Needlestick injuries': risk assessment and post-exposure management in practice].
Guideline 'Needle stick injuries': risk assessment and post-exposure management in practice The objective of the national guideline 'Needle stick injuries' is to make the assessment of needle stick injuries more structured and uniform. The injury is classified as high risk or low risk according to the volume of blood transmitted. For high-risk injuries measures to prevent hepatitis B, hepatitis C and HIV infection have to be considered, whereas for low-risk injuries only measures to prevent hepatitis B. The need for post-exposure prophylaxis is determined by the victim's immunity to hepatitis B and the presence of hepatitis B virus, hepatitis C virus or HIV in the source person. Post-exposure prophylaxis against hepatitis B consists primarily of hepatitis B vaccination; hepatitis B immunoglobulin is added in the case of a high-risk injury with a hepatitis B positive source or a source belonging to a risk group for hepatitis B. In high-risk injuries the victim is tested for hepatitis C and HIV transmission (except in case of a seronegative source). Antiretroviral postexposure prophylaxis is advised for high-risk injuries with a HIV seropositive source or a source belonging to a risk group for HIV.


Stimulation of deoxycytidine kinase results in prolonged maintenance of the enzyme activity.
A number of genotoxic and antiproliferative agents such as 2-chlorodeoxyadenosine (Cladribine; CdA) and aphidicolin (APC) have been shown to stimulate the activity of deoxycytidine kinase, the main deoxynucleoside salvage enzyme in lymphocytes. Here we show that enzyme activation could be prevented by treating cells with the membrane-permeant calcium chelator BAPTA-AM. Long-term incubations demonstrated that CdA and APC not only stimulated but also sustained deoxycytidine kinase activity in the cellular context, as compared to the control and BAPTA-AM treated enzyme activities.


Differential effects of trazodone and imipramine on intracardiac conduction in the anesthetized dog.
Intra-atrial, ventricular septal and left ventricular free wall conduction rates as well as lead II EKG intervals and heart rate were measured in pentobarbital-anesthetized, open-chest dogs given increasing doses of either trazodone (0.3-30 mg/kg) or imipramine (0.1-10 mg/kg) intravenously. Conduction intervals were measured during periods of spontaneous nodal rhythm or fixed rate (150 b/min) of atrial pacing. Trazodone, at cumulative doses up to 44.3 mg/kg, did not significantly depress any measured index of cardiac conduction but did lower heart rate (36%) and prolong the Q-Tc interval (19%). Imipramine, particularly at doses of 3 and 10 mg/kg, caused bradycardia (32%) and significantly slowed both atrial (23-46%) and ventricular (21-55%) conduction as well as repolarization interval (14-35%). The data indicate the differing effects of these two compounds on the heart and represent suggestive evidence of the potentially greater safety of trazodone as a new and structurally distinct antidepressant drug.


Biology and mechano-response of tendon cells: Progress overview and perspectives.
In this review, we summarize the group discussions on Cell Biology & Mechanics from the 2014 ORS/ISMMS New Frontiers in Tendon Research Conference. The major discussion topics included: (1) the biology of tendon stem/progenitor cells (TSPCs) and the potential of stem cell-based tendon therapy using TSPCs and other types of stem cells, namely, embryonic and/or induced pluripotent stem cells (iPSCs), (2) the biological concept and potential impact of cellular senescence on tendon aging, tendon injury repair and the development of degenerative disease, and (3) the effects of tendon cells' mechano-response on tendon cell fate and metabolism. For each topic, a brief overview is presented which summarizes the major points discussed by the group participants. The focus of the discussions ranged from current research progress, challenges and opportunities, to future directions on these topics. In the preparation of this manuscript, authors consulted relevant references as a part of their efforts to present an accurate view on the topics discussed.


Actions of intravenous magnesium on ventricular arrhythmias caused by acute myocardial infarction.
Although the antiarrhythmic properties of magnesium are well recognized, its mechanisms of antiarrhythmic action are poorly understood. This study was designed to characterize the effects of magnesium on ventricular tachyarrhythmias related to acute myocardial infarction (MI) in dogs. When the circumflex coronary artery was occluded repeatedly for 10 min at 30-min intervals, ventricular fibrillation (VF) occurred in 30, 35 and 33% of dogs during occlusions 1, 2 and 3, respectively. Magnesium pretreatment reduced the incidence of VF to 14% during occlusion 3 (P less than .05 compared to occlusions without magnesium pretreatment). Neither the prevalence of ventricular ectopic complexes 24 h after MI nor arrhythmia inducibility 4 days after infarction were significantly altered by i.v. magnesium. Magnesium significantly attenuated the ST segment elevation (an index of ischemic injury) and ventricular conduction slowing caused by MI. Because magnesium has been reported to reverse the effects of hyperkalemia, we evaluated the role of this action by infusing potassium directly into a coronary artery (to mimic ischemia-induced hyperkalemia) and administered i.v. magnesium. Potassium infusion markedly slowed intraventricular conduction, an effect fully reversed by discontinuing potassium administration but unaffected by i.v. magnesium. We conclude that magnesium has antiarrhythmic actions only during the early phases of an experimental MI, and that these actions are associated with attenuation of indices of ischemic injury and conduction slowing. These properties of magnesium are similar to those of calcium antagonists, and suggest that magnesium's calcium antagonist properties may be important in its antiarrhythmic actions.


MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.
MECP2 mutations cause the X-linked neurodevelopmental disorder Rett Syndrome (RTT) by consistently altering the protein encoded by the MECP2e1 alternative transcript. While mutations that simultaneously affect both MECP2e1 and MECP2e2 isoforms have been widely studied, the consequence of MECP2e1 deficiency on human neurons remains unknown. Here we report the first isoform-specific patient induced pluripotent stem cell (iPSC) model of RTT. RTTe1 patient iPS cell-derived neurons retain an inactive X-chromosome and express only the mutant allele. Single-cell mRNA analysis demonstrated they have a molecular signature of cortical neurons. Mutant neurons exhibited a decrease in soma size, reduced dendritic complexity and decreased cell capacitance, consistent with impaired neuronal maturation. The soma size phenotype was rescued cell-autonomously by MECP2e1 transduction in a level-dependent manner but not by MECP2e2 gene transfer. Importantly, MECP2e1 mutant neurons showed a dysfunction in action potential generation, voltage-gated Na(+) currents, and miniature excitatory synaptic current frequency and amplitude. We conclude that MECP2e1 mutation affects soma size, information encoding properties and synaptic connectivity in human neurons that are defective in RTT.


Precision Recruitment and Engagement of Individuals at Risk for Diabetes and Hypertension in Clinical Trials (PREDHICT): A Randomized Trial for an E-Persuasive Mobile Application to Inform Decision Making about Clinical Trials.
The primary objective of this randomized trial was to test the effectiveness of the PREDHiCT digital application, which provides educational and supportive navigation to increase willingness to participate in a future clinical trial. The second objective was to test whether PREDHiCT increased clinical trial literacy or enhanced psychological facilitators of clinical trial participation, such as altruism. To test these two objectives, we conducted a 1-month remote decentralized trial with 100 participants who either have a personal or family history of cardiometabolic health conditions, such as hypertension, diabetes, and obesity. Results indicated significant changes in altruism (mean: -2.94 vs. 0.83; p-value = 0.011) and clinical trial literacy (mean: 0.55 vs. 2.59; p-value = 0.001) from baseline to 1-month follow-up between the control and intervention groups. Additionally, participants exposed to personalized clinical trial navigation had greater clinical trial literacy at the end of the study relative to the individuals in the control arm of the study. Our findings indicate that tailored education, navigation, and access to clinical trials-three unique features of our PREDHiCT app-increased altruism and clinical trial literacy but not willingness to participate in a trial.


Methoxyethylamino-numonafide is an efficacious and minimally toxic amonafide derivative in murine models of human cancer.
Amonafide is a DNA intercalator in clinical development for the treatment of cancer. The drug has a 5-position amine that is variably acetylated to form a toxic metabolite in humans, increasing adverse effects and complicating the dosing of amonafide. Numonafides, 6-amino derivatives of amonafide that avoid the toxic acetylation, also show in vitro anticancer activity, as we have previously described. Here, we report the in vitro and in vivo activities of two numonafides, 6-methoxyethylamino-numonafide (MEAN) and 6-amino-numonafide (AN) with comparisons to amonafide. The in vitro potencies and cellular anticancer mechanisms are similar for the two numonafides and amonafide. Results from several mouse models of human cancer demonstrate that AN and MEAN require slightly higher doses than amonafide for equal efficacy in short-term dosing models, but the same dose of all three compounds in long-term dosing models are equally efficacious. MEAN is tolerated much better than amonafide and AN at equally efficacious doses based on weight change, activity, stool consistency, and dose tolerance with survival as the end point. The studies presented here demonstrate that MEAN is much less toxic than amonafide or AN in mouse models of human liver and gastric cancers while being equally efficacious in vivo and inhibiting cancer cells through similar mechanisms. These findings demonstrate that numonafides can be less toxic than amonafide and support further preclinical development and novel anticancer agents or as replacements or amonafide.


The color isolation effect in free recall by adults with Down syndrome.
The free recall of an isolated picture by 40 institutionalized adults with Down syndrome was investigated. Subjects were matched on the basis of IQ, CA, and length of institutionalization and divided into two groups. They were shown 10 pictures of common objects with (experimental) or without (control) the 6th picture printed in vivid color. Oral free recall immediately followed. The serial position curve of the control group lacked both the primacy and recency effects. Although overall recall performance remained unaffected, the experimental group recalled the isolated picture more frequently than did the control group. Results suggested that better memory of the isolate resulted from selective attention-encoding, which was induced by isolation. There appears to be a similarity between the adults with Down syndrome and nonretarded individuals in learning an isolated item.


Isotachophoresis of proteins in a networked microfluidic chip: experiment and 2-D simulation.
This paper reports both the experimental application and 2-D simulation of ITP of proteins in a networked microfluidic chip. Experiments demonstrate that a mixture of three fluorescent proteins can be concentrated and stacked into adjacent zones of pure protein under a constant voltage of 100 V over a 2 cm long microchannel. Measurements of the isotachophoretic velocity of the moving zones demonstrates that, during ITP under a constant voltage, the zone velocity decreases as more of the channel is occupied by the terminating electrolyte. A 2-D ITP model based on the Nernst-Planck equations illustrates the stacking and separation features of ITP using simulations of three virtual proteins. The self-sharpening behavior of ITP zones dispersed by a T-junction is clearly demonstrated both by experiment and by simulation. Comparison of 2-D simulations of ITP and zone electrophoresis (ZE) confirms that ZE lacks the ability to resharpen protein zones after they pass through a T-junction.


Case Report: Remote Scleral Lens Fitting for High Toric Scleras in a Keratoconus Patient.
Technology plays a crucial role in customizing scleral lenses and improving lens alignment, especially in challenging scleral shapes. Additionally, remote fitting technology allows optometrists to extend their expertise globally, empowering patients to access to customized lenses without travel expenses. The objective of this study was to document the difficulties encountered in fitting a scleral lens in a patient with keratoconus and pronounced scleral toricity. Additionally, the study aimed to present the successful remote fitting achieved by utilizing advanced technology. An Irish male diagnosed with keratoconus exhibited high scleral toricity. Generally, keratoconus eyes often exhibit significant scleral asymmetry associated with cone decentration and disease severity. Improperly aligned scleral lenses can lead to regional changes in scleral shape, lens decentration, discomfort, and visual disturbances. Indeed, previous scleral lens fits were unsuccessful due to these issues. Corneo-scleral profilometry was acquired in Ireland and then used in Italy to design customized lenses, which were then delivered to the patient's optometrist in Ireland. The first lenses designed and delivered demonstrated excellent overall performance without requiring adjustments. This report highlights the importance of corneo-scleral profilometry to increase efficiency and reduce lens reorders and chair time, and the remote fitting in overcoming barriers to accessing specialized lens fitting.


Disparities in access to emergency general surgery care in the United States.
As fewer surgeons take emergency general surgery call and hospitals decrease emergency services, a crisis in access looms in the United States. We examined national emergency general surgery capacity and county-level determinants of access to emergency general surgery care with special attention to disparities. To identify potential emergency general surgery hospitals, we queried the database of the American Hospital Association for "acute care general hospital," with "surgical services," and "emergency department," and ≥1 "operating room." Internet search and direct contact confirmed emergency general surgery services that covered the emergency room 7 days a week, 24 hours a day. Geographic and population-level emergency general surgery access was derived from Geographic Information Systems and US Census. Of the 6,356 hospitals in the 2013 American Hospital Association database, only 2,811 were emergency general surgery hospitals. Counties with greater percentages of black, Hispanic, uninsured, and low-education individuals and rural counties disproportionately lacked access to emergency general surgery care. For example, counties above the 75th percentile of African American population (10.2%) had >80% odds of not having an emergency general surgery hospital compared with counties below the 25th percentile of African American population (0.6%). Gaps in access to emergency general surgery services exist across the United States, disproportionately affecting underserved, rural communities. Policy initiatives need to increase emergency general surgery capacity nationwide.


Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations.
Lynch syndrome or hereditary non-polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan-Meier analysis of risk to 70 years was calculated. One hundred and eighty-four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9-50.8). The risk to males is 26.5% (95% CI 22.6-30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high-risk clinic.


Analysis of global research hotspots and trends in immune cells in intervertebral disc degeneration: A bibliometric study.
Intervertebral disc degeneration is an important pathological basis for spinal degenerative diseases. The imbalance of the immune microenvironment and the involvement of immune cells has been shown to lead to nucleus pulposus cells death. This article presents a bibliometric analysis of studies on immune cells in IDD in order to clarify the current status and hotspots. We searched the WOSCC, Scopus and PubMed databases from 01/01/2001 to 08/03/2023. We analyzed and visualized the content using software such as Citespace, Vosviewer and the bibliometrix. This study found that the number of annual publications is increasing year on year. The journal study found that Spine had the highest number of articles and citations. The country/regions analysis showed that China had the highest number of publications, the USA had the highest number of citations and total link strength. The institutional analysis found that Shanghai Jiao Tong University and Huazhong University of Science Technology had the highest number of publications, Tokai University had the highest citations, and the University of Bern had the highest total link strength. Sakai D and Risbud MV had the highest number of publications. Sakai D had the highest total link strength, and Risbud MV had the highest number of citations. The results of the keyword analysis suggested that the current research hotspots and future directions continue to be the study of the mechanisms of immune cells in IDD, the therapeutic role of immune cells in IDD and the role of immune cells in tissue engineering for IDD.


Somatosensory-evoked potentials and cortical activities evoked by magnetic stimulation on acupoint in human.
Two acupuncture manipulations are clinically used: manual manipulation and electrical acupuncture. There is little published on the EEG changes during magnetic stimulation on an acupuncture site. In this study, EEG data in response to magnetic stimulation on HeGu (LI 4) acupoint were measured to determine whether magnetic acupoint stimulation might modulate ongoing EEG or not. Eighteen healthy volunteers (13 male, 5 female) 20 to 35 years old were chosen in this experiment, with consent obtained before the study. The highest evoked potential was recorded in FCZ electrode, at about 140-170 ms (P150) after acupoint stimulation, but not mock point stimulation. Comparison of the somatosensory-evoked potentials in response to acupoint stimulation and mock point stimulation showed that P150 was specific to acupoint stimulation. With regard to the location of P150 in the human brain, we suggest that magnetic stimulation on HeGu acupoint would affect specific brain areas compared with the mock point. The difference in the anatomical structure of acupoint and non-acupoint may explain the specific acupoint-brain correlation, and P150 may be a characteristic activation in response to acupoint afferent.


Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy.
Reports of better results at national referral centers than at low-volume community hospitals have prompted calls for regionalizing pancreaticoduodenectomy (the Whipple procedure). We examined the relationship between hospital volume and mortality with this procedure across all US hospitals. Using information from the Medicare claims database, we performed a national cohort study of 7229 Medicare patients more than 65 years old undergoing pancreaticoduodenectomy between 1992 and 1995. We divided the study population into approximate quartiles according to the hospital's average annual volume of pancreaticoduodenectomies in Medicare patients: very low (< 1/y), low (1-2/y), medium (2-5/y), and high (5+/y). Using multivariate logistic regression to account for potentially confounding patient characteristics, we examined the association between institutional volume and in-hospital mortality, our primary outcome measure. More than 50% of Medicare patients a undergoing pancreaticoduodenectomy received care at hospitals performing fewer than 2 such procedures per year. In-hospital mortality rates at these low- and very-low-volume hospitals were 3- to 4-fold higher than at high-volume hospitals (12% and 16%, respectively, vs 4%, P < .001). Within the high-volume quartile, the 10 hospitals with the nation's highest volumes had lower mortality rates than the remaining high-volume centers (2.1% vs 6.2%, P < .01). The strong association between institutional volume and mortality could not be attributed to patient case-mix differences or referral bias. Although volume-outcome relationships have been reported for many complex surgical procedures, hospital experience is particularly important with pancreaticoduodenectomy. Patients considering this procedure should be given the option of care at a high-volume referral center.


Melatonin attenuates brain contusion-induced oxidative insult, inactivation of signal transducers and activators of transcription 1, and upregulation of suppressor of cytokine signaling-3 in rats.
The induction of oxidative stress and inflammation has been closely linked in traumatic brain injury (TBI). Transcriptional factors of signal transducers and activators of transcription (STAT) proteins are redox sensitive and participate in the regulation of cytokine signaling. Previous studies demonstrated that melatonin protects neurons through its antioxidative and anti-inflammatory effects in various neuropathological conditions. However, the effect of melatonin on STAT activity after TBI has not yet been explored. In this study, we used a controlled weight-drop TBI model and found that brain contusion induced oxidative stress (a decreased level of total glutathione and an increased ratio of oxidized glutathione to total glutathione), a reduction in STAT1 DNA-binding activity, and consequently neuronal loss in a contusion depth-dependent manner. A significant increased mRNA expression of suppressor of cytokine signaling (SOCS3), inducible nitric oxide synthetase (iNOS), and interleukine-6 (IL-6), but a decreased protein expression of protein inhibitor of activated STAT (PIAS1), was found 24 hr after brain contusion. SOCS3 and PIAS1 are endogenous negative regulators of STAT1. Moreover, the combination of intraperitoneal and local (presoaked in gelfoam and placed on the traumatic cortex) administration of melatonin had the most pronounced influence in inhibiting all effects except the PIAS1 downregulation induced by brain contusion. The results suggest that SOCS-3 upregulation and oxidative stress may contribute to the STAT1 inactivation after TBI. Melatonin protects neurons from TBI by reducing oxidative stress, STAT1 inactivation, and upregulation of SOCS-3 and pro-inflammatory cytokines.


Ten-year clinical outcomes of first-generation drug-eluting stents: the Sirolimus-Eluting vs. Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) VERY LATE trial.
Compared with bare metal stents, first-generation drug-eluting stents (DES) are associated with an increased risk of late restenosis and stent thrombosis (ST). Whether this risk continues or attenuates during long-term follow-up remains unknown. We extended the follow-up of 1012 patients [sirolimus-eluting stent (SES): N = 503 and paclitaxel-eluting stent (PES): N = 509] included in the all-comers, randomized Sirolimus-Eluting vs. Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) trial to 10 years. Follow-up was complete in 895 patients (88.4%) at 10 years. At 1, 5, and 10 years of follow-up, rates of ischaemia-driven target lesion revascularization (ID-TLR) were 8.1%, 14.6% and 17.7%, respectively, and rates of ST were 1.9%, 4.5% and 5.6%, respectively. The annual risks of ID-TLR and definite ST were significantly higher between 1 and 5 years as compared with the 5- to 10-year period [ID-TLR: 1.8% vs. 0.7%/year, hazard ratio (HR) 0.36, 95% confidence intervals (95% CI) 0.21-0.62, P < 0.001; definite ST: 0.67% vs. 0.23%/year, HR 0.31, 95% CI 0.13-0.75, P = 0.01]. The attenuation of the risk of ID-TLR and ST beyond 5 years was independent of age. Major adverse events (cardiac death, myocardial infarction, and ID-TLR) occurred in 33.7% of SES- and 33.8% of PES-treated patients (P = 0.72). During long-term follow-up through 10 years, the annual risks of ID-TLR and definite ST significantly decreased beyond 5 years after first-generation DES implantation. These findings may have important implications for secondary prevention after percutaneous coronary intervention with first-generation DES including long-term antiplatelet therapy. http://www.clinicaltrials.gov. Unique identifier: NCT00297661.


Follicle-stimulating hormone induction of luteinizing hormone receptor in cultured rat granulosa cells: an examination of the need for steroids in the induction process.
The induction of LH receptors by FSH in cultured rat granulosa cells and the effects of ovarian steroids on this process were examined. Granulosa cells were isolated from the ovaries of untreated immature rats (25 days old) and cultured with highly purified FSH (Sairam; 250 ng/ml). After culture (48-96 h in chemically defined media), both the binding of [125I]hCG and the responsiveness (cAMP and progesterone production) to an acute LH stimulus (100 ng/ml; NIH B8) were measured. The appearance of LH/hCG-binding sites and LH responsiveness indicates the presence of functional LH receptors. The induction of LH receptors by FSH requires a lag period of 24-48 h. After 48 h, the concentration of LH receptors in cultured granulosa cells continues to increase with time in culture with FSH; the continuous presence of FSH is required to maintain the induction process. If granulosa cells are cultured without hormone for 24-48 h before FSH is added, no induction of LH receptors occurs. However, if 17 beta-estradiol (5 X 10(-7) M) is added during this initial period, then the cells are responsive to the later addition of FSH. This maintenance of FSH responsiveness is not observed when dihydrotestosterone or progesterone is substituted for 17 beta-estradiol in the initial culture period. The FSH-dependent induction of LH receptors in cultured rat granulosa cells can be blocked if an inhibitor of steroidogenesis, such as aminoglutethimide phosphate (AGP; 1 mM), is added along with FSH at the initiation of the culture. The inclusion of progesterone, dihydrotestosterone, or 17 beta-estradiol (but not 20 alpha-dihydroprogesterone) in the culture together with FSH and AGP will overcome the inhibition by AGP and restore the induction of LH receptors. The results suggest that steroids produced by the developing follicle can modulate the FSH-dependent induction of LH receptors, and this may play a role in the development of follicular responsiveness to LH.


A curated genome-scale metabolic model of Bordetella pertussis metabolism.
The Gram-negative bacterium Bordetella pertussis is the causative agent of whooping cough, a serious respiratory infection causing hundreds of thousands of deaths annually worldwide. There are effective vaccines, but their production requires growing large quantities of B. pertussis. Unfortunately, B. pertussis has relatively slow growth in culture, with low biomass yields and variable growth characteristics. B. pertussis also requires a relatively expensive growth medium. We present a new, curated flux balance analysis-based model of B. pertussis metabolism. We enhance the model with an experimentally-determined biomass objective function, and we perform extensive manual curation. We test the model's predictions with a genome-wide screen for essential genes using a transposon-directed insertional sequencing (TraDIS) approach. We test its predictions of growth for different carbon sources in the medium. The model predicts essentiality with an accuracy of 83% and correctly predicts improvements in growth under increased glutamate:fumarate ratios. We provide the model in SBML format, along with gene essentiality predictions.


How does the reductase help to regulate the catalytic cycle of cytochrome P450 3A4 using the conserved water channel?
Water molecules play a major role in the P450 catalytic cycle. Here, we locate the preferred water pathways and their gating mechanisms for the human cytochrome P450 3A4 (CYP3A4) and elucidate the role of the cytochrome P450 reductase (CPR) in turning on and activating these water channels. We perform explicit solvent molecular dynamic simulations of CYP3A4, unbound and bound to two substrates, and with and without the flavin mononucleotide (FMN)-binding domain of CPR. We observe in/out passage of water molecules via a water-specific and conserved channel (aqueduct) located between the active site and the heme proximal side. We find that the aqueduct gating mechanism is mediated by R375, the conserved arginine that salt bridges with the heme 7-propionate. When R375 rotates, it opens the aqueduct and establishes a connection between a cluster of active site water molecules network and the bulk solvent. The aqueduct region overlaps with the CPR binding-site to CYP3A4. Indeed, we find that when the FMN domain of CPR binds to CYP3A4, the aqueduct fully opens up, thereby allowing a flow of water molecules. The aqueduct's opening can permit proton transfer, shuttling the protons to the active site through ordered water molecules. In addition, the expulsion of water molecules via the aqueduct contributes to substrate binding. As such, the CPR binding has a function: it triggers the aqueduct's opening and thereby enables a proton shuttle pathway, which is needed for the dioxygen activation. This mechanism could be a general paradigm in P450s.


Surgery for adolescent hallux valgus.
Attention is directed to the large number of operations for the correction of hallux valgus in the adolescent and important variations among the most popular surgical procedures, as well as the factors influencing the outcome of these operations. A consistently reliable operation is the modified Wilson procedure, a metatarsal shaft osteotomy. Its merits are its technical simplicity, minimal damage to soft tissue, and pleasing correction of deformity. The operation narrows the forefoot, relaxes soft tissues, and maintains excellent mobility of the first metatarsophalangeal joint.


Effects of mutations in the effector domain of influenza A virus NS1 protein.
The multifunctional NS1 protein of influenza A virus has roles in antagonising cellular innate immune responses and promoting viral gene expression. To better understand the interplay between these functions, we tested the effects of NS1 effector domain mutations known to affect homo-dimerisation or interactions with cellular PI3 kinase or Trim25 on NS1 ability to promote nuclear export of viral mRNAs. The NS1 dimerisation mutant W187R retained the functions of binding cellular NXF1 as well as stabilising NXF1 interaction with viral segment 7 mRNAs and promoting their nuclear export. Two PI3K-binding mutants, NS1 Y89F and Y89A still bound NXF1 but no longer promoted NXF1 interactions with segment 7 mRNA or its nuclear export. The Trim25-binding mutant NS1 E96A/E97A bound NXF1 and supported NXF1 interactions with segment 7 mRNA but no longer supported mRNA nuclear export. Analysis of WT and mutant NS1 interaction partners identified hsp70 as specifically binding to NS1 E96A/E97A. Whilst these data suggest the possibility of functional links between NS1's effects on intracellular signalling and its role in viral mRNA nuclear export, they also indicate potential pleiotropic effects of the NS1 mutations; in the case of E96A/E97A possibly via disrupted protein folding leading to chaperone recruitment.


Automatic detection of subsolid pulmonary nodules in thoracic computed tomography images.
Subsolid pulmonary nodules occur less often than solid pulmonary nodules, but show a much higher malignancy rate. Therefore, accurate detection of this type of pulmonary nodules is crucial. In this work, a computer-aided detection (CAD) system for subsolid nodules in computed tomography images is presented and evaluated on a large data set from a multi-center lung cancer screening trial. The paper describes the different components of the CAD system and presents experiments to optimize the performance of the proposed CAD system. A rich set of 128 features is defined for subsolid nodule candidates. In addition to previously used intensity, shape and texture features, a novel set of context features is introduced. Experiments show that these features significantly improve the classification performance. Optimization and training of the CAD system is performed on a large training set from one site of a lung cancer screening trial. Performance analysis on an independent test from another site of the trial shows that the proposed system reaches a sensitivity of 80% at an average of only 1.0 false positive detections per scan. A retrospective analysis of the output of the CAD system by an experienced thoracic radiologist shows that the CAD system is able to find subsolid nodules which were not contained in the screening database.


[Transport of amino acids in the splanchnic bed by blood plasma and blood in the preruminant calf].
Three preruminant calves were fitted with catheters in portal and hepatic veins and in a mesenteric artery. Two electromagnetic flowmeter probes were clipped around the portal vein and the hepatic artery. The calves were fed either a diet with a low (L) or a high (R) abomasal emptying rate for dietary proteins. Blood flow and free amino acid levels in plasma (P) and blood (S) were determined before the morning meal and during the following 7 h. In the portal vein, for most amino acids P/S ratios were correlated to the net amino acid balance of the digestive tract measured in plasma. By contrast in the hepatic vein, these ratios were mainly correlated to hepatic balance measured in whole blood. Correlations between digestive tract and hepatic balance calculated using either plasma or whole blood pool were different for some amino acids. This suggests that amino acid exchange between plasma and blood cells is low and absorbed amino acids are mainly transported to the liver by plasma, whereas whole blood rather than plasma is concerned in amino acid exchanges in the liver.


[Leukoaraiosis. Clinical importance and prognosis].
Advance in the health care systems, in medical knowledge and improvements in quality of life have contributed to the fact that life expectancy of the persons in developed countries exceeds 80 years of age. This has made it possible to observe the increase in frequency of common diseases of the elderly, one of the most relevant of which is dementia. The two most frequent etiologies of dementia are the degenerative one, with Alzheimer's disease (AD) as the main cause, and those of vascular etiology or vascular dementia, within which subcortical arteriosclerotic encephalopaty or Binswanger's disease (BD) are found with low prevalence. Since, on one hand, diagnosis of the dementias is not enough or definitive by clinical means, and on the other hand, the pathological diagnosis does not modify the evolution of disease, emphasis is presently placed on diagnosis by neuroimaging studies. In recent years, with the coming of the computerized tomography (CT) and the magnetic resonance (MR), it has been possible to observe lesions in the white matter of the brain hemisphere in patients with these two etiologic groups of dementias, that is, degenerative and vascular, as well as in elderly patient without cognitive deterioration, with or without vascular risk factors.


Expertise or performance? Questioning the rhetoric of contemporary narrative use in nursing.
In the early 1980s there emerged in nursing a self-conscious and well-articulated concern to articulate nursing's contribution to patient care. This has fostered the production of a large volume of practice narratives that today form the basis of professional self-understanding. First-person practice narratives are now widely used as the evidence base for nursing expertise, not only in their natural home, the world of interpretative research, but also in the bureaucratic-judicial domain of professional regulation, health care organizations, trades unions and professional associations. The aim of this paper is to question the use of individual narrative accounts of nursing practice as evidence of nursing expertise. We examine the model, method, and continuing consequences of these discursive formations of practice. First, we present a methodological discussion of how personal narratives are produced by the interplay between discourse and subjectivity. Second, we explore clinical narratives of expertise in the work of Patricia Benner and others to uncover the common template for contemporary narrative. Narrative production in nursing has led to particular constructions, rather than free representations of practice. It is these particular constructions that we call into question. Rather than viewing these narratives as revelatory of nursing practice, we argue that they place a 'spotlight' on the individual actor - the nurse - with an absence of structural practice context. We make the case that treatment of these narratives as individual evidence of expertise fundamentally misunderstands their function and purpose, and reduces the constitution of nursing expertise to the performance of a palatable and highly desirable discourse for a nursing audience.


Risk of radiation induced skin injuries from arrhythmia ablation procedures.
Catheter guided ablation of cardiac arrhythmias is an effective and safe procedure for the treatment of most supraventricular and selected ventricular tachycardias. Because catheter manipulation is fluoroscopically guided, there is risk of radiation induced injury, especially during prolonged procedures. The Food and Drug Administration has recently issued a bulletin warning of the risks of acute skin injury occurring during fluoroscopically guided procedures that result in an exposure level exceeding 2 Gray units (Gy). This study was performed as an investigation into the risk of radiation induced skin injury during arrhythmia ablation procedures. The amount of radiation exposure for 500 patients who underwent ablation was calculated based upon fluoroscopy times and the entrance dose of radiation (0.02 Gy/min). The mean radiation exposure was 0.93 +/- 0.62 Gy. Although 5.6% of patients (n = 28) received enough radiation exposure to reach the threshold dose (2 Gy) for early transient erythema, no clinical manifestations of acute radiation induced skin injury were observed. No patients achieved the threshold dose for irreversible skin injury. Patients undergoing AV node ablation or modification received significantly less radiation (0.39 +/- 0.40 Gy and 0.79 +/- 0.44 Gy, respectively) than patients undergoing other ablation procedures (0.94-1.45 Gy, P < 0.05). There was no association between the magnitude of radiation exposure and the presence of underlying heart disease. Patients undergoing ablation of accessory pathways were exposed to more radiation if there was a right-sided pathway (1.69 +/- 0.93 Gy) compared to other sites (0.87-1.24 Gy, P < 0.05). This study demonstrates that the risk of significant radiation induced skin injury during arrhythmia ablation procedures is low provided that precautions are taken to minimize radiation exposure.


Fertility and reproduction in women with anorexia nervosa: a controlled study.
Women who have anorexia nervosa may experience difficulties with fertility and reproduction. We examined fertility and reproductive history in 66 women who had a history of anorexia nervosa (DSM-III-R) and 98 randomly selected community controls as part of a follow-up investigation examining the course of anorexia nervosa. Although women with a history of anorexia nervosa and controls did not differ on rate of pregnancy, mean number of pregnancies per woman, or age at first pregnancy, women with anorexia nervosa had significantly more miscarriages and cesarean deliveries, and the offspring of women with anorexia nervosa were significantly more likely to be born prematurely and were of lower birth weight than offspring of controls. There were no differences between women with active versus remitted anorexia nervosa on any of these measures; however, offspring of anorexic women with no history of bulimia nervosa had significantly lower body weight than offspring of anorexic women with a lifetime history of bulimia nervosa. Our results argue for intensive prenatal care for women with both active and remitted anorexia nervosa to ensure adequate prenatal nutrition and fetal development.