Retino-protective effect of Bucida buceras against oxidative stress induced by H2O2 in human retinal pigment epithelial cells line.
Reactive Oxygen Species (ROS) impair the physiological functions of Retinal Pigment Epithelial (RPE) cells, which are known as one major cause of age-related macular degeneration and retinopathy diseases. The purpose of this study is to explore the cytoprotective effects of the antioxidant Bucida buceras extract in co-treatment with hydrogen peroxide (H2O2) delivery as a single addition or with continuous generation using glucose oxidase (GOx) in ARPE-19 cell cultures. The mechanism of Bucida buceras extract is believed to be associated with their antioxidant capacity to protect cells against oxidative stress. A comparative oxidative stress H2O2-induced was performed by addition and enzymatic generation using glucose oxidase on human retinal pigment epithelial cells line. H2O2-induced injury was measured by toxic effects (cell death and apoptotic pathway) and intracellular redox status: glutathione (GSH), antioxidant enzymes (catalase and glutathione peroxidase) and reducing power (FRAP). The retino-protective effect of co-treatment with Bucida buceras extract on H2O2-induced human RPE cell injury was investigated by cell death (MTT assay) and oxidative stress biomarkers (H2O2, GSH, CAT, GPx and FRAP). Bucida buceras L. extract is believed to be associated with the ability to prevent cellular oxidative stress. When added as a pulse, H2O2 is rapidly depleted and the cytotoxicity analyses show that cells can tolerate short exposure to high peroxide doses delivered as a pulse but are susceptible to lower chronic doses. Co-treatment with Bucida buceras was able to protect the cells against H2O2-induced injury. In addition to preventing cell death treatment with antioxidant plant could also reverse the significant decrease in GSH level, catalase activity and reducing power caused by H2O2. These findings suggest that Bucida buceras could protect RPE against ocular pathogenesis associated with oxidative stress induced by H2O2-delivered by addition and enzymatic generation.


Reproductive biology and spatiotemporal patterns of spawning in striped marlin Kajikia audax.
This study presents the first histology-based assessment of the reproductive dynamics of south-west Pacific striped marlin Kajikia audax. Maturity and reproductive status were assessed from histological sections of ovaries (n = 234) and testes (n = 243) of fish caught in commercial longline and recreational fisheries between 2006 and 2009. Spawning peaked in the Coral Sea during November and December at sea surface temperatures between 24.8 and 28.3° C. Lower jaw fork length (L(LJF)) at 50% maturity (L(LJF50)), a key variable for stock assessment, was estimated to be 2100 ± 102 mm (mean + s.e.) for females and 1668 ± 18 mm for males. Unlike large pelagic tunas Thunnus spp., the proportion of females increased with length and spawning fish formed multiple large-scale aggregations within a broad latitudinal band. This study provides a starting point for biological parameters needed for stock assessment and conservation of K. audax and introduces the multiple aggregation spawning concept as a reproductive mechanism to explain genetic heterogeneity observed in some highly migratory species.


Difficult but Close Relationships: Children's Perspectives on Relationships With Their Mothers in the Context of Domestic Violence.
This article reports findings from a participative and qualitative study conducted with children who had experienced domestic violence, focusing on their perspectives on their relationships with their mothers. Three focus groups and 46 individual interviews were conducted with children to gather their experiences. The research findings demonstrate that women's and children's victimizations are inextricably linked, and that domestic violence affects mother-child relationships. They also show that, despite the challenges and difficulties, children generally consider their mothers as very significant individuals in their lives, and have close relationships with them. The findings also reveal a dynamic of mutual protectiveness.


The Welfare Cost of Vaccine Misallocation, Delays and Nationalism.
I calibrate an eco-epidemiological age-structured Susceptible-Infected-Recovered (SIR) model of the B.1.1.7 covid variant on the eve of the vaccination campaign in France, under a stop-and-go lockdown policy. Three-quarters of the welfare benefit of the vaccine can be achieved with a speed of 100,000 full vaccination per day. A 1-week delay in the vaccination campaign raises the death toll by approximately 2500, and it reduces wealth by 8 billion euros. Because of the large heterogeneity of the rates of hospitalization and mortality across age classes, it is critically important for the number of lives saved and for the economy to vaccinate older people first. Any departure from this policy has a welfare cost. Prioritizing the allocation of vaccines to the most vulnerable people save 70,000 seniors, but it also increases the death toll of younger people by 14,000. Vaccine nationalism is modeled by assuming two identical Frances, one with a vaccine production capacity and the other without it. If the production country vaccinates its entire population before exporting to the other, the global death toll would be increased by 20 %. I also measure the welfare impact of the strong French anti-vax movement, and of the prohibition of an immunity passport.


Occupational exposure to cobalt is not associated with incipient signs of dilated cardiomyopathy in a Belgian refinery.
Excessive absorption of cobalt has been associated with cases of dilated cardiomyopathy in the past, but it is unclear whether occupationally exposed populations are at risk. To assess the possible relationship between occupational exposure to cobalt and incipient signs of dilated cardiomyopathy. A cross-sectional survey was conducted in a cobalt production facility in Belgium constituting one of the largest occupational populations worldwide (n=256 male workers). Exposure to cobalt was assessed by measuring urinary cobalt concentration (µg/gcreat), reflecting recent exposure, and by computing an integrated exposure index (µg/gcreat×years), reflecting long-term exposure. The effect on the myocardium was investigated by echocardiography and electrocardiography, and dose-effect relations with cobalt exposure were traced by multiple regression analysis. No dose-effect relationship between exposure to cobalt and parameters reflecting dilated cardiomyopathy was found in a population of workers characterised by a median recent cobalturia of 4 µg/gcreat and a median long-term cobalturia of 100 µg/gcreat×years. A reduction in the dimensions of the left ventricular internal cavity was associated with recent exposure to cobalt. Occupational exposure to cobalt does not appear associated with incipient signs of dilated cardiomyopathy within the gradient of exposure recorded in this population.


Expression profiles of the immune genes CD4, CD8β, IFNγ, IL-4, IL-6 and IL-10 in mitogen-stimulated koala lymphocytes (Phascolarctos cinereus) by qRT-PCR.
Investigation of the immune response of the koala (Phascolarctos cinereus) is needed urgently, but has been limited by scarcity of species-specific reagents and methods for this unique and divergent marsupial. Infectious disease is an important threat to wild populations of koalas; the most widespread and important of these is Chlamydial disease, caused by Chlamydia pecorum and Chlamydia pneumoniae. In addition, koala retrovirus (KoRV), which is of 100% prevalence in northern Australia, has been proposed as an important agent of immune suppression that could explain the koala's susceptibility to disease. The correct balance of T regulatory, T helper 1 (Th1) and Th2 lymphocyte responses are important to an individual's susceptibility or resistance to chlamydial infection. The ability to study chlamydial or KoRV pathogenesis, effects of environmental stressors on immunity, and the response of koalas to vaccines under development, by examining the koala's adaptive response to natural infection or in-vitro stimulation, has been limited to date by a paucity of species- specific reagents. In this study we have used cytokine sequences from four marsupial genomes to identify mRNA sequences for key T regulatory, Th1 and Th2 cytokines interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10) and interferon gamma (IFNγ) along with CD4 and CD8β. The koala sequences used for primer design showed >58% homology with grey short-tailed opossum, >71% with tammar wallaby and 78% with Tasmanian devil amino acid sequences. We report the development of real-time RT-PCR assays to measure the expression of these genes in unstimulated cells and after three common mitogen stimulation protocols (phorbol myristate acetate/ionomycin, phorbol myristate acetate/phytohemagglutinin and concanavalin A). Phorbol myristate acetate/ionomycin was found to be the most effective mitogen to up-regulate the production of IL-4, IL-10 and IFNγ. IL-6 production was not consistently up-regulated by any of the protocols. Expression of CD4 and CD8β was down-regulated by mitogen stimulation. We found that the reference genes GAPDH and 28s are valid for normalising cytokine expression by koala lymphocytes after mitogen stimulation.


Storing Object-Dependent Sparse Codes in a Willshaw Associative Network.
Willshaw networks are single-layered neural networks that store associations between binary vectors. Using only binary weights, these networks can be implemented efficiently to store large numbers of patterns and allow for fault-tolerant recovery of those patterns from noisy cues. However, this is only the case when the involved codes are sparse and randomly generated. In this letter, we use a recently proposed approach that maps visual patterns into informative binary features. By doing so, we manage to transform MNIST handwritten digits into well-distributed codes that we then store in a Willshaw network in autoassociation. We perform experiments with both noisy and noiseless cues and verify a tenuous impact on the recovered pattern's relevant information. More specifically, we were able to perform retrieval after filling the memory to several factors of its number of units while preserving the information of the class to which the pattern belongs.


EEGLAB, SIFT, NFT, BCILAB, and ERICA: new tools for advanced EEG processing.
We describe a set of complementary EEG data collection and processing tools recently developed at the Swartz Center for Computational Neuroscience (SCCN) that connect to and extend the EEGLAB software environment, a freely available and readily extensible processing environment running under Matlab. The new tools include (1) a new and flexible EEGLAB STUDY design facility for framing and performing statistical analyses on data from multiple subjects; (2) a neuroelectromagnetic forward head modeling toolbox (NFT) for building realistic electrical head models from available data; (3) a source information flow toolbox (SIFT) for modeling ongoing or event-related effective connectivity between cortical areas; (4) a BCILAB toolbox for building online brain-computer interface (BCI) models from available data, and (5) an experimental real-time interactive control and analysis (ERICA) environment for real-time production and coordination of interactive, multimodal experiments.


Sexual risk behaviour and HAART: a comparative study of HIV-infected persons on HAART and on preventive therapy in Kenya.
Unprotected sex (UPS) among persons receiving highly active antiretroviral therapy (HAART) remains a concern because of the risk of HIV-transmission. A cross-sectional study comparing the sexual risk behaviour of 179 people living with HIV/AIDS (PLHA) receiving HAART with that of 143 PLHA receiving preventive therapy (PT) with cotrimoxazole/isoniazid was conducted in Mombasa, Kenya. Forty-five percent of all participants were sexually active in the last six months. Participants receiving PT were more likely to report > or =2 partners (13% vs.1%; P = 0.006). Participants receiving PT reported more UPS with regular partners (odds ratio [OR]: 3.9; 95% confidence interval [CI]: 1.8-8.4) and also more sexually transmitted infections (STI) symptoms (OR: 1.7; 95% CI: 1.0-2.8; P = 0.059). More than 40% of all participants did not know the HIV-status of regular partners. Therefore, HAART was not associated with increased sexual risk behaviours though considerable risk of HIV-transmission remains. HIV-care services need to emphasize partner testing and consistent condom use with all partners.


Predicting the composition and formation of solid products in lithium-sulfur batteries by using an experimental phase diagram.
Lithium-sulfur batteries discharge via the transformation of solid sulfur to solid lithium sulfide via the formation of several polysulfide species that have only been observed in solution. Reported here is the first experimental phase diagram of a S8-Li2S-electrolyte system, which is shown to be a practical tool to determine the solution composition and formation of solid (S8 and Li2S) phases in lithium-sulfur batteries. The phase diagram is constructed by the combination of measurements of the total sulfur concentration [S]T and average oxidation state (Sm-) of polysulfide solutions prepared by reaction of S8 and Li2S. The phase diagram is used to predict the equilibrium discharge/charge profile of lithium-sulfur batteries as a function of the amount of electrolyte and the onset of precipitation and dissolution of solid products. High energy batteries should operate with a minimum amount of electrolyte, where both solid S8 and Li2S will be present during most of the charge and discharge of the cell, in which case we predict the observation of only one voltage plateau, instead of the two voltage plateaus commonly reported.


Cabozantinib (XL184) Inhibits Growth and Invasion of Preclinical TNBC Models.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is associated with poor clinical outcome. There is a vital need for effective targeted therapeutics for TNBC patients, yet treatment strategies are challenged by the significant intertumoral heterogeneity within the TNBC subtype and its surrounding microenvironment. Receptor tyrosine kinases (RTK) are highly expressed in several TNBC subtypes and are promising therapeutic targets. In this study, we targeted the MET receptor, which is highly expressed across several TNBC subtypes. Using the small-molecule inhibitor cabozantinib (XL184), we examined the efficacy of MET inhibition in preclinical models that recapitulate human TNBC and its microenvironment. To analyze the dynamic interactions between TNBC cells and fibroblasts over time, we utilized a 3D model referred to as MAME (Mammary Architecture and Microenvironment Engineering) with quantitative image analysis. To investigate cabozantinib inhibition in vivo, we used a novel xenograft model that expresses human HGF and supports paracrine MET signaling. XL184 treatment of MAME cultures of MDA-MB-231 and HCC70 cells (± HGF-expressing fibroblasts) was cytotoxic and significantly reduced multicellular invasive outgrowths, even in cultures with HGF-expressing fibroblasts. Treatment with XL184 had no significant effects on MET(neg) breast cancer cell growth. In vivo assays demonstrated that cabozantinib treatment significantly inhibited TNBC growth and metastasis. Using preclinical TNBC models that recapitulate the breast tumor microenvironment, we demonstrate that cabozantinib inhibition is an effective therapeutic strategy in several TNBC subtypes.


Supplement of bamboo extract lowers serum monocyte chemoattractant protein-1 concentration in mice fed a diet containing a high level of saturated fat.
Monocyte chemoattractant protein-1 (MCP-1) is an inflammatory chemokine up-regulated in obese subjects, contributing to the development of type 2 diabetes. The present study investigated the inhibitory effect of an ethanol-water extract from bamboo (BEX, Phyllostachys edulis) on the blood concentration of MCP-1. C57BL/6J mice were fed a standard diet or a high-fat diet with or without the BEX supplement (11 g dry mass/17 000 kJ) for 6 months. A total of ten mice were used in each group. Body weight and food consumption were measured weekly. After euthanisation, the weight of visceral fat and circulating MCP-1 concentration were measured. In comparison with the standard control group, the high-fat control group had increased body weight, abdominal fat storage and serum MCP-1 concentration by 60 % (P < 0·001), 266 % (P < 0·001) and 180 % (P < 0·01), respectively. In comparison with the high-fat control group, the high-fat BEX group showed a 3 % decrease in body weight (P < 0·01), 24 % decrease in mesenteric fat depot (P < 0·01) and 49 % decrease in serum MCP-1 concentration (P < 0·05). The present study suggests that the BEX supplement in the high-fat diet ameliorates elevated MCP-1 concentrations in the blood, and whether this is related to modulated endocrine properties of the visceral fat is to be studied.


Cardiac index is associated with brain aging: the Framingham Heart Study.
Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61+/-9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.


The strictly conserved Arg-321 residue in the active site of Escherichia coli topoisomerase I plays a critical role in DNA rejoining.
The strictly conserved arginine residue proximal to the active site tyrosine of type IA topoisomerases is required for the relaxation of supercoiled DNA and was hypothesized to be required for positioning of the scissile phosphate for DNA cleavage to take place. Mutants of recombinant Yersinia pestis topoisomerase I with hydrophobic substitutions at this position were found in genetic screening to exhibit a dominant lethal phenotype, resulting in drastic loss in Escherichia coli viability when overexpressed. In depth biochemical analysis of E. coli topoisomerase I with the corresponding Arg-321 mutation showed that DNA cleavage can still take place in the absence of this arginine function if Mg(2+) is present to enhance the interaction of the enzyme with the scissile phosphate. However, DNA rejoining is inhibited in the absence of this conserved arginine, resulting in accumulation of the cleaved covalent intermediate and loss of relaxation activity. These new experimental results demonstrate that catalysis of DNA rejoining by type IA topoisomerases has a more stringent requirement than DNA cleavage. In addition to the divalent metal ions, the side chain of this arginine residue is required for the precise positioning of the phosphotyrosine linkage for nucleophilic attack by the 3'-OH end to result in DNA rejoining. Small molecules that can interfere or distort the enzyme-DNA interactions required for DNA rejoining by bacterial type IA topoisomerases could be developed into novel antibacterial drugs.


The prevalence of diabetes, pre-diabetes and the metabolic syndrome in an Irish regional homeless population.
Diabetes is a major chronic health condition. Prevalence is rising, superseding public health estimates. Chronic diseases are more common among lower socioeconomic groups, for example, the homeless population. There is paucity of data on the health status of the homeless population in Ireland, and the prevalence of diabetes and associated cardiovascular risk factors is unknown. We aimed to assess the prevalence of diabetes, pre-diabetes and the metabolic syndrome (MetS) in an Irish regional homeless population. This study is a cross-sectional study of the homeless population living in a regional university city of Ireland. After informed consent and following an overnight fast, blood was drawn for fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein and glycosylated haemoglobin (HbA1c). A 75 g glucose load was given orally and an oral glucose tolerance test completed. Anthropometric measurements and blood pressure were recorded. Smoking, alcohol and drug status were noted. Of the 252 participants, 8% (n = 20), 10% (n = 24) and 21% (n = 54) were diagnosed with type 2 diabetes, pre-diabetes and MetS, respectively. Obesity (body mass index >30) was present in 22%, while 90% displayed abdominal obesity. Participants who screened positive for diabetes, pre-diabetes and MetS demonstrated an inferior cardiovascular risk profile. The prevalence of diabetes, pre-diabetes and MetS in this homeless population is in keeping with national estimates. As this cohort is less likely to seek health care, this may result in later diagnosis and a greater risk of diabetic complications at presentation.


S1P/S1P Receptor Signaling in Neuromuscolar Disorders.
The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot-Marie-Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.


Trends in 'poor responder' research: lessons learned from RCTs in assisted conception.
A substantial minority of women undergoing IVF will under-respond to controlled ovarian hyperstimulation. These women-so-called 'poor responders'-suffer persistently reduced success rates after IVF. Currently, no single intervention is unanimously accepted as beneficial in overcoming poor ovarian response (POR). This has been supported by the available research on POR, which consists mainly of randomized controlled trials (RCTs ) with an inherent high-risk of bias. The aim of this review was to critically appraise the available experimental trials on POR and provide guidance towards more useful-less wasteful-future research. A comprehensive review was undertaken of RCTs on 'poor responders' published in the last 15 years. Data on various methodological traits as well as important clinical characteristics were extracted from the included studies and summarized, with a view to identifying deficiencies from which lessons can be learned. Based on this analysis, recommendations were provided for further research in this field of assisted conception. We selected and analysed 75 RCTs. A valid, 'low-risk' randomization method was reported in three out of four RCTs. An improving trend in reporting concealment of patient allocation was also evident over the 15-year period. In contrast, <1 in 10 RCTs 'blinded' patients and <1 in 5 RCTs 'blinded' staff to the proposed intervention. Only 1 in 10 RCTs 'blinded' ultrasound practitioners to patient allocation, when assessing the outcome of early pregnancy. The majority of trials reported an intention-to-treat analysis for at least one of their outcomes, with an improving trend in the recent years. Substantial variation was noted in the definitions used for 'poor responders', the most popular being 'low ovarian response at previous stimulation'. The preferred cut-off value for defining previous low response has been 'less or equal to three retrieved oocytes'. The most popular tests used for diagnosing diminished ovarian reserve have been antral follicle count and FSH. Although the Bologna criteria for POR were only recently introduced, they are expected to become a popular definition in future 'poor responder' trials. Numerous interventions have been studied on 'poor responders'. Most of these have been applied before/during controlled ovarian hyperstimulation. The antagonist protocol, the microdose flare protocol and the long down-regulation protocol have been among the most popular interventions. The analysis of outcomes revealed a clear improving trend in reporting live birth. In contrast, only 10% of RCTs reported significant improvement in reproductive outcomes among tested interventions. Twelve 'significant' interventions were reported, each supported by a single 'positive' RCT. Finally, trials of higher methodological quality were more likely to have been published in a high-impact journal. Overall, the majority of published trials on POR suffer from methodological flaws and are, thus, regarded as being high-risk for bias. The same trials have used a variety of definitions for their poor responders and a variety of interventions for their head-to-head comparisons. Not surprisingly, discrepancies are also evident in the findings of trials comparing similar interventions. Based on the identified deficiencies, this novel type of 'methodology and clinical' review has introduced custom recommendations on how to improve future experimental research in the 'poor responder' population.


[Honokiol attenuates lipopolysaccharide-induced acute respiratory distress syndrome via activation of mitochondrion-dependent Sirt3/AMPK pathway].
To explore the effects of honokiol (HKL) on pulmonary microvascular endothelial cells in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and the underlying mechanisms. Methods: In animal experiment, a total of 40 C57BL/6J mice were randomly divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+honokiol (HKL) intervention group (HKL group) and a LPS+HKL+nicotinamide (NAM) intervention group (NAM group) (n=10 in each group). In the cell experiment, the experiment cells were divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+HKL intervention group (HKL group), a LPS+HKL+NAM intervention group (NAM group), and a LPS+HKL+compound C (CMC) intervention group (CMC group). The pathological changes of the lung tissues were evaluated by hematoxylin and eosin (HE) staining; the protein concentration, total cells and neutrophils in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung tissues were detected; the changes of pulmonary microvascular permeability were determined by Evans blue assay; the effect of HKL on the vitality of human pulmonary microvascular endothelial cells were examined by cell counting kit-8 (CCK-8); the inhibitors including NAM and CMC were applied to explore the molecular mechanism of the protective effects of HKL. The expression levels of Sirt3, caspase-3, cleaved caspase-3, Bcl-2, Bax, p-adenosine monophosphate activated protein kinase (p-AMPK) and AMPK in lung tissues or cells were detected by Western blot. Results: In animal models, compared with the Con group, the mice in the LPS group displayed typical ARDS pathological changes, and the ratio of lung wet/dry weight (W/D) and MPO activity in the lung tissues, protein concentration, total cells and neutrophils in BALF, Evans blue leaking index (ELI), expression levels of cleaved caspase-3 were significantly increased (all P<0.05), while the expression levels of Sirt3 was obviously decreased (P<0.05). Compared with the LPS group, the above changes in the LPS group were significantly improved in the HKL group (all P<0.05); Compared with the HKL group, the curative effect of HKL intervention could be partly inhibited in the NAM group (P<0.05). In cell experiments, compared with the LPS group, the HPMECs viability in the HKL group was markedly improved (P<0.05), while the expression levels of Bcl-2 and Sirt3 were significantly upregulated (P<0.05), and the expression levels of Bax and cleaved caspase-3 were significantly downregulated (P<0.05), accompanied by the activation of AMPK pathway (P<0.05) in the HKL group. Compared with the HKL group, the curative effect of HKL intervention was partly inhibited in the CMC group (P<0.05). Conclusion: HKL can significantly attenuate LPS-induced lung injury and inhibit the apoptosis of pulmonary microvascular endothelial cells through regulation of Sirt3/AMPK pathway.


Kinesthetic taping improves walking function in patients with stroke: a pilot cohort study.
Stroke is an important cause of severe disability and impaired motor function. Treatment modalities that improve motor function in patients with stroke are needed. The objective of this study was to investigate the effect of kinesthetic taping of the anterior thigh and knee on maximal walking speed and clinical indices of spasticity in patients with stroke. Thirty-two patients (9 women) receiving rehabilitation after stroke (average, 50 days since stroke) who had impaired walking ability were recruited. Primary outcome was maximal walking speed measured by the 10-meter walk test. Secondary outcomes were number of steps taken during the test and clinical signs of spasticity measured by the Tardieu Scale. Tests were conducted before and immediately after application of kinesthetic tape to the anterior thigh and knee of the paretic lower limb. After application of the tape, the maximal walking speed increased, on average, by 0.08 m/s (95% CI, 0.04 to 0.12; P < .0001). The number of steps taken during the test was significantly decreased by 1.4 steps (95% CI, -2.3 to -0.5; P < .0031). The Tardieu scores were not significantly changed by the tape intervention, although a trend was observed indicating a lesser degree of spasticity. The results of this study indicate that kinesthetic taping of the anterior thigh and knee provides an immediate improvement in walking function in patients with stroke. Such a positive effect on motor function could be a valuable adjunct in physical therapy and rehabilitation of patients with stroke.


Interlaminar connections of the superior colliculus in the tree shrew. III: The optic layer.
These experiments were designed to test the idea that the optic layer in the tree shrew, Tupaia belangeri, is functionally distinct and provides a link between the visuosensory superficial and the premotor intermediate layers of the superior colliculus. First, cells in the optic layer were intracellularly labeled with biocytin in living brain slices. Compared to cells in the adjacent lower part of the superficial gray layer, which have apical dendrites that ascend toward the tectal surface, optic layer cells have dendritic fields that are restricted for the most part to the optic layer itself. The differences in dendritic-field location imply that superficial gray and optic layer cells have different patterns of input. The axons of optic layer cells terminate densely within the optic layer and, in addition, project in a horizontally restricted fashion to the overlying superficial gray and subjacent intermediate gray layers. This pattern also is different from the predominantly descending interlaminar projections of lower superficial gray layer cells. Next, cells in the intermediate gray layer were labeled in order to examine the relationships between optic layer cells and these subjacent neurons that project from the superior colliculus to oculomotor centers of the brain stem. Neurons in the upper part of the intermediate gray layer send apical dendrites into the optic layer and therefore can receive signals from the superficial gray layer either directly, from descending axons of lower superficial gray layer cells, or indirectly, through intervening optic layer cells. In contrast, lower intermediate gray layer cells have more radiate dendritic fields that are restricted to the intermediate gray layer. Thus, these lower cells must depend on descending projections from optic or upper intermediate gray layer cells for signals from the superficial gray layer. Together, these results support the idea that the optic layer is a distinct lamina that provides a link between the superficial and intermediate gray layers. They also are consistent with the traditional view that descending intracollicular projections play a role in the selection of visual targets for saccades.


Derivation and validation of a risk stratification model to identify coronary artery disease in women who present to the emergency department with potential acute coronary syndromes.
To derive and validate a model to identify women who would benefit from further evaluation of chest pain after an initial negative emergency department (ED) evaluation for acute coronary syndrome (ACS). The derivation and validation cohorts were comprised of women who presented to the ED with chest pain at two university hospitals. Patients were excluded if the initial electrocardiogram (ECG) or cardiac markers were consistent with ACS. Patients were followed for 30 days after the index visit to identify evidence of coronary artery disease (CAD), which was defined as a positive diagnostic study, myocardial infarction, or death. The authors performed a logistic regression analysis to identify significant predictors of CAD. A scoring system was developed based on the B-coefficient of these significant predictors. Levels of risk were assigned by summing and categorizing the cumulative risk score into low-, moderate-, and high-risk groups. The derivation and validation sets were comprised of 733 and 2,440 women, respectively. From the derivation set predictors of CAD (score) were history of CAD (1), age > or = 60 years (1), and high clinical suspicion (3). Low risk was defined as a score = 0, moderate risk score = 1-2, high risk score > or = 3. In the validation set, the numbers of patients with evidence of CAD were four of 1,348 (0.30%), 18 of 498 (3.6%), and 71 of 594 (11.9%) in the low-, moderate-, and high-risk groups, respectively. The risk of underlying CAD in women who present to the ED with potential ACS may be determined using a simple risk stratification score.


Multiple roles for CCR2 during fracture healing.
Bone injury induces an inflammatory response that involves neutrophils, macrophages and other inflammatory cells. The recruitment of inflammatory cells to sites of injury occurs in response to specific signaling pathways. The CC chemokine receptor type 2 (CCR2) is crucial for recruiting macrophages, as well as regulating osteoclast function. In this study, we examined fracture healing in Ccr2-/- mice. We first demonstrated that the expression of Ccr2 transcripts and the filtration of macrophages into fracture calluses were most robust during the early phases of fracture healing. We then determined that the number of macrophages at the fracture site was significantly lower in Ccr2-/- mice compared with wild-type controls at 3 days after injury. As a result, impaired vascularization, decreased formation of callus, and delayed maturation of cartilage were observed at 7 days after injury in mutant mice. At day 14, Ccr2-/- mice had less bone in their calluses. At day 21, Ccr2-/- mice had larger calluses and more bone compared with wild-type mice, suggesting a delayed remodeling. In addition, we examined the effect of Ccr2 mutation on osteoclasts. We found that a lack of Ccr2 did not affect the number of osteoclasts within fracture calluses at 21 days after injury. However, Ccr2-/- osteoclasts exhibited a decreased ability to resorb bone compared with wild-type cells, which could contribute to the delayed remodeling of fracture calluses observed in Ccr2-/- mice. Collectively, these results indicate that a deficiency of Ccr2 reduces the infiltration of macrophages and impairs the function of osteoclasts, leading to delayed fracture healing.


The application of co-melt-extruded poly(ε-caprolactone) as a controlled release drug delivery device when combined with novel bioactive drug candidates: Membrane permeation and Hanson dissolution studies.
Eight bioactive drug compounds (abamectin, amoxicillin, dexamethasone, dexamethasone valerate, ketoprofen, melatonin, oestradiol 17β, and oestradiol benzoate) were combined via melt extrusion and disc pressing processes with a polycaprolactone (PCL) matrix and were then evaluated and compared via membrane diffusion and Hanson dissolution studies. This investigation was to determine the potential of this matrix to act as a controlled release drug delivery vehicle for a number of drugs not previously combined with PCL in a melt extrusion mix. The inclusion of the progesterone/PCL system, for which the drug release behaviour has been well studied before was intended for comparison with the PCL systems incorporating drugs that have received little research attention in the past. Initial studies centred on an evaluation of the permeation ability of the bioactive drugs dissolved in aqueous cyclodextrin solutions through a poly(ε-caprolactone) (PCL) membrane using Valia-Chien side-by-side cells. Permeation rates were mostly low and found to range from 0 to 122 μg h(-1) with only ketoprofen, melatonin, and progesterone displaying rates exceeding 20 μg h(-1). Hanson dissolution release profiles in aqueous alcohol were subsequently measured for the 9 melt extruded PCL/drug combinations and led to Hanson release rates of 0-556 μg cm(-2) h(-0.5) with dexamethasone, dexamethasone valerate, ketoprofen, melatonin, and progesterone giving values exceeding 100 μg cm(-2) h(-0.5). A number of drugs such as the dexamethasones probably performed better than they did in the permeability rate measurements because of the less polar aqueous alcoholic solvent used. In searching for useful correlations between the drug physicochemical properties and release rate, only a moderate correlation (R (2)=0.5675) between Hanson dissolution release rate and permeation rate was found. This suggests that the release rate and the permeation are both controlled by the rate of drug diffusion through the PCL with release rate involving an additional dissolution process (of the drug) before permeation occurs accounting for the moderate correlation. In general, of the eight drugs considered, it was clear that the oestradiol-based drugs, abamectin, and amoxicillin were generally not suited to drug delivery via PCL under the conditions used. However, ketoprofen was found to be very suitable as a drug candidate for melt extrusion with PCL with dexamethasone valerate, dexamethasone, and melatonin also showing potential as candidates though to a much lesser extent.


Oxidative stress-mediated cytotoxicity and apoptosis induction by TiO2 nanofibers in HeLa cells.
Titanium dioxide nanoparticles are increasingly being used in pharmaceutical and cosmetic products. The high aspect ratio of fibrous nanomaterials, such as carbon nanotubes and TiO(2) nanofibers (TiO(2)NFs), similar to the one used in this study makes them an attractive structural material and has attracted a lot of attention due to their possible negative health effects as suggested by their morphological similarities with asbestos. In the present study, therefore, toxicity of TiO(2)NFs was evaluated in human cervical adenocarcinoma HeLa cells. The TEM and XRD analyses showed that TiO(2)NFs used in this study are pure with uniform diameter of around 200 nm, and their length to width aspect ratio ranged between 5 and 15. Exposure of HeLa cells to TiO(2)NFs induced significant cytotoxicity even at doses as low as 2 μg/ml. The intracellular uptake of TiO(2)NFs in cells was shown by Alizarin Red S (ARS) labeled nanofibers. The mechanism of toxicity is mainly due to the induction of cellular oxidative stress, as revealed by elevated ROS levels, reduced antioxidant levels, and increased lipid peroxidation leading to apoptosis. The cell cycle analysis indicated G(2)/M cell cycle arrest in the cells exposed to TiO(2)NF. TiO(2)NFs treatment to HeLa cells resulted in increased expression of proapoptotic proteins Bax with an increase in cytosolic Cytochrome-C and inhibition of anti-apoptotic protein Bcl-2. Our results revealed the potential mechanism of cellular effects of TiO(2)NFs.


Fighting polyglutamine disease by wrestling with SUMO.
Spinobulbar muscular atrophy (SBMA) is an X-linked disease characterized by degeneration of motor neurons, muscle atrophy, and progressive weakness. It is caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR), a transcription factor that is activated upon hormone binding. The polyQ expansion in AR causes it to form intracellular aggregates and impairs transcriptional activity. Intriguingly, SUMOylation (where SUMO indicates small ubiquitin-like modifier) of AR inhibits its transcriptional activity and reduces aggregation of the polyQ form of this protein, but it is unclear whether SUMOylation plays a pathogenic or protective role in SBMA. In this issue of the JCI, Chua et al. address this question by generating knockin mice in which the native AR is replaced by either a polyQ AR or a polyQ AR lacking the two lysine residues that are SUMOylated. The results from this study demonstrate that inhibiting SUMOylation of polyQ AR restores much of its transcriptional activity and prevents many (but not all) SBMA-associated symptoms in this mouse model.


Haemodynamic characteristics of low-renin hypertension.
1. Intra-arterial pressure, cardiac output, renal blood flow and glomerular filtration rate were measured in 19 patients with low-renin hypertension and in 30 patients with normal-renin hypertension. 2. Cardiac output and renal blood flow were significantly lower in low-renin hypertension. Total peripheral and renal vascular resistance were markedly higher in this group. 3. Plasma renin concentration correlated inversely with both total peripheral and renal vascular resistance as well as with age. Multiple regression analysis indicated that part of the relationship between renin and haemodynamic variables did not depend on age. Furthermore, plasma renin concentration did not decrease with age in a group of 40 normotensive control subjects of similar age to the hypertensive patients. 4. The results provide further confirmation that renin decreases as hypertension progresses.


Anger Self-Management Training for Chronic Moderate to Severe Traumatic Brain Injury: Results of a Randomized Controlled Trial.
To test efficacy of 8-session, 1:1 treatment, anger self-management training (ASMT), for chronic moderate to severe traumatic brain injury (TBI). Three US outpatient treatment facilities. Ninety people with TBI and elevated self-reported anger; 76 significant others (SOs) provided collateral data. Multicenter randomized controlled trial with 2:1 randomization to ASMT or structurally equivalent comparison treatment, personal readjustment and education (PRE). Primary outcome assessment 1 week posttreatment; 8-week follow-up. Response to treatment defined as 1 or more standard deviation change in self-reported anger. SO-rated anger, emotional and behavioral status, satisfaction with life, timing of treatment response, participant and SO-rated global change, and treatment satisfaction. State-Trait Anger Expression Inventory-Revised Trait Anger (TA) and Anger Expression-Out (AX-O) subscales; Brief Anger-Aggression Questionnaire (BAAQ); Likert-type ratings of treatment satisfaction, global changes in anger and well-being. After treatment, ASMT response rate (68%) exceeded that of PRE (47%) on TA but not AX-O or BAAQ; this finding persisted at 8-week follow-up. No significant between-group differences in SO-reported response rates, emotional/behavioral status, or life satisfaction. ASMT participants were more satisfied with treatment and rated global change in anger as significantly better; SO ratings of global change in both anger and well-being were superior for ASMT. ASMT was efficacious and persistent for some aspects of problematic anger. More research is needed to determine optimal dose and essential ingredients of behavioral treatment for anger after TBI.


Update on some epidemiologic features of intermittent claudication: the Framingham Study.
During 26 years of surveillance of the Framingham Study Cohort of 5,209 subjects, 176 men and 119 women developed occlusive peripheral arterial disease manifested as intermittent claudication (IC). The incidence increased sharply with age until the age of 75, with about a twofold male predominance at all ages. An incidence of IC comparable to that of angina pectoris was obtained ten years later in life than for angina pectoris. Cigarette smoking, impaired glucose tolerance, and hypertension were powerful predisposing factors. Impaired glucose tolerance was a greater risk in women than in men, and glycosuria carried a greater risk than other indicators of impaired glucose tolerance. Cigarette smoking had about the same impact in men and women, approximately doubling the risk, and the impact was discernible into advanced age. Hypertension increased risk 2.5- to fourfold, respectively, in men and women. A low vital capacity was associated with a substantial excess risk. Electrocardiographic evidence of left ventricular hypertrophy predicted IC in both sexes. Serum cholesterol, relative weight, and hematocrit were weak risk factors. A risk profile made up of the major cardiovascular risk factors was better for predicting IC than for predicting coronary heart disease. Mortality was increased two- to fourfold in men and women, respectively, mainly because of coexistent cardiovascular disease.


Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET.
D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2 dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85 to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.


Analysis of the interactions of cytochrome b5 with flavocytochrome P450 BM3 and its domains.
Interactions between a soluble form of microsomal cytochrome b(5) (b(5)) from Musca domestica (housefly) and Bacillus megaterium flavocytochrome P450 BM3 and its component reductase (CPR), heme (P450) and FAD/NADPH-binding (FAD) domains were analyzed by a combination of steady-state and stopped-flow kinetics methods, and optical spectroscopy techniques. The high affinity binding of b(5) to P450 BM3 induced a low-spin to high-spin transition in the P450 heme iron (K(d) for b(5) binding = 0.44 microM and 0.72 microM for the heme domain and intact flavocytochrome, respectively). The b(5) had modest inhibitory effects on steady-state turnover of P450 BM3 with fatty acids, and the ferrous-carbon monoxy P450 complex was substantially stabilized on binding b(5). Single turnover reduction of b(5) by BM3 using stopped-flow absorption spectroscopy (k(lim) = 116 s(-1)) was substantially faster than steady-state reduction of b(5) by P450 BM3 (or its CPR and FAD domains), indicating rate-limiting step(s) other than BM3 flavin-to-b(5) heme electron transfer in the steady-state reaction. Steady-state b(5) reduction by P450 BM3 was considerably accelerated at high ionic strength. Pre-reduction of P450 BM3 by NADPH decreased the k(lim) for b(5) reduction approximately 10-fold, and also resulted in a lag phase in steady-state b(5) reduction that was likely due to BM3 conformational perturbations sensitive to the reduction state of the flavocytochrome. Ferrous b(5) could not reduce the ferric P450 BM3 heme domain under anaerobic conditions, consistent with heme iron reduction potentials of the two proteins. However, rapid oxidation of both hemoproteins occurred on aeration of the ferrous protein mixture (and despite the much slower autoxidation rate of b(5) in isolation), consistent with electron transfer occurring from b(5) to the oxyferrous P450 BM3 in the complex. The results demonstrate that strong interactions occur between a eukaryotic b(5) and a model prokaryotic P450. Binding of b(5) perturbs BM3 heme iron spin-state equilibrium, as is seen in many physiologically relevant b(5) interactions with eukaryotic P450s. These results are consistent with the conservation of structure of P450s (particularly at the heme proximal face) between prokaryotes and eukaryotes, and may point to as yet undiscovered roles for b(5)-like proteins in the control of activities of certain prokaryotic P450s.


Stent-graft repair of thoracic aortic aneurysms.
Aneurysmal disease of the thoracic aorta continues to be a very challenging management problem for physicians because of the many comorbidities harbored by these patients, as well as the morbidity of the conventional open repair via left thoracotomy. In a combined effort between interventional radiology and cardiovascular surgery, an endovascular stent graft repair has been devised for these patients in an effort to reduce morbidity. This report documents the results in the first 108 patients so treated. The graft itself, custom-made for each individual, is composed of interlocked, self-expanding "Z" stents covered with a woven Dacron graft. Compressed in a loading capsule, the graft can then be advanced through a 27-French (outside diameter; OD) sheath, which is positioned within the aneurysm under fluoroscopic guidance. Relatively normal 2- to 3-cm segments of proximal and distal aorta allow an adequate friction seal to prevent stent graft dislodgement and also provide a hemostatic seal to obliterate aneurysm filling. Complete aneurysm thrombosis was achieved primarily in 103 patients. There were 10 deaths (9.25%) within the first 30 days, four of which were directly attributable to the stent graft procedure. Perioperative strokes occurred in four patients, and there were four instances of paraplegia. There have been two documented stent graft failures in a mean follow-up of 21.8 months (range, 1 to 57 months). Although the long-term durability of this procedure remains unknown, we believe this less invasive endovascular approach will prove to be an effective and less morbid treatment for aneurysmal disease of the descending thoracic aorta.


Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss.
Fibrosis is a newly appreciated hallmark of the pathological alteration of human white adipose tissue (WAT). We investigated the composition of subcutaneous (scWAT) and omental WAT (oWAT) fibrosis in obesity and its relationship with metabolic alterations and surgery-induced weight loss. Surgical biopsies for scWAT and oWAT were obtained in 65 obese (BMI 48.2 ± 0.8 kg/m(2)) and 9 lean subjects (BMI 22.8 ± 0.7 kg/m(2)). Obese subjects who were candidates for bariatric surgery were clinically characterized before, 3, 6, and 12 months after surgery, including fat mass evaluation by dual energy X-ray absorptiometry. WAT fibrosis was quantified and characterized using quantitative PCR, microscopic observation, and immunohistochemistry. Fibrosis amount, distribution and collagen types (I, III, and VI) present distinct characteristics in lean and obese subjects and with WAT depots localization (subcutaneous or omental). Obese subjects had more total fibrosis in oWAT and had more pericellular fibrosis around adipocytes than lean subjects in both depots. Macrophages and mastocytes were highly represented in fibrotic bundles in oWAT, whereas scWAT was more frequently characterized by hypocellular fibrosis. The oWAT fibrosis negatively correlated with omental adipocyte diameters (R = -0.30, P = 0.02), and with triglyceride levels (R = -0.42, P < 0.01), and positively with apoA1 (R = 0.25, P = 0.05). Importantly, scWAT fibrosis correlated negatively with fat mass loss measured at the three time points after surgery. Our data suggest differential clinical consequences of fibrosis in human WAT. In oWAT, fibrosis could contribute to limit adipocyte hypertrophy and is associated with a better lipid profile, whereas scWAT fibrosis may hamper fat mass loss induced by surgery.


The Task-force in Europe for Drug Development for the Young (TEDDY) Network of Excellence.
The Task-force in Europe for Drug Development for the Young (TEDDY) was established in 2005 to contribute to the promotion of safe and efficacious medicines for children in the context of the impending European Paediatric Regulation that finally came into force in January 2007. The project includes seven objectives and 12 Work-Packages encompassing the main aspects of the development and use of pediatric drugs. TEDDY represents a new entity in the pediatric pharmaceutical field, differing from a Scientific Society, a network for developing research or trials, or a consultative regulatory body. The ambition of TEDDY is to support the existing pediatric networks, societies, and regulatory bodies in performing innovative initiatives, including those in areas in which such undertakings would not be feasible without supportive action. To accomplish its aim, TEDDY has focused on three different actions: (i) increasing awareness about the Paediatric Regulation revolution; (ii) reaching consensus on terms and instruments to be used for common research; and (iii) favoring close relationships among different stakeholders and partners from different EU Member States. After 3 years of activities, many results have been produced by the Network: surveys, databases, expert opinions, and recommendations. Linking together different stakeholders, including industry and patient associations, as well as academia and research centers, the Network has contributed to increasing awareness and participation in the Paediatric Regulation. In addition, many papers detailing original results have either been published or submitted for publication in peer-reviewed journals. TEDDY is an original Network whose identity and role as a catalyzer of initiatives related to the use and development of pediatric drugs needs to be better clarified in the near future. Of particular importance is the need to reach consensus on best practices. The lack of a common view on pediatric research requirements among stakeholders across Member States remains the main challenge to be overcome.


Uterine Transplantation: Review of Livebirths and Reproductive Implications.
Uterine transplantation (UTx) is a fertility restoring treatment for women with absolute uterine factor infertility. At a time when there is no question of the procedure's feasibility, and as the number of livebirths begins to increase exponentially, various important reproductive, fetal, and maternal medicine implications have emerged. Detailed outcomes from 17 livebirths following UTx are now available, which are reviewed herein, along with contextualized extrapolation from pregnancy outcomes in other solid organ transplants. Differences in recipient demographics and reproductive aspirations between UTx and other transplant recipients make extrapolating management strategies and outcomes in other solid organ transplants inappropriate. Whereas preterm delivery remains prominent, small for gestational age or hypertensive disorders do not appear to be as prevalent following UTx when compared to other solid organ transplants. Given the primary objective of undertaking UTx is to achieve a livebirth, publication of reproductive outcomes is essential at this early stage, to reflect on and optimize the management of future cases.


Sampling, testing and modeling particle size distribution in urban catch basins.
The study analyzed the particle size distribution of particulate matter (PM) retained in two catch basins located, respectively, near a parking lot and a traffic intersection with common high levels of traffic activity. Also, the treatment performance of a filter medium was evaluated by laboratory testing. The experimental treatment results and the field data were then used as inputs to a numerical model which described on a qualitative basis the hydrological response of the two catchments draining into each catch basin, respectively, and the quality of treatment provided by the filter during the measured rainfall. The results show that PM concentrations were on average around 300 mg/L (parking lot site) and 400 mg/L (road site) for the 10 rainfall-runoff events observed. PM with a particle diameter of <45 μm represented 40-50% of the total PM mass. The numerical model showed that a catch basin with a filter unit can remove 30 to 40% of the PM load depending on the storm characteristics.


Gene movement and genetic association with regional climate gradients in California valley oak (Quercus lobata Née) in the face of climate change.
Rapid climate change jeopardizes tree populations by shifting current climate zones. To avoid extinction, tree populations must tolerate, adapt, or migrate. Here we investigate geographic patterns of genetic variation in valley oak, Quercus lobata Née, to assess how underlying genetic structure of populations might influence this species' ability to survive climate change. First, to understand how genetic lineages shape spatial genetic patterns, we examine historical patterns of colonization. Second, we examine the correlation between multivariate nuclear genetic variation and climatic variation. Third, to illustrate how geographic genetic variation could interact with regional patterns of 21st Century climate change, we produce region-specific bioclimatic distributions of valley oak using Maximum Entropy (MAXENT) models based on downscaled historical (1971-2000) and future (2070-2100) climate grids. Future climatologies are based on a moderate-high (A2) carbon emission scenario and two different global climate models. Chloroplast markers indicate historical range-wide connectivity via colonization, especially in the north. Multivariate nuclear genotypes show a strong association with climate variation that provides opportunity for local adaptation to the conditions within their climatic envelope. Comparison of regional current and projected patterns of climate suitability indicates that valley oaks grow in distinctly different climate conditions in different parts of their range. Our models predict widely different regional outcomes from local displacement of a few kilometres to hundreds of kilometres. We conclude that the relative importance of migration, adaptation, and tolerance are likely to vary widely for populations among regions, and that late 21st Century conditions could lead to regional extinctions.


[The cost of violence for the public health system in Brazil: available data and possibilities for estimation].
The Brazilian public budget for health was R$ 53 billion (approximately U$ 20 billion) in 2003. What share of this total was to treat victims of violence? It is impossible to estimate that proportion directly, due to limitations in the available data. This paper proposes a methodology to estimate the cost of violence for the public health system, using data from the Unified National Health System, the government budget, and the demand for public medical services (National Household Sample Survey). According to our estimates, in 2004 the costs of treatment for victims of external causes, aggressions, and traffic accidents were R$ 2.2 billion, R$ 119 million, and R$ 453 million, respectively. These findings were approximately four times higher than those observed in other studies.


The Influence of Oily Vehicle Composition and Vehicle-Membrane Interactions on the Diffusion of Model Permeants across Barrier Membranes.
In many instances, one or more components of a pharmaceutical or cosmetic formulation is an oil. The aims of this study were two-fold. First, to examine the potential of preferential uptake of one oily vehicle component over another into a model barrier membrane (silicone) from blended vehicles (comprising two from the common excipients isohexadecane (IHD), hexadecane (HD), isopropyl myristate (IPM), oleic acid (OA) and liquid paraffin). Second, to study the effect of membrane-vehicle interactions on the diffusion of model permeants (caffeine (CF), methyl paraben (MP) and butyl paraben (BP)) from blended vehicles. Selective sorption and partition of some oils (especially IHD and IPM) at the expense of other oils (such as OA) was demonstrated to take place. For example, the membrane composition of IHD was enriched compared to a donor solution of IHD-OA: 41%, 63% and 82% IHD, compared to donor solution composition of 25%, 50% and 75% IHD, respectively. Pre-soaking the membrane in IHD, HD or LP, rather than phosphate buffer, enhanced the flux of MP through the membrane by 2.6, 1.7 and 1.3 times, respectively. The preferential sorption of individual oil components from mixtures altered the barrier properties of silicone membrane, and enhanced the permeation of CF, MP and BP, which are typically co-formulated in topical products.


Isolated absence of right pulmonary artery.
Absence of right pulmonary artery (RPA) is a rare congenital abnormality with variable presentation. The diagnosis is often missed in infants The aim of this study was to describe infantile presentation of isolated absence of RPA along with a brief review of the literature. The details of five patients diagnosed with isolated absence of RPA from April 2007 to October 2009 were reviewed retrospectively Five patients were identified with this anomaly. The median age of presentation was 86 days (range, 40-120 days) and the median weight was 3.65 kg (range, 3.1-5.5 kg). All patients presented with breathing difficulty and had severe pulmonary hypertension (PHT) along with absent RPA on echocardiography. A multidetector computed tomographic scan was performed to confirm the diagnosis in four cases. Three patients had major aortopulmonary collateral and the hilar RPA was not well developed in all. A correct diagnosis was made before referral in one patient only. Differential vascularity in chest X-ray, a useful clue, was seen in four of five cases. Surgical correction was not considered in view of the small hilar pulmonary artery. The patients were all managed medically with diuretics and Sildenafil. Isolated absence of RPA is a rare congenital abnormality with varied presentation. Infantile presentation is marked with congestive cardiac failure and PHT. Specific diagnostic clue includes differential vascularity on the chest X-ray.


Temporal trends in the presentation of cardiovascular and cerebrovascular emergencies during the COVID-19 pandemic in Germany: an analysis of health insurance claims.
The first reports of declining hospital admissions for major cardiovascular emergencies during the COVID-19 pandemic attracted public attention. However, systematic evidence on this subject is sparse. We aimed to investigate the rate of emergent hospital admissions, subsequent invasive treatments and comorbidities during the COVID-19 pandemic in Germany. This was a retrospective analysis of health insurance claims data from the second largest insurance fund in Germany, BARMER. Patients hospitalized for acute myocardial infarction, acute limb ischemia, aortic rupture, stroke or transient ischemic attack (TIA) between January 1, 2019, and May 31, 2020, were included. Admission rates per 100,000 insured, invasive treatments and comorbidities were compared from January-May 2019 (pre-COVID) to January-May 2020 (COVID). A total of 115,720 hospitalizations were included in the current analysis (51.3% females, mean age 72.9 years). Monthly admission rates declined from 78.6/100,000 insured (pre-COVID) to 70.6/100,000 (COVID). The lowest admission rate was observed in April 2020 (61.6/100,000). Administration rates for ST-segment elevation myocardial infarction (7.3-6.6), non-ST-segment elevation myocardial infarction (16.8-14.6), acute limb ischemia (5.1-4.6), stroke (35.0-32.5) and TIA (13.7-11.9) decreased from pre-COVID to COVID. Baseline comorbidities and the percentage of these patients treated with interventional or open-surgical procedures remained similar over time across all entities. In-hospital mortality in hospitalizations for stroke increased from pre-COVID to COVID (8.5-9.8%). Admission rates for cardiovascular and cerebrovascular emergencies declined during the pandemic in Germany, while patients' comorbidities and treatment allocations remained unchanged. Further investigation is warranted to identify underlying reasons and potential implications on patients' outcomes.


Caenorhabditis elegans Muscleblind homolog mbl-1 functions in neurons to regulate synapse formation.
The sequestration of Muscleblind splicing regulators results in myotonic dystrophy. Previous work on Muscleblind has largely focused on its roles in muscle development and maintenance due to the skeletal and cardiac muscle degeneration phenotype observed in individuals with the disorder. However, a number of reported nervous system defects suggest that Muscleblind proteins function in other tissues as well. We have identified a mutation in the Caenorhabditis elegans homolog of Muscleblind, mbl-1, that is required for proper formation of neuromuscular junction (NMJ) synapses. mbl-1 mutants exhibit selective loss of the most distal NMJ synapses in a C. elegans motorneuron, DA9, visualized using the vesicle-associated protein RAB-3, as well as the active zone proteins SYD-2/liprin-α and UNC-10/Rim. The proximal NMJs appear to have normal pre- and postsynaptic specializations. Surprisingly, expressing a mbl-1 transgene in the presynaptic neuron is sufficient to rescue the synaptic defect, while muscle expression has no effect. Consistent with this result, mbl-1 is also expressed in neurons. Based on these results, we conclude that in addition to its functions in muscle, the Muscleblind splice regulators also function in neurons to regulate synapse formation.


Image mapping spectrometry: calibration and characterization.
Image mapping spectrometry (IMS) is a hyperspectral imaging technique that simultaneously captures spatial and spectral information about an object in real-time. We present a new calibration procedure for the IMS as well as the first detailed evaluation of system performance. We correlate optical components and device calibration to performance metrics such as light throughput, scattered light, distortion, spectral image coregistration, and spatial/spectral resolution. Spectral sensitivity and motion artifacts are also evaluated with a dynamic biological experiment. The presented methodology of evaluation is useful in assessment of a variety of hyperspectral and multi-spectral modalities. Results are important to any potential users/developers of an IMS instrument and to anyone who may wish to compare the IMS to other imaging spectrometers.


Association Between Prior Insurance and Health Service Utilization Among the Long-Term Uninsured in South Carolina.
Purpose: Strong evidence supports the relationship between health coverage and improved health status. Little is known about the lasting impact of prior health insurance on the prior insured's use of health services. We aimed to examine the association between prior insurance status and health service utilization (HSU) among the long-term uninsured (LTU) in South Carolina. Methods: The current study used data from in-person interviews of the LTU collected in a 2014 cross-sectional South Carolina survey. Men and women between 18-64 years of age who reported not having health insurance for at least 24 months at the time of data collection were included. Propensity score analysis was used to examine the associations between prior insurance status and three outcome variables: (1) having a usual source of care, (2) HSU, and (3) delaying health care needs. Results: Prior health insurance significantly predicted a greater likelihood of having a usual source of care (effect size: 9.2%, p=0.004) and having had at least one preventive visit during the past 2 years (effect size: 6.4%, p=0.035). Prior insurance coverage was positively associated with delayed health care utilization, but the result was not statistically significant (p=0.703). Conclusions: Among the LTU, ever having insurance coverage was positively associated with having a usual source of care and HSU. The lasting impact of insurance coverage on HSU behavior extends beyond the period of insurance coverage, which provides a more comprehensive and deeper understanding of the long-term implications of national and local efforts in expanding insurance coverage.


Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2.
Both human and murine cytotoxic T cells (CTL) elicited in response to infection with influenza A viruses have been shown to be specific for internal viral proteins, such as the matrix and nucleoprotein. Individual CTL epitopes have been identified in the nucleoprotein by successfully substituting short synthetic peptides for the intact virus in the preparation of target cells in cytotoxicity assays. The defined peptide epitopes have each been recognized by CTL in association with individual class I major histocompatibility complex (MHC) proteins, H-2Db, H-2Kk, H-2Kd (Taylor, P. et al., unpublished data) and HLA-B37. A logical strategy to investigate the molecular details of the interaction between antigen and MHC class I proteins would be to define an epitope recognized by the MHC class I molecule HLA-A2. This is because the amino-acid sequence is known, several variants of A2 have been characterized and the protein has been purified and crystallized. Here we describe a peptide derived from the influenza matrix protein that is recognized by human CTL in association with the HLA-A2 molecule.


Simultaneous dispersion measurements of multiple fiber modes using virtual reference interferometry.
We present the simultaneous measurement of first and second order dispersion in short length (< 1 m) few mode fibers (polarization and transverse) using virtual reference interferometry. This technique generates results equivalent to balanced spectral interferometry, without the complexity associated with physical balancing. This is achieved by simulating a virtual reference with a group delay equal to that of the physical interferometer. The amplitude modulation that results from mixing the interferograms, generated in both the unbalanced interferometer and the virtual reference, is equivalent to the first order interference that would be produced by physical balancing. The advantages of the technique include speed, simplicity, convenience and the capability for simultaneous measurement of multiple modes. The theoretical framework is first developed and then verified experimentally.


Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington's disease model system.
Huntington's disease (HD) results from expansions of polyglutamine stretches (polyQ) in the huntingtin protein (Htt) that promote protein aggregation, neurodegeneration, and death. Since the diversity and sizes of the soluble Htt-polyQ aggregates that have been linked to cytotoxicity are unknown, we investigated soluble Htt-polyQ aggregates using analytical ultracentrifugation. Soon after induction in a yeast HD model system, non-toxic Htt-25Q and cytotoxic Htt-103Q both formed soluble aggregates 29S to 200S in size. Because current models indicate that Htt-25Q does not form soluble aggregates, reevaluation of previous studies may be necessary. Only Htt-103Q aggregation behavior changed, however, with time. At 6 hr mid-sized aggregates (33S to 84S) and large aggregates (greater than 100S) became present while at 24 hr primarily only mid-sized aggregates (20S to 80S) existed. Multiple factors that decreased cytotoxicity of Htt-103Q (changing the length of or sequences adjacent to the polyQ, altering ploidy or chaperone dosage, or deleting anti-aging factors) altered the Htt-103Q aggregation pattern in which the suite of mid-sized aggregates at 6 hr were most correlative with cytotoxicity. Hence, the amelioration of HD and other neurodegenerative diseases may require increased attention to and discrimination of the dynamic alterations in soluble aggregation processes.


Differential roles of frequency-following and frequency-doubling visual responses revealed by evoked neural harmonics.
Frequency-following and frequency-doubling neurons are ubiquitous in both striate and extrastriate visual areas. However, responses from these two types of neural populations have not been effectively compared in humans because previous EEG studies have not successfully dissociated responses from these populations. We devised a light-dark flicker stimulus that unambiguously distinguished these responses as reflected in the first and second harmonics in the steady-state visual evoked potentials. These harmonics revealed the spatial and functional segregation of frequency-following (the first harmonic) and frequency-doubling (the second harmonic) neural populations. Spatially, the first and second harmonics in steady-state visual evoked potentials exhibited divergent posterior scalp topographies for a broad range of EEG frequencies. The scalp maximum was medial for the first harmonic and contralateral for the second harmonic, a divergence not attributable to absolute response frequency. Functionally, voluntary visual-spatial attention strongly modulated the second harmonic but had negligible effects on the simultaneously elicited first harmonic. These dissociations suggest an intriguing possibility that frequency-following and frequency-doubling neural populations may contribute complementary functions to resolve the conflicting demands of attentional enhancement and signal fidelity--the frequency-doubling population may mediate substantial top-down signal modulation for attentional selection, whereas the frequency-following population may simultaneously preserve relatively undistorted sensory qualities regardless of the observer's cognitive state.


Freezing of Gait in Parkinson's Disease: An Overload Problem?
Freezing of gait (FOG) is arguably the most severe symptom associated with Parkinson's disease (PD), and often occurs while performing dual tasks or approaching narrowed and cluttered spaces. While it is well known that visual cues alleviate FOG, it is not clear if this effect may be the result of cognitive or sensorimotor mechanisms. Nevertheless, the role of vision may be a critical link that might allow us to disentangle this question. Gaze behaviour has yet to be carefully investigated while freezers approach narrow spaces, thus the overall objective of this study was to explore the interaction between cognitive and sensory-perceptual influences on FOG. In experiment #1, if cognitive load is the underlying factor leading to FOG, then one might expect that a dual-task would elicit FOG episodes even in the presence of visual cues, since the load on attention would interfere with utilization of visual cues. Alternatively, if visual cues alleviate gait despite performance of a dual-task, then it may be more probable that sensory mechanisms are at play. In compliment to this, the aim of experiment#2 was to further challenge the sensory systems, by removing vision of the lower-limbs and thereby forcing participants to rely on other forms of sensory feedback rather than vision while walking toward the narrow space. Spatiotemporal aspects of gait, percentage of gaze fixation frequency and duration, as well as skin conductance levels were measured in freezers and non-freezers across both experiments. Results from experiment#1 indicated that although freezers and non-freezers both walked with worse gait while performing the dual-task, in freezers, gait was relieved by visual cues regardless of whether the cognitive demands of the dual-task were present. At baseline and while dual-tasking, freezers demonstrated a gaze behaviour that neglected the doorway and instead focused primarily on the pathway, a strategy that non-freezers adopted only when performing the dual-task. Interestingly, with the combination of visual cues and dual-task, freezers increased the frequency and duration of fixations toward the doorway, compared to non-freezers. These results suggest that although increasing demand on attention does significantly deteriorate gait in freezers, an increase in cognitive demand is not exclusively responsible for freezing (since visual cues were able to overcome any interference elicited by the dual-task). When vision of the lower limbs was removed in experiment#2, only the freezers' gait was affected. However, when visual cues were present, freezers' gait improved regardless of the dual-task. This gait behaviour was accompanied by greater amount of time spent looking at the visual cues irrespective of the dual-task. Since removing vision of the lower-limbs hindered gait even under low attentional demand, restricted sensory feedback may be an important factor to the mechanisms underlying FOG.


GABAergic inhibition at dendrodendritic synapses tunes gamma oscillations in the olfactory bulb.
In the olfactory bulb (OB), odorants induce oscillations in the gamma range (20-80 Hz) that play an important role in the processing of sensory information. Synaptic transmission between dendrites is a major contributor to this processing. Glutamate released from mitral cell dendrites excites the dendrites of granule cells, which in turn mediate GABAergic inhibition back onto mitral cells. Although this reciprocal synapse is thought to be a key element supporting oscillatory activity, the mechanisms by which dendrodendritic inhibition induces and maintains gamma oscillations remain unknown. Here, we assessed the role of the dendrodendritic inhibition, using mice lacking the GABA(A) receptor alpha1-subunit, which is specifically expressed in mitral cells but not in granule cells. The spontaneous inhibitory postsynaptic current frequency in these mutants was low and was consistent with the reduction of GABA(A) receptor clusters detected by immunohistochemistry. The remaining GABA(A) receptors in mitral cells contained the alpha3-subunit and supported slower decaying currents of unchanged amplitude. Overall, inhibitory-mediated interactions between mitral cells were smaller and slower in mutant than in WT mice, although the strength of sensory afferent inputs remained unchanged. Consequently, both experimental and theoretical approaches revealed slower gamma oscillations in the OB network of mutant mice. We conclude, therefore, that fast oscillations in the OB circuit are strongly constrained by the precise location, subunit composition and kinetics of GABA(A) receptors expressed in mitral cells.


Identification of functionally important amino acid residues within the C2-domain of human factor V using alanine-scanning mutagenesis.
We have previously determined that the C2-domain of human factor V (residues 2037-2196) is required for expression of cofactor activity and binding to phosphatidylserine (PS)-containing membranes. Naturally occurring factor V inhibitors and a monoclonal antibody (HV-1) recognized epitopes in the amino terminus of the C2-domain (residues 2037-2087) and blocked PS binding. We have now investigated the function of individual amino acids within the C2-domain using charge to alanine mutagenesis. Charged residues located within the C2-domain were changed to alanine in clusters of 1-3 mutations per construct. In addition, mutants W2063A, W2064A, (W2063, W2064)A, and L2116A were constructed as well. The resultant 30 mutants were expressed in COS cells using a B-domain deleted factor V construct (rHFV des B). All mutants were expressed efficiently based on the polyclonal antibody ELISA. The charged residues, Arg(2074), Asp(2098), Arg(2171), Arg(2174), and Glu(2189) are required for maintaining the structural integrity of the C2-domain of factor V. Four of these residues (Arg(2074), Asp(2098), Arg(2171), and Arg(2174)) correspond to positions in the factor VIII C-type domains that have been identified as point mutations in patients with hemophilia A. The epitope for the inhibitory monoclonal antibody HV-1 has been localized to Lys(2060) through Glu(2069) in the factor V C2-domain. The epitope for the inhibitory monoclonal antibody 6A5 is composed of amino acids His(2128) through Lys(2137). The PS-binding site in the factor V C2-domain includes amino acid residues Trp(2063) and Trp(2064). This site overlaps with the epitope for monoclonal antibody HV-1. These factor V C2-domain mutants should provide valuable tools for further defining the molecular interactions responsible for factor V binding to phospholipid membranes.


Automated Detection of Real-World Falls: Modeled From People With Multiple Sclerosis.
Falls are a major health problem with one in three people over the age of 65 falling each year, oftentimes causing hip fractures, disability, reduced mobility, hospitalization and death. A major limitation in fall detection algorithm development is an absence of real-world falls data. Fall detection algorithms are typically trained on simulated fall data that contain a well-balanced number of examples of falls and activities of daily living. However, real-world falls occur infrequently, making them difficult to capture and causing severe data imbalance. People with multiple sclerosis (MS) fall frequently, and their risk of falling increases with disease progression. Because of their high fall incidence, people with MS provide an ideal model for studying falls. This paper describes the development of a context-aware fall detection system based on inertial sensors and time of flight sensors that is robust to imbalance, which is trained and evaluated on real-world falls in people with MS. The algorithm uses an auto-encoder that detects fall candidates using reconstruction error of accelerometer signals followed by a hyper-ensemble of balanced random forests trained using both acceleration and movement features. On a clinical dataset obtained from 25 people with MS monitored over eight weeks during free-living conditions, 54 falls were observed and our system achieved a sensitivity of 92.14%, and false-positive rate of 0.65 false alarms per day.


Household impacts of AIDS: using a life course approach to identify effective, poverty-reducing interventions for prevention, treatment and care.
A life course approach was used to assess household level impacts and inform interventions around HIV risk and AIDS vulnerability across seven major age-related stages of life. Our focus was sub-Saharan Africa. We provided a qualitative review of evidence from published literature, particularly multicountry reviews on impacts of AIDS, on determinants of risk and vulnerability, and reports of large surveys. Areas of potential stress from birth to old age in households affected by AIDS, and interventions for dealing with these specific stresses were identified. While specific interventions for HIV are important at different stages, achieving survival and development outcomes demands a wider set of health, social security and development interventions. One way to determine the priorities amongst these actions is to give weighting to interventions that address factors that have latent impacts later in life, which interrupt accumulating risk, or that change pathways to reduce the risk of both immediate and later stress. This qualitative review suggested that interventions, important for life cycle transitions in generalised epidemics where HIV risk and AIDS vulnerability is high, lie within and outside the health sector, and suggested examples of such interventions.


Roles of galectins in vivo.
The mutational analysis of the galectin family is shedding a different light of this class of molecules. On the one hand, it appears that galectin 1 and galectin 3 are not required for the survival of mice in normal animal house conditions, while on the other hand, there seems to be several subtle, but very complex, consequences of lacking galectins during development.


A movable surface: formation of Yersinia sp. biofilms on motile Caenorhabditis elegans.
Bubonic plague is transmitted by fleas whose feeding is blocked by a mass of Yersinia pestis in the digestive tract. Y. pestis and the closely related Y. pseudotuberculosis also block the feeding of Caenorhabditis elegans by forming a biofilm on the nematode head. C. elegans mutants with severe motility defects acquire almost no biofilm, indicating that normal animals accumulate the biofilm matrix as they move through a Yersinia lawn. Using the lectin wheat germ agglutinin as a probe, we show that the matrix on C. elegans contains carbohydrate produced by Yersinia. The carbohydrate is present in bacterial lawns prior to addition of nematodes, indicating that biofilm formation does not involve signaling between the two organisms. Furthermore, biofilm accumulation depends on continuous C. elegans exposure to a lawn of Yersinia bacteria.


Current status of intestinal transplantation in Japan.
The development of total parenteral nutrition (TPN) has dramatically improved the prognosis of patients afflicted with intestinal failure. However, TPN-related complications, which remain a problem for patients with intestinal failure can be addressed by intestinal transplantation, which can significantly improve their prognosis and quality of life. The first intestinal transplantation in Japan occurred in 1996. Of the 17 intestinal transplantations performed to date, six were obtained from deceased donors and 11 from living donors. The primary indications were: short gut syndrome (n = 8), intestinal function disorder (n = 7), and retransplantation (n = 2). In our experience, the 1-year and 5-year patient survival rates are 87% and 69%. All nine patients receiving transplants in the last 7 years have survived, which seem to be acceptable results for the treatment of intestinal failure. Relatively few intestinal transplantations have been performed to date, mainly due to the lack of national health insurance coverage for the procedure and the ban of the use of donors below 15 years of age. Liver failure patients are also ineligible because liver-intestine or multiorgan transplants are not allowed by current guidelines. Case numbers may increase in the future as the result of allowing for pediatric donors in the new Act on Organ Transplantation, which went into effect in July 2010. We continue to work on reforming national insurance coverage to cover multiorgan transplantations.


Exceptional ballistic transport in epitaxial graphene nanoribbons.
Graphene nanoribbons will be essential components in future graphene nanoelectronics. However, in typical nanoribbons produced from lithographically patterned exfoliated graphene, the charge carriers travel only about ten nanometres between scattering events, resulting in minimum sheet resistances of about one kilohm per square. Here we show that 40-nanometre-wide graphene nanoribbons epitaxially grown on silicon carbide are single-channel room-temperature ballistic conductors on a length scale greater than ten micrometres, which is similar to the performance of metallic carbon nanotubes. This is equivalent to sheet resistances below 1 ohm per square, surpassing theoretical predictions for perfect graphene by at least an order of magnitude. In neutral graphene ribbons, we show that transport is dominated by two modes. One is ballistic and temperature independent; the other is thermally activated. Transport is protected from back-scattering, possibly reflecting ground-state properties of neutral graphene. At room temperature, the resistance of both modes is found to increase abruptly at a particular length--the ballistic mode at 16 micrometres and the other at 160 nanometres. Our epitaxial graphene nanoribbons will be important not only in fundamental science, but also--because they can be readily produced in thousands--in advanced nanoelectronics, which can make use of their room-temperature ballistic transport properties.


Evaluation of anorectal physiology in patients with increased mast cells.
Diarrhea, urgency, and fecal incontinence are common complaints in systemic mastocytosis and in patients with increased gastrointestinal mucosal mast cells. We performed anorectal manometry on six patients with clinical symptoms of mastocytosis and histologic evidence of increased mast cells and compared the results to anorectal manometry of six age- and sex-matched controls, with no bowel symptoms. Standard techniques with balloon volumes were used to measure maximal basal pressure, maximal squeeze pressure, smallest volume sensed, degree of relaxation of the internal sphincter, and the volume causing: (1) a strong urge to defecate and (2) pain. Patients with mastocytosis, compared with controls, had smaller balloon volumes induce rectal urgency (97 vs 164 ml) and pain (117 vs 278 ml). A trend was present for lower maximal basal pressure in mastocytosis, but was not statistically significant. Sensitivity to balloon inflation suggests decreased rectal compliance or overreactive rectal contractility. These findings provide an explanation for the anorectal symptoms in patients with increased mast cells.


Clinical performance of a new magnetic bone conduction hearing implant system: results from a prospective, multicenter, clinical investigation.
The aim of the investigation was to prospectively evaluate, in a multicenter setting, the clinical performance of a new magnetic bone conduction hearing implant system. The test device was the Cochlear Baha Attract System (Cochlear Bone Anchored Solutions AB, Mölnlycke, Sweden). Instead of the skin-penetrating abutment of traditional bone conduction hearing implants, the test device uses an implantable and an external magnet to transmit sound from the sound processor (SP) through intact skin to the skull bone. Twenty-seven adult patients with a conductive or mild mixed hearing loss or single-sided sensorineural deafness were included in the clinical investigation across four investigational sites. The patients were followed for 9 months after implantation. The study evaluated efficacy in terms of hearing performance compared with unaided hearing and with hearing with the SP on a softband. Patient benefit, soft tissue status, device retention, and safety parameters were monitored continuously throughout the investigation. Surgery and healing was uneventful. Statistically significant improvements in audibility and speech understanding in noise and quiet were recorded for the test device compared with preoperative unaided hearing. Speech recognition was similar or better than tests performed with the same SP on a softband. Good soft tissue outcomes were reported, without major pressure-related complications. At the end of the investigation, all patients continued to use and benefit from the device. The test device provides good hearing performance in patients with a conductive hearing loss or single-sided sensorineural deafness, with good wearing comfort and minimal soft tissue complications.


Stimulation of osteoclast differentiation in vitro by mouse oncostatin M, leukaemia inhibitory factor, cardiotrophin-1 and interleukin 6: synergy with dexamethasone.
The role of oncostatin M in bone metabolism is not clearly defined, and the actions of mouse oncostatin M (mOSM) on osteoclast development has not been previously determined. We therefore examined the ability of recombinant mOSM to stimulate osteoclast formation and activity using cocultures of murine calvaria and bone marrow cells, and compared the responses to other members of the interleukin 6 family of cytokines including mouse leukaemia inhibitory factor (LIF), cardiotrophin-1 (CT-1) and IL-6. Mouse OSM, LIF and CT-1 strongly induced the formation of tartrate resistant acid phosphatase positive (TRAP(+)) multinucleated cells (MNC) in a dose-dependent fashion. OSM, LIF or CT-1 also elevated the number and size of resorptive pits when cocultures were added to smooth cortical bone slices, indicating enhancement of osteoclast activity. The activity of OSM was reduced by indomethacin (10(-8)-10(-6) M), whereas addition of dexamethasone (DEX) at 10(-7)-10(-5) M synergistically enhanced OSM-induced numbers of TRAP(+)MNC. DEX (10(-7) M) costimulation also synergistically enhanced TRAP(+)cell numbers of LIF, and CT-1 treated cocultures. IL-6 had no activity alone, but further enhanced TRAP(+)cell formation in mOSM or DEX (10(-7) M) treated cocultures. When added to mouse calvarial osteoblast cultures, mOSM induced secretion of IL-6 protein and elevation of mRNA whereas LIF or CT-1 did not. IL-6 mRNA levels and protein secretion were reduced in osteoblasts by costimulation with DEX. These results show that mouse OSM, LIF and CT-1 induce osteoclast differentiation and activation, that DEX synergizes with each in this activity, and that mouse OSM induces responses in osteoblasts that are not shown by LIF or CT-1. Collectively these data suggest an important role of these cytokines in osteoporosis caused by high levels of corticosteroid.


Plant mitochondrial recombination surveillance requires unusual RecA and MutS homologs.
For >20 years, the enigmatic behavior of plant mitochondrial genomes has been well described but not well understood. Chimeric genes appear, and occasionally are differentially replicated or expressed, with significant effects on plant phenotype, most notably on male fertility, yet the mechanisms of DNA replication, chimera formation, and recombination have remained elusive. Using mutations in two important genes of mitochondrial DNA metabolism, we have observed reproducible asymmetric recombination events occurring at specific locations in the mitochondrial genome. Based on these experiments and existing models of double-strand break repair, we propose a model for plant mitochondrial DNA replication, chimeric gene formation, and the illegitimate recombination events that lead to stoichiometric changes. We also address the physiological and developmental effects of aberrant events in mitochondrial genome maintenance, showing that mitochondrial genome rearrangements, when controlled, influence plant reproduction, but when uncontrolled, lead to aberrant growth phenotypes and dramatic reduction of the cell cycle.


Fusobacterium in colonic flora and molecular features of colorectal carcinoma.
Fusobacterium species are part of the gut microbiome in humans. Recent studies have identified overrepresentation of Fusobacterium in colorectal cancer tissues, but it is not yet clear whether this is pathogenic or simply an epiphenomenon. In this study, we evaluated the relationship between Fusobacterium status and molecular features in colorectal cancers through quantitative real-time PCR in 149 colorectal cancer tissues, 89 adjacent normal appearing mucosae and 72 colonic mucosae from cancer-free individuals. Results were correlated with CpG island methylator phenotype (CIMP) status, microsatellite instability (MSI), and mutations in BRAF, KRAS, TP53, CHD7, and CHD8. Whole-exome capture sequencing data were also available in 11 cases. Fusobacterium was detectable in 111 of 149 (74%) colorectal cancer tissues and heavily enriched in 9% (14/149) of the cases. As expected, Fusobacterium was also detected in normal appearing mucosae from both cancer and cancer-free individuals, but the amount of bacteria was much lower compared with colorectal cancer tissues (a mean of 250-fold lower for Pan-fusobacterium). We found the Fusobacterium-high colorectal cancer group (FB-high) to be associated with CIMP positivity (P = 0.001), TP53 wild-type (P = 0.015), hMLH1 methylation positivity (P = 0.0028), MSI (P = 0.018), and CHD7/8 mutation positivity (P = 0.002). Among the 11 cases where whole-exome sequencing data were available, two that were FB-high cases also had the highest number of somatic mutations (a mean of 736 per case in FB-high vs. 225 per case in all others). Taken together, our findings show that Fusobacterium enrichment is associated with specific molecular subsets of colorectal cancers, offering support for a pathogenic role in colorectal cancer for this gut microbiome component.