Systemic therapy of brain metastases.
Brain metastases are a common complication of cancer and continue to be associated with a poor prognosis. Management of brain metastases typically requires a multidisciplinary approach which may include whole-brain radiation therapy, stereotactic radiosurgery, surgery, and systemic therapy. Historically, the use of systemic therapy in brain metastases has been challenging because of the resistance to conventional chemotherapies secondary to the blood-brain barrier and an often heavily pre-treated patient population, and the paucity of well-conducted randomized trials in these heterogeneous patient populations. Newer agents, including immunotherapy and targeted therapies, are playing increasingly important roles in the up-front management of brain metastases. In this overview, we review recent advances in systemic therapies for brain metastases and the evidence supporting their use in this patient population.


Overexpression of auxin-binding protein enhances the sensitivity of guard cells to auxin.
To explore the role of auxin-binding protein (ABP1) in planta, a number of transgenic tobacco (Nicotiana tabacum) lines were generated. The wild-type KDEL endoplasmic reticulum targeting signal was mutated to HDEL, another common retention sequence in plants, and to KEQL or KDELGL to compromise its activity. The auxin-binding kinetics of these forms of ABP1 were found to be similar to those of ABP1 purified from maize (Zea mays). To test for a physiological response mediated by auxin, intact guard cells of the transgenic plants were impaled with double-barreled microelectrodes, and auxin-dependent changes in K(+) currents were recorded under voltage clamp. Exogenous auxin affected inwardly and outwardly rectifying K(+) currents in a dose-dependent manner. Auxin sensitivity was markedly enhanced in all plants overexpressing ABP1, irrespective of the form present. Immunogold electron microscopy was used to investigate the localization of ABP1 in the transgenic plants. All forms were detected in the endoplasmic reticulum and the KEQL and KDELGL forms passed further across the Golgi stacks than KDEL and HDEL forms. However, neither electron microscopy nor silver-enhanced immunogold epipolarization microscopy revealed differences in cell surface ABP1 abundance for any of the plants, including control plants, which indicated that overexpression of ABP1 alone was sufficient to confer increased sensitivity to added auxin. Jones et al. ([1998] Science 282: 1114-1117) found increased cell expansion in transgenic plants overexpressing wild-type ABP1. Single cell recordings extend this observation, with the demonstration that the auxin sensitivity of guard cell K(+) currents is mediated, at least in part, by ABP1.


Polar oceans in a changing climate.
Most of Earth's surface is blue or white, but how much of each would depend on the time of observation. Our planet has been through phases of snowball (all frozen), greenhouse (all liquid seas) and icehouse (frozen and liquid). Even during current icehouse conditions, the extent of ice versus water has changed considerably between ice ages and interglacial periods. Water has been vital for life on Earth and has driven and been influenced by transitions between greenhouse and icehouse. However, neither the possession of water nor having liquid and frozen seas are unique to Earth (Figure 1). Frozen water oceans on the moons Enceladus and Europa (and possibly others) and the liquid and frozen hydrocarbon oceans on Titan probably represent the most likely areas to find extraterrestrial life. We know very little about life in Earth's polar oceans, yet they are the engine of the thermohaline 'conveyor-belt', driving global circulation of heat, oxygen, carbon and nutrients as well as setting sea level through change in ice-mass balance. In regions of polar seas, where surface water is particularly cold and dense, it sinks to generate a tropic-ward flow on the ocean floor of the Pacific, Atlantic and Indian Oceans. Cold water holds more gas, so this sinking water exports O2 and nutrients, thereby supporting life in the deep sea, as well as soaking up CO2 from the atmosphere. Water from mid-depths at lower latitudes flows in to replace the sinking polar surface water. This brings heat. The poles are cold because they receive the least energy from the sun, and this extreme light climate varies on many different time scales. To us, the current warm, interglacial conditions seem normal, yet such phases have represented only ∼10% of Homo sapiens' existence. Variations in Earth's orbit (so called 'Milankovitch cycles') have driven cyclical alternation of glaciations (ice ages) and warmer interglacials. Despite this, Earth's polar regions have been our planet's most environmentally constant surface regions for several millions of years, with most land ice-covered and much of the ocean seasonally freezing. The two poles have much in common, such as light climate, temperature and water viscosity, winter calm and summer (iceberg and storm) disturbance and resources. However, they are also regions of striking contrasts: the Arctic Ocean is near surrounded by land compared with the Antarctic continent, which is surrounded by the Southern Ocean. Polar oceans contrast in size, age, isolation, depth, oceanography, biology and human factors, such as governance and human habitation. The simplest foodwebs with the smallest residents live on the 1% of Antarctica that is ice free, whilst the largest animals that have ever lived on Earth (Blue and Fin whales) feed in the Arctic and Southern Oceans.


Axon bundle spacing in the anterior cingulate cortex of the human brain.
The anterior cingulate cortex (ACC) is implicated in neuropsychiatric disorders. Post-mortem axon bundle data will be important to complement novel MRI methods for analysing cortical diffusion data. [Jespersen SN, Kroenke CD, Ostergaard L, et al. Modeling dendrite density from magnetic resonance diffusion measurements. Neuroimage. 2007;34:1473-86] Therefore we aimed to assess perimeter, area, density and spacing of axon bundles in BA24 not previously measured in the human ACC using image analysis of 10 microm-thick tangential sections of layer IV in 4 normal patients. Axon bundle mean perimeter was 53.8 microm, mean area was 197.1 microm(2), mean density was 226.3/mm(2), and mean spacing was 73.8 microm. Thus, axon bundles were widely spaced relative to cell body minicolumns and other prelimbic areas. A review of the literature suggests that there is hierarchical regional variation of bundle and column spacing.


Cenozoic evolution of the steppe-desert biome in Central Asia.
The origins and development of the arid and highly seasonal steppe-desert biome in Central Asia, the largest of its kind in the world, remain largely unconstrained by existing records. It is unclear how Cenozoic climatic, geological, and biological forces, acting at diverse spatial and temporal scales, shaped Central Asian ecosystems through time. Our synthesis shows that the Central Asian steppe-desert has existed since at least Eocene times but experienced no less than two regime shifts, one at the Eocene-Oligocene Transition and one in the mid-Miocene. These shifts separated three successive "stable states," each characterized by unique floral and faunal structures. Past responses to disturbance in the Asian steppe-desert imply that modern ecosystems are unlikely to recover their present structures and diversity if forced into a new regime. This is of concern for Asian steppes today, which are being modified for human use and lost to desertification at unprecedented rates.


Influence of endothelin-1 on cholinergic nerve-mediated contractions and acetylcholine release in rat isolated tracheal smooth muscle.
The aim of this study was to assess the influence of endothelin-1 (ET-1) on cholinergic nerve-mediated contractions in rat isolated tracheal smooth muscle by use of electrical-field stimulation (EFS) and [3H]choline efflux studies. EFS (80 V, 0.5 ms, 0.1-30 Hz for 10 s) evoked transient, frequency-dependent contractions of isolated tracheal preparations. Contractions were abolished in the presence of atropine or tetrodotoxin, which suggests they were mediated by acetylcholine (ACh) release from cholinergic nerves. The ETB receptor-selective agonist sarafotoxin S6c (1 nM) augmented EFS (0.6-1 Hz)-induced contractions by 179%. These effects were significantly attenuated in the presence of the ETB receptor-selective antagonist N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl-leucyl-D-1- methoxycarbonyltryptophanyl-D-norleucine (BQ-788; 1 microM). ET-1 (1 nM) also markedly potentiated EFS-induced contractions (153%). This was apparently not a postjunctional effect, because ET-1 did not alter contractile responses to exogenously applied ACh. Cyclo[D-Trp-D-Asp-L-Pro-D-Val-L-Leu] (BQ-123;3 microM) and BQ-788 when used alone, failed to inhibit ET-1-induced potentiation of EFS-evoked contractions. However, in their combined presence, BQ-123 and BQ-788 significantly attenuated ET-1-induced potentiation of EFS responses. EFS (100 V, 0.5 ms, 3 Hz for 2 min) applied to tracheal preparations preloaded with [3H]choline, caused airway smooth muscle contraction and an efflux of radioactivity. Both sarafotoxin S6c (10 nM) and ET-1 (10 nM) significantly enhanced the EFS-induced 3H-efflux and the latter was abolished only in the combined presence of BQ-123 and BQ-788. These data indicated that ET-1 enhances cholinergic nerve-mediated contractions in rat isolated trachea via activation of prejunctional ETA and ETB receptors that were linked to increased ACh release from cholinergic nerves.


Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample.
To establish the prevalence of Fc epsilon RI-beta polymorphisms Leu181 and Leu181/Leu183 on chromosome 11q13 in the general population and to examine whether when maternally inherited they confer a risk of atopy. A population based survey for measures of atopy (skin prick test reactions, specific IgE titres, total serum IgE concentration), bronchial hyperresponsiveness, and carriage of Fc epsilon RI-beta Leu181 and Leu181/Leu183. The rural coastal town of Busselton, Western Australia. 1004 members of 230 two generation families identified through adults aged under 55. Fc epsilon RI-beta Leu181/Leu183 was identified in 45 subjects (4.5%). All 13 children who had inherited the variant maternally were atopic. Six had asthma and nine rhinitis. The odds ratio of a positive skin prick test reaction to house dust mite or grass pollen in these children compared with the other 523 children was 7.37 (95% confidence interval 1.62 to 33.60). The 95% confidence interval for the odds ratio of a positive specific IgE response (radio-allergosorbent test) was 3.00 to infinity, and the odds ratio for bronchial hyperresponsiveness was 3.70 (1.21 to 11.60). By contrast, the eight children who had derived the variant paternally had negative skin prick and radioallergosorbent test results and did not have increased bronchial responsiveness. Fc epsilon RI"' beta Leu181/Leu183 when inherited maternally identifies a genetic risk factor for atopy and bronchial hyperresponsiveness.


Impacts of biodiversity loss escalate through time as redundancy fades.
Plant diversity generally promotes biomass production, but how the shape of the response curve changes with time remains unclear. This is a critical knowledge gap because the shape of this relationship indicates the extent to which loss of the first few species will influence biomass production. Using two long-term (≥13 years) biodiversity experiments, we show that the effects of diversity on biomass productivity increased and became less saturating over time. Our analyses suggest that effects of diversity-dependent ecosystem feedbacks and interspecific complementarity accumulate over time, causing high-diversity species combinations that appeared functionally redundant during early years to become more functionally unique through time. Consequently, simplification of diverse ecosystems will likely have greater negative impacts on ecosystem functioning than has been suggested by short-term experiments.


Functional and Structural Brain Damage in Friedreich's Ataxia.
Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the FXN gene. There is still no cure or quantitative biomarkers reliaby correlating with the progression rate and disease severity. Investigation of functional and structural alterations characterizing white (WM) and gray matter (GM) in FRDA are needed prerequisite to monitor progression and response to treatment. Here we report the results of a multimodal cross-sectional MRI study of FRDA including Voxel-Based Morphometry (VBM), diffusion-tensor imaging (DTI), functional MRI (fMRI), and a correlation analysis with clinical severity scores. Twenty-one early-onset FRDA patients and 18 age-matched healthy controls (HCs) were imaged at 3T. All patients underwent a complete cognitive and clinical assessment with ataxia scales. VBM analysis showed GM volume reduction in FRDA compared to HCs bilaterally in lobules V, VI, VIII (L>R), as well as in the crus of cerebellum, posterior lobe of the vermis, in the flocculi and in the left tonsil. Voxel-wise DTI analysis showed a diffuse fractional anisotropy reduction and mean, radial, axial (AD) diffusivity increase in both infratentorial and supratentorial WM. ROI-based analysis confirmed the results showing differences of the same DTI metrics in cortico-spinal-tracts, forceps major, corpus callosum, posterior thalamic radiations, cerebellar penduncles. Additionally, we observed increased AD in superior (SCP) and middle cerebellar peduncles. The WM findings correlated with age at onset (AAO), short-allelle GAA, and disease severity. The intragroup analysis of fMRI data from right-handed 14 FRDA and 15 HCs showed similar findings in both groups, including activation in M1, insula and superior cerebellar hemisphere (lobules V-VIII). Significant differences emerged only during the non-dominant hand movement, with HCs showing a stronger activation in the left superior cerebellar hemisphere compared to FRDA. Significant correlations were found between AAO and the fMRI activation in cerebellar anterior and posterior lobes, insula and temporal lobe. Our multimodal neuroimaging protocol suggests that MRI is a useful tool to document the extension of the neurological impairment in FRDA.


Phase-dependent filtering of sensory information in the oscillatory olfactory center of a terrestrial mollusk.
With electrophysiological techniques, we found phase-dependent modification of the efficacy of signal transmission in the procerebrum (PC), the oscillatory olfactory center, of the terrestrial mollusk Limax marginatus and elucidated its neuronal mechanism. Previous studies have indicated that about 10(5) PC neurons can be classified into only two types: bursting (B) neurons and nonbursting (NB) neurons, and both types of neurons have ongoing and phase-locked periodic oscillation of their membrane potentials. On olfactory nerve stimulation, excitatory postsynaptic potentials (EPSPs) were evoked with a constant latency in NB neurons, while EPSPs with a variable latency were evoked in B neurons. These findings suggest a monosynaptic connection from the olfactory nerve to NB neurons, but a polysynaptic connection between the olfactory nerve and B neurons. This polysynaptic transmission is most likely mediated by NB neurons because the olfactory nerve makes synaptic connection only with NB neurons in the PC. The latency of the evoked EPSPs in B neurons depended on the phase of the PC oscillatory activity, presumably because of the oscillation of the intervening NB neurons. These results suggest that the efficacy of olfactory nerve-B neuron polysynaptic transmission is regulated by the activity level of the phasically oscillating NB neurons. Thus, the intrinsic oscillation in the PC can serve as a filter for olfactory information conveyed from the olfactory nerve as a train of neuronal spikes. This filtering system may also produce a phase-dependent modification by the olfactory input of the PC oscillation frequency.


Structural Basis for a New Templated Activity by Terminal Deoxynucleotidyl Transferase: Implications for V(D)J Recombination.
Eukaryotic DNA polymerase of the polX family, such as pol μ and terminal deoxynucleotidyl transferase (TdT), are key components of the non-homologous end-joining or V(D)J recombination machinery, respectively. The established role of TdT is to add random nucleotides during V(D)J recombination. Here we show that TdT also has a templated-polymerase activity, similar to pol μ, in the presence of higher concentrations of a downstream DNA duplex, and performs a micro-homology single base-pair search to align the DNA synapsis. To understand the molecular basis of this alignment, we solve crystal structures of TdT with four DNA strands and study the influence of the 3' protruding end. Two mutations in TdT inspired by sequence alignments with pol μ further improve the templated activity. We propose that both templated and untemplated activities of TdT are needed to explain the distributions of lengths of N regions observed experimentally in T cell receptors and antibodies.


Ex vivo bio-compatibility of honey-alginate fibrous matrix for HaCaT and 3T3 with prime molecular expressions.
Honey's inherent compositional diversity, bio-compatibility and time tested therapeutic efficacy, especially in tissue repair as a topical agent, attract researchers towards harnessing its biomaterial potential particularly in developing matrix for tissue engineering applications. Hence, this study fabricates fibrous mat from optimum honey-alginate formulation and alginate solution using wet spinning technology. The physical and morphological properties of the scaffolds are assessed and finally their comparative biological performances are evaluated through in vitro studies on adherence, viability and prime molecular expression of HaCaT and 3T3 cells. The honey-alginate scaffold demonstrates better performance than that of alginate in terms of cellular adherence, viability and proper expression of cell-cell adhesion molecule (E-cadherin) and prime molecules of extra cellular matrix (Collagen I and III) by HaCaT and 3T3 respectively.


Fano feature induced by a bound state in the continuum via resonant state expansion.
We consider light scattering by an anisotropic defect layer embedded into anisotropic photonic crystal in the spectral vicinity of an optical bound state in the continuum (BIC). Using a resonant state expansion method we derive an analytic solution for reflection and transmission amplitudes. The analytic solution is constructed via a perturbative approach with the BIC as the zeroth order approximation. The solution is found to describe the collapsing Fano feature in the spectral vicinity of the BIC. The findings are confirmed via comparison against direct numerical simulations with the Berreman transfer matrix method.


The prevalence of dental caries and gingivitis and their relationship to social class amongst nursery-school children in Nairobi, Kenya.
Four hundred and forty-six children attending nursery schools in Nairobi were examined for caries and gingivitis. Assessment of social class was based on the occupation of the head of the child's household. Amongst 3-year-old children, 62% were caries-free and the mean dmft was 1.35. Amongst 5-year-olds 50% were caries-free and the mean dmft was 1.88. Thirty-seven per cent of the children had evidence of gingivitis, with the proportion changing little with age. There was no evidence of either caries or gingivitis being significantly related to social class, although children in the higher classes had more filled teeth.


Protein arginine methyltransferases interact with intraflagellar transport particles and change location during flagellar growth and resorption.
Changes in protein by posttranslational modifications comprise an important mechanism for the control of many cellular processes. Several flagellar proteins are methylated on arginine residues during flagellar resorption; however, the function is not understood. To learn more about the role of protein methylation during flagellar dynamics, we focused on protein arginine methyltransferases (PRMTs) 1, 3, 5, and 10. These PRMTs localize to the tip of flagella and in a punctate pattern along the length, very similar, but not identical, to that of intraflagellar transport (IFT) components. In addition, we found that PRMT 1 and 3 are also highly enriched at the base of the flagella, and the basal localization of these PRMTs changes during flagellar regeneration and resorption. Proteins with methyl arginine residues are also enriched at the tip and base of flagella, and their localization also changes during flagellar assembly and disassembly. PRMTs are lost from the flagella of fla10-1 cells, which carry a temperature-sensitive mutation in the anterograde motor for IFT. The data define the distribution of specific PRMTs and their target proteins in flagella and demonstrate that PRMTs are cargo for translocation within flagella by the process of IFT.


IS THE WAIST/HEIGHT RATIO A BETTER PARAMETER THAN BMI IN DETERMINING THE CARDIOMETABOLIC RISK PROFILE OF OBESE PEOPLE?
The increased prevalence of obesity has led to a significant increase in the occurrence of metabolic syndrome, a recognized risk factor for increased morbidity and mortality from cardiovascular diseases. Hyperglycemia or type 2 diabetes mellitus, dyslipidemia and arterial hypertension are its main components. Since 2015, international guidelines have recognized the benefits of bariatric surgery in each isolated factor of this syndrome. To evaluate the impact of Roux-en-Y gastric bypass in this syndrome comparing pre- and postoperative periods with laboratory analysis and to compare waist/height ratio and BMI in relation to the determination of the cardiometabolic risk profile. A retrospective study was carried out, selecting 80 patients undergoing Roux-en-Y gastric bypass. Total cholesterol, HDL, LDL, triglycerides, fasting glucose, glycated hemoglobin, insulin, body mass index (BMI), vitamin D, vitamin B12, waist circumference and waist/height ratio in three periods were analyzed: the preoperative period from 1 to 6 months, postoperative from 1 to 6 months and postoperative from 1 to 2 years. There was an improvement in all parameters of the clinical analyses. The preoperative BMI had a mean value of 39.8, in the preoperative period from 1 to 6 months, the values dropped to 33.2 and in the postoperative period of 1 year, the mean was 26. The perimeter mean values of 118.5 preoperatively, 105.2 postoperatively from 1 to 6 months and 90.3 postoperatively from 1 to 2 years. Waist/height ratio was 0.73, 0.65 and 0.56 in pre, post 1 to 6 months and 1 to 2 years respectively. Roux-en-Y gastric bypass improves metabolic syndrome and waist-to-height ratio is superior to BMI in the assessment of the cardiometabolic risk profile.


Low Varicella Zoster Virus Seroprevalence Among Young Children in the Democratic Republic of the Congo.
Varicella zoster virus (VZV) causes both varicella (chickenpox) and herpes zoster (shingles) and is associated with significant global morbidity. Most epidemiological data on VZV come from high-income countries, and to date there are limited data on the burden of VZV in Africa. We assessed the seroprevalence of VZV antibodies among children in the Democratic Republic of Congo in collaboration with the 2013-2014 Demographic and Health Survey. Dried blood spot samples collected from children 6-59 months of age were run on Dynex™ Technologies Multiplier FLEX® chemiluminescent immunoassay platform to assess serologic response. Multivariate logistic regression was then used to determine risk factors for VZV seropositivity. Serologic and survey data were matched for 7,195 children 6-59 months of age, among whom 8% were positive and 2% indeterminate for VZV antibodies in weighted analyses. In multivariate analyses, the odds of seropositivity increased with increasing age, increasing socioeconomic status, mother's education level, rural residence, and province (South Kivu, North Kivu, Bandundu, Bas Congo had the highest odds of a positive test result compared with Kinshasa). Our data suggest that VZV is circulating in DRC, and seropositivity is low among children 6-59 months. Seropositivity increased with age and varied by other sociodemographic factors, such as geographic location. This study provides the first nationally representative estimates of VZV infection among children in the DRC.


Penile vibratory stimulation in the recovery of urinary continence and erectile function after nerve-sparing radical prostatectomy: a randomized, controlled trial.
To examine the effect of penile vibratory stimulation (PVS) in the preservation and restoration of erectile function and urinary continence in conjunction with nerve-sparing radical prostatectomy (RP). The present study was conducted between July 2010 and March 2013 as a randomized prospective trial at two university hospitals. Eligible participants were continent men with an International Index of Erectile Function-5 (IIEF-5) score of at least 18, scheduled to undergo nerve-sparing RP. Patients were randomized to a PVS group or a control group. Patients in the PVS group were instructed in using a PVS device (FERTI CARE(®) vibrator). Stimulation was performed at the frenulum once daily by the patients in their own homes for at least 1 week before surgery. After catheter removal, daily PVS was re-initiated for a period of 6 weeks. Participants were evaluated at 3, 6 and 12 months after surgery with the IIEF-5 questionnaire and questions regarding urinary bother. Patients using up to one pad daily for security reasons only were considered continent. The study was registered at http://clinicaltrials.gov/ (NCT01067261). Data from 68 patients were available for analyses (30 patients randomized to PVS and 38 patients randomized to the control group). The IIEF-5 score was highest in the PVS group at all time points after surgery with a median score of 18 vs 7.5 in the control group at 12 months (P = 0.09), but the difference only reached borderline significance. At 12 months, 16/30 (53%) patients in the PVS group had reached an IIEF-5 score of at least 18, while this was the case for 12/38 (32%) patients in the control group (P = 0.07). There were no significant differences in the proportions of continent patients between groups at 3, 6 or 12 months. At 12 months 90% of the PVS patients were continent, while 94.7% of the control patients were continent (P = 0.46). The present study did not document a significant effect of PVS. However, the method proved to be acceptable for most patients and there was a trend towards better erectile function with PVS. More studies are needed to explore this possible effect further.


Measures of harm reduction service provision for people who inject drugs.
Coverage is an important dimension in measuring the effectiveness of needle and syringe programmes in providing sterile injecting equipment for people who inject drugs. The World Health Organization (WHO), the United Nations Office on Drugs and Crime (UNODC) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) currently recommend methods for measuring coverage at the population level, that is, across an estimated population of people who inject drugs within a given geographical area. However, population-level measures of coverage rely on highly uncertain population estimates and cannot capture the different levels of syringe acquisition and injecting episodes among individual users. Consequently, such measures only broadly evaluate the extent of programme service delivery, rather than describe how people who inject drugs as individuals and sub-groups interact with needle and syringe programmes. In response to these limitations, several researchers have proposed measuring coverage at the individual level, by the percentage of injecting episodes in relation to the number of sterile needles and syringes acquired. These measures evaluate coverage according to each individual's needs. Such measures provide enhanced information for planning and monitoring of harm reduction programmes and have now been used in multiple international research studies. We advise that WHO, UNODC and UNAIDS add individual-level coverage measurement methods to their international monitoring guidelines for harm reduction programmes. By doing this, more responsive and effective programmes can be created to better reduce injecting risk behaviours and blood-borne virus transmission among people who inject drugs.


Short-term low-magnesium diet reduces autoimmune arthritis severity and synovial tissue gene expression.
Magnesium has been suggested to have anti-inflammatory properties in short-term, mostly in vitro studies. To examine the effect of dietary magnesium modifications in arthritis severity and joint damage DA rats were placed on one of three diet regimens before the induction of autoimmune pristane-induced arthritis (PIA): a 4 wk low-magnesium diet, normal diet, and a magnesium-supplemented diet. The diets were switched to a normal diet 14 days after the induction of PIA (typical time of disease onset). Arthritis severity was scored for 38 days, and joints were examined by histology and quantitative PCR for proinflammatory genes. Rats on the low-magnesium diet were significantly and reproducibly protected and had 70% lower median arthritis severity score, with preservation of normal joint histology without erosive changes. Rats on the normal or magnesium-supplemented diets were not protected and developed equally severe and erosive disease. While the dietary modifications were at disease onset (day 14 postinduction), the protective effect of the short-term low-magnesium diet persisted, suggesting a lasting effect on a critical pathogenic pathway. Rats on the low-magnesium diet had significant reduction in synovial tissue expression of IL-6, RORA, and RORC, which are genes required for the development of Th17 T cells. This study revealed a novel role for dietary magnesium in the regulation of autoimmune arthritis and opens new possibilities for the treatment of autoimmune diseases such as rheumatoid arthritis and psoriatic arthritis with short courses of dietary or drug-induced modulations of magnesium levels.


The emerging role of QSOX1 in cancer.
Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme that oxidizes thiols during protein folding, reducing molecular oxygen to hydrogen peroxide. Tumor cells may take advantage of oxidative environments at different stages of tumorigenesis, but QSOX1 may also serve additional functions in tumors. Several groups have reported the over-expression of QSOX1 in breast, pancreas, and prostate cancers. A consensus is building that QSOX1 over-expression is important during tumor cell invasion, facilitating tumor cell migration at the tumor-stroma interface. As such, QSOX1 may be considered a prognostic indicator of metastatic potential or even indicate that cancer is present in a host. However, some controversy exists between QSOX1 as a marker of poor or favorable outcome in breast cancer. More studies are required to reveal what advantage QSOX1 provides to breast and other types of cancer. More specifically, it is critical to learn which tumor types over-express QSOX1 and use its enzymatic activity to their advantage. As interest increases in understanding the mechanisms of tumorigenesis within the extracellular matrix and how tumor cells influence fibroblasts and other stromal cells, QSOX1 may be revealed as an important player in cancer detection and prognosis. Defining the mechanism(s) of QSOX1 activity in tumors and in in vivo models will provide important insights into how to target QSOX1 with anti-neoplastic agents.


The Epstein-Barr virus (EBV) DR enhancer contains two functionally different domains: domain A is constitutive and cell specific, domain B is transactivated by the EBV early protein R.
The Epstein-Barr virus (EBV) DR promoter is located upstream of the PstI repeats, and besides the TATA box, it contains two cis-acting regulatory elements. One of them has enhancer properties. To define more precisely the functional region(s) in the DR enhancer, we generated 5' and 3' deletion mutants. These deletion mutants, which were transfected into various recipient cells of different origins, allowed us to identify two functionally distinct domains, A and B. Domain A was constitutively active in all cell lines tested, except in lymphoid B cells. Domain B was active in lymphoid B cells, and its activity required both EB1 (the BZLF1-encoded EBV trans-acting factor) and the presence of the EBV genome. This suggested that an EBV-encoded, EB1-inducible factor was activating the enhancer B domain. In effect, the B domain was trans-activated by R, an EBV early product encoded by the open reading frame BRLF1, and the activation by R occurred in epithelial, fibroblastic, and lymphoid cells. The R-responsive element has been reduced to 28 base pairs containing the double palindromic sequence TTGTCCCGTGGACAATGTCC. Both domains A and B act by increasing the initiation of specific RNAs.


The expression of arginase-1, keratin (K) 8 and K18 in combined hepatocellular-cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell type.
The WHO classification describes that combined hepatocellular-cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell subtype (CHC-INT) is composed of tumour cells with features intermediate between hepatocytes and cholangiocytes. However, we previously reported that CHC-INT showed a high positive rate of biliary markers, but the expression of hepatocyte paraffin (HepPar)-1 was low. In this study, we examined the expression of other hepatocyte markers, such as arginase-1 (Arg-1), keratin (K) 8 and K18 in CHC-INT in order to examine the utility of pathological diagnosis in CHC-INT. We performed immunohistochemistry (IHC) of Arg-1, K8 and K18 using 32 previously diagnosed as CHC-INT. Immunoreactivity was evaluated with grading from 0 to 4 according to the distribution area of positive cells. The obtained findings of Arg-1, K8 and K18 were compared with those of K7, K19 and HepPar-1. Out of the 32 cases, 22 (68.8%) cases were positive for Arg-1. Twenty-five (78.1%) were positive for K8. The IHC scores of Arg-1 and K8 were significantly higher than those of HepPar-1, but significantly lower than those of K7 and K19. The K18 expression was widely observed in all cases (100%). The IHC score of Arg-1 and K8 in CHC-INT was intermediate between hepatocellular carcinoma and cholangiocarcinoma. Arg-1 and K8 were good markers to identify intermediate cells between hepatocytes and cholangiocytes. These can be useful markers for pathological diagnosis of CHC-INT, which usually has wide histological diversities, in combination with other hepatocytic and/or cholangiocytic markers.


Effect of oxygen tension on chondrocyte extracellular matrix accumulation.
Since cartilage is mainly an avascular tissue, chondrocytes exist in a low-level oxygen environment in vivo. In the present study, we investigated the effect of oxygen tension (20%, 5% and 1% gas phase oxygen concentrations) over a 20-day period on the extracellular matrix accumulation of bovine articular chondrocytes in confluent surface cultures. Matrix accumulation was assessed by the amount of glycosaminoglycan and collagen deposited in the matrix. From initially confluent monolayers, the chondrocytes became distributed throughout a thick layer of extracellular matrix, thus forming a multicell-layer of tissue. Cells maintained their normal rounded shape, indicative of the differentiated phenotype, throughout the 20-day culture period. On a per culture and a per cell basis, the amount of collagen and glycosaminoglycan accumulation in the matrix was lower at the reduced oxygen tensions. Specifically, in 1% oxygen, matrix GAG content reached a steady-state level, with no net increase in GAG levels after two weeks, whereas in 20% oxygen, matrix GAG increased with time. It is concluded that oxygen has a significant effect on the amount of macromolecules accumulated in the extracellular matrix. The implications of these findings in growing cartilage constructs in vitro are discussed.


Use of stable nitrogen isotope signatures of riparian macrophytes as an indicator of anthropogenic N inputs to river ecosystems.
Deterioration of aquatic ecosystems resulting from enhanced anthropogenic N loading has become an issue of increasing concern worldwide, and methods are needed to trace sources of N in rivers. Because nitrate from sewage is enriched in 15N relative to nitrate from natural soils, delta(15)N values of stream nitrate (delta(15)Nnitrate) should be an appropriate index of anthropogenic N loading to rivers, as should the delta(15)N values of riparian plants (delta(15)Nplant) because they are consumers of nitrate. We determined the delta(15)N values of stream nitrate and six species of riparian macrophytes in 31 rivers in the Lake Biwa Basin in Japan. We then tested the correlation between these values and various land-use parameters, including the percentage of land used for residential and agricultural purposes as well as for natural areas. These delta(15)N values were significantly positively correlated with land use (%) that had a high N load (i.e., residential or agricultural use) and significantly negatively correlated with forest (%). These findings indicate that delta(15)N values of stream nitrate and riparian plants might be good indicators of anthropogenic inputs of nitrogen.


Sensitivity and detection limit of concentration and adsorption measurements by laser-induced surface-plasmon resonance.
The shot noise limitation as well as other factors that influence the sensitivity of measurements with a surface plasmon resonance (SPR) sensor are considered. It is demonstrated that minute changes in the refractive index of a medium close to the surface of a metal film can be detected owing to a shift in the resonance angle. In particular, changes in the adsorption layer of only a fraction of a biomolecular monolayer could be measured. Data for SPR are presented with adjacent media of air, water, as well as aqueous solutions of ethanol and sodium chloride at different concentrations. The immobilization of the protein bovine serum albumin to a specially prepared surface was monitored with the SPR technique. Specific responses to changes in the concentration and thickness of the adsorption layer were determined. The angular resolution of the present apparatus is approximately 1 millidegree, corresponding to a detection limit for an adsorbed protein layer of 15 pg/mm(2), which is still 2 to 3 orders of magnitude larger than the shot-noise limit, and therefore a further improvement in sensitivity is possible.


American Burn Association consensus conference to define sepsis and infection in burns.
Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have "systemic inflammatory response syndrome." Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.


Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Determining the pathogenesis and pathophysiology of human NAFLD will allow for evidence-based prevention strategies, and more targeted mechanistic investigations. Various in vivo, ex situ and in vitro models may be utilised to study NAFLD; but all come with their own specific caveats. Here, we review the human-based models and discuss their advantages and limitations in regards to studying the development and progression of NAFLD. Overall, in vivo whole-body human studies are advantageous in that they allow for investigation within the physiological setting, however, limited accessibility to the liver makes direct investigations challenging. Non-invasive imaging techniques are able to somewhat overcome this challenge, whilst the use of stable-isotope tracers enables mechanistic insight to be obtained. Recent technological advances (i.e. normothermic machine perfusion) have opened new opportunities to investigate whole-organ metabolism, thus ex situ livers can be investigated directly. Therefore, investigations that cannot be performed in vivo in humans have the potential to be undertaken. In vitro models offer the ability to perform investigations at a cellular level, aiding in elucidating the molecular mechanisms of NAFLD. However, a number of current models do not closely resemble the human condition and work is ongoing to optimise culturing parameters in order to recapitulate this. In summary, no single model currently provides insight into the development, pathophysiology and progression across the NAFLD spectrum, each experimental model has limitations, which need to be taken into consideration to ensure appropriate conclusions and extrapolation of findings are made.


Autonomic Findings in Takotsubo Cardiomyopathy.
Takotsubo cardiomyopathy (TC) often occurs after emotional or physical stress. Norepinephrine levels are unusually high in the acute phase, suggesting a hyperadrenergic mechanism. Comparatively little is known about parasympathetic function in patients with TC. We sought to characterize autonomic function at rest and in response to physical and emotional stimuli in 10 women with a confirmed history of TC and 10 age-matched healthy women. Sympathetic and parasympathetic activity was assessed at rest and during baroreflex stimulation (Valsalva maneuver and tilt testing), cognitive stimulation (Stroop test), and emotional stimulation (event recall, patients). Ambulatory blood pressure monitoring and measurement of brachial artery flow-mediated vasodilation were also performed. TC women (tested an average of 37 months after the event) had excessive pressor responses to cognitive stress (Stroop test: p <0.001 vs baseline and p = 0.03 vs controls) and emotional arousal (recall of TC event: p = 0.03 vs baseline). Pressor responses to hemodynamic stimuli were also amplified (Valsalva overshoot: p <0.05) and prolonged (duration: p <0.01) in the TC women compared with controls. Plasma catecholamine levels did not differ between TC women and controls. Indexes of parasympathetic (vagal) modulation of heart rate induced by respiration and cardiovagal baroreflex gain were significantly decreased in the TC women versus controls. In conclusion, even long after the initial episode, women with previous episode of TC have excessive sympathetic responsiveness and reduced parasympathetic modulation of heart rate. Impaired baroreflex control may therefore play a role in TC.


Conceptions of decision-making capacity in psychiatry: interviews with Swedish psychiatrists.
Decision-making capacity is a key concept in contemporary healthcare ethics. Previous research has mainly focused on philosophical, conceptual issues or on evaluation of different tools for assessing patients' capacity. The aim of the present study is to investigate how the concept and its normative role are understood in Swedish psychiatric care. Of special interest for present purposes are the relationships between decisional capacity and psychiatric disorders and between health law and practical ethics. Eight in-depth interviews were conducted with Swedish psychiatrists. The interviews were analysed according to descriptive qualitative content analysis in which categories and sub-categories were distilled from the material. Decision-making capacity was seen as dependent on understanding, insight, evaluation, reasoning, and abilities related to making and communicating a choice. However, also the actual content of the decision was held as relevant. There was an ambivalence regarding the relationship between psychiatric disorders and capacity and a tendency to regard psychiatric patients who made unwise treatment decisions as decisionally incapable. However, in cases relating to patients with somatic illnesses, the assumption was rather that patients who made unwise decisions were imprudent but yet decisionally capable. The respondents' conceptions of decision-making capacity were mainly in line with standard theories. However, the idea that capacity also includes aspects relating to the content of the decision clearly deviates from the standard view. The tendency to regard imprudent choices by psychiatric patients as betokening lack of decision-making capacity differs from the view taken of such choices in somatic care. This difference merits further investigations.


Diagnostic biomarkers in murine Cryptosporidiosis: dose- and age-related infection.
Increasing prevalence of Cryptosporidium raises the importance to explore different aspects of its infection. In the absence of reproducible in vitro culturing, animal model is the only experimental method to study Cryptosporidium. Our study evaluated Cryptosporidium infection using coproscopy, copro-antigen and copro-DNA for early detection of murine cryptosporidiosis. Hundred and forty albino mice (neonates and adult) were divided into two groups, control group received sterile PBS solution, and infected groups were inoculated with molecularly characterized Cryptosporidium parvum oocysts and further subdivided into three subgroups for infectious dose response detection. Mice fecal samples were collected every 4 h on the first day and then daily and examined for fecal oocysts, copro-antigen and copro-DNA. Four mice from each subgroup were killed at 12, 24 and 48 h post-infection (P-I), and their intestines were examined for cryptosporidial mucosal DNA. Cryptosporidium copro-antigen and copro-DNA were detected 4 and 8 h P-I in infected neonatal and adult mice, respectively, and intestinal mucosal DNA was detected after 12 h in both. Microscopy was able to detect oocysts 48 h P-I. Inoculated C. parvum oocysts were recovered in feces of infected mice without genotypic changes. Neonate mice showed higher susceptibility for cryptosporidial infection than adults without statistical differences for the given infectious doses. Both copro-immunoassay and copro-nPCR assays can early detect Cryptosporidium infection; however, nPCR was able to identify Cryptosporidium species, making nPCR a reliable biomarker for early detection in murine model.


Prevalence of Low Back and Cervical Back Pain in Military Helicopter Crews: An Underestimated Italian Problem.
Studies have highlighted the incidence and prevalence of chronic pain, which is an epidemic problem in all career sectors, as well as estimated the economic loss that follows its pathology. Several studies have indicated a high incidence of chronic osteoarticular pain in military service members, particularly in flight personnel. To date, no studies have estimated the incidence of pain pathology in the Italian military population, despite the implications related to flight qualification. A survey was conducted on helicopter flight personnel undergoing periodic annual evaluation. A statistically significantly higher incidence of pain pathology than that reported in the global civilian population was demonstrated. More than 80% of the interviewed population reported moderate-to-severe back pain (45% in the lumbar tract and 38% in the cervical tract). Further, it was found that most staff with chronic pain do not use drugs or other treatments for severe pain because of concerns that such treatment approaches may compromise flight qualifications. The present study observed a high incidence of pain in Italian military flight personnel and examined the degree to which this problem is undertreated in these individuals. To address this problem, further in-depth and larger investigations that include therapeutic protocols to resolve such pain pathologies should be conducted. Such investigations could help to reduce pain experienced by flight personnel and enhance the productivity of the Italian military forces while considering the pharmacologic limitations related to the task. Chronic lumbar and neck pain is more common in military helicopter crews than in the civilian population. The true figure is frequently underestimated because of staff concerns regarding the potential influence of therapies on work activity.


Interactive local super-resolution reconstruction of whole-body MRI mouse data: a pilot study with applications to bone and kidney metastases.
In small animal imaging studies, when the locations of the micro-structures of interest are unknown a priori, there is a simultaneous need for full-body coverage and high resolution. In MRI, additional requirements to image contrast and acquisition time will often make it impossible to acquire such images directly. Recently, a resolution enhancing post-processing technique called super-resolution reconstruction (SRR) has been demonstrated to improve visualization and localization of micro-structures in small animal MRI by combining multiple low-resolution acquisitions. However, when the field-of-view is large relative to the desired voxel size, solving the SRR problem becomes very expensive, in terms of both memory requirements and computation time. In this paper we introduce a novel local approach to SRR that aims to overcome the computational problems and allow researchers to efficiently explore both global and local characteristics in whole-body small animal MRI. The method integrates state-of-the-art image processing techniques from the areas of articulated atlas-based segmentation, planar reformation, and SRR. A proof-of-concept is provided with two case studies involving CT, BLI, and MRI data of bone and kidney tumors in a mouse model. We show that local SRR-MRI is a computationally efficient complementary imaging modality for the precise characterization of tumor metastases, and that the method provides a feasible high-resolution alternative to conventional MRI.


Natural occurrence and clastogenic effects of nivalenol, deoxynivalenol, 3-acetyl-deoxynivalenol, 15-acetyl-deoxynivalenol, and zearalenone in corn from a high-risk area of esophageal cancer.
This is the first report of the natural coexistence of a group of Fusarium mycotoxins (nivalenol [NIV], deoxynivalenol [DON], 3-acetyl-deoxynivalenol [3-ADON], 15-acetyl-deoxynivalenol [15-ADON], and zearalenone [ZEN]) in corn from Linxian, China, an area with a high risk of esophageal cancer. Using thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), and gas chromatography (GC), 107 corn samples from Linxian were analyzed. The average levels of NIV and DON were 757 +/- 707 (54-2,760) ng/g and 5,376 +/- 4,460 (360-12,670) ng/g, respectively, with 100% positivity in 24 corn samples consumed as staple food by esophageal cancer patients and their families. Other corn samples collected from five villages in Linxian at different seasons in 1984-1986 also revealed high levels of NIV and DON contamination, with 100% positivity, suggesting that they are consistently and widely present in corn in that area. Levels of 3-ADON and 15-ADON in Linxian corn were 113 +/- 57 and 495 +/- 538 ng/g, respectively. Crude extracts of corn samples collected from esophageal cancer patients' families and the HPLC-purified NIV and DON fractions induced significant chromosome aberrations in V79 cells. Pure toxins of NIV, DON, T-2, and 3-ADON also induced chromosome aberrations in V79 cells at very low concentrations (ng levels/ml medium). Cytotoxic effects were observed at slightly higher concentrations. The levels and kinds of trichothecenes were in positive co-relation with the incidence of esophageal cancer. The data suggest that trichothecenes in food may possibly be associated with esophagitis and esophageal cancer in Linxian.


Prevention of anterior cruciate ligament injuries in soccer. A prospective controlled study of proprioceptive training.
Proprioceptive training has been shown to reduce the incidence of ankle sprains in different sports. It can also improve rehabilitation after anterior cruciate ligament (ACL) injuries whether treated operatively or nonoperatively. Since ACL injuries lead to long absence from sports and are one of the main causes of permanent sports disability, it is essential to try to prevent them. In a prospective controlled study of 600 soccer players in 40 semiprofessional or amateur teams, we studied the possible preventive effect of a gradually increasing proprioceptive training on four different types of wobble-boards during three soccer seasons. Three hundred players were instructed to train 20 min per day with 5 different phases of increasing difficulty. The first phase consisted of balance training without any balance board; phase 2 of training on a rectangular balance board; phase 3 of training on a round board; phase 4 of training on a combined round and rectangular board; phase 5 of training on a so-called BABS board. A control group of 300 players from other, comparable teams trained "normally" and received no special balance training. Both groups were observed for three whole soccer seasons, and possible ACL lesions were diagnosed by clinical examination, KT-1000 measurements, magnetic resonance imaging or computed tomography, and arthroscopy. We found an incidence of 1.15 ACL injuries per team per year in the proprioceptively trained group (P < 0.001). Proprioceptive training can thus significantly reduce the incidence of ACL injuries in soccer players.


CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation.
Oxidative stress from ozone (O(3)) exposure augments airway neutrophil recruitment and chemokine production. We and others have shown that severe and sudden asthma is associated with airway neutrophilia, and that O(3) oxidative stress is likely to augment neutrophilic airway inflammation in severe asthma. However, very little is known about chemokines that orchestrate oxidative stress-induced neutrophilic airway inflammation in vivo. To identify these chemokines, three groups of BALB/c mice were exposed to sham air, 0.2 ppm O(3), or 0.8 ppm O(3) for 6 h. Compared with sham air, 0.8 ppm O(3), but not 0.2 ppm O(3), induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm O(3) up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene-alpha and macrophage-inflammatory protein-2), CXCL10 (IFN-gamma-inducible protein-10), CCL3 (macrophage-inflammatory protein-1alpha), CCL7 (monocyte chemoattractant protein-3), and CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10, CCL3, and CCL7 mRNA was sustained 18 h postexposure. O(3) increased lung protein levels of CXCL10, CCL7, and CCR3 (CCL7R). The airway epithelium was identified as a source of CCL7. The role of up-regulated chemokines was determined by administering control IgG or IgG Abs against six murine chemokines before O(3) exposure. As expected, anti-mouse growth-related oncogene-alpha inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10 also decreased neutrophil recruitment by 63 and 72%, respectively. These findings indicate that CCL7 and CXCL10, two chemokines not previously reported to orchestrate neutrophilic inflammation, play a critical role in mediating oxidative stress-induced neutrophilic airway inflammation. These observations may have relevance in induction of neutrophilia in severe asthma.


Evidence for Viral Interference and Cross-reactive Protective Immunity Between Influenza B Virus Lineages.
Two influenza B virus lineages, B/Victoria and B/Yamagata, cocirculate in the human population. While the lineages are serologically distinct, cross-reactive responses to both lineages have been detected. Viral interference describes the situation whereby infection with one virus limits infection and replication of a second virus. We investigated the potential for viral interference between the influenza B virus lineages. Ferrets were infected and then challenged 3, 10, or 28 days later with pairs of influenza B/Victoria and B/Yamagata viruses. Viral interference occurred at challenge intervals of 3 and 10 days and occasionally at 28 days. At the longer interval, shedding of challenge virus was reduced, and this correlated with cross-reactive interferon γ responses from lymph nodes from virus-infected animals. Viruses from both lineages could prevent or significantly limit subsequent infection with a virus from the other lineage. Coinfections were rare, indicating the potential for reassortment between lineages is limited. These data suggest that innate and cross-reactive immunity mediate viral interference and that this may contribute to the dominance of a specific influenza B virus lineage in any given influenza season. Furthermore, infection with one influenza B virus lineage may be beneficial in protecting against subsequent infection with either influenza B virus lineage.


Hormonal and molecular genetic findings in 46,XX subjects with sexual ambiguity and testicular differentiation.
Ten patients were studied who had sexual ambiguity having in common a 46.XX karyotype and testicular tissue. They were aged from one month to 23 years; some of them were followed through puberty. Eight cases were sporadic and two familial. They were divided into two groups according to finding of surgery and histology: 46, XX males with sexual ambiguity and 46 XX true hermaphrodites (TH). They were no differences in phenotypes (except uterus and ovotestis in TH). The endocrinological data were identical in the two groups: testosterone levels were in the normal range during puberty, then decreased in adulthood. Gonadotrophins were above the normal range at mid-puberty. Gonadal biopsies, regardless of the ovarian part of the ovotestis, were identical in two groups, i.e., normal in the youngest patients, then spermatogonia disappeared afterwards and dysgenesis became obvious. In one case, the ovarian zone of the ovotestis was only detected on serial cuts after gonadectomy. Southern blots displayed the presence of Y specific material in tow cases (PABY-SRY-PO.9). Otherwise, in all other patients, there was the lack of any Y sequences without any differences between the two groups. These data suggests that 46, XX males with sexual ambiguity and 46 XX true hermaphrodites may be alternative expressions of two genetic defects: one, a minimal interchange between Yp and Xp, another, a mutation of an autosomal testis determining factor for the patients without Y detectable material.


Anatomical and functional abnormalities on MRI in kabuki syndrome.
Kabuki syndrome (KS) is a rare congenital disorder (1/32000 births) characterized by distinctive facial features, intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities. In the last decade, mutations in KMT2D and KDM6A were identified as a major cause of kabuki syndrome. Although genetic abnormalities have been highlighted in KS, brain abnormalities have been little explored. Here, we have investigated brain abnormalities in 6 patients with KS (4 males; Mage = 10.96 years, SD = 2.97 years) with KMT2D mutation in comparison with 26 healthy controls (17 males; Mage = 10.31 years, SD = 2.96 years). We have used MRI to explore anatomical and functional brain abnormalities in patients with KS. Anatomical abnormalities in grey matter volume were assessed by cortical and subcortical analyses. Functional abnormalities were assessed by comparing rest cerebral blood flow measured with arterial spin labeling-MRI. When compared to healthy controls, KS patients had anatomical alterations characterized by grey matter decrease localized in the bilateral precentral gyrus and middle frontal gyrus. In addition, KS patients also presented functional alterations characterized by cerebral blood flow decrease in the left precentral gyrus and middle frontal gyrus. Moreover, subcortical analyses revealed significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus in patients with KS. Our results strongly indicate anatomical and functional brain abnormalities in KS. They suggest a possible neural basis of the cognitive symptoms observed in KS, such as fine motor impairment, and indicate the need to further explore the consequences of such brain abnormalities in this disorder. Finally, our results encourage further imaging-genetics studies investigating the link between genetics, anatomical and functional brain alterations in KS.


Sports participation after shoulder replacement surgery.
Return to sports after total hip or knee replacement surgery has been extensively described. However, the return to general sporting activities after shoulder replacement surgery has not been well documented. With improved implant survivorship, patient expectation of function is high. The purpose of this study was to assess the outcome and ability of patients returning to sports after shoulder replacement surgery. Case series; Level of evidence, 4. Seventy-five patients (86 shoulder replacements) who participated in sports or recreational activities before surgery were followed for a minimum of 2 years. Their preoperative and postoperative sports participation and level of competition were assessed. The frequency of their activity, modifications in activity, and length of time it took to resume sports participation after the operation were all reviewed. The mean age at follow-up was 65.5 years (range, 24-88). The average follow-up was 3.7 years (range, 2-9.4). Sixty-four percent of the patients stated that one of the reasons they had the surgery performed was participation in sports. Thirty-four of 48 of these patients (71%) demonstrated an improvement in their ability to play their sport and 50% increased their frequency of participation postoperatively. Softball athletes demonstrated the least favorable return; only 2 of 10 patients returned. Swimming, tennis, and golf were the most popular sports; participants in these sports showed the most favorable improvement and actual return. The mean time to partial return to sports was 3.6 months, and 5.8 months to full participation. Patients are able to successfully return to sports after shoulder arthroplasty. Many returned with improved performance and increased frequency in participation in a timely manner.


The cytoplasmic domain of proEGF negatively regulates motility and elastinolytic activity in thyroid carcinoma cells.
The intracellular domains of the membrane-anchoring regions of some precursors of epidermal growth factor (EGF) family members have intrinsic biologic activities. We have determined the role of the human proEGF cytoplasmic domain (proEGFcyt) as part of the proEGF transmembrane-anchored region (proEGFctF) in the regulation of motility and elastinolytic invasion in human thyroid cancer cells. We found proEGFctF to act as a negative regulator of motility and elastin matrix penetration and the presence of proEGFcyt or proEGF22.23 resulted in a similar reduction in motility and elastinolytic migration. This activity was counteracted by EGF-induced activation of EGF receptor signaling. Decreased elastinolytic migratory activity in the presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with decreased secretion of elastinolytic procathepsin L. The presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with the specific transcriptional up-regulation of t-SNARE member SNAP25. Treatment with siRNA-SNAP25 resulted in motility and elastin migration being restored to normal levels. Epidermal growth factor treatment down-regulated SNAP25 protein by activating EGF receptor-mediated proteasomal degradation of SNAP25. These data provide first evidence for an important function of the cytoplasmic domain of the human proEGF transmembrane region as a novel suppressor of motility and cathepsin L-mediated elastinolytic invasion in human thyroid carcinoma cells and suggest important clinical implications for EGF-expressing tumors.


Accounting for tagging-to-harvest mortality in a Brownie tag-recovery model by incorporating radio-telemetry data.
The Brownie tag-recovery model is useful for estimating harvest rates but assumes all tagged individuals survive to the first hunting season; otherwise, mortality between time of tagging and the hunting season will cause the Brownie estimator to be negatively biased. Alternatively, fitting animals with radio transmitters can be used to accurately estimate harvest rate but may be more costly. We developed a joint model to estimate harvest and annual survival rates that combines known-fate data from animals fitted with transmitters to estimate the probability of surviving the period from capture to the first hunting season, and data from reward-tagged animals in a Brownie tag-recovery model. We evaluated bias and precision of the joint estimator, and how to optimally allocate effort between animals fitted with radio transmitters and inexpensive ear tags or leg bands. Tagging-to-harvest survival rates from >20 individuals with radio transmitters combined with 50-100 reward tags resulted in an unbiased and precise estimator of harvest rates. In addition, the joint model can test whether transmitters affect an individual's probability of being harvested. We illustrate application of the model using data from wild turkey, Meleagris gallapavo, to estimate harvest rates, and data from white-tailed deer, Odocoileus virginianus, to evaluate whether the presence of a visible radio transmitter is related to the probability of a deer being harvested. The joint known-fate tag-recovery model eliminates the requirement to capture and mark animals immediately prior to the hunting season to obtain accurate and precise estimates of harvest rate. In addition, the joint model can assess whether marking animals with radio transmitters affects the individual's probability of being harvested, caused by hunter selectivity or changes in a marked animal's behavior.


Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease.
An imbalance of nephroprotective factors and renal damaging molecules contributes to development and progression of chronic kidney disease (CKD). We investigated associations of renoprotective factor gene expression patterns with CKD severity and outcome. Gene expression profiles of 197 previously reported renoprotective factors were analyzed in a discovery cohort in renal biopsies of 63 CKD patients. Downregulation of dicarbonyl and L-xylulose reductase (DCXR) showed the strongest association with disease progression. This significant association was validated in an independent set of 225 patients with nephrotic syndrome from the multicenter NEPTUNE cohort. Reduced expression of DCXR was significantly associated with degree of histological damage as well as with lower estimated glomerular filtration rate and increased urinary protein levels. DCXR downregulation in CKD was confirmed in 3 publicly available transcriptomics data sets in the context of CKD. Expression of DCXR showed positive correlations to enzymes that are involved in dicarbonyl stress detoxification based on transcriptomics profiles. The sodium glucose cotransporter-2 (SGLT2) inhibitors canagliflozin and empagliflozin showed a beneficial effect on renal proximal tubular cells under diabetic stimuli-enhanced DCXR gene expression. In summary, lower expression of the renoprotective factor DCXR in renal tissue is associated with more severe disease and worse outcome in human CKD.


Congenital Glioblastoma: Lessons Learned from a Rare Case with Unusual Presentation.
Congenital glioblastomas are uncommon tumors of infancy with unique molecular features and usually better prognosis compared to their pediatric and adult counterparts. A 15-day old newborn harboring a congenital glioblastoma undiagnosed at pregnancy presented to our emergencies with rapid neurological deterioration. Radiological investigations revealed an 8 by 9 cm space occupying and enhancing lesion in the left temporoparietooccipital region with intratumoral hemorrhage. The patient was immediately transferred to the operative theater and was operated in a poor condition. Unfortunately he showed no improvement post-operatively and died within two days in the intensive care unit. As such presentation is unique; we present the case and review the relevant literature concerning the potential pitfalls in diagnosis, management strategies and improvements in outcome.


Ginsenoside Rb1 prevents homocysteine-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation.
Hyperhomocystinemia (HHcy) is known as an independent risk factor for cardiovascular disease. Our previous study showed that ginsenoside Rb1, the major active constituent of ginseng, prevents homocysteine (Hcy)-induced endothelial damage. However, the role of ginsenoside Rb1 in Hcy-induced dysfunction in endothelial progenitor cells (EPCs) remains unknown. In the study, we found that ginsenoside Rb1 reversed the Hcy-induced impairment of adhesive and migratory ability in EPCs which were significantly abolished by CXCR4 antagonist AMD3100 and VEGFR2 inhibitor SU5416. Ginsenoside Rb1 significantly reversed Hcy-induced SDF-1 reduction in the supernatant and in the serum. Ginsenoside Rb1 reversed downregulation of SDF-1 and VEGFR2 protein expression, inhibition of p38MAPK phosphorylation induced by Hcy. Re-endothelialization in balloon-injured carotid arteries significantly increased with EPCs transplant, and was even better with Rb1 treatment. This effect was significantly abolished by AMD3100. AMD3100 also decreased the number of CM-DiI labeled EPCs in injured arteries. Here we show for the first time that Rb1 prevents Hcy-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation. These findings demonstrate a novel mechanism of the action of Rb1 that may have value in prevention of HHcy associated cardiovascular disease.


Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS.
Cellular and interpatient heterogeneity and the involvement of different stem and progenitor compartments in leukemogenesis are challenges for the identification of common pathways contributing to the initiation and maintenance of acute myeloid leukemia (AML). Here we used a strategy of parallel transcriptional analysis of phenotypic long-term hematopoietic stem cells (HSCs), short-term HSCs, and granulocyte-monocyte progenitors from individuals with high-risk (-7/7q-) AML and compared them with the corresponding cell populations from healthy controls. This analysis revealed dysregulated expression of 11 genes, including IL-1 receptor accessory protein (IL1RAP), in all leukemic stem and progenitor cell compartments. IL1RAP protein was found to be overexpressed on the surface of HSCs of AML patients, and marked cells with the -7/7q- anomaly. IL1RAP was also overexpressed on HSCs of patients with normal karyotype AML and high-risk myelodysplastic syndrome, suggesting a pervasive role in different disease subtypes. High IL1RAP expression was independently associated with poor overall survival in 3 independent cohorts of AML patients (P = 2.2 × 10(-7)). Knockdown of IL1RAP decreased clonogenicity and increased cell death of AML cells. Our study identified genes dysregulated in stem and progenitor cells in -7/7q- AML, and suggests that IL1RAP may be a promising therapeutic and prognostic target in AML and high-risk myelodysplastic syndrome.


Genetic heterogeneity of diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.


Multiple-wavelength plasmonic nanoantennas.
We propose a type of photonic-plasmonic antennas capable of focusing light into subwavelength focal point(s) at several wavelengths, which are formed by embedding conventional dimer gap or bow-tie nanoantennas into multiple-periodic gratings. Fano-type coupling between localized surface plasmon resonances of dimer antennas and photonic modes in the gratings adds new functionalities, including multiple-wavelength operation and controllable enhancement of the field intensity in the focal point. Multiple-wavelength operation of nanoantennas provides tremendous opportunities for broadband single-molecule fluorescence and Raman sensing, emission enhancement, and near-field imaging.


Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group.
The aging process is associated with gradual and progressive loss of muscle mass along with lowered strength and physical endurance. This condition, sarcopenia, has been widely observed with aging in sedentary adults. Regular aerobic and resistance exercise programs have been shown to counteract most aspects of sarcopenia. In addition, good nutrition, especially adequate protein and energy intake, can help limit and treat age-related declines in muscle mass, strength, and functional abilities. Protein nutrition in combination with exercise is considered optimal for maintaining muscle function. With the goal of providing recommendations for health care professionals to help older adults sustain muscle strength and function into older age, the European Society for Clinical Nutrition and Metabolism (ESPEN) hosted a Workshop on Protein Requirements in the Elderly, held in Dubrovnik on November 24 and 25, 2013. Based on the evidence presented and discussed, the following recommendations are made (a) for healthy older people, the diet should provide at least 1.0-1.2 g protein/kg body weight/day, (b) for older people who are malnourished or at risk of malnutrition because they have acute or chronic illness, the diet should provide 1.2-1.5 g protein/kg body weight/day, with even higher intake for individuals with severe illness or injury, and (c) daily physical activity or exercise (resistance training, aerobic exercise) should be undertaken by all older people, for as long as possible.


The ELBA force field for coarse-grain modeling of lipid membranes.
A new coarse-grain model for molecular dynamics simulation of lipid membranes is presented. Following a simple and conventional approach, lipid molecules are modeled by spherical sites, each representing a group of several atoms. In contrast to common coarse-grain methods, two original (interdependent) features are here adopted. First, the main electrostatics are modeled explicitly by charges and dipoles, which interact realistically through a relative dielectric constant of unity (ε(r) = 1). Second, water molecules are represented individually through a new parametrization of the simple Stockmayer potential for polar fluids; each water molecule is therefore described by a single spherical site embedded with a point dipole. The force field is shown to accurately reproduce the main physical properties of single-species phospholipid bilayers comprising dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylethanolamine (DOPE) in the liquid crystal phase, as well as distearoylphosphatidylcholine (DSPC) in the liquid crystal and gel phases. Insights are presented into fundamental properties and phenomena that can be difficult or impossible to study with alternative computational or experimental methods. For example, we investigate the internal pressure distribution, dipole potential, lipid diffusion, and spontaneous self-assembly. Simulations lasting up to 1.5 microseconds were conducted for systems of different sizes (128, 512 and 1058 lipids); this also allowed us to identify size-dependent artifacts that are expected to affect membrane simulations in general. Future extensions and applications are discussed, particularly in relation to the methodology's inherent multiscale capabilities.


Neural Substrates of Drosophila Larval Anemotaxis.
Animals use sensory information to move toward more favorable conditions. Drosophila larvae can move up or down gradients of odors (chemotax), light (phototax), and temperature (thermotax) by modulating the probability, direction, and size of turns based on sensory input. Whether larvae can anemotax in gradients of mechanosensory cues is unknown. Further, although many of the sensory neurons that mediate taxis have been described, the central circuits are not well understood. Here, we used high-throughput, quantitative behavioral assays to demonstrate Drosophila larvae anemotax in gradients of wind speeds and to characterize the behavioral strategies involved. We found that larvae modulate the probability, direction, and size of turns to move away from higher wind speeds. This suggests that similar central decision-making mechanisms underlie taxis in somatosensory and other sensory modalities. By silencing the activity of single or very few neuron types in a behavioral screen, we found two sensory (chordotonal and multidendritic class III) and six nerve cord neuron types involved in anemotaxis. We reconstructed the identified neurons in an electron microscopy volume that spans the entire larval nervous system and found they received direct input from the mechanosensory neurons or from each other. In this way, we identified local interneurons and first- and second-order subesophageal zone (SEZ) and brain projection neurons. Finally, silencing a dopaminergic brain neuron type impairs anemotaxis. These findings suggest that anemotaxis involves both nerve cord and brain circuits. The candidate neurons and circuitry identified in our study provide a basis for future detailed mechanistic understanding of the circuit principles of anemotaxis.


Impacts of nutrient additions and digging for human waste disposal in natural environments, Tasmania, Australia.
Very little research has been undertaken on the impacts of human toilet waste disposal in non-serviced sites in the wild. The objective of the present project was to determine the relative impacts of the mechanical disturbance of digging during the burial of toilet waste (faeces and toilet paper), and urination, on Tasmanian vegetation types that occur in areas used for wild country camping, in order to develop appropriate guidelines. The mechanical disturbance of digging cat-holes 15 cm deep, typical of those used for toilet disposal in the Tasmanian wild, had largely negative effects on the growth of a few native plant species. These effects were of little or no conservation significance. The nutrient additions simulated by the addition of artificial urine to undug ground and dug ground had largely positive effects on nine distinct types of native vegetation, encouraging the growth of many plant species at many sites, while discouraging the growth of moss at one site. No weed species found at any of the sites were significantly affected by the treatments. Thus, it appears that scattered disposal of urine, even combined with digging, is unlikely to present a major conservation problem in the Tasmania's wild country, and that present guidelines are appropriate, where achievable.


Naturally occurring glycoalkaloids in potatoes aggravate intestinal inflammation in two mouse models of inflammatory bowel disease.
Inflammatory bowel disease (IBD) may be initiated following disruption of the intestinal epithelial barrier. This disruption, in turn, permits luminal antigens unfettered access to the mucosal immune system and leads to an uncontrolled inflammatory response. Glycoalkaloids, which are found in potatoes, disrupt cholesterol-containing membranes such as those of the intestinal epithelium. Glycoalkaloid ingestion through potatoes may play a role in the initiation and/or perpetuation of IBD. To determine if commercial and high glycoalkaloids containing fried potato skins aggravate intestinal inflammation using two different animal models of IBD. Fried potato skins from commercial potatoes containing low/medium glycoalkaloid levels and high glycoalkaloids potatoes were fed for 20 days to interleukin 10 gene-deficient mice and dextran sodium sulfate-induced colitic mice. Intestinal permeability, mucosal cytokine and myeloperoxidase levels and body weight were determined to assess intestinal injury. Deep frying potato skins markedly increased glycoalkaloid content. Interleukin 10 gene-deficient mice fed fried commercial potato skins with medium glycoalkaloid content exhibited significantly elevated levels of ileal IFN-γ relative to controls. Mice in the dextran sodium sulfate colitis model that were fed the same strain of potatoes demonstrated significantly elevated levels of pro-inflammatory cytokines IFN-γ, TNF-α, and IL-17 in the colon in addition to an enhanced colonic permeability. Inflammatory response was intensified when the mice were fed potatoes with higher glycoalkaloid contents. Our results demonstrate that consumption of potato skins containing glycoalkaloids can significantly aggravate intestinal inflammation in predisposed individuals.


Gastrointestinal complications of AIDS: radiologic features.
The radiologic features were examined in a retrospective review of 25 patients with gastrointestinal complications of acquired immunodeficiency syndrome (AIDS). Factors of risk for AIDS present in these patients included homosexuality (n = 10), intravenous drug abuse (n = 7), multiple blood transfusions (n = 1), and unconfirmed or unknown factors (n = 7). Gastrointestinal abnormalities identified on radiologic studies (including upper gastrointestinal, small bowel, and barium enema studies) were correlated with histopathologic specimens and the results of bacteriologic, viral, fungal, and parasitologic studies. The most common disorders (88%) were candidal esophagitis and cytomegaloviral colitis; neoplastic involvement of the gastrointestinal tract was far less common (12%), with only two patients (8%) having Kaposi sarcoma. Gastrointestinal studies, which can provide useful if not always definitive diagnostic information, are recommended to precede more invasive diagnostic studies in evaluating patients with suspected AIDS.


[Characteristics of impaired gas exchange in patients with chronic obstructive pulmonary disease].
Eleven patients with chronic obstructive pulmonary disease (COPD), placed in a supine position, were given a mixture of 0.1% CO and 21% O2 in N2 as inspired gas and normal saline containing the six inert gases including SF6, ethane, cyclopropane, halothane, diethyl ether and acetone via the antecubital vein. After the steady state was established, the expired gas was collected and both arterial and mixed venous blood were simultaneously sampled through the catheter inserted either into the femoral or pulmonary artery. Assuming that mass transfer efficiency of a given indicator gas at each gas exchange unit would be limited by the ratio of ventilation to perfusion (VA/Q) and by that of diffusive conductance to perfusion (G/Q), the data were analyzed by means of a lung model with 20 units along the VA/Q and G/Q axes, respectively. By application of the method of weighted least-squares combined with the idea of constrained optimization, the data were transformed into a virtually continuous distribution of Q against VA/Q and G/Q axes. Analytical results revealed that: 1) patients with advanced COPD show widening of VA/Q distribution accompanied with a significant contribution of either high VA/Q (emphysematous change) or low VA/Q area (peripheral airway involvement). and 2) their Q distributions along the G/Q axis are unimodal but have an area with a relatively low G/Q, indicating a small but appreciable contribution of diffusion limitation to their hypoxemia. In conclusion, the findings consistently suggest that inhomogeneity of G/Q may partly be responsible for the impaired gas exchange in the cases of COPD.


Blood flow reactivity to hypercapnia in strictly unilateral carotid disease: preliminary results.
To show relationship between degree of carotid arterial stenosis and cerebral blood flow reactivity (RES%) to induced hypercapnia, fluorine-18-fluoromethane and positron emission tomography (PET) was used to study 18 patients with carotid distribution transient ischaemic attacks (TIA), all free of stroke, who had angiographic-proven unilateral arterial disease. Non-involved carotid arteries were either normal or had non-stenotic plaque. Either normal arteries or nonstenotic ulcerations in the symptomatic carotid arteries were present in five of 18 (28%), ipsilateral carotid stenosis from 50-99% was present in eight of 18 (44%), and ipsilateral internal carotid occlusion was present in five of 18 (28%) patients. In comparison with 14 normal controls, all patients with symptomatic middle cerebral artery (MCA) flow territories had significantly lower mean (SEM) RES% [5.0' (0.2) vs 4.0 (0.9), p less than 0.04]. Symptomatic anterior borderzone (ABZ) RES% was also significantly lower [4.6 (0.4) vs 3.3 (0.9), p less than 0.04], than controls. In patient subgroup comparisons, the 50-99% stenosis subgroup clearly had the lowest MCA RES% [3.4 (0.2)] as well as the lowest ABZ RES% [2.8 (0.4)] on their symptomatic sides. Age, expired pCO2, mean arterial blood pressure, serum glucose, serum haematocrit and number, type and estimated duration of TIAs were not significantly different between subgroups. Linear regression showed a significant relationship between RES% and both measured percentage-stenosis (p = 0.04) and residual luminal diameter (p = 0.05) in symptomatic MCA territories. This approached significance in symptomatic ABZ regions. This preliminary data set suggests that unilateral carotid stenosis can and does result in impaired CO2 reactivity following hypercapnia. The relative normality of CO2 reactivity in those with carotid occlusion is discussed.


Adverse reactions to contrast material: recognition, prevention, and treatment.
Adverse reactions to contrast agents range from a mild inconvenience, such as itching associated with hives, to a life-threatening emergency. Renal toxicity is a well known adverse reaction associated with the use of intravenous contrast material. Other forms of adverse reactions include delayed allergic reactions, anaphylactic reactions, and local tissue damage. Previous allergic reactions to contrast material, asthma, and allergies are factors associated with an increased risk of developing an adverse reaction. Pretreatment of patients who have such risk factors with a corticosteroid and diphenhydramine decreases the chance of allergic reactions, including anaphylaxis, renal failure, or a possible life-threatening emergency. Awareness of the different types of risk factors and prescreening for their presence allows for early recognition and prompt treatment. Prophylactic treatment before administration of contrast material can prevent potential adverse reactions. If such reactions do occur, prompt recognition allows them to be treated immediately. Using the smallest amount of contrast material possible and low-molecular, nonionic agents also decreases the relative risk of reactions. Renal insufficiency induced by contrast material may be prevented by ensuring adequate hydration and discontinuing other nephrotoxic medications before the procedure. Low-osmolar, nonionic agents are helpful in patients with known conditions associated with adverse reactions.


Proteome analysis of the plasma membrane of Mycobacterium tuberculosis.
The plasma membrane of Mycobacterium tuberculosis is likely to contain proteins that could serve as novel drug targets, diagnostic probes or even components of a vaccine against tuberculosis. With this in mind, we have undertaken proteome analysis of the membrane of M. tuberculosis H37Rv. Isolated membrane vesicles were extracted with either a detergent (Triton X114) or an alkaline buffer (carbonate) following two of the protocols recommended for membrane protein enrichment. Proteins were resolved by 2D-GE using immobilized pH gradient (IPG) strips, and identified by peptide mass mapping utilizing the M. tuberculosis genome database. The two extraction procedures yielded patterns with minimal overlap. Only two proteins, both HSPs, showed a common presence. MALDI-MS analysis of 61 spots led to the identification of 32 proteins, 17 of which were new to the M. tuberculosis proteome database. We classified 19 of the identified proteins as 'membrane-associated'; 14 of these were further classified as 'membrane-bound', three of which were lipoproteins. The remaining proteins included four heat-shock proteins and several enzymes involved in energy or lipid metabolism. Extraction with Triton X114 was found to be more effective than carbonate for detecting 'putative' M. tuberculosis membrane proteins. The protocol was also found to be suitable for comparing BCG and M. tuberculosis membranes, identifying ESAT-6 as being expressed selectively in M. tuberculosis. While this study demonstrates for the first time some of the membrane proteins of M. tuberculosis, it also underscores the problems associated with proteomic analysis of a complex membrane such as that of a mycobacterium.


Evaluation of an Automated Information Extraction Tool for Imaging Data Elements to Populate a Breast Cancer Screening Registry.
Breast cancer screening is central to early breast cancer detection. Identifying and monitoring process measures for screening is a focus of the National Cancer Institute's Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) initiative, which requires participating centers to report structured data across the cancer screening continuum. We evaluate the accuracy of automated information extraction of imaging findings from radiology reports, which are available as unstructured text. We present prevalence estimates of imaging findings for breast imaging received by women who obtained care in a primary care network participating in PROSPR (n = 139,953 radiology reports) and compared automatically extracted data elements to a "gold standard" based on manual review for a validation sample of 941 randomly selected radiology reports, including mammograms, digital breast tomosynthesis, ultrasound, and magnetic resonance imaging (MRI). The prevalence of imaging findings vary by data element and modality (e.g., suspicious calcification noted in 2.6% of screening mammograms, 12.1% of diagnostic mammograms, and 9.4% of tomosynthesis exams). In the validation sample, the accuracy of identifying imaging findings, including suspicious calcifications, masses, and architectural distortion (on mammogram and tomosynthesis); masses, cysts, non-mass enhancement, and enhancing foci (on MRI); and masses and cysts (on ultrasound), range from 0.8 to1.0 for recall, precision, and F-measure. Information extraction tools can be used for accurate documentation of imaging findings as structured data elements from text reports for a variety of breast imaging modalities. These data can be used to populate screening registries to help elucidate more effective breast cancer screening processes.


High-energy diode-pumped D2O-cooled multislab Yb:YAG and Yb:QX-glass lasers.
We investigated the lasing performance of a multislab Yb:QX and Yb:YAG laser amplifiers using a facet-cooled design. Di-deuterium oxide (D2O) was used as the coolant flowing between the active slabs with the pump and laser light passing through the very low absorbing heavy-water films. A square pump profile at a maximum intensity of 40 kW/cm2 drove the amplifier with a peak fluence of 5.5 J/cm2 and a pulse duration of 6 ns. We demonstrated a maximum pulse energy of 1 J for each gain medium as well as a repetition rate of 10 Hz for Yb:YAG and 1 Hz for Yb:QX glass, thus showing the feasibility and scalability of directly water-cooled, diode-pumped, high-energy short-pulse lasers.


Morphological features of trypanosomes from squirrel monkeys from the Brazilian Amazon.
A morphometric analysis of blood trypomastigotes identified as Trypanosoma minasense, T. saimirii, and T. rangeli harbored by squirrel monkeys from the Brazilian Amazon was performed. Additionally, morphological and biological comparative analyses were conducted of T. saimirii-like and T. rangeli development forms from haemoculture and xenodiagnosis. Illustrations are given of blood trypomastigotes as well as of developing flagellates in triatomine and axenic culture. Mean values of blood trypomastigotes of T. saimirii differ statistically from those of T. rangeli in only two out of ten morphological characters measured, and ranges overlapped. The developing forms of T. saimrii-like parasites were essentially identical in both xenodiagnosis and haemoculture to those of T. rangeli. Trypanosomes confirmed as T. rangeli were transmitted to mice by the bites of the great majority of triatomines that fed on T. saimirii-like infected monkeys. We conclude that, based on morphology and on the development in triatomine bugs and haemoculture, T. saimirii should not be considered a distinct species. We therefore propose T. saimirii to be a junior synonym of T. rangeli.


Amyloid-beta 1-40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro.
The population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid-beta (Aβ) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and Aβ1-40 levels in AD patients. We further demonstrate, using in vitro studies, an aggregation-dependent impact of Aβ1-40 on human NG2+ pericytes. Fibril-EP Aβ1-40 exposure reduced pericyte viability and proliferation and increased caspase 3/7 activity. Monomer Aβ1-40 had quite the opposite effect: increased pericyte viability and proliferation and reduced caspase 3/7 activity. Oligomer-EP Aβ1-40 had no impact on either of the cellular events. Our findings add to the growing number of studies suggesting a significant impact on pericytes in the brains of AD patients and suggest different aggregation forms of Aβ1-40 as potential key regulators of the brain pericyte population size.


Use of hepatitis B vaccination for adults with diabetes mellitus: recommendations of the Advisory Committee on Immunization Practices (ACIP).
Hepatitis B virus (HBV) causes acute and chronic infection of the liver leading to substantial morbidity and mortality. In the United States, since 1996, a total of 29 outbreaks of HBV infection in one or multiple long-term-care (LTC) facilities, including nursing homes and assisted-living facilities, were reported to CDC; of these, 25 involved adults with diabetes receiving assisted blood glucose monitoring. These outbreaks prompted the Hepatitis Vaccines Work Group of the Advisory Committee on Immunization Practices (ACIP) to evaluate the risk for HBV infection among all adults with diagnosed diabetes. The Work Group reviewed HBV infection-related morbidity and mortality and the effectiveness of implementing infection prevention and control measures. The strength of scientific evidence regarding protection was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology,* and safety, values, and cost-effectiveness were incorporated into a recommendation using the GRADE system. Based on the Work Group findings, on October 25, 2011, ACIP recommended that all previously unvaccinated adults aged 19 through 59 years with diabetes mellitus (type 1 and type 2) be vaccinated against hepatitis B as soon as possible after a diagnosis of diabetes is made (recommendation category A). Data on the risk for hepatitis B among adults aged ≥60 years are less robust. Therefore, ACIP recommended that unvaccinated adults aged ≥60 years with diabetes may be vaccinated at the discretion of the treating clinician after assessing their risk and the likelihood of an adequate immune response to vaccination (recommendation category B). This report summarizes these recommendations and provides the rationale used by ACIP to inform their decision making.