Clinical characteristics of patients with cancer referred for outpatient physical therapy.
Cancer rehabilitation is a developing area, with an increasing number of survivors of cancer in the United States. The increase in survivorship occurs alongside impairments arising directly from cancer or from treatment-related side effects. This study described clinical characteristics of patients with cancer referred for outpatient physical therapy and explored patterns in frequency of impairments between type of cancer and mode of cancer treatment. This was a retrospective chart review of patients with cancer referred to a tertiary care physical therapy clinic over a 2-year period. Characteristics such as age, sex, cancer type, mode of treatment, and neuromusculoskeletal impairments were identified. Impairment frequencies were computed based on cancer type and mode of treatment. Data from 418 patients (mean age=57.9 years, SD=14.3; 41.1% female) were examined. Genitourinary cancer (n=169) and breast cancer (n=90) were the most prevalent types of cancer reported in this sample. Impairments in strength (83.6%) and soft tissue (71.3%) were the most common examination findings. Lymphedema was most common in patients with breast cancer, and incontinence was most common in patients with genitourinary cancer. The types of cancer identified in this study may be reflective of this tertiary center and may not generalize to other facilities. Impairment identification during the initial physical therapist evaluation was not performed systematically. These data reinforce that physical therapists should screen for lymphedema in patients with breast cancer and incontinence in urogenital cancers. Strength and soft tissue integrity should be evaluated in most patients with cancer. Assessing pain and fatigue levels is recommended for patients who have had radiation therapy.


Walnut-enriched diet increases the association of LDL from hypercholesterolemic men with human HepG2 cells.
In a randomized, cross-over feeding trial involving 10 men with polygenic hypercholesterolemia, a control, Mediterranean-type cholesterol-lowering diet, and a diet of similar composition in which walnuts replaced approximately 35% of energy from unsaturated fat, were given for 6 weeks each. Compared with the control diet, the walnut diet reduced serum total and LDL cholesterol by 4.2% (P = 0.176), and 6.0% (P = 0.087), respectively. No changes were observed in HDL cholesterol, triglycerides, and apolipoprotein A-I levels or in the relative proportion of protein, triglycerides, phospholipids, and cholesteryl esters in LDL particles. The apolipoprotein B level declined in parallel with LDL cholesterol (6.0% reduction). Whole LDL, particularly the triglyceride fraction, was enriched in polyunsaturated fatty acids from walnuts (linoleic and alpha-linolenic acids). In comparison with LDL obtained during the control diet, LDL obtained during the walnut diet showed a 50% increase in association rates to the LDL receptor in human hepatoma HepG2 cells. LDL uptake by HepG2 cells was correlated with alpha-linolenic acid content of the triglyceride plus cholesteryl ester fractions of LDL particles (r(2) = 0.42, P < 0.05). Changes in the quantity and quality of LDL lipid fatty acids after a walnut-enriched diet facilitate receptor-mediated LDL clearance and may contribute to the cholesterol-lowering effect of walnut consumption.


Root growth models: towards a new generation of continuous approaches.
Models of root system growth emerged in the early 1970s, and were based on mathematical representations of root length distribution in soil. The last decade has seen the development of more complex architectural models and the use of computer-intensive approaches to study developmental and environmental processes in greater detail. There is a pressing need for predictive technologies that can integrate root system knowledge, scaling from molecular to ensembles of plants. This paper makes the case for more widespread use of simpler models of root systems based on continuous descriptions of their structure. A new theoretical framework is presented that describes the dynamics of root density distributions as a function of individual root developmental parameters such as rates of lateral root initiation, elongation, mortality, and gravitropsm. The simulations resulting from such equations can be performed most efficiently in discretized domains that deform as a result of growth, and that can be used to model the growth of many interacting root systems. The modelling principles described help to bridge the gap between continuum and architectural approaches, and enhance our understanding of the spatial development of root systems. Our simulations suggest that root systems develop in travelling wave patterns of meristems, revealing order in otherwise spatially complex and heterogeneous systems. Such knowledge should assist physiologists and geneticists to appreciate how meristem dynamics contribute to the pattern of growth and functioning of root systems in the field.


Mesodermal iPSC-derived progenitor cells functionally regenerate cardiac and skeletal muscle.
Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles.


Weak orientation and direction selectivity in lateral geniculate nucleus representing central vision in the gray squirrel Sciurus carolinensis.
Classic studies of lateral geniculate nucleus (LGN) and visual cortex (V1) in carnivores and primates have found that a majority of neurons in LGN exhibit a center-surround organization, while V1 neurons exhibit strong orientation selectivity and, in many species, direction selectivity. Recent work in the mouse and the monkey has discovered previously unknown classes of orientation- and direction-selective neurons in LGN. Furthermore, some recent studies in the mouse report that many LGN cells exhibit pronounced orientation biases that are of comparable strength to the subthreshold inputs to V1 neurons. These results raise the possibility that, in rodents, orientation biases of individual LGN cells make a substantial contribution to cortical orientation selectivity. Alternatively, the size and contribution of orientation- or direction-selective channels from LGN to V1 may vary across mammals. To address this question, we examined orientation and direction selectivity in LGN and V1 neurons of a highly visual diurnal rodent: the gray squirrel. In the representation of central vision, only a few LGN neurons exhibited strong orientation or direction selectivity. Across the population, LGN neurons showed weak orientation biases and were much less selective for orientation compared with V1 neurons. Although direction selectivity was weak overall, LGN layers 3abc, which contain neurons that express calbindin, exhibited elevated direction selectivity index values compared with LGN layers 1 and 2. These results suggest that, for central visual fields, the contribution of orientation- and direction-selective channels from the LGN to V1 is small in the squirrel. As in other mammals, this small contribution is elevated in the calbindin-positive layers of the LGN.


[Use of an artificial neural network for detecting excess deaths due to cholera in Ceará, Brazil].
To evaluate recurrent neural networks as a predictive technique for time-series in the health field. The study was carried out during a cholera epidemic which took place in 1993 and 1994 in the state of Ceará, northeastern Brazil, and was based on excess deaths having 'poorly defined intestinal infections' as the underlying cause (ICD-9). The monthly number of deaths with due to this cause between 1979 and 1995 in the state of Ceará was obtained from the Ministry of Health's Mortality Information System (SIM). A network comprising two neurons in the input layer, twelve in the hidden layer, one in the output layer, and one in the memory layer was trained by backpropagation using the fist 150 observations, with 0.01 learning rate and 0.9 momentum. Training was ended after 22,000 epochs. We compare the results with those of a negative binomial regression. ANN forecasting was adequate. Excessive mortality (number of deaths above the upper limit of the confidence interval) was detected in December 1993 and October/November 1994. However, negative binomial regression detected excess mortality from March 1992 onwards. The artificial neural network showed good predictive ability, especially in the initial period, and was able to detect alterations concomitant and a subsequent to the cholera epidemic. However, it was less precise that the binomial regression model, which was more sensitive to abnormal data concomitant with cholera circulation.


The famous versus the inconvenient - or the dawn and the rise of 3D-culture systems.
One of the greatest impacts on in vitro cell biology was the introduction of three-dimensional (3D) culture systems more than six decades ago and this era may be called the dawn of 3D-tissue culture. Although the advantages were obvious, this field of research was a "sleeping beauty" until the 1970s when multicellular spheroids were discovered as ideal tumor models. With this rebirth, organotypical culture systems became valuable tools and this trend continues to increase. While in the beginning, simple approaches, such as aggregation culture techniques, were favored due to their simplicity and convenience, now more sophisticated systems are used and are still being developed. One of the boosts in the development of new culture techniques arises from elaborate manufacturing and surface modification techniques, especially micro and nano system technologies that have either improved dramatically or have evolved very recently. With the help of these tools, it will soon be possible to generate even more sophisticated and more organotypic-like culture systems. Since 3D perfused or superfused systems are much more complex to set up and maintain compared to use of petri dishes and culture flasks, the added value of 3D approaches still needs to be demonstrated.


Toxicogenomics to Evaluate Endocrine Disrupting Effects of Environmental Chemicals Using the Zebrafish Model.
The extent of our knowledge on the number of chemical compounds related to anthropogenic activities that can cause damage to the environment and to organisms is increasing. Endocrine disrupting chemicals (EDCs) are one group of potentially hazardous substances that include natural and synthetic chemicals and have the ability to mimic endogenous hormones, interfering with their biosynthesis, metabolism, and normal functions. Adverse effects associated with EDC exposure have been documented in aquatic biota and there is widespread interest in the characterization and understanding of their modes of action. Fish are considered one of the primary risk organisms for EDCs. Zebrafish (Danio rerio) are increasingly used as an animal model to study the effects of endocrine disruptors, due to their advantages compared to other model organisms. One approach to assess the toxicity of a compound is to identify those patterns of gene expression found in a tissue or organ exposed to particular classes of chemicals, through new technologies in genomics (toxicogenomics), such as microarrays or whole-genome sequencing. Application of these technologies permit the quantitative analysis of thousands of gene expression changes simultaneously in a single experiment and offer the opportunity to use transcript profiling as a tool to predict toxic outcomes of exposure to particular compounds. The application of toxicogenomic tools for identification of chemicals with endocrine disrupting capacity using the zebrafish model system is reviewed.


Health-related quality of life in elderly patients hospitalized with chronic heart failure.
Chronic heart failure is a very common condition in the elderly, characterized not only by high mortality rates, but also by a strong impact on health-related quality of life (HRQOL). Previous studies of HRQOL in elderly heart failure subjects have included mostly outpatients, and little is known about determinants of HRQOL in hospitalized elderly population, especially in Serbia. In this study, we tried to identify factors that influence HRQOL in elderly patients hospitalized with chronic heart failure in Serbia. The study population consisted of 136 patients aged 65 years or older hospitalized for chronic heart failure. HRQOL was assessed using the Minnesota Living with Heart Failure questionnaire. Predictors of HRQOL were identified by multiple linear regression analysis. Univariate analysis showed that patients with lower income, a longer history of chronic heart failure, and longer length of hospital stay, as well as those receiving aldosterone antagonists and digoxin, taking multiple medications, in a higher NYHA class, and showing signs of depression and cognitive impairment had significantly worse HRQOL. Presence of depressive symptoms (P<0.001), higher NYHA class (P=0.021), lower income (P=0.029), and longer duration of heart failure (P=0.049) were independent predictors of poor HRQOL. Depressive symptoms, higher NYHA class, lower income, and longer duration of chronic heart failure are independent predictors of poor HRQOL in elderly patients hospitalized with chronic heart failure in Serbia. Further, there is an association between multiple medication usage and poor HRQOL, as well as a negative impact of cognitive impairment on HRQOL. Hence, measures should be implemented to identify such patients, especially those with depressive symptoms, and appropriate interventions undertaken in order to improve their HRQOL.


The effect of cannabis use and cognitive reserve on age at onset and psychosis outcomes in first-episode schizophrenia.
Cannabis use is associated with a younger age at onset of psychosis, an indicator of poor prognosis, but better cognitive function, a positive prognostic indicator. We aimed to clarify the role of age at onset and cognition on outcomes in cannabis users with first-episode schizophrenia as well as the effect of cannabis dose and cessation of use. Ninety-nine patients without alcohol or substance abuse other than cannabis were divided into lifetime users and never-users of cannabis and compared on measures of premorbid function, cognition, and clinical outcome. Cannabis users demonstrated better cognition at psychosis onset, which was explained by higher premorbid IQ. They also showed better social function and neither measure changed over the subsequent 15 months. Cannabis users had an earlier age at onset of psychosis, and there was a strong linear relationship between age at first cannabis use and age at onset of both prodromal and psychotic symptoms. Cannabis use spontaneously declined over time with 3-quarters of users giving up altogether. Later age at first cannabis use predicted earlier cessation of use and this in turn was linked to fewer positive psychotic symptoms and days in hospital during the first 2 years. Cannabis use brings forward the onset of psychosis in people who otherwise have good prognostic features indicating that an early age at onset can be due to a toxic action of cannabis rather than an intrinsically more severe illness. Many patients abstain over time, but in those who persist, psychosis is more difficult to treat.


Evaluating a trait-based approach to compare natural enemy and pest communities in agroforestry vs. arable systems.
Diversified farming systems, for example those that incorporate agroforestry elements, have been proposed as a solution that could maintain and improve multiple ecosystem services. However, habitat diversification in and around arable fields has complex and inconsistent effects on invertebrate crop pests and their natural enemies. This hinders the development of policy recommendations to promote the adoption of such management strategies for the provision of natural pest control services. Here, for the first time, we conducted a trait-based approach to investigate the effect of farming system on plant, invertebrate herbivore, and invertebrate natural enemy communities. We then evaluated this approach by comparing the results to those generated using a traditional taxonomic approach. At each of three working farms, we sampled within an agroforestry field (a diverse farming system comprising alleys of arable crops separated by tree rows), and within a paired non-diversified area of the farm (arable control field). Each of 96 sample points was sampled between 8 and 10 times, yielding 393,318 invertebrate specimens from 344 taxonomic groups. Diet specialization or granivory, lack of a pupal stage, and wing traits in invertebrates, along with late flowering, short flowering duration, creeping habit, and perenniality in plants, were traits more strongly associated with agroforestry crop alleys than the arable control fields. We hypothesize that this is a result of reduced habitat disturbance and increased habitat complexity in the agroforestry system. Taxonomic richness and diversity were higher in the agroforestry crop alleys compared to the arable control fields, but these effects were stronger at lower trophic levels. However, functional trait diversity of natural enemies was significantly higher in the agroforestry crop alleys than the arable control fields, suggesting an improved level of biocontrol, which was not detected by traditional diversity metrics. Of eight key pest taxa, three were significantly suppressed in the agroforestry system, while two were more abundant, compared to the arable control fields. Trait-based approaches can provide a better mechanistic understanding of farming system effects on pests and their natural enemies, therefore we recommend their application and testing in future studies of diversified farming systems.


Cannabidiol antidepressant-like effect in the lipopolysaccharide model in mice: Modulation of inflammatory pathways.
Major Depression is a severe psychiatric condition with a still poorly understood etiology. In the last years, evidence supporting the neuroinflammatory hypothesis of depression has increased. In the current clinical scenario, in which the available treatments for depression is far from optimal, there is an urgent need to develop fast-acting drugs with fewer side effects. In this regard, recent pieces of evidence suggest that cannabidiol (CBD), the major non-psychotropic component of Cannabis sativa with anti-inflammatory properties, appears as a drug with antidepressant properties. In this work, CBD 30 mg/kg was administered systemically to mice 30 min before lipopolysaccharide (LPS; 0.83 mg/kg) administration as a neuroinflammatory model, and behavioral tests for depressive-, anhedonic- and anxious-like behavior were performed. NF-ĸB, IκBα and PPARγ levels were analyzed by western blot in nuclear and cytosolic fractions of cortical samples. IL-6 and TNFα levels were determined in plasma and prefrontal cortex using ELISA and qPCR techniques, respectively. The precursor tryptophan (TRP), and its metabolites kynurenine (KYN) and serotonin (5-HT) were measured in hippocampus and cortex by HPLC. The ratios KYN/TRP and KYN/5-HT were used to estimate indoleamine 2,3-dioxygenase (IDO) activity and the balance of both metabolic pathways, respectively. CBD reduced the immobility time in the tail suspension test and increased sucrose preference in the LPS model, without affecting locomotion and central activity in the open-field test. CBD diminished cortical NF-ĸB activation, IL-6 levels in plasma and brain, and the increased KYN/TRP and KYN/5-HT ratios in hippocampus and cortex in the LPS model. Our results demonstrate that CBD produced antidepressant-like effects in the LPS neuroinflammatory model, associated to a reduction in the kynurenine pathway activation, IL-6 levels and NF-ĸB activation. As CBD stands out as a promising antidepressant drug, more research is needed to completely understand its mechanisms of action in depression linked to inflammation.


Response to cognitive therapy in depression: the role of maladaptive beliefs and personality disorders.
This study examined whether personality disorder status and beliefs that characterize personality disorders affect response to cognitive therapy. In a naturalistic study, 162 depressed outpatients with and without a personality disorder were followed over the course of cognitive therapy. As would be hypothesized by cognitive theory (A. T. Beck & A. Freeman, 1990), it was not personality disorder status but rather maladaptive avoidant and paranoid beliefs that predicted variance in outcome. However, pre- to posttherapy comparisons suggested that although patients with or without comorbidity respond comparably to "real-world" cognitive therapy, they report more severe depressive symptomatology at intake and more residual symptoms at termination.


Does living near a constellation of petrochemical, steel, and other industries impair health?
To investigate concern that local industrial air pollution in Teesside, England, was causing poor health, several areas there were compared with parts of the City of Sunderland. Populations in similar social and economic circumstances but varying in their proximity to major industries were compared. Study populations lived in 27 housing estates in Teesside and Sunderland, north east England, with some data from subsets of estates. The estates were aggregated into zones (designated as A, B, and C in Teesside where A is closest to and C furthest from industry, and S in Sunderland). Zone S provided a reference area. The hypothesis was that a health gradient both within Teesside (A > B > C) and between Teesside and Sunderland (ABC > S) would indicate a possible health effect of local industrial air pollution. Data presented were: mortality (1981-91) from 27 housing estates; population self completion questionnaire survey data (1993, 9115 subjects) from 15 housing estates; and general practitioner (GP) consultation data (1989-94) from 2201 subjects in 12 Teesside estates. The populations in the four zones were comparable for indicators including smoking habits, residential histories, and unemployment. All cause and cause specific mortalities were high compared with England and Wales. Mortality in all Teesside zones (ABC) combined was mostly higher than in zone S. In people aged 0-64, lung cancer and respiratory disease showed gradients with highest mortality in areas closest to industry (A > B > C and ABC > S). The association was clearest for lung cancer in women (0-64 years old, trend across zones ABC, p = 0.07, directly standardised rate ratio relative to zone S was 169 (95% confidence interval (95% CI) 116-122)). There were no important, consistent gradients in the hypothesised direction between zones in consultation rates in general practice, and self reported respiratory and nonrespiratory health including asthma. There was no clear evidence that living close to industry was associated with morbidity, including asthma, or for most measures of mortality. For lung cancer in women the gradients indicated a health effect of local industrial air pollution. In the age group 0-64 observed gradients in lung cancer in men and mortality from respiratory disease in men and women were consistent with the study hypothesis, although not significant. The reasons for the different patterns at different ages, and between men and women, remain a puzzle.


STUDIES ON EXPERIMENTAL PNEUMONIA : IX. PRODUCTION IN MONKEYS OF AN ACUTE RESPIRATORY DISEASE RESEMBLING INFLUENZA BY INOCULATION WITH BACILLUS INFLUENZAE.
Twelve normal monkeys inoculated on the mucous membranes of the nose or nose and mouth with a strain of Bacillus influenzae; originally isolated in pure culture from the pleural exudate of a case of empyema following influenzal pneumonia in man and subsequently raised in virulence by animal passage, developed an acute self-limited respiratory disease of from 3 to 5 days duration, characterized by sudden onset with profound prostration, the development of rhinitis and tracheobronchitis, with sneezing, cough, and the outpouring of a scanty mucoid, or mucopurulent exudate, a variable febrile reaction, and either a leucopenia or no significant change in the leucocyte count. This disease was complicated in five instances by purulent sinusitis of one or both antra, in three by bronchopneumonia. Bacillus influenzae was recovered at autopsy from the lesions of the disease either in pure culture or in association with organisms that are normal inhabitants of the upper respiratory tract of monkeys. Of ten normal monkeys injected intratracheally with the same strain of Bacillus influenzae, seven developed bronchopneumonia, two developed tracheobronchitis without pneumonia, and one resisted infection. The general symptoms and duration of the disease were similar to those of the preceding group. There were a severe cough and accelerated respirations. Bacillus influenzae was recovered in pure culture from the lungs, bronchi, or trachea in the animals killed during the active stage of the disease. It disappeared promptly from the respiratory tract with recovery. The significance of the first series of experiments in which monkeys were inoculated in the upper respiratory tract is twofold. First, they establish the fact that Bacillus influenzae can initiate in monkeys an acute infection of the normal mucous membranes of the upper respiratory tract; that is, it can act as a primary incitant of respiratory infection without the assistance of a preceding or concomitant contributing cause. In this respect it differs radically from the pneumococcus and Streptococcus haemolyticus, since experiments previously reported(2, 4) have shown that neither of these organisms possesses the property of initiating an infection of the normal mucous membranes of the upper respiratory tract of monkeys, even though the strains used were incalculably more virulent for monkeys than the strain of Bacillus influenzae used in the foregoing experiments. Secondly, the experiments show that Bacillus influenzae infection of the mucous membranes of the upper respiratory tract may spread by continuity to the paranasal sinuses, setting up an acute sinusitis, that it spreads readily to the lower respiratory tract, producing a tracheobronchitis and permitting the ready invasion of secondary bacteria, and that it may penetrate as far as the terminal bronchioles, alveolar ducts, atria, and alveoli, there setting up a bronchiolitis and true bronchopneumonia. In these respects it likewise differs radically from the pneumococcus and Streptococcus haemolyticus which do not possess these pathogenic properties as previous experiments have shown.(2, 4) The bearing of these facts on the possible etiologic relation of Bacillus influenzae to influenza is important, since they show that Bacillus influenzae possesses certain definite primary pathogenic properties which distinguish it and therefore separate it from the group of recognized secondary organisms in influenzal complications, of which the pneumococcus and the streptococcus are the most frequent. The possible etiologic relation of Bacillus influenzae to influenza is further supported by the character of the respiratory disease that occurred in the monkeys. The sudden onset with profound prostration, the absence of leucocytosis or often a leucopenia, the congestion of the mucous membranes of the respiratory tract, the development on the 2nd or 3rd day of an irritative cough due to an inflammatory tracheitis or tracheobronchitis, the brief self-limited course of the infection, and the irregular febrile reactions are all characteristic of influenza. Many of these symptoms were in striking contrast with the symptoms and course of pneumococcus or streptococcus infections in monkeys in which there were no prostration at onset, invariable leucocytosis, and infrequent cough developing only late in the disease. While all the above features of the disease produced in monkeys are characteristic of influenza in man, none are pathognomonic and, in fact, it is doubtful whether uncomplicated influenza possesses any pathognomonic features by which it may be diagnosed certainly in the absence of an epidemic. Even during epidemic times many respiratory infections arise which, though presumably influenza, it is impossible to diagnose as such with certainty. Nor does pathology help in this respect, since there would appear to be no established distinctive lesions of uncomplicated influenza in man, nor for that matter of the complications of influenza, apart from the complications which have been ascribed by Pfeiffer,(5) MacCallum,(6) Wolbach,(7) and others to infection with Bacillus influenzae because of the association of Bacillus influenzae in pure culture with these complications. For these reasons, although the disease produced in monkeys appears to be essentially identical with influenza in man with respect to its clinical course and complications, it is impossible to determine certainly whether it is actually so. The experiments are advanced, therefore, as evidence in favor of the etiologic relation of Bacillus influenzae to influenza, though they do not permit of a definite conclusion in this respect. Their bearing upon the relation of Bacillus influenzae to certain of the complications of influenza would appear to be reasonably conclusive. The recovery of Bacillus influenzae in pure culture at autopsy from the antra, from the trachea and bronchi, and from the lungs in some of the animals developing sinusitis, bronchiolitis, and a characteristic type of bronchopneumonia confirms by animal experiment the etiologic relation of Bacillus influenzae to these complications of influenza, which hitherto has rested solely upon the frequent association of the influenza bacillus with these lesions in man. The production of tracheobronchitis and the same type of bronchopneumonia by the intratracheal injection of Bacillus influenzae in the second series of experiments serves as additional confirmation of this, but has no direct bearing on the etiologic relation of Bacillus influenzae to uncomplicated influenzae.


Transfer of arthroscopic skills from computer simulation training to the operating theatre: a review of evidence from two randomised controlled studies.
There is paucity in the research on transfer validity of arthroscopic simulator training. The aim of this article is to determine whether skills derived from arthroscopic simulation are transferrable to the operating theatre and retained over time. A systematic review with rigorous criteria to identify the highest level of evidence available was carried out. The studies were critically appraised with narrative data synthesis. Twenty-one studies on arthroscopic simulation were identified. Only two studies were randomised controlled trials. The first article demonstrated improved performance of basic knee arthroscopic tasks following a fixed period of training. The second article showed improved performance of arthroscopic tasks and no deterioration in the levels of skills following a period of six months. In addition, the two studies succeeded in demonstrating the importance of 3D motion analysis using computer simulators in the assessment of technical skills. Components of evaluation such as time to task completion, distance travelled by instruments and incidence of instruments collisions were associated with the highest validity and reliability of assessment. This systematic review highlighted the limitations of these two randomised studies. Evidence from the two trials suggests that knee arthroscopy simulator training can result in improved performance. This review helped highlight the contribution of the two studies in terms of internal validity and consistency of using arthroscopic skills training. Further level I studies are however required to demonstrate the evidence for transfer and predictive validity of computer simulation as a training instrument.


Hematopoietic effect of deer antler extract fermented by Bacillus subtilis on murine marrow cells.
We examined the chemical composition and the effect of fermented deer antler on hematopoietic factors in bone marrow cells. For the preparation of fermented deer antler extract (FAB), fermentation was carried out using Bacillus subtilis at 30℃ for 7 days. The hematopoietic effect of FAB was investigated hematopoietic factors in marrow cells. The contents of total sugar, sulfated glycosaminoglycans, and uronic acid and the dry weight gradually increased with fermentation time. The sialic acid content (from 0.14 mg/mL to 0.54 mg/mL) was the highest on the 4th day of fermentation after which it decreased. The proliferating activity of bone marrow cells increased with fermentation times. The levels of various hematopoietic growth factors were determined to verify the beneficial effect of deer antler extract fermented by B. subtilis on hematopoiesis. FAB increased the number of stem cell factors and granulocyte colony-stimulating factor in bone marrow cells. In addition, FAB augmented the burst-forming unit erythroid and total colonies in splenocyte-conditioned medium compared with non-fermented antler extract (NFA). However, FAB did not affect the mRNA levels of erythropoietin, an important factor for erythropoiesis. FAB, like NFA, did not directly affect hematopoiesis, but contributed to hematopoiesis by stimulating the production of hematopoietic factors.


Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.
The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.


Deimination stabilizes histone H2A/H2B dimers as revealed by electrospray ionization mass spectrometry.
Post-translational modifications of histones for reversibly changing chromosomal structures in promoter regions of genes are a prerequisite for transcriptional activation and repression of genes. Peptidylarginine deiminase 4 (PAD4), which mediates histone deimination by converting arginine residues into citrulline residues, is involved in the repression of gene transcription. However, the mechanism is still unclear. We studied the effects of deimination on the reconstituted histone H2A/H2B dimer structure by electrospray ionization mass spectrometry. Deimination of the H2A/H2B dimer by PAD4 indicated that the mass of H2A increased 2.7 Da, suggesting that two or three Arg residues of H2A were deiminated. Deimination of H2A monomer alone showed a 6.6-Da increase in mass. This indicates that about four more Arg residues of H2A are modified in the monomer state than in the H2A/H2B dimer state. Taking account of the finding that the unstructured portions in proteins are susceptible to deimination by PAD4, it is likely that H2A in the monomer state has a more flexible structure than that in the dimer state. Furthermore, analysis of the association of the H2A/H2B dimer in 2 or 4 M ammonium acetate with nano-electrospray ionization mass spectrometry showed that a modified H2A/H2B dimer was less dissociated into H2A and H2B monomers than an unmodified dimer when high voltages were applied to the sample cone. This study provides convincing evidence that PAD4 deimination stabilizes the histone H2A/H2B dimer.


A role for RNAi in the selective correction of DNA methylation defects.
DNA methylation is essential for silencing transposable elements and some genes in higher eukaryotes, which suggests that this modification must be tightly controlled. However, accidental changes in DNA methylation can be transmitted through mitosis (as in cancer) or meiosis, leading to epiallelic variation. We demonstrated the existence of an efficient mechanism that protects against transgenerational loss of DNA methylation in Arabidopsis. Remethylation is specific to the subset of heavily methylated repeats that are targeted by the RNA interference (RNAi) machinery. This process does not spread into flanking regions, is usually progressive over several generations, and faithfully restores wild-type methylation over target sequences in an RNAi-dependent manner. Our findings suggest an important role for RNAi in protecting genomes against long-term epigenetic defects.


Extracting shape from curvature evolution in moving surfaces.
Shape is a crucial geometric property of surfaces, interfaces, and membranes in biology, colloidal and interface science, and many areas of physics. This paper presents theory, simulation and scaling of local shape and curvedness changes in moving surfaces and interfaces, under uniform normal motion, as in phase ordering transitions in liquid crystals. Previously presented measures of shape and curvedness are introduced in quantities and equations used in colloidal science and interfacial transport phenomena to separate shape effects from those of curvedness. Considering in parallel the new shape formalism with the classical curvature formalism, this paper sheds new light on what effects originate only from shape. The new shape evolution equations are solved under uniform normal surface flow. It is found that the solutions obey the so-called "astigmatism equation" fixing the linear relation between the radii of curvature. Astigmatic trajectories in the shape-curvedness phase plane, can be clearly classified into two modes: (i) constant shape evolution, and (ii) variable shape-variable curvedness. Shapes between spheres and cylinders follow the former mode for large curvedness and transition at smaller curvedness into the latter. Shapes' transitions between cylinder and saddles only follow the second mode. Under geometry-driven stagnation (i.e. zero normal velocity) shapes can be frozen. Evolving spheres and cylinders freeze into the same original shape, but perturbed cylinders can freeze into a variety of shapes including saddles. The results provide a useful complementary view on how to describe and control shape evolution in surfaces and interfaces, of wide interest in soft matter materials.


Amygdala and anterior insula control the passage from nociception to pain.
Activation of the spinothalamic system does not always result in a subjective pain perception. While the cerebral network processing nociception is relatively well known, the one underlying its transition to conscious pain remains poorly described. We used intracranial electroencephalography in epileptic patients to investigate whether the amplitudes and functional connectivity of posterior and anterior insulae (PI and AI) and amygdala differ according to the subjective reports to laser stimuli delivered at a constant intensity set at nociceptive threshold. Despite the constant intensity of stimuli, all patients reported variable subjective perceptions from one stimulus to the other. Responses in the sensory PI remained stable throughout the experiment, hence reflecting accurately the stability of the stimulus. In contrast, both AI and amygdala responses showed significant enhancements associated with painful relative to nonpainful reports, in a time window corresponding to the conscious integration of the stimulus. Functional connectivity in the gamma band between these two regions increased significantly, both before and after stimuli perceived as painful. While the PI appears to transmit faithfully the actual stimulus intensity received via the spinothalamic tract, the AI and the amygdala appear to play a major role in the transformation of nociceptive signals into a painful perception.


Hyaluronic Acid Fillers in Soft Tissue Regeneration.
Over the last years, hyaluronic acid (HA) injectable dermal fillers (DFs) have become the most popular agents for soft tissue contouring and volumizing. HA fillers are characterized by most of the properties that an ideal DF should have, due to HA unique chemical-physical properties, biocompatibility, biodegradability, and versatility. Therefore, HA DFs have revolutionized the filler market with a high number of products, which differ in terms of HA source, cross-linkage (agent and degree), HA concentration, hardness, cohesivity, consistency, inclusion or lack of anesthetic, indication, and longevity of correction. The article first provides a general introduction to DF world, and an overview of the different materials is available for fillers. Second, it describes the characteristics and the peculiarities of HA fillers, their differences from the other available materials, and therefore the reasons at the base of their success. Moreover, an update regarding the main Food and Drug Administration (FDA) approved fillers is presented.


Puerarin protects against cadmium-induced proximal tubular cell apoptosis by restoring mitochondrial function.
Puerarin (PU) is a potent free radical scavenger with a protective effect in nephrotoxin-mediated oxidative damage. Here, we show a novel molecular mechanism by which PU exerts its anti-apoptotic effects in cadmium (Cd)-exposed primary rat proximal tubular (rPT) cells. Morphological assessment and flow cytometric analysis revealed that PU significantly decreased Cd-induced apoptotic cell death of rPT cells. Administration of PU protected cells against Cd-induced depletion of mitochondrial membrane potential (ΔΨm) and lipid peroxidation. Cd-mediated mitochondrial permeability transition pore (MPTP) opening, disruption of mitochondrial ultrastructure, mitochondrial cytochrome c (cyt-c) release, caspase-3 activation and subsequently poly ADP-ribose polymerase (PARP) cleavage could be effectively blocked by the addition of PU. Moreover, up-regulation of Bcl-2 and down-regulation of Bax and hence increased Bcl-2/Bax ratio were observed with the PU administration. In addition, PU reversed Cd-induced ATP depletion by restoring ΔΨm to affect ATP production and by regulating expression levels of ANT-1 and ANT-2 to improve ATP transport. In summary, PU inhibited Cd-induced apoptosis in rPT cells by ameliorating the mitochondrial dysfunction.


How do you measure trust in the health system? A systematic review of the literature.
People's trust in the health system plays a role in explaining one's access to and utilization of medical care, adherence to medications, continuity of care, and even self-reported health status. Yet it is not easy to find trust measures and understand what they are measuring. A systematic review of scales and indices identified 45 measures of trust within the health system with an average of 12 questions each, which quantified levels of trust among various relationships across the health system. Existing evidence was narrow in scope, where half examined the relationship between doctors/nurses and patients, and the majority were designed, tested and validated in the United States. We developed a health systems trust content area framework, where we identified that honesty, communication, confidence and competence were captured frequently in these measures, with less focus on concepts such as fidelity, system trust, confidentiality and fairness. Half of the measures employed a qualitative method in the design of these measures and 33% were pilot tested. Reporting of test-retest reliability and inter-rater reliability were less common. This review identifies a need to develop measurements of trust beyond doctor-patient relationships and outside of U.S. contexts, and strengthen the rigor of existing trust measures. Greater development and use of trust measures in the health system could improve monitoring and evaluation efforts, which may in turn result in better health outcomes.


Mixture models and exploratory analysis in networks.
Networks are widely used in the biological, physical, and social sciences as a concise mathematical representation of the topology of systems of interacting components. Understanding the structure of these networks is one of the outstanding challenges in the study of complex systems. Here we describe a general technique for detecting structural features in large-scale network data that works by dividing the nodes of a network into classes such that the members of each class have similar patterns of connection to other nodes. Using the machinery of probabilistic mixture models and the expectation-maximization algorithm, we show that it is possible to detect, without prior knowledge of what we are looking for, a very broad range of types of structure in networks. We give a number of examples demonstrating how the method can be used to shed light on the properties of real-world networks, including social and information networks.


Identifying predictors of survey mode preference.
To increase the likelihood of response, many survey organizations attempt to provide sample members with a mode they are thought to prefer. Mode assignment is typically based on conventional wisdom or results from mode choice studies that presented only limited options. In this paper we draw heavily on research and theory from the mode effects and the survey participation literatures to develop a framework for understanding what characteristics should predict mode preferences. We then test these characteristics using data from two different surveys. We find that measures of familiarity with and access to a mode are the strongest predictors of mode preference and measures of safety concerns, physical abilities, and normative concerns are unexpectedly weak predictors. Our findings suggest that variables that may exist on sample frames can be used to inform the assignment of "preferred" modes to sample members.


Transcription factor Nrf2 protects renal dopamine D1 receptor function during oxidative stress.
The renal dopaminergic system plays a significant role in controlling sodium excretion and blood pressure (BP). Overwhelming evidence shows that oxidative stress downregulates renal dopamine receptors (D1R), and antioxidant supplementation protects D1R function. However, the mechanisms for benefits of antioxidants in protecting D1R function are unknown. We investigated the role of nuclear factor E2-related factor 2 (Nrf2), a redox-sensitive transcription factor, in reducing oxidative stress, protecting renal D1R function and lowering BP in rats. Male Sprague-Dawley rats were treated with L-buthionine-sulfoximine (BSO) and sulforaphane for 4 weeks. Rats treated with BSO exhibited significant increase in oxidative stress and BP. BSO treatment reduced renal D1R expression and abolished SKF38393 (a D1R agonist)-induced Na/K-ATPase and Na/H-exchanger (NHE3) inhibition. Also, in these rats, SKF38393 failed to promote sodium excretion. BSO caused an increase in nuclear factor-κB expression, a modest nuclear translocation of Nrf2 and a moderate activation of phase II antioxidant enzymes. Treatment of rats with sulforaphane alone induced modest activation of Nrf2 and phase II antioxidant enzymes, although having no effect on BP, redox status, or D1R function. However, sulforaphane prevented oxidative stress, protected D1R function, and abrogated hypertension in BSO-treated rats. In these animals, sulforaphane, whereas attenuating nuclear factor-κB activation, caused a robust stimulation of Nrf2 and phase II antioxidant enzyme pathway. In conclusion, oxidative stress via nuclear factor-κB activation downregulated D1R function causing a decrease in sodium excretion, which contributed to an increase in BP. Sulforaphane via activation of Nrf2-phase II antioxidant enzyme pathway mitigated oxidative stress and nuclear factor-κB activation, preserved D1R function, and prevented hypertension.


Inhibition of DNA synthesis in cultured lymphocytes and tumor cells by extracts of betel nut, tobacco, and miang leaf, plant substances associated with cancer of the ororespiratory epithelium.
The high incidence of oropharyngeal, esophageal, and laryngeal cancers in certain parts of the world has been ascribed to conjugated tannins found in certain folk medicinal herbs. We extracted miang leaf and betel nut with phosphate-buffered saline (0.14 M NaCl, 0.15 M potassium phosphate buffer, pH 7.4) and found that the extracts inhibited [3H]thymidine incorporation by phytohemagglutinin-stimulated human lymphocytes and by rat mammary tumor and mouse L-cells in logarithmic growth. Pretreating the lymphocytes for 1 or 4 hr with the extracts inhibited phytohemagglutinin-induced thymidine incorporation 72 hr later. At concentrations of 2.5 volumes % or lower, miang and betel nut extracts inhibited thymidine incorporation by 40 to 98% without any apparent signs of toxicity as demonstrated by the 66Rb equilibrium assay. In addition, neither extract inhibited cytotoxicity of rat mammary tumor cells by immune syngeneic spleen cells. The molecular weights of the inhibitory factors were between 1,000 and 10,000 daltons as determined by ultrafiltration and were unaffected by boiling for 3 min or by treatment with alcohol and, therefore, are probably not proteins. This in vitro demonstration of inhibition of DNA synthesis by these plant extracts presumably enriched for conjugated tannins may relate to inhibition of growth of rats and chicks fed conjugated tanin-contaminated sorghum feed. The carcinogenic potential of either these extracts or conjugated tannins is not yet established.


Systematic Review with Meta-Analysis: The Effects of Probiotics in Nonalcoholic Fatty Liver Disease.
Probiotics was considered as a potential therapy for nonalcoholic fatty liver disease (NAFLD) without approval and comprehensive assessment in recent years, which call for a meta-analysis. We performed electronic and manual searches including English and Chinese databases published before April 2019, with the use of mesh term and free text of "nonalcoholic fatty liver disease" and "probiotics." Clinical trials evaluating the efficacy of probiotic therapy in NAFLD patients were included according to the eligibility criteria. With the use of random effects models, clinical outcomes were presented as weighted mean difference (WMD) with 95% confidence interval (CI), while heterogeneity and meta-regression were also assessed. 28 clinical trials enrolling 1555 criterion proven NAFLD patients with the use of probiotics from 4 to 28 weeks were included. Overall, probiotic therapy had beneficial effects on body mass index (WMD: -1.46, 95% CI: [-2.44, -0.48]), alanine aminotransferase (WMD: -13.40, 95% CI: [-17.03, -9.77]), aspartate transaminase (WMD: -13.54, 95% CI: [-17.86, -9.22]), gamma-glutamyl transpeptidase (WMD: -9.88, 95% CI: [-17.77, -1.99]), insulin (WMD: -1.32, 95% CI: [-2.43, -0.21]), homeostasis model assessment-insulin resistance (WMD: -0.42, 95% CI: [-0.73, -0.12]), and total cholesterol (WMD: -15.38, 95% CI: [-26.50, -4.25]), but not in fasting blood sugar, lipid profiles, or tumor necrosis factor-alpha. The systematic review and meta-analysis support that probiotics are superior to placebo in NAFLD patients and could be utilized as a common complementary therapeutic approach.


Effect of Time Spent Outdoors at School on the Development of Myopia Among Children in China: A Randomized Clinical Trial.
Myopia has reached epidemic levels in parts of East and Southeast Asia. However, there is no effective intervention to prevent the development of myopia. To assess the efficacy of increasing time spent outdoors at school in preventing incident myopia. Cluster randomized trial of children in grade 1 from 12 primary schools in Guangzhou, China, conducted between October 2010 and October 2013. For 6 intervention schools (n = 952 students), 1 additional 40-minute class of outdoor activities was added to each school day, and parents were encouraged to engage their children in outdoor activities after school hours, especially during weekends and holidays. Children and parents in the 6 control schools (n = 951 students) continued their usual pattern of activity. The primary outcome measure was the 3-year cumulative incidence rate of myopia (defined using the Refractive Error Study in Children spherical equivalent refractive error standard of ≤-0.5 diopters [D]) among the students without established myopia at baseline. Secondary outcome measures were changes in spherical equivalent refraction and axial length among all students, analyzed using mixed linear models and intention-to-treat principles. Data from the right eyes were used for the analysis. There were 952 children in the intervention group and 951 in the control group with a mean (SD) age of 6.6 (0.34) years. The cumulative incidence rate of myopia was 30.4% in the intervention group (259 incident cases among 853 eligible participants) and 39.5% (287 incident cases among 726 eligible participants) in the control group (difference of -9.1% [95% CI, -14.1% to -4.1%]; P < .001). There was also a significant difference in the 3-year change in spherical equivalent refraction for the intervention group (-1.42 D) compared with the control group (-1.59 D) (difference of 0.17 D [95% CI, 0.01 to 0.33 D]; P = .04). Elongation of axial length was not significantly different between the intervention group (0.95 mm) and the control group (0.98 mm) (difference of -0.03 mm [95% CI, -0.07 to 0.003 mm]; P = .07). Among 6-year-old children in Guangzhou, China, the addition of 40 minutes of outdoor activity at school compared with usual activity resulted in a reduced incidence rate of myopia over the next 3 years. Further studies are needed to assess long-term follow-up of these children and the generalizability of these findings. clinicaltrials.gov Identifier: NCT00848900.


Sociosexual and communication deficits after traumatic injury to the developing murine brain.
Despite the life-long implications of social and communication dysfunction after pediatric traumatic brain injury, there is a poor understanding of these deficits in terms of their developmental trajectory and underlying mechanisms. In a well-characterized murine model of pediatric brain injury, we recently demonstrated that pronounced deficits in social interactions emerge across maturation to adulthood after injury at postnatal day (p) 21, approximating a toddler-aged child. Extending these findings, we here hypothesized that these social deficits are dependent upon brain maturation at the time of injury, and coincide with abnormal sociosexual behaviors and communication. Age-dependent vulnerability of the developing brain to social deficits was addressed by comparing behavioral and neuroanatomical outcomes in mice injured at either a pediatric age (p21) or during adolescence (p35). Sociosexual behaviors including social investigation and mounting were evaluated in a resident-intruder paradigm at adulthood. These outcomes were complemented by assays of urine scent marking and ultrasonic vocalizations as indices of social communication. We provide evidence of sociosexual deficits after brain injury at p21, which manifest as reduced mounting behavior and scent marking towards an unfamiliar female at adulthood. In contrast, with the exception of the loss of social recognition in a three-chamber social approach task, mice that received TBI at adolescence were remarkably resilient to social deficits at adulthood. Increased emission of ultrasonic vocalizations (USVs) as well as preferential emission of high frequency USVs after injury was dependent upon both the stimulus and prior social experience. Contrary to the hypothesis that changes in white matter volume may underlie social dysfunction, injury at both p21 and p35 resulted in a similar degree of atrophy of the corpus callosum by adulthood. However, loss of hippocampal tissue was greater after p21 compared to p35 injury, suggesting that a longer period of lesion progression or differences in the kinetics of secondary pathogenesis after p21 injury may contribute to observed behavioral differences. Together, these findings indicate vulnerability of the developing brain to social dysfunction, and suggest that a younger age-at-insult results in poorer social and sociosexual outcomes.


What are subcutaneous adipocytes really good for?
Our acute awareness of the cosmetic, psychosocial and sexual importance of subcutaneous adipose tissue contrasts dramatically with how poorly we have understood the biology of this massive, enigmatic, often ignored and much-abused skin compartment. Therefore, it is timely to recall the exciting, steadily growing, yet underappreciated body of evidence that subcutaneous adipocytes are so much more than just 'fat guys', hanging around passively to conspire, at most, against your desperate attempts to maintain ideal weight. Although the subcutis, quantitatively, tends to represent the dominant architectural component of human skin, conventional wisdom confines its biological key functions to those of energy storage, physical buffer, thermoregulation and thermoinsulation. However, already the distribution of human superficial adipose tissue, by itself, questions how justified the popular belief is that 'skin fat' (which actually may be more diverse than often assumed) serves primarily thermoinsulatory purposes. And although the metabolic complications of obesity are well appreciated, our understanding of how exactly subcutaneous adipocytes contribute to extracutaneous disease - and even influence important immune and brain functions! - is far from complete. The increasing insights recently won into subcutaneous adipose tissue as a cytokine depot that regulates innate immunity and cell growth exemplarily serve to illustrate the vast open research expanses that remain to be fully explored in the subcutis. The following public debate carries you from the evolutionary origins and the key functional purposes of adipose tissue, via adipose-derived stem cells and adipokines straight to the neuroendocrine, immunomodulatory and central nervous effects of signals that originate in the subcutis - perhaps, the most underestimated tissue of the human body. The editors are confident that, at the end, you shall agree: No basic scientist and no doctor with a serious interest in skin, and hardly anyone else in the life sciences, can afford to ignore the subcutaneous adipocyte - beyond its ample impact on beauty, benessence and body mass.


[Prevalence of overweight and obesity, and associated factors in adolescents, at the central west area of the state São Paulo (SP, Brazil)].
The aim of the study was to evaluate the relationship between the Body Mass Index (BMI) and the DMFT index, in 207 adolescents aged 12 years old, from 8 public and private schools of the central west area of São Paulo State. From a sample of 380 12 year-old adolescents, both genders, 207 were examined. We used the index DMFT, CBI for weight, measured of stature and applied a questionnaire about alimentary habits, characteristic anthropometrics and physical activity. Regarding body weight, 55.93% was normal, 35.59% had low weight, and 8.47% were pre-obese in private schools. In the public schools, 52.03% had normal weight, 41.22% had low weight, 4.73% were pre-obese and 2.03% were obese, without significant difference (p=0.45). The DMFT of public schools was 2.16, compared to 0.23 in private schools (p<0.05), with 39.2% of caries-free individuals in public schools and 88.1% in private schools. There was no correlation between the increase in BMI and the increase in DMFT. There was negative correlation between socioeconomic conditions and dental caries. It was concluded that, even though the pre-obese and obese groups presented a higher frequency of food ingestion, obesity was not correlated with the increase in dental caries. However, the socioeconomic conditions were determinant for this occurrence.


Cyclosporin A inhibits positive selection and delays negative selection in alpha beta TCR transgenic mice.
Cyclosporin A (CsA) is an immunosuppressive drug that inhibits TCR-mediated signal transduction. This drug has two major effects on developing alpha beta thymocytes in normal mice: it blocks the development of most mature CD4+8- and CD4-8+ thymocytes and inhibits the deletion of some but not all self-specific thymocytes. The latter effect may explain how CsA treatment can paradoxically induce autoimmunity in certain situations. Here we investigated the effects of CsA on thymocyte development in transgenic mice that express on most of their T cells an alpha beta TCR specific for male H-Y Ag bound to H-2 Db class I molecules, a model system in which positive and negative selection have been clearly defined. Positive selection occurs in female mice, resulting in the development of mature CD4-CD8+ T cells, whereas negative selection occurs in male mice, resulting in the deletion of self-reactive CD4+8+ thymocytes. CsA blocked positive selection, as evidenced by the finding that most of the cells present in the thymuses of CsA-treated female mice were functionally immature precursors that expressed heat-stable Ag. In male mice, CsA delayed but did not prevent the deletion of most CD4+8+ thymocytes. A few transgenic thymocytes, however, were not deleted and achieved the TCR+, CD4-8+ phenotype of positively selected cells. Therefore, for a small subset of thymocytes, CsA may convert a normally negatively selecting TCR signal to a positively selecting one.


Survival from malignant digestive endocrine tumors in England and Wales: a population-based study.
Little is known about the prognosis of patients with malignant digestive endocrine tumors (MDETs), primarily because of their rarity. Survival from these tumors has been evaluated in a large, well-defined, national population. All patients diagnosed and registered in England and Wales during the 14-year period from 1986 to 1999 were followed up for vital status to the end of 2001. Relative survival was estimated and the impact of age, sex, period, histology, and anatomic site modeled. Among 4104 cases of MDETs, 21.2% were small cell tumors. Relative survival for all MDETs combined was 45.9% at 5 years and 38.4% at 10 years. Five-year survival was 56.8% for well-differentiated tumors but only 5.2% for small cell tumors (P < .0001). Survival was highest for large bowel tumors and lowest for esophageal tumors. Among well-differentiated pancreatic tumors, 5-year relative survival was 49.2% for insulinomas, 39.9% for gastrinomas, 17.1% for glucagonomas, 26.3% for carcinoid tumors, and 29.3% for nonfunctioning tumors. There was no difference in survival between socioeconomic groups. Five-year survival did not improve between 1986 and 2001. Survival was higher for women and for younger patients. Gender, age at diagnosis, and anatomic site were independent prognostic factors. The prognosis of patients with MDETs in the general population is considerably worse than is often reported from small hospital case series. Prognosis varies with tumor differentiation, anatomic site, and histologic type. Early diagnosis is difficult; new therapeutic options appear to represent the best approach to improved prognosis.


Cytoprophet: a Cytoscape plug-in for protein and domain interaction networks inference.
Cytoprophet is a software tool that allows prediction and visualization of protein and domain interaction networks. It is implemented as a plug-in of Cytoscape, an open source software framework for analysis and visualization of molecular networks. Cytoprophet implements three algorithms that predict new potential physical interactions using the domain composition of proteins and experimental assays. The algorithms for protein and domain interaction inference include maximum likelihood estimation (MLE) using expectation maximization (EM); the set cover approach maximum specificity set cover (MSSC) and the sum-product algorithm (SPA). After accepting an input set of proteins with Uniprot ID/Accession numbers and a selected prediction algorithm, Cytoprophet draws a network of potential interactions with probability scores and GO distances as edge attributes. A network of domain interactions between the domains of the initial protein list can also be generated. Cytoprophet was designed to take advantage of the visual capabilities of Cytoscape and be simple to use. An example of inference in a signaling network of myxobacterium Myxococcus xanthus is presented and available at Cytoprophet's website. http://cytoprophet.cse.nd.edu.


A Retrospective Multicentric Study of Ewing Sarcoma Family of Tumors in Patients Older Than 50: Management and Outcome.
Ewing's sarcoma family of tumors (EFTs) is a group of rare and aggressive tumors. Data on EFTs in patients (pts) ≥ 50 years are limited and these pts are often not eligible for clinical trials. Some, but not all, studies have reported inferior outcome for older pts with EFTs. We conducted an IRB-approved retrospective analysis among centers of the French Sarcoma Group on pts diagnosed with EFTs at age ≥50 between 2000 and 2012. Clinical features, treatment modality and outcomes were analyzed. Seventy-seven pts were identified, including 36 females (46.8%) and the median age at diagnosis was 56 years (range: 50-86). The primary tumor was located in soft tissue in 59 pts (76.6%). Fifty-six pts (72.7%) had localized disease, among them 49 (87.5%) received chemotherapy in addition to local therapy. Their estimated 3-yr OS and event-free survival (EFS) rates were respectively 73.3% and 62.2%. Recurrence occurred in 43 pts. The estimated 3-yr OS rate was 37% in pts with metastatic disease at presentation. EFTs in pts ≥50 years are more likely to originate from soft tissue and their outcomes appear to be worse than that of younger pts treated with modern protocols.


X-Pol Potential: An Electronic Structure-Based Force Field for Molecular Dynamics Simulation of a Solvated Protein in Water.
A recently proposed electronic structure-based force field called the explicit polarization (X-Pol) potential is used to study many-body electronic polarization effects in a protein, in particular by carrying out a molecular dynamics (MD) simulation of bovine pancreatic trypsin inhibitor (BPTI) in water with periodic boundary conditions. The primary unit cell is cubic with dimensions ~54 × 54 × 54 Å(3), and the total number of atoms in this cell is 14281. An approximate electronic wave function, consisting of 29026 basis functions for the entire system, is variationally optimized to give the minimum Born-Oppenheimer energy at every MD step; this allows the efficient evaluation of the required analytic forces for the dynamics. Intramolecular and intermolecular polarization and intramolecular charge transfer effects are examined and are found to be significant; for example, 17 out of 58 backbone carbonyls differ from neutrality on average by more than 0.1 electron, and the average charge on the six alanines varies from -0.05 to +0.09. The instantaneous excess charges vary even more widely; the backbone carbonyls have standard deviations in their fluctuating net charges from 0.03 to 0.05, and more than half of the residues have excess charges whose standard deviation exceeds 0.05. We conclude that the new-generation X-Pol force field permits the inclusion of time-dependent quantum mechanical polarization and charge transfer effects in much larger systems than was previously possible.


Developing sustainable capacity-building in mental health research: implementation outcomes of training of trainers in systematic reviewing.
Less than 1% of biomedical research papers originate in Africa. Locally relevant mental health research, including synthesis of existing evidence, is essential for developing interventions and strengthening health systems, but institutions may lack the capacity to deliver training on systematic reviewing for publication in international journals. This paper describes the development and implementation of a training-of-trainers (ToT) course on systematic reviewing. The ToT prepared junior faculty ('trainers') from universities in Ethiopia, Malawi, and Zimbabwe to lead a five-day systematic reviewing workshop. Using an evaluation framework based on implementation science outcomes, the feasibility of the ToT was assessed by tracking the number of workshops the trainers subsequently conducted and the number of trainers and trainees who participated; acceptability was assessed through post-workshop surveys on trainee perspectives; impact was evaluated through trainee scores on a 15-item multiple choice test on systematic reviewing concepts; and sustainability was assessed based on whether the workshop was integrated into university curricula. Twelve trainers (86% of those trained) facilitated a total of seven workshops in their home countries (total 103 trainees). The first workshop run in each country was evaluated, and there was a significant improvement in mean knowledge scores between pre- and post-tests among trainees (MD= 3.07, t= 5.90, 95% CI 2.02-4.11). In two of the three countries, there are efforts to integrate the systematic review workshop into university curricula. The cost of the workshop led by the international trainer was $1480 per participant, whereas the trainer-led workshops cost approximately $240 per participant. Overall, ToT is relatively new to research capacity building, although it has been used widely in clinical settings. Our findings suggest ToT is a promising, low-cost way to develop both technical skills of individuals and the pedagogical capacity of universities, and to promote sustainability of research capacity building programs that often have time-limited grant funding.


Greater male than female variability in regional brain structure across the lifespan.
For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.


The Protective Effects of Religiosity on Depression: A 2-Year Prospective Study.
Approximately 20% of older adults are diagnosed with depression in the United States. Extant research suggests that engagement in religious activity, or religiosity, may serve as a protective factor against depression. This prospective study examines whether religiosity protects against depression and/or aids in recovery. Study data are drawn from the 2006 and 2008 waves of the Health and Retirement Study. The sample consists of 1,992 depressed and 5,740 nondepressed older adults (mean age = 68.12 years), at baseline (2006), for an overall sample size of 7,732. Logistic regressions analyzed the relationship between organizational (service attendance), nonorganizational (private prayer), and intrinsic measures of religiosity and depression onset (in the baseline nondepressed group) and depression recovery (in the baseline depressed group) at follow-up (2008), controlling for other baseline factors. Religiosity was found to both protect against and help individuals recover from depression. Individuals not depressed at baseline remained nondepressed 2 years later if they frequently attended religious services, whereas those depressed at baseline were less likely to be depressed at follow-up if they more frequently engaged in private prayer. Findings suggest that both organizational and nonorganizational forms of religiosity affect depression outcomes in different circumstances (i.e., onset and recovery, respectively). Important strategies to prevent and relieve depression among older adults may include improving access and transportation to places of worship among those interested in attending services and facilitating discussions about religious activities and beliefs with clinicians.


Towards pervasive computing in health care - a literature review.
The evolving concepts of pervasive computing, ubiquitous computing and ambient intelligence are increasingly influencing health care and medicine. Summarizing published research, this literature review provides an overview of recent developments and implementations of pervasive computing systems in health care. It also highlights some of the experiences reported in deployment processes. There is no clear definition of pervasive computing in the current literature. Thus specific inclusion criteria for selecting articles about relevant systems were developed. Searches were conducted in four scientific databases alongside manual journal searches for the period of 2002 to 2006. Articles included present prototypes, case studies and pilot studies, clinical trials and systems that are already in routine use. The searches identified 69 articles describing 67 different systems. In a quantitative analysis, these systems were categorized into project status, health care settings, user groups, improvement aims, and systems features (i.e., component types, data gathering, data transmission, systems functions). The focus is on the types of systems implemented, their frequency of occurrence and their characteristics. Qualitative analyses were performed of deployment issues, such as organizational and personnel issues, privacy and security issues, and financial issues. This paper provides a comprehensive access to the literature of the emerging field by addressing specific topics of application settings, systems features, and deployment experiences. Both an overview and an analysis of the literature on a broad and heterogeneous range of systems are provided. Most systems are described in their prototype stages. Deployment issues, such as implications on organization or personnel, privacy concerns, or financial issues are mentioned rarely, though their solution is regarded as decisive in transferring promising systems to a stage of regular operation. There is a need for further research on the deployment of pervasive computing systems, including clinical studies, economic and social analyses, user studies, etc.


The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis.
Post-translational modifications (PTM) of proteins are crucial for fine-tuning a cell's response to both intracellular and extracellular cues. ADP-ribosylation is a PTM, which occurs in two flavours: modification of a target with multiple ADP-ribose moieties (poly(ADP-ribosyl)ation or PARylation) or with only one unit (MARylation), which are added by the different enzymes of the PARP family (also known as the ARTD family). PARylation has been relatively well-studied, particularly in the DNA damage response. This has resulted in the development of PARP inhibitors such as olaparib, which are increasingly employed in cancer chemotherapeutic approaches. Despite the fact that the majority of PARP enzymes catalyse MARylation, MARylation is not as well understood as PARylation. MARylation is a dynamic process: the enzymes reversing intracellular MARylation of acidic amino acids (MACROD1, MACROD2, and TARG1) were discovered in 2013. Since then, however, little information has been published about their physiological function. MACROD1, MACROD2, and TARG1 have a 'macrodomain' harbouring the catalytic site, but no other domains have been identified. Despite the lack of information regarding their cellular roles, there are a number of studies linking them to cancer. However, some of these publications oppose each other, some rely on poorly-characterised antibodies, or on aberrant localisation of overexpressed rather than native protein. In this review, we critically assess the available literature on a role for the hydrolases in cancer and find that, currently, there is limited evidence for a role for MACROD1, MACROD2, or TARG1 in tumorigenesis.


20 Years of Olympic Media Research: Trends and Future Directions.
The Olympic Games is the largest multisport event in the world, regularly drawing global audiences in the billions to watch coverage of athletes from hundreds of nations. It has received a great deal of scholarly attention, especially in terms of media coverage, consumption, and co-creation. As coverage has the ability to impact media consumers' perceptions of nations, cultures, and issues, it is important to develop an understanding of research trends relating to the Olympic Games and media in order to uncover gaps in the literature which may be filled by future scholarly work. Therefore, in order to highlight trends in the established literature and uncover areas for development, a systematic literature review was conducted to examine the state of Olympic media research over a 20-year time period (1999-2018). A total of 221 articles were examined, revealing insights into the types of research being produced from theoretical, methodological, and contextual perspectives. Results revealed a significant proportion of scholarship focused on the Summer Olympic Games, the United States, newspaper accounts of the Games, and utilized media framing and agenda setting frameworks and the content analysis methodology. Just over half of the studies utilized a theoretical or conceptual framework, the prevalence of which increased over time. Core areas for continued development in the Olympic media space include embracing and grounding research in theory, diversification in research context, and expanding upon the definition of the Olympic Games within the greater Olympic Movement.


Alterations of the retinoblastoma gene in human prostate adenocarcinoma.
The loss or mutational inactivation of the RB1 tumor suppressor gene has been implicated in the development of a diverse group of human malignancies. However, the contribution of the RB1 gene alteration to human prostatic carcinogenesis has been poorly understood. Thus far, deletion of the promoter sequence and exon 21 from one primary tumor specimen and the alterations found in the cell line DU-145, are the only cases of RB1 mutations reported in human carcinoma of the prostate. This study was designed to determine whether alterations in the structure or expression of the RB1 gene occur in human prostate carcinoma, and to determine the nature of these changes and the frequency with which they occur. One hundred twelve primary prostate tumor tissues and four metastatic lesions were obtained immediately after surgical resection. The RB1 gene was characterized in 68 tumor DNA samples using Southern analysis and the PG3.8M or H3-8 probes. Band profiles were analyzed by scanning densitometry. Sixty-three tumor DNA samples were analyzed for defects in the RB1 promoter using polymerase chain reaction (PCR) and heteroduplex analysis. Alterations in the expression of exons 1-27 were analyzed in 79 primary and four metastatic tumor RNAs using RT-PCR. Three of 68 tumors were identified to have gross rearrangement of the RB1 gene or deletion of one allele. One of four stage D tumor specimens showed truncated RT-PCR products indicating an internal deletion of RB1 transcripts. In all, 14 of 83 (17%) specimens displayed abnormally low levels of RB1 mRNA expression. Furthermore, these alterations of RB1 expression showed a correlation with increasing tumor stage and grade. These results suggest alterations of RB1 mRNA expression occur more frequently in higher stages and grades of prostate cancer and, thus, may be contributing to the malignant progression of a subset of human prostate cancer.


Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study.
Ventricular arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot are devastating complications in adult survivors of early surgery, but their prediction remains difficult. We examined surgical, electrocardiographic, and late haemodynamic data, and their relation to clinical arrhythmia and sudden death occurring over 10 years, in a multicentre cohort of patients with repaired tetralogy, who were alive in 1985. Of 793 patients (mean age at repair 8.2 years [SD 8], mean time from repair 21.1 years [8.7]) who entered the study, 33 patients developed sustained monomorphic ventricular tachycardia, 16 died suddenly, and 29 had new-onset sustained atrial flutter or fibrillation. Electrocardiographic markers (QRS duration, QRS rate of change between 1985 and 1995) were significantly greater in the ventricular tachycardia and sudden-death groups. Older age at repair was associated with a higher risk of sudden death and atrial tachyarrhythmia. Pulmonary regurgitation was the main underlying haemodynamic lesion for patients with ventricular tachycardia and sudden death, whereas tricuspid regurgitation was for those with atrial flutter/fibrillation. Despite adverse haemodynamics, no patient who died suddenly had undergone late reoperation. Arrhythmia and sudden death are important late sequelae for patients after repair of tetralogy of Fallot. The electrophysiological and haemodynamic substrate of sudden death resembled that of sustained ventricular tachycardia, with pulmonary regurgitation being the predominant haemodynamic lesion. Preservation or restoration of pulmonary valve function may thus reduce the risk of sudden death. Furthermore, electrocardiographic markers can help to identify patients at risk.


Raw milk producers with high levels of hygiene and safety.
There is world-wide increasing interest in the consumption of unprocessed, natural food commodities including fresh (unpasteurised) milk and milk products. Consumers are actively seeking out raw milk, partly due to health reasons, but also for taste, freshness, closeness to the producer and to support local agriculture. The need for high levels of hygiene and safety in farms producing raw milk for direct consumption has long been recognised and has led to federal and industry-initiated systems for safe raw milk production. Raw milk producers in North America and Europe have demonstrated that raw milk, intended for direct consumption, can be produced safe and hygienic. The aim of this paper is to describe practices that have been developed for safe raw milk production. The German Vorzugsmilch is a federally regulated programme for legal raw milk production that was established already in the 1930s to provide raw milk with high hygienic standards controlled for zoonotic diseases to consumers. The Raw Milk Institute is a non-profit organisation established in California that has developed a voluntary safe raw milk programme in North America. RAWMI has developed a risk analysis and management system for raw milk dairy farmers to assist farmers in making individually tailored solutions for various production systems. In British Colombia, Canada, small herd share farms have employed good manufacturing practices, a risk management approach and performed monthly samples for pathogens and indicator bacteria to demonstrate safety and consistency. The major components of the raw milk systems applied, and the results of regular milk microbial indicator bacteria are presented. For the German system, the results from standard monthly pathogen tests are compared to zoonotic pathogen tests from other milk sources. The overall results indicate that raw milk can be produced with a high level of hygiene and safety in various systems.


The influence of phenylephrine outward potassium currents in single smooth muscle cells from the rabbit mesenteric artery.
In mesenteric artery smooth muscle cells, depolarizing voltage steps activated outward K+ currents whose amplitude was decreased by about 20% with phenylephrine (1-10 microM: n = 14 cells). Attenuation of outward current was only partly dependent on [Ca2+]i, because it persisted, although reduced, with 10 mM BAPTA in the patch pipette and was abolished in the presence of 3 mM 3,4-diaminopyridine (n = 13). In outside-out patches, phenylephrine did not exert any direct effect on the unitary current amplitude or open probability of large conductance K+ channels. Outward current was significantly increased (>100% in both cases) by 10 mM caffeine, presumably owing to the release of internal Ca2+ stores. With 10 mM BAPTA in the pipette, the only response to caffeine was a small decrease (9 +/- 3.7%, n = 10) in the K+ current. These observations show that a minor effect of phenylephrine is to reduce outward K+ current (probably Kv) in mesenteric cells.


SU-F-BRCD-05: Mean Regional Dose to the Esophagus Predicts Acute Toxicity Rate for Lung Cancer Patients.
The relationship between spatial aspects of the dose distribution and incidence of acute radiation esophagitis for non-small-cell lung cancer (NSCLC) patients is not well understood. Specifically, the location of dose along the superior-inferior (SI) axis of the esophagus has not been previously considered. We introduce the concept of mean regional dose (MRD) calculated for esophageal subvolumes, and test for significance for prediction of acute esophagitis (AE). The 3D dose distribution within the esophagus was extracted for 541 NSCLC patients treated with definitive photon therapy. The esophagus contour was divided into equal geometric halves, thirds, and fourths along the SI direction of the structure. MRD in each subvolume was calculated. Univariate logistic regression was performed to determine the correlation between MRD and CTCAE3.0 AE grade = 2 (medical intervention). The MRD was incorporated into an existing NTCP model (based on mean dose for the total esophageal volume) as a separate additive factor. Univariate analysis indicated a significant correlation between AE grade = 2 and MRD in each of the esophageal subvolumes except for the inferior third and inferior-most quarter. There was a statistically significant improvement when including the additive MRD factor for the superior/inferior halves, superior/inferior thirds, and superior-most/inferior-most quarters into the NTCP model. This study investigates previously unexplored regional differences in delivered dose to the esophagus of patients treated for NSCLC. There is evidence to suggest that dose to the superior portions of the esophagus is more important as it relates to the potential for acute toxicity. The 541 patient cohort is the largest database used to investigate AE in patients treated for NSCLC, strengthening the power of the statistical results. Additional methods to incorporate dose in individual esophagus voxels (along the SI axis) into the NTCP model are also being explored.


Selection and characterization of HIV-1 variants resistant to the (+) and (-) enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC).
Human immunodeficiency virus type 1 (HIV-1) variants were selected for resistance against the (+) and (-) enantiomers of a novel nucleoside analogue, 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC), using the infectious molecular clone HXB2D grown in the MT-4 line of human T cells. The variants selected with (+) dOTC were approximately 6-7-fold less sensitive than wild-type virus to this drug. Cloning and sequencing of the complete reverse transcriptase (RT) coding region of these variants identified the M1841 mutation and further selection with virus containing the M1841 substitution led to the appearance of an M184V mutation. In contrast, selection experiments performed with (-) dOTC yielded variants capable of growing in drug concentrations as high as 100 microM, but phenotypic analysis of these viruses revealed near wild-type 50% inhibitory concentration (IC50) values for this compound. Site-directed mutagenesis experiments in which the M1841 and M184V mutations were introduced into HXB2D confirmed the importance of these mutations when viruses were grown in MT4 cells. However, wild-type IC50 values in regard to both (-) and (+) dOTC were obtained when these recombinant viruses were grown in cord blood mononuclear cells (CBMC). Clinical isolates of HIV-1 resistant to lamivudine and containing the M184V substitution also displayed low-level resistance to both (-) and (+) dOTC when grown in CBMC. Finally, cell-free RT assays were performed in the presence of either (-) dOTC triphosphate, (+) dOTC triphosphate, or the triphosphate of a racemic mixture of (+) and (-) dOTC with wild-type and mutated M184V-containing recombinant RT. The data demonstrate chain termination effects of these compounds with regard to both wild-type and mutated enzyme and that the latter was approximately twofold less sensitive than the former to these drugs.


Perceived benefits of sharing health data between people with epilepsy on an online platform.
An epilepsy community was developed on PatientsLikeMe.com to share data between patients to improve their outcomes by finding other patients like them. In a 14-day response period, 221 patients with epilepsy (mean age: 40 years, SD: 12, range: 17-72, 66% female) completed a survey about benefits they perceived. Prior to using the site, a third of respondents (30%) did not know anyone else with epilepsy with whom they could talk; of these, 63% now had at least one other patient with whom they could connect. Perceived benefits included: finding another patient experiencing the same symptoms (59%), gaining a better understanding of seizures (58%), and learning more about symptoms or treatments (55%). Number of benefits was associated with number of relationships with other patients, F(4,216)=8.173, P<0.001). Patients with epilepsy reported an array of perceived benefits similar to those reported by populations with other diseases. Controlled sharing of health data may have the potential to improve disease self-management of people with epilepsy.


Effects of proteasome inhibitors MG132, ZL3VS and AdaAhx3L3VS on protein metabolism in septic rats.
Proteasome inhibitors are novel therapeutic agents for the treatment of cancer and other severe disorders. One of the possible side effects is influencing the metabolism of proteins. The aim of our study was to evaluate the influence of three proteasome inhibitors MG132, ZL(3)VS and AdaAhx(3)L(3)VS on protein metabolism and leucine oxidation in incubated skeletal muscle of control and septic rats. Total proteolysis was determined according to the rates of tyrosine release into the medium during incubation. The rates of protein synthesis and leucine oxidation were measured in a medium containing L-[1-(14)C]leucine. Protein synthesis was determined as the amount of L-[1-(14)C]leucine incorporated into proteins, and leucine oxidation was evaluated according to the release of (14)CO(2) during incubation. Sepsis was induced in rats by means of caecal ligation and puncture. MG132 reduced proteolysis by more than 50% and protein synthesis by 10-20% in the muscles of healthy rats. In septic rats, proteasome inhibitors, except ZL(3)VS, decreased proteolysis in both soleus and extensor digitorum longus (EDL) muscles, although none of the inhibitors had any effect on protein synthesis. Leucine oxidation was increased by AdaAhx(3)L(3)VS in the septic EDL muscle and decreased by MG132 in intact EDL muscle. We conclude that MG132 and AdaAhx(3)L(3)VS reversed protein catabolism in septic rat muscles.


Hypothalamic gene expression rapidly changes in response to photoperiod in juvenile Siberian hamsters (Phodopus sungorus).
Siberian hamsters are seasonal mammals that survive a winter climate by making adaptations in physiology and behaviour. This includes gonadal atrophy, reduced food intake and body weight. The underlying central mechanisms responsible for the physiological adaptations are not fully established but involve reducing hypothalamic tri-iodthyronine (T3) levels. Juvenile Siberian hamsters born or raised in short days (SD) respond in a similar manner, although with an inhibition of gonadal development and growth instead of reversing an established long day (LD) phenotype. Using juvenile male hamsters, the present study aimed to investigate whether the central mechanisms are similar before the establishment of the mature LD phenotype. By in situ hybridisation, we examined the response of genes involved in thyroid hormone (Dio2 and Dio3, which determine hypothalamic T3 levels) and glucose/glutamate metabolism in the ependymal layer, histamine H3 receptor and VGF as representatives of the highly responsive dorsomedial posterior arcuate nucleus (dmpARC), and somatostatin, a hypothalamic neuropeptide involved in regulating the growth axis. Differential gene expression of type 2 and type 3 deiodinase in the ependymal layer, histamine H3 receptor in the dmpARC and somatostatin in the ARC was established by the eighth day in SD. These changes are followed by alterations in glucose metabolism related genes in the ependymal layer by day 16 and increased secretogranin expression in the dmpARC by day 32. In conclusion, our data demonstrate similar but rapid and highly responsive changes in gene expression in the brain of juvenile Siberian hamsters in response to a switch from LD to SD. The data also provide a temporal definition of gene expression changes relative to physiological adaptations of body weight and testicular development and highlight the likely importance of thyroid hormone availability as an early event in the adaptation of physiology to a winter climate in juvenile Siberian hamsters.


Imaging as a biomarker in drug discovery for Alzheimer's disease: is MRI a suitable technology?
This review provides perspectives on the utility of magnetic resonance imaging (MRI) as a neuroimaging approach in the development of novel treatments for Alzheimer's disease. These considerations were generated in a roundtable at a recent Wellcome Trust meeting that included experts from academia and industry. It was agreed that MRI, either structural or functional, could be used as a diagnostic, for assessing worsening of disease status, for monitoring vascular pathology, and for stratifying clinical trial populations. It was agreed also that MRI implementation is in its infancy, requiring more evidence of association with the disease states, test-retest data, better standardization across multiple clinical sites, and application in multimodal approaches which include other imaging technologies, such as positron emission tomography, electroencephalography, and magnetoencephalography.


Enhanced polarization-sensitive terahertz emission from vertically grown graphene by a dynamical photon drag effect.
Improving terahertz (THz) emission from graphene is a challenge for graphene-based THz photonics as graphene demonstrates a weak light-matter interaction. With a unique ultra-black surface structure, vertically grown graphene (VGG) is proposed to enhance the light-matter interaction and further enhance THz emission. Herein, enhanced THz radiation is observed by THz time-domain emission spectroscopy from VGG compared with single-layer graphene. The radiated THz amplitude shows a linear dependence on pump power, which demonstrates a second order nonlinear effect. Considering the symmetry of VGG on a substrate, we can exclude the optical rectification effect and photogalvanic effect (PGE) by the D6h point group with centrosymmetry. Thus we analyze the transient photocurrent related to THz emission only by the photon drag effect (PDE). The polarization-sensitive THz radiation signals are wave-vector reliant and demonstrate cos 2φ and sin 2φ dependence on the polarization angles of the pump laser. This is consistent with the theoretical analysis of PDE. Our results show the enhanced, ultrafast, broadband THz radiation property of VGG, which paves the way for high performance THz emitters and THz detectors based on graphene materials.