Determination of alkylphenols in eluates from pyrolysis solid residues using dispersive liquid-liquid microextraction.
Dispersive liquid-liquid microextraction (DLLME) coupled with gas chromatography-mass spectrometry (GC-MS) was applied for the determination of 11 alkylphenols in eluates of chars produced in the co-pyrolysis of different wastes. The optimized DLLME procedure, 4 mL of sample solution, 15 microL of trichloroethylene as extraction solvent, 1 mL of acetone as dispersion solvent and addition of 15% (w/v) of NaCl, was validated. Under the optimum conditions, the enrichment factors were in the range of 82-180. Calibration curves were constructed for each analyte in pure water in the concentration range of 0.5-8 microg/L with correlation coefficients higher than 0.999. The limits of detection were between 0.07 and 0.17 microg/L. The repeatability of the method was evaluated using water samples fortified with the analyte mixture at two concentration levels: the relative standard deviation (RSD) values were between 3.7% and 8.0% for a concentration of 0.5 microg/L, and between 4.2% and 6.4% for a concentration of 3 microg/L. The recoveries of the analytes evaluated by fortification of real eluate samples were in the range of 67.9-97.9% for eluate 1 (obtained from a decontaminated char) and in the range of 61.9-101.4% for eluate 2 (obtained from the untreated char). o-Methylphenol presented low recoveries for both eluates showing a possible matrix effect. The results obtained show that this method is adequate for the determination of alkylphenols in environmental aqueous samples and presents itself as a fast and inexpensive technique, using minor amounts of organic solvents.


Nectin-like molecules/SynCAMs are required for post-crossing commissural axon guidance.
The Necl/SynCAM subgroup of immunoglobulin superfamily cell adhesion molecules has been implicated in late stages of neural circuit formation. They were shown to be sufficient for synaptogenesis by their trans-synaptic interactions. Additionally, they are involved in myelination, both in the central and the peripheral nervous system, by mediating adhesion between glia cells and axons. Here, we show that Necls/SynCAMs are also required for early stages of neural circuit formation. We demonstrate a role for Necls/SynCAMs in post-crossing commissural axon guidance in the developing spinal cord in vivo. Necl3/SynCAM2, the family member that has not been characterized functionally so far, plays a crucial role in this process. It is expressed by floorplate cells and interacts with Necls/SynCAMs expressed by commissural axons to mediate a turning response in post-crossing commissural axons.


The impact of heterogeneity in individual frailty on the dynamics of mortality.
Life table methods are developed for populations whose members differ in their endowment for longevity. Unlike standard methods, which ignore such heterogeneity, these methods use different calculations to construct cohort, period, and individual life tables. The results imply that standard methods overestimate current life expectancy and potential gains in life expectancy from health and safety interventions, while underestimating rates of individual aging, past progress in reducing mortality, and mortality differentials between pairs of populations. Calculations based on Swedish mortality data suggest that these errors may be important, especially in old age.


Association of khat chewing with increased risk of stroke and death in patients presenting with acute coronary syndrome.
To evaluate the prevalence and significance of khat chewing in patients with acute coronary syndrome (ACS). From January 29, 2007, through July 29, 2007, 8176 consecutive patients presenting with ACS were enrolled in a prospective, multicenter study from 6 adjacent Middle Eastern countries. Of the 8176 study patients, 7242 (88.6%) were non-khat chewers, and 934 (11.4%) were khat chewers, mainly of Yemeni origin. Khat chewers were older (57 vs 56 years; P=.01) and more likely to be men (85.7% vs 74.5%) compared with non-khat chewers. Non-khat chewers were more likely to have diabetes mellitus, hypertension, dyslipidemia, obesity, and prior history of coronary artery disease and revascularization. Cigarette smoking was more prevalent in khat chewers, and they were more likely to present greater than 12 hours after onset of symptoms compared with non-khat chewers. At admission, khat chewers had higher heart rate, Killip class, and Global Registry of Acute Coronary Events risk scores. Khat chewers had a significantly higher risk of cardiogenic shock, stroke, and mortality. After adjustment of baseline variables, khat chewing was an independent risk factor for in-hospital mortality (odds ratio, 1.9; 95% confidence interval, 1.3-2.7; P<.001) and stroke (odds ratio, 2.7; 95% confidence interval, 1.3-5.9; P=.01). In this large cohort of patients with ACS, khat chewing was prevalent and was associated with increased risk of stroke and death. In the context of increasing global migration, a greater awareness of potential widespread practices is essential.


Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.
Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.


Three dimensional echocardiographic imaging of multiple recurrent myxomas.
We report a case of a recurrence of 5 cardiac myxomas in both atria with atypical anatomical features difficult to image. Although a multimodality imaging was performed, three-dimensional echocardiography (3DE) was the only technique able to correctly identify all the recurrences and the anatomical characteristics of the myxomas. MRI detected the blood supply of the mass but even after careful review was able to identify only 4 of the 5 lesions. Even though it was already reported the usefulness of 3DE to better delineate the site of attachment of cardiac tumors, it was never reported its sensibility in the setting of multiple myxomas; this case highlights the ability of the 3DE in this challenging scenario and its potential for being considered the key adjunctive modality for the anatomy when advanced surgical plan is required.


Occurrence of antibodies against insect virus proteins in mammals: simple model to differentiate between passive exposure and active virus growth.
Antibodies against an "enterovirus-like" virus of insects, cricket paralysis virus, occur in the sera of domestic animals. When these antibodies were used in combination with the immunoprecipitation of radiolabeled virus proteins from infected Drosophila cells in culture, it could be demonstrated that the animals were exposed to preformed virus.


Interactions of benzodiazepines with warfarin.
Administration of nitrazepam (10 mg nightly), diazepam (15 mg/day), and chlordiazepoxide (15 and 30 mg/day) had no effect on steady-state plasma warfarin concentrations, the plasma half-life of warfarin, or anticoagulant control in patients and it appears safe to prescribe these agents to patients on long-term oral anticoagulants. Urinary excretion of 6 beta-hydroxycortisol, however, increased in two out of five patients given chlordiazepoxide. In rats pretreatment with chlordiazepoxide (40 mg/kg for four days) caused stimulation of liver microsomal enzyme activity but neither diazepam nor nitrazepam had this effect.


Remote sensing of the fram strait marginal ice zone.
Sequential remote sensing images of the Fram Strait marginal ice zone played a key role in elucidating the complex interactions of the atmosphere, ocean, and sea ice. Analysis of a subset of these images covering a 1-week period provided quantitative data on the mesoscale ice morphology, including ice edge positions, ice concentrations, floe size distribution, and ice kinematics. The analysis showed that, under light to moderate wind conditions, the morphology of the marginal ice zone reflects the underlying ocean circulation. High-resolution radar observations showed the location and size of ocean eddies near the ice edge. Ice kinematics from sequential radar images revealed an ocean eddy beneath the interior pack ice that was verified by in situ oceanographic measurements.


Plowing-Induced Structuring of Compliant Surfaces.
The structures produced by a sharp tip scraping a compliant surface are modeled in the illustrative case of scan patterns formed by a series of parallel lines. This is made possible by a modified version of the Prandtl model for stick-slip friction, with an interaction energy landscape replicating the morphology of the evolving surface. As a result, a ripple motif emerges with a tilt angle increasing linearly with the distance between the scan lines, except for the region close to the left boundary of the scanned area, where the ripples are oriented at 90°. This region can penetrate considerably to the right, forming a complex branched pattern. These predictions are substantiated by atomic force microscopy nanolithography experiments on polystyrene surfaces at room temperature. A simple and robust theoretical protocol for reproducing early-stage wear processes (potentially going beyond single contacts) is thus made available.


Astragaloside protects myocardial cells from apoptosis through suppression of the TLR4/NF-κB signaling pathway.
Astragaloside is a monomer isolated from Astragalus membranaceus, a flowering plant in the family Fabaceae. The aim of the present study was to investigate the anti-apoptotic affect of astragaloside on myocardial cells through the TLR4/NF-κB signaling pathway. Astragaloside, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and Toll-like receptor 4 (TLR4) blocking antibody solution were prepared in vitro, and myocardial cells were incubated and cultured in serum-free medium overnight. Cells were divided into five groups: the normal control group, serum-free group, astragaloside group, TLR4 blocking antibody group and NF-κB inhibitor PDTC group. The myocardial cell apoptosis in each group was detected using flow cytometry, and the expression levels of TLR4 and NF-κB were detected via western blotting. The apoptosis rate in the serum-free group was significantly higher than that in the normal control group. The apoptosis rate of myocardial cells in the TLR4 blocking antibody group and NF-κB inhibitor PDTC group was lower than that in the serum-free group. In addition, the myocardial cell apoptosis was more obviously decreased in the astragaloside group, and the protein expression levels of TLR4 and NF-κB in the serum-free group were significantly higher than those in normal control group. The protein expression levels of TLR4 and NF-κB in the astragaloside group were obviously lower than those in the serum-free group, and the protein expression levels of TLR4 and NF-κB in the TLR4 blocking antibody group and NF-κB inhibitor PDTC group were decreased. In conclusion, astragaloside reduced myocardial cell apoptosis and protected myocardial cells, which may be one of the mechanisms of a traditional Chinese medicine monomer in treating heart failure.


Dual energy pulses for Electrical Impedance Spectroscopy with the stochastic Gabor function.
This paper introduces the stochastic Gabor function (SGF), an excitation waveform that can be used to design optimal excitation pulses for Electrical Impedance Spectroscopy (EIS) of the brain. The SGF is a Gaussian function modulated by uniformly distributed noise; it has wide frequency spectrum representation regardless of the stimuli pulse length. The SGF was studied in the time-frequency domain. As shown by frequency concentration measurements, the SGF is least compact in the sample frequency phase plane. Numerical results obtained by using a realistic human head model indicate that the SGF may allow for both shallow and deeper tissue penetration than is currently obtainable with conventional stimulus paradigms, potentially facilitating tissue subtraction assessment of parenchymal dielectric changes in frequency. This could be of value in advancing EIS of stroke and hemorrhage.


Stability and change in mothers' representations of their relationship with their toddlers.
This study examined several issues in the developmental dynamics of parents' representations of their relationship with their toddlers. The authors studied 125 mothers and their firstborn toddler sons over a 13-month period. Mothers took the Parent Development Interview twice, when children were 15 and 28 months of age. Home observations of parent-child interactions and maternal ratings of daily hassles were collected when children were 21 and 27 months of age. The 3 factors that characterized mothers' representations of their 15-month-old firstborn sons (Joy-Pleasure/Coherence, Anger, Guilt-Separation Distress) also fit the data very well for their 28-month-old sons. Although there were no changes in average levels of mothers' (a) joy, pleasure, and coherence and (b) guilt and separation distress from 15 to 28 months, there was a significant increase in mothers' levels of anger. Stability analyses suggested a dynamic relationship between mothers' representations of joy, pleasure, and coherence and of anger over the 13-month period. Finally, changes in mothers' representations were predictable by positive mothering (which led to increased joy, pleasure, and coherence) and by parenting daily hassles (which led to more anger).


Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis.
The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-associated tuberculous meningitis is unknown. We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, per-protocol, and prespecified subgroup analyses. A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration. ISRCTN63659091.


Steroid hormones and neurosteroids in normal and pathological aging of the nervous system.
Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the beta-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to Delta5-androstene-3beta,17beta-diol and to 7alpha-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of beta-amyloid deposits.


The Effect of Cycling Through a Projection-Based Virtual Environment System on Generalized Anxiety Disorder.
Virtual reality (VR) has the potential to help clinical medicine manage generalized anxiety disorder (GAD). However, patients with GAD who use traditional head-mounted VR to cycle may cause them to feel motion sickness and fatigue. To solve this problem, a projection-based virtual environment (VE) system was built to provide GAD patients with a sense of immersion while they are cycling. This projection-based VE system allows patients with GAD to interact with the virtual environment and produce experiences similar to cycling in the outdoors. Sixty GAD patients met several screening criteria and were selected as participants. All participants were randomly assigned to one of the two 20-min conditions: (1) Observing watercolor paintings projected by the projector while engaged in cycling with a stationary bicycle; or (2) observing the scenes (i.e., forest or park) projected by the VE system and engaging in cycling with a stationary bicycle. Finally, this study confirmed that patients with GAD in the projection-based VE group exhibited higher alpha values and lower galvanic skin responses (GSR) after cycling than those cycling in the control group. These results showed that cycling in the projection-based VE group allowed the patient with GAD to achieve higher exercise intensity and lower perceived emotional stress.


Genetic association analysis of 300 genes identifies a risk haplotype in SLC18A2 for post-traumatic stress disorder in two independent samples.
The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N=2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR)=1.4, p=2.1E-05) in SLC18A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC18A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p=0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p=0.049; N=748, men and women). SLC18A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (p<0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects.


Tumorigenicity of green turtle fibropapilloma-derived fibroblast lines in immunodeficient mice.
Fibroblast lines derived from normal skin and spontaneous or experimentally induced fibropapillomas of green turtles (Chelonia mydas) were established and propagated in medium composed of a combination of Dulbecco's minimal essential with F12 medium plus 10% fetal bovine serum at 30 degrees C. Fibropapilloma-derived fibroblasts were indistinguishable from normal skin fibroblasts in vitro. Tumor lines did not exhibit loss of contact inhibition, anchorage independence, or reduced serum requirements. Inoculation of primary and early-passage tumor cells into the medial margin of the pinna of C57BL/6J-nu/nu, C.B17-scid/scid, or NOD-scid/scid mice, however, resulted in fibroma formation, whereas inoculation of normal skin fibroblasts did not. Tumor-derived cells inoculated into the flanks of mice did not form tumors. The turtle origin of fibroblasts in tumors from mouse ears was confirmed by immunohistochemical and karyotype analysis. Fibroblast lines that were established from mouse ear fibromas had the normal karyotype (modal 2N = 55) of C. mydas. The cooler anatomic sites (ears) of immunodeficient mice are useful for confirming the tumorigenic (transformed) phenotype of green turtle fibropapillomatosis-derived fibroblasts. This mouse ear tumorigenicity test should facilitate studies of mechanisms of cellular transformation in green turtle fibropapillomatosis and other neoplastic diseases of poikilothermic vertebrates.


Does recipient age impact functional outcomes of orthotopic heart transplantation?
This study evaluated changes in physical functional performance after orthotopic heart transplantation (OHT) with particular attention to the impact of recipient age on functional outcomes. Retrospective review of all first-time, single-organ adult OHTs in the United States between 2005 and 2010. Patients were primarily stratified by age. The validated Karnofsky performance scale, which ranges from 0 (death) to 100 (fully independent with no evidence of disease and no complaints), was used to measure functional status. A total of 10,049 OHT recipients were identified, with 1,431 (14%) aged 65 years or greater. Mean Karnofsky score prior to OHT was comparable between cohorts (younger: 50.7±25.2 versus older: 50.1±25.0; p=0.38). At a median follow-up of 2.1 years (interquartile range 0.7 to 3.3 years), 64% of OHT recipients had improved functional performance. The mean improvement in Karnofsky score was similar between younger and older patients (19.6±42.0 vs 17.5±41.8; p=0.10). Twenty percent of younger patients were functionally independent prior to OHT, with 67% being functionally independent at last follow-up (p<0.001). Similarly, in the older cohort, 20% were functionally independent prior to OHT, with 66% being functionally independent at last follow-up (p<0.001). Multivariable analysis adjusting for potential confounders confirmed that age, both as a continuous and categoric variable, did not impact odds of functional improvement after OHT. Subanalysis using 70 years as the age cutoff produced similar results. In the modern era, OHT is associated with improvements in functional performance in most recipients, and this beneficial effect is preserved across the age spectrum. These data provide a benchmark for functional outcomes after OHT and may have important implications in organ allocation.


Mirrored feedback in chronic stroke: recruitment and effective connectivity of ipsilesional sensorimotor networks.
Mirrored feedback has potential as a therapeutic intervention to restore hand function after stroke. However, the functional (effective) connectivity of neural networks involved in processing mirrored feedback after stroke is not known. To determine if regions recruited by mirrored feedback topographically overlap with those involved in control of the paretic hand and to identify the effective connectivity of activated nodes within the mirrored feedback network. Fifteen patients with chronic stroke performed a finger flexion task with their unaffected hand during event-related functional magnetic resonance imaging (fMRI). Real-time hand kinematics was recorded during fMRI and used to actuate hand models presented in virtual reality (VR). Visual feedback of the unaffected hand motion was manipulated pseudorandomly by either actuating the VR hand corresponding to the moving unaffected side (veridical feedback) or the affected side (mirrored feedback). In 2 control conditions, the VR hands were replaced with moving nonanthropomorphic shapes. Mirrored feedback was associated with significant activation of regions within and outside the ipsilesional sensorimotor cortex, overlapping with areas engaged when patients performed the task with their affected hand. Effective connectivity analysis showed a significantly interconnected ipsilesional somatosensory and motor cortex in the mirrored feedback condition. Mirrored feedback recruits ipsilesional brain areas relevant for control of the affected hand. These data provide a neurophysiological basis by which mirrored feedback may be beneficial as a therapy for restoring function after stroke.


Intra-operative fluorescence-based detection of positive surgical margins during radical prostatectomy: Lessons learned from a pilot ex vivo translational study.
Nerve-sparing techniques during radical prostatectomy have been associated with an increased risk of positive surgical margins. The intra-operative detection of residual prostatic tissue could help mitigate this risk. The objectives of the present study were to assess the feasibility of using an anti-prostate-specific membrane antigen (anti-PSMA) antibody conjugated with a fluorophore to characterize fresh prostate tissue as prostatic or non-prostatic for intra-operative surgical margin detection. Fresh prostatic tissue samples were collected from transurethral resections of the prostate (TURP) or prostate biopsies, and either immunolabelled with anti-PSMA antibody conjugated with Alexa Fluor 488 or used as controls. A dedicated, laparoscopy-compliant fluorescence device was developed for real-time fluorescence detection. Confocal microscopy was used as the gold standard for comparison. Spectral unmixing was used to distinguish specific, Alexa Fluor 488 fluorescence from nonspecific autofluorescence. The average peak wavelength of the immuno-labeled TURP samples (n = 4) was 541.7 ± 0.9 nm and of the control samples (n = 4) was 540.8 ± 2.2 nm. Spectral unmixing revealed that these similar measures were explained by significant autofluorescence, linked to electrocautery. Three biopsy samples were then obtained from seven patients and also displayed significant nonspecific fluorescence, raising questions regarding the reproducibility of the fixation of the anti-PSMA antibodies on the samples. Comparing the fluorescence results with final pathology proved challenging due to the small sample size and tissue alterations. This study showed similar fluorescence of immuno-labeled prostate tissue samples and controls, failing to demonstrate the feasibility of intra-operative margin detection using PSMA immuno-labeling, due to marked tissue autofluorescence. We successfully developed a fluorescence device that could be used intraoperatively in a laparoscopic setting. Use of the infrared range as well as newly available antibodies could prove interesting options for future research.


t(7;12)(q36;p13) and t(7;12)(q32;p13)--translocations involving ETV6 in children 18 months of age or younger with myeloid disorders.
Our retrospective karyotype review revealed two rare recurrent translocations affecting ETV6 (TEL): t(7;12)(q36;p13) and t(7;12)(q32;p13). Five patients with a t(7;12) were from a group of 125 successfully karyotyped pediatric patients enrolled in consecutive clinical AML trials of the Dutch Childhood Leukemia Study Group over a period of 7 years. During a search of available cytogenetic databases, we found 7q and 12p abnormalities in two additional Dutch patients and in three participants in Pediatric Oncology Group trials. A del(12p) had been initially identified in four of these patients and re-examination of the original karyograms revealed a t(7;12)(q36;p13) in two instances and a probable t(7;12) in the other two. FISH confirmed the presence of a t(7;12)(q36;p13) in the latter. Most (n = 7) also had trisomy 19. The t(7;12)(q36;p13) (n = 9) was more common than the t(7;12)(q32;p13) (n = 1). These subtle translocations were found only in children 18 months of age or younger. A literature search revealed that the t(7;12) with break-points at 7q31-q36 and 12p12-p13 had been reported in six children with myeloid disorders and in two with acute lymphoblastic leukemia; all were 12 months of age or younger. Only two of the 17 for whom survival data were available, were alive after at least 22 months of continuous complete remission. Our findings suggest that ETV6 rearrangements due to a t(7;12) may play an adverse role in myeloid disorders in children 18 months of age or younger. Therefore, children in this age group with myeloid disorders should be screened for both MLL and ETV6 rearrangements.


Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.
Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1β. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1β. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1β was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL-18 and IL-1β) known to be produced by uric acid-activated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression.


YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] inhibits neointima formation in balloon-injured rat carotid through suppression of expressions and activities of matrix metalloproteinases 2 and 9.
Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, and postrevascularization production of vascular smooth muscle cells may play key roles in development of arterial restenosis. We investigated the inhibitory effect of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a benzyl indazole compound, on MMP-2 and MMP-9 activity in a balloon-injury rat carotid artery model. Injury was induced by inserting a balloon catheter through the common carotid artery; after 14 days, histopathological analysis using immunostaining and Western blotting revealed significant restenosis with neointimal formation that was associated with enhanced protein expression of MMP-2 and MMP-9. However, these effects were dose-dependently reduced by orally administered YC-1 (1-10 mg/kg). In addition, gelatin zymography demonstrated that increased MMP-2 and MMP-9 activity was diminished by YC-1 treatment. On the other hand, YC-1 inhibited hydrolysis of the fluorogenic quenching substrate Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH(2) by recombinant MMP-2 and MMP-9 with IC(50) values = 2.07 and 8.20 muM, respectively. Reverse transcription-polymerase chain reaction analysis of MMP-2 and MMP-9 mRNA revealed that YC-1 significantly inhibited mRNA levels of MMPs. Finally, for the YC-1 treatment group, we did not observe elevation of cGMP levels using enzyme-linked immunosorbent assay, suggesting that YC-1 inhibition of neointimal formation is not through a cGMP-elevating pathway. These data show YC-1 suppression of neointimal formation is dependent on its influence on MMP-2 and MMP-9 protein, mRNA expression, and activity, but not through a cGMP-elevating effect. YC-1 shows therapeutic potential for treatment of restenosis after angioplasty.


Differentiation of human embryonal carcinomas in vitro and in vivo reveals expression profiles relevant to normal development.
Embryonal carcinoma is a histologic subgroup of testicular germ cell tumors (TGCTs), and its cells may follow differentiation lineages in a manner similar to early embryogenesis. To acquire new knowledge about the transcriptional programs operating in this tumor development model, we used 22k oligo DNA microarrays to analyze normal and neoplastic tissue samples from human testis. Additionally, retinoic acid-induced in vitro differentiation was studied in relevant cell lines. We identified genes characterizing each of the known histologic subtypes, adding up to a total set of 687 differentially expressed genes. Among these, there was a significant overrepresentation of gene categories, such as genomic imprinting and gene transcripts associated to embryonic stem cells. Selection for genes highly expressed in the undifferentiated embryonal carcinomas resulted in the identification of 58 genes, including pluripotency markers, such as the homeobox genes NANOG and POU5F1 (OCT3/4), as well as GAL, DPPA4, and NALP7. Interestingly, abundant expression of several of the pluripotency genes was also detected in precursor lesions and seminomas. By use of tissue microarrays containing 510 clinical testicular samples, GAL and POU5F1 were up-regulated in TGCT also at the protein level and hence validated as diagnostic markers for undifferentiated tumor cells. The present study shows the unique gene expression profiles of each histologic subtype of TGCT from which we have identified deregulated components in selected processes operating in normal development, such as WNT signaling and DNA methylation.


Modeling the Transmission of Vibrio aestuarianus in Pacific Oysters Using Experimental Infection Data.
Vibrio aestuarianus is a bacterium related to mortality outbreaks in Pacific oysters, Crassostrea gigas, in France, Ireland, and Scotland since 2011. Knowledge about its transmission dynamics is still lacking, impairing guidance to prevent and control the related disease spread. Mathematical modeling is a relevant approach to better understand the determinants of a disease and predict its dynamics in imperfectly observed pathosystems. We developed here the first marine epidemiological model to estimate the key parameters of V. aestuarianus infection at a local scale in a small and closed oyster population under controlled laboratory conditions. Using a compartmental model accounting for free-living bacteria in seawater, we predicted the infection dynamics using dedicated and model-driven collected laboratory experimental transmission data. We estimated parameters and showed that waterborne transmission of V. aestuarianus is possible under experimental conditions, with a basic reproduction number R0 of 2.88 (95% CI: 1.86; 3.35), and a generation time of 5.5 days. Our results highlighted a bacterial dose-dependent transmission of vibriosis at local scale. Global sensitivity analyses indicated that the bacteria shedding rate, the concentration of bacteria in seawater that yields a 50% chance of catching the infection, and the initial bacterial exposure dose W0 were three critical parameters explaining most of the variation in the selected model outputs related to disease spread, i.e., R0, the maximum prevalence, oyster survival curve, and bacteria concentration in seawater. Prevention and control should target the exposure of oysters to bacterial concentration in seawater. This combined laboratory-modeling approach enabled us to maximize the use of information obtained through experiments. The identified key epidemiological parameters should be better refined by further dedicated laboratory experiments. These results revealed the importance of multidisciplinary approaches to gain consistent insights into the marine epidemiology of oyster diseases.


Microbial contamination of multiply used preservative-free artificial tears packed in reclosable containers.
To evaluate microbial contamination of multiply used preservative-free artificial tears packed in reclosable containers after daily use. Subjects were provided with preservative-free artificial tears (Groups 1 and 2) and artificial tears containing a preservative (Group 3). After administration three times or more per 10 h, bottles were collected, and any remaining fluid in the bottles was cultured. A risk factor analysis for microbial contamination was performed by the use of univariate and multivariate analysis. A total of 242 eye-drop bottles were evaluated. Five (2.0%) of the 242 bottles had bacterial contamination. In group 1, four (3.9%) of 102 bottles were contaminated, and identified bacteria were all coagulase-negative Staphylococcus. In group 2, one (1.0%) of 105 bottles was contaminated, and it was a Gram-negative Acinetobacter species. No bottles from group 3 showed any contamination. Based on multivariate analysis, advanced age and fingertip touch were statistically significant risk factors for microbial contamination (p<0.05). Preservative-free artificial tears in reclosable containers are at risk of contamination in a daily and multiple use setting, especially in patients with a poor administering technique, which is associated with fingertip touch and advanced age.


Integrating Social And Medical Data To Improve Population Health: Opportunities And Barriers.
Recent efforts in medical settings to identify social determinants of health have focused primarily on screening for the purpose of improving care for individual patients and getting standardized data into electronic health records (EHRs). Relatively little attention has been given to processes needed to extract data on social determinants of health out of medical records with adequate validity and efficiency to facilitate analysis across individual encounters to inform population health efforts relevant to the health care sector. In this article we describe the rationale for extracting data on social determinants of health from EHRs, including the potential influence of aggregated data on quality improvement activities and health care payment reform. We then discuss opportunities and challenges to pulling these data from EHRs to enable population-level applications, focusing on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, as one potential data aggregation resource. Standardizing methods for extracting data on social determinants of health from EHRs will require understanding current challenges and refining existing translation tools.


Preventing environmental enteric dysfunction through improved water, sanitation and hygiene: an opportunity for stunting reduction in developing countries.
In 2011, one in every four (26%) children under 5 years of age worldwide was stunted. The realization that most stunting cannot be explained by poor diet or by diarrhoea, nor completely reversed by optimized diet and reduced diarrhoea has led to the hypothesis that a primary underlying cause of stunting is subclinical gut disease. Essentially, ingested microbes set in motion two overlapping and interacting pathways that result in linear growth impairment. Firstly, partial villous atrophy results in a reduced absorptive surface area and loss of digestive enzymes. This in turn results in maldigestion and malabsorption of much needed nutrients. Secondly, microbes and their products make the gut leaky, allowing luminal contents to translocate into systemic circulation. This creates a condition of chronic immune activation, which (i) diverts nutrient resources towards the metabolically expensive business of infection fighting rather than growth; (ii) suppresses the growth hormone-IGF axis and inhibits bone growth, leading to growth impairment; and (iii) causes further damage to the intestinal mucosa thereby exacerbating the problem. As such, the unhygienic environments in which infants and young children live and grow must contribute to, if not be the overriding cause of, this environmental enteric dysfunction. We suggest that a package of baby-WASH interventions (sanitation and water improvement, handwashing with soap, ensuring a clean play and infant feeding environment and food hygiene) that interrupt specific pathways through which feco-oral transmission occurs in the first two years of a child's life may be central to global stunting reduction efforts.


[Cholera].
Cholera is an acute intestinal infection that has reached pandemic proportions and presents a major international health concern. Every year, more than 100000 cholera cases and 2000-3000 deaths are officially reported to WHO. The real figures for cholera are thought to be much higher, however, due to underreporting and other limitations of surveillance systems. Cholera is caused by two serogroups (O1 and O139) of a gram-negative bacterium, Vibrio cholerae. Cholera toxins cause a massive outpouring of electrolyte-rich isotonic fluid into the bowel and can lead to volume depletion and shock. In poor sanitary and individual hygiene conditions, the massive release of cholera vibrios into the environment intensifies and exacerbates cholera epidemics, which thus serve as clear markers of poverty and lack of basic sanitation. Rehydration therapy, either intravenous or oral, considerably decreases the number of deaths. The WHO recommends antibiotics for cholera cases with severe dehydration. If left untreated, cholera has a 25-50% mortality rate. Treatment reduces this to less than 1%. Bacteriological diagnosis of cholera is reasonably easy because cholera bacteria are abundant in stool. Epidemics, however, often occur in areas with either limited or no laboratory facilities. A rapid and accurate diagnosis of cholera is essential to mobilize resources for treatment and containment of the epidemic. Therefore, the Pasteur Institute has developed a rapid diagnostic test based on a one-step immunochromatographic technique, which should be commercially available soon. To date, two oral cholera vaccines have been shown to offer good (more than 70%) short-term (one year) protection. WHO recommends these vaccines as an additional public health tool to be implemented with the standard cholera control measures, including provision of safe drinking water and adequate sanitation. Nonetheless, a cholera vaccine that can offer a long-term protection for all age groups, including children younger than five years, is still needed.


Long-term sea-level fluctuations driven by ocean basin dynamics.
Earth's long-term sea-level history is characterized by widespread continental flooding in the Cretaceous period (approximately 145 to 65 million years ago), followed by gradual regression of inland seas. However, published estimates of the Late Cretaceous sea-level high differ by half an order of magnitude, from approximately 40 to approximately 250 meters above the present level. The low estimate is based on the stratigraphy of the New Jersey margin. By assimilating marine geophysical data into reconstructions of ancient ocean basins, we model a Late Cretaceous sea level that is 170 (85 to 270) meters higher than it is today. We use a mantle convection model to suggest that New Jersey subsided by 105 to 180 meters in the past 70 million years because of North America's westward passage over the subducted Farallon plate. This mechanism reconciles New Jersey margin-based sea-level estimates with ocean basin reconstructions.


Perspectives of quantum annealing: methods and implementations.
Quantum annealing is a computing paradigm that has the ambitious goal of efficiently solving large-scale combinatorial optimization problems of practical importance. However, many challenges have yet to be overcome before this goal can be reached. This perspectives article first gives a brief introduction to the concept of quantum annealing, and then highlights new pathways that may clear the way towards feasible and large scale quantum annealing. Moreover, since this field of research is to a strong degree driven by a synergy between experiment and theory, we discuss both in this work. An important focus in this article is on future perspectives, which complements other review articles, and which we hope will motivate further research.


Dermatological manifestations of Down's syndrome.
Down's syndrome (DS) is associated with rare dermatological disorders and increased frequency of some common dermatoses. Owing to advances in medical care and changes in attitude, the median age of death in this population has increased to 49 years, and the life expectancy of a 1-year-old person with DS today is more than 60 years and is likely to improve. With the increase in the number of individuals with DS in the population and an increased life span, dermatologists are more likely to encounter the wide spectrum of dermatological disorders that occurs in these patients. Furthermore, new reports of possible associations are frequent in the literature. The purpose of this article is to discuss the various dermatological conditions that affect DS individuals. A brief overview is given of the new information on genetics and the immunology of DS. We also discuss the molecular mechanisms of premature ageing, to which DS individuals are prone. We review the literature and discuss the known dermatological manifestations, concentrating on recent reports.


Ranibizumab as an adjunct to laser for macular edema secondary to branch retinal vein occlusion.
To compare the safety, efficacy, and dosing regimen of intravitreal ranibizumab as an adjunct to laser therapy for the treatment of macular edema secondary to branch retinal vein occlusion (BRVO). Thirty eyes of 30 patients of BRVO of at least 6 weeks duration were randomized into three groups: Group 1 received grid laser treatment alone, Group 2 received a single dose of intravitreal injection of ranibizumab (0.5 mg / 0.05 ml) followed by grid laser treatment on 7 th day following injection, while Group 3 received three loading doses of intravitreal ranibizumab at monthly interval (i.e. 0, 1, & 2 months) + standard laser treatment 7 days after the 1 st injection. Outcome measure noted at 6 months follow-up were the improvement in best-corrected visual acuity (BCVA) and central macular thickness (CMT). At 6 months follow-up, there was an average gain of 12 letters (P=0.05), 17.5 letters (P=0.05) and 19 letters (P=0.05) in groups 1, 2, and 3, respectively, with the decrease in CMT being 208.7 μm (P=0.05), 312.9 μm (P= 0.05) and 326.8 μm (P=0.05), respectively, in these groups. Gain in BCVA of more than 3 lines was noted in 1/10 patients in Group 1(10%) as compared to 3/10 (30%) and 4/10 (40%) patients in groups 2 and 3, respectively. The gain in BCVA and reduction in CMT were better with combination therapy (single- and triple- dose regimen) compared to grid laser alone. Single dose of intravitreal ranibizumab with grid laser seems to be an effective therapy.


In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope.
Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200-1:300) that is induced by dietary exposure to wheat gliadins (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (alpha1*0501, beta1*0201), which is present in over 90% of CD patients. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge, it has been unclear whether a 'dominant' T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from individual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57-73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56-75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.


Comparative analysis of the alpha-like globin clusters in mouse, rat, and human chromosomes indicates a mechanism underlying breaks in conserved synteny.
We have sequenced and fully annotated a 65,871-bp region of mouse Chromosome 17 including the Hba-ps4 alpha-globin pseudogene. Comparative sequence analysis with the functional alpha-globin loci at human Chromosome 16p13.3 and mouse Chromosome 11 shows that this segment of mouse Chromosome 17 contains a group of three alpha-like pseudogenes (Hba-psm-Hba-ps4-Hba-q3), similar to the duplicated sets found at the functional mouse cluster on Chromosome 11. In addition, exons 7 to 12 of the mLuc7L gene are present just downstream from the pseudogene cluster, indicating that this clone contains the region in which human 16p13.3 switches in synteny between mouse Chromosomes 11 and 17. Comparison of the sequences around the alpha-like clusters on the two mouse chromosomes reveals the presence of conserved tandem repeats. We propose that these repetitive elements have played a role in the fragmentation of the mouse alpha cluster during evolution.


Lack of carboxyl-terminal tyrosine distinguishes the B*2706-bound peptide repertoire from those of B*2704 and other HLA-B27 subtypes associated with ankylosing spondylitis.
B*2704 and B*2706 are two closely related HLA-B27 subtypes, which differ from the common B*2705 by the Asp > Ser77, Val > Glu152, and Ala > Gly211 amino acid changes. In addition, B*2706 differs from B*2704 by the His > Asp114 and Asp > Tyr116 changes. In spite of their similarity B*2704, but not B*2706, was associated to ankylosing spondylitis in a same population. We have carried out pool sequence analyses of the peptides naturally bound to each of these subtypes, and of several individual peptide ligands. B*2704 and B*2706 shared with B*2705, among other features, their selectivity for Arg2 and their allowance for some aliphatic and aromatic C-terminal residues in their bound peptides. The main features that distinguished both subtypes from B*2705 were: 1) their failure to present peptides with C-terminal basic residues, and 2) their allowance for both polar and nonpolar residues at peptide position 3. A major difference between B*2704 and B*2706 was that C-terminal Tyr was prominent among the peptides bound to B*2704, but was not detected among those from B*2706. The use of Tyr as a C-terminal anchor motif is the only functional feature shared by the disease-associated B*2705, B*2702, and B*2704 subtypes that is absent in B*2706. This suggests that the ability of HLA-B27 to present peptides with C-terminal Tyr might be critical for its association to spondyloarthropathy.


Strategies to reduce inappropriate laboratory blood test orders in intensive care are effective and safe: a before-and-after quality improvement study.
Unnecessary pathology tests performed in intensive care units (ICU) might lead to increased costs of care and potential patient harm due to unnecessary phlebotomy. We hypothesised that a multimodal intervention program could result in a safe and effective reduction in the pathology tests ordered in our ICU. We conducted a single-centre pre- and post-study using multimodal interventions to address commonly ordered routine tests. The study was performed during the same six month period (August to February) over three years: 2012 to 2013 (pre-intervention), 2013 to 2014 (intervention) and 2014 to 2015 (post-intervention). Interventions consisted of staff education, designing new pathology forms, consultant-led pathology test ordering and intensive monitoring for a six-month period. The results of the study showed that there was a net savings of over A$213,000 in the intervention period and A$175,000 in the post-intervention period compared to the pre-intervention period. There was a 28% reduction in the tests performed in the intervention period (P <0.0001 compared to pre-intervention period) and 26% in the post-intervention period (P <0.0001 compared to pre-intervention period). There were no ICU or hospital mortality differences between the groups. There were no significant haemoglobin differences between the groups. A multimodal intervention safely reduced pathology test ordering in the ICU, resulting in substantial cost savings.


Testosterone affects language areas of the adult human brain.
Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high-dose hormone application in adult female-to-male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel-based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting-state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone-dependent neuroplastic adaptations in adulthood within language-specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738-1748, 2016. © 2016 Wiley Periodicals, Inc.


Involvement of PrP(C) in kainate-induced excitotoxicity in several mouse strains.
The cellular prion protein (PrP(C)) has been associated with a plethora of cellular functions ranging from cell cycle to neuroprotection. Mice lacking PrP(C) show an increased susceptibility to epileptic seizures; the protein, then, is neuroprotective. However, lack of experimental reproducibility has led to considering the possibility that other factors besides PrP(C) deletion, such as the genetic background of mice or the presence of so-called "Prnp flanking genes", might contribute to the reported susceptibility. Here, we performed a comparative analysis of seizure-susceptibility using characterized Prnp(+/+) and Prnp(0/0) mice of B6129, B6.129, 129/Ola or FVB/N genetic backgrounds. Our study indicates that PrP(C) plays a role in neuroprotection in KA-treated cells and mice. For this function, PrP(C) should contain the aa32-93 region and needs to be linked to the membrane. In addition, some unidentified "Prnp-flanking genes" play a role parallel to PrP(C) in the KA-mediated responses in B6129 and B6.129 Prnp(0/0) mice.


T cell-dendritic cell immunological synapses contain TCR-dependent CD28-CD80 clusters that recruit protein kinase C theta.
Short-lived TCR microclusters and a longer-lived protein kinase Ctheta-focusing central supramolecular activation cluster (cSMAC) have been defined in model immunological synapses (IS). In different model systems, CD28-mediated costimulatory interactions have been detected in microclusters, the cSMAC, or segregated from the TCR forming multiple distinct foci. The relationship between TCR and costimulatory molecules in the physiological IS of T cell-dendritic cell (DC) is obscure. To study the dynamic relationship of CD28-CD80 and TCR interactions in the T cell-DC IS during Ag-specific T cell activation, we generated CD80-eCFP mice using bacterial artificial chromosome transgenic technology. In splenic DCs, endogenous CD80 and CD80-eCFP localized to plasma membrane and Golgi apparatus, and CD80-eCFP was functional in vivo. In the OT-II T cell-DC IS, multiple segregated TCR, CD80, and LFA-1 clusters were detected. In the T cell-DC synapse CD80 clusters were colocalized with CD28 and PKCtheta, a characteristic of the cSMAC. Acute blockade of TCR signaling with anti-MHC Ab resulted in a rapid reduction in Ca(2+) signaling and the number and size of the CD80 clusters, a characteristic of TCR microclusters. Thus, the T cell-DC interface contains dynamic costimulatory foci that share characteristics of microclusters and cSMACs.


Characterization of Mediterranean Durum Wheat for Resistance to Pyrenophora tritici-repentis.
Tan spot (TS), caused by the fugus Pyrenophora tritici-repentis (Ptr), has gained significant importance in the last few years, thereby representing a threat to wheat production in all major wheat-growing regions, including Tunisia. In this context, we evaluated a Mediterranean collection of 549 durum wheat accessions under field conditions for resistance to Ptr over two cropping seasons in Jendouba (Tunisia), a hot spot for Ptr. The relative disease severities showed significant phenotypic variation from resistance to susceptibility. The correlation between disease scores over the two trials was significant, as 50% of the accessions maintained good levels of resistance (resistant-moderately resistant). Seedling and adult-stage reactions were significantly correlated. The ANOVA analysis revealed that the genotype term is highly significant at the adult stage, thus emphasizing the high genetic variability of the tested accessions. Reaction-type comparison among and between countries revealed a high diversity of TS resistance. Plant height (PH) was negatively correlated to disease scores, indicating that PH might either have a significant effect on TS severity or that it can be a potential disease escape trait. The evaluation of this collection allowed for the identification of potential diverse resistance sources to Ptr that can be incorporated in breeding programs.


Somatic Tinnitus.
Modulation of tinnitus characteristics such as pitch and loudness has been extensively described following movements of the head, neck and limbs, vertical or horizontal eye gaze, pressure on myofascial trigger points, cutaneous stimulation of the hands, electrical stimulation of the median nerve, and transcranial direct current stimulation. Modulation of tinnitus follows complex interactions between auditory and somatosensory afferents and can be favored by underlying somatic disorders. When tinnitus appears to be preceded or strictly linked to a somatic disorder, and therefore related to problems of the musculoskeletal system rather than of the ear, it is defined somatic tinnitus. A correct diagnosis and treatment of somatic disorders underlying tinnitus play a central role for a correct management of somatic tinnitus. However, the identification of somatic tinnitus may be complex in some cases. In this paper, after a general review of the current evidences for somatic tinnitus available in the literature, we present and discuss some cases of patients in which somatic modulation of tinnitus played a role-although different from case to case-in their tinnitus, describing the diagnostic and therapeutic approaches followed in each individual case and the results obtained, also highlighting unexpected findings and pitfalls that may be encountered when approaching somatic tinnitus patients.


Acute disseminated encephalomyelitis in 228 patients: A retrospective, multicenter US study.
To analyze the range of demographic, clinical, MRI, and CSF features of acute disseminated encephalomyelitis (ADEM), a rare, typically monophasic demyelinating disorder, and analyze long-term outcomes including time and risk factors for subsequent clinical events as well as competing diagnoses. We performed a retrospective, multicenter study in 4 US academic medical centers of all patients clinically diagnosed with ADEM. Initial presentation of pediatric and adult ADEM and monophasic and multiphasic disease were compared. The Aalen-Johansen estimator was used to produce estimates of the probability of transitioning to a multiphasic diagnosis as a function of time since initial diagnosis, treating death and alternative diagnoses as competing risks. Of 228 patients (122 children, age range 1-72 years, 106 male, median follow-up 24 months [25th-75th percentile 6-67], 7 deaths), approximately one quarter (n = 55, 24%) experienced at least one relapse. Relapsing disease in children was more often diagnosed as multiphasic ADEM than in adults (58% vs 21%, p = 0.007), in whom MS was diagnosed more often. Encephalopathy at initial presentation (hazard ratio [HR] 0.383, p = 0.001), male sex (HR 0.394, p = 0.002), and increasing age at onset (HR 0.984, p = 0.035) were independently associated with a longer time to a demyelinating disease relapse in a multivariable model. In 17 patients, diagnoses other than demyelinating disease were concluded in long-term follow-up. Relapsing disease after ADEM is fairly common and associated with a few potentially predictive features at initial presentation. Age-specific guidelines for ADEM diagnosis and treatment may be valuable, and vigilance for other, mostly rare, diseases is imperative.


The experimental production of combination forms of virus. II. A study of serial passage in the allantoic sac of agents that combine the antigens of two distinct influenza A strains.
Double infection of the allantoic sac with Melbourne and WSN viruses induced the formation of a combination virus, which had some of the antigenic properties of both parents and which maintained itself through serial passage in the chorioallantoic sac. In the course of prolonged passage in the egg, three varieties of combination virus were found. The first (X(1)) occurred in ten passages and was characterized as follows: X(1) was produced in and could be successfully passed from those chick embryos that had received very large inocula of virus. The X(1) hemagglutinin was efficiently inhibited by both M and W antisera. Each passage fluid, containing X(1) as the predominant strain, also contained large amounts of the parent forms M and W. It is very likely that X(1) reverted to parent types of virus at a high rate. The second variety (X(2)) arose from the passage series of X(1) and was carried for approximately 20 passages without definite alteration in its character. It differed from X(1) in that it had the ability to appear as the predominant form occasionally in embryos that had received a limiting infective dilution of virus. Because of this, it seems probable that X(2) reverted to parent types at a slower rate than X(1). Like X(1), this virus was never obtained in pure form and suspensions in which it predominated contained large amounts of M and W, especially the former. Good evidence was obtained that X(2) reverted to M and W virus while multiplying in the chorioallantoic sac. X(3) was derived from passage of X(2) virus after 32 transfers and can be characterized in several ways: (a) X(3) yielded the only X(3) fluids on passage in eggs. This was in striking contrast to X(2) which could not be passed without giving rise to some fluids in which M and W predominated, (b) The X(3) hemagglutinin was weakly inhibited by all but the highest concentrations of M serum, but was strongly inhibited by W serum. X(2) was readily inhibited by relatively small amounts of both sera. (c) X(3) virus, after several passages at limiting dilutions, was neutralized to a highly significant degree by specific M and W sera. This is not necessarily an essential difference from the behavior of X(2) since technical difficulties (large amounts of M and W in X(2) fluids) may have prevented the demonstration of equally striking double neutralization of this virus, (d) After five limiting dilution passages, the X(3) virus retained the characteristics listed under (a) to (c). It is felt that the foregoing facts justify the conclusion that X(3) is a stable virus which combines some of the specific antigens of two parent types.


Epilogue: Early lessons from CAHPS Demonstrations and Evaluations. Consumer Assessment of Health Plans Study.
The Consumer Assessment of Health Plans Study (CAHPS) was developed to provide an integrated set of tested, standardized surveys to obtain meaningful information from health plan enrollees and their experiences. Many organizations began to implement CAHPS in 1997. Formal evaluations of the experiences of three demonstration sites with implementing CAHPS (ie, process evaluations) and the impact of CAHPS on consumer's choices (ie, outcome evaluations) were conducted. This article reports on the early findings and feedback from our process evaluations about the sites' experiences with using CAHPS. Results are presented from the first round demonstration sites, including the lessons learned during the demonstrations. Our plans for future demonstrations and evaluations are included. A similar evaluation design and instruments were used across demonstration sites. The process evaluation to monitor program intervention included on-site interviews, off-site review of documents, and focus groups with consumers. There are 4 early results from the CAHPS demonstrations: (1) the CAHPS survey covers topics of importance to sponsors, is of reasonable length, and can be administered quickly; (2) the report templates are being used effectively, but sponsors vary widely in their preferences for summarizing and presenting CAHPS ratings; (3) standardized or off-the-shelf products are aspects of CAHPS that sponsors value highly, while emphasizing need for further development; and (4) because surveys like CAHPS require multiple within-plan samples to make plan comparisons, they require a substantial investment and may be affordable only for large sponsors. The first round CAHPS demonstrations highlighted the strengths of the integrated surveys and the areas for improving the products and the implementation process.


The biological relevance of a medieval king's DNA.
The discovery of the presumably lost grave of the controversial English king Richard III in Leicester (U.K.) was one of the most important archaeological achievements of the last decennium. The skeleton was identified beyond reasonable doubt, mainly by the match of mitochondrial DNA to that of living maternal relatives, along with the specific archaeological context. Since the genetic genealogical analysis only involved the DNA sequences of a single 15th century individual and a few reference persons, biologists might consider this investigation a mere curiosity. This mini-review shows that the unique context of a historical king's DNA also has relevance for biological research per se - in addition to the more obvious historical, societal and educational value. In the first place, the historical identification appeared to be a renewed forensic case realising a conservative statement with statistical power based on genetic and non-genetic data, including discordant elements. Secondly, the observation of historical non-paternity events within Richard III's patrilineage has given rise to new research questions about potential factors influencing the extra-pair paternity rate in humans and the importance of biological relatedness for the legal recognition of a child in the past. Thirdly, the identification of a named and dated skeleton with the known historical context serves as a reference for bioarchaeological investigations and studies on the spatio-temporal distribution of particular genetic variance. Finally, the Richard III case revealed privacy issues for living relatives which appear to be inherent to any publication of genetic genealogical data.


Specific detection of Campylobacter jejuni using the bacteriophage NCTC 12673 receptor binding protein as a probe.
Campylobacter jejuni is found in the intestines of poultry, cattle, swine, wild birds and pet animals and is the major cause of foodborne gastroenteritis in developed countries. We report the use of the receptor binding protein (RBP) of Campylobacter bacteriophage NCTC 12673 for the specific capture of Campylobacter jejuni bacteria using RBP-derivatized capturing surfaces. The Gp48 RBP was expressed as a glutathione S-transferase-Gp48 (GST-Gp48) fusion protein and immobilized onto surface plasmon resonance (SPR) surfaces using glutathione self-assembled monolayers (GSH SAM). Bovine serum albumin (BSA) was used to block any non-specific binding. Glutathione SAM leads to an oriented attachment of the protein, resulting in a two- to three-fold improvement of bacterial capture when compared to dithiobis(succinimidyl propionate) (DTSP) SAM-based unoriented attachment. The specificity of recognition was confirmed using Salmonella enterica subsp. enterica serovar Typhimurium as a negative control, which indeed showed negligible binding. The detection limit of the RBP-derivatized SPR surfaces was found to be 10(2) cfu/ml. Finally, GST-Gp48 was also immobilized onto magnetic beads that were successfully used to capture and pre-concentrate the host pathogen from suspension.


Molecular characteristics of non-small cell lung cancer.
We used hierarchical clustering to examine gene expression profiles generated by serial analysis of gene expression (SAGE) in a total of nine normal lung epithelial cells and non-small cell lung cancers. Separation of normal and tumor, as well as histopathological subtypes, was evident by using the 3,921 most abundant transcript tags. This distinction remained when only 115 highly differentially expressed tags were used. Furthermore, these 115 transcript tags clustered into groups suggestive of the unique biological and pathological features of the different tissues examined. Adenocarcinomas were characterized by high-level expression of small airway-associated or immunologically related proteins, whereas squamous cell carcinomas overexpressed genes involved in cellular detoxification or antioxidation. The messages of two p53-regulated genes, p21(WAF1/CIP1) and 14-3-3final sigma, were consistently underexpressed in the adenocarcinomas, suggesting that the p53 pathway itself might be compromised in this cancer type. Gene expression patterns observed by SAGE were consistent with results obtained by quantitative real-time PCR or cDNA array analyses by using a total of 43 lung tumor and normal samples. Thus, although derived from only a few tissue libraries, gene expression profiles obtained by using SAGE most likely represent an unbiased yet distinctive molecular signature for the most common forms of human lung cancer.


Predicting the risk of mortality during hospitalization in sick severely malnourished children using daily evaluation of key clinical warning signs.
Despite adherence to WHO guidelines, inpatient mortality among sick children admitted to hospital with complicated severe acute malnutrition (SAM) remains unacceptably high. Several studies have examined risk factors present at admission for mortality. However, risks may evolve during admission with medical and nutritional treatment or deterioration. Currently, no specific guidance exists for assessing daily treatment response. This study aimed to determine the prognostic value of monitoring clinical signs on a daily basis for assessing mortality risk during hospitalization in children with SAM. This is a secondary analysis of data from a randomized trial (NCT02246296) among 843 hospitalized children with SAM. Daily clinical signs were prospectively collected during ward rounds. Multivariable extended Cox regression using backward feature selection was performed to identify daily clinical warning signs (CWS) associated with time to death within the first 21 days of hospitalization. Predictive models were subsequently developed, and their prognostic performance evaluated using Harrell's concordance index (C-index) and time-dependent area under the curve (tAUC). Inpatient case fatality ratio was 16.3% (n=127). The presence of the following CWS during daily assessment were found to be independent predictors of inpatient mortality: symptomatic hypoglycemia, reduced consciousness, chest indrawing, not able to complete feeds, nutritional edema, diarrhea, and fever. Daily risk scores computed using these 7 CWS together with MUAC<10.5cm at admission as additional CWS predict survival outcome of children with SAM with a C-index of 0.81 (95% CI 0.77-0.86). Moreover, counting signs among the top 5 CWS (reduced consciousness, symptomatic hypoglycemia, chest indrawing, not able to complete foods, and MUAC<10.5cm) provided a simpler tool with similar prognostic performance (C-index of 0.79; 95% CI 0.74-0.84). Having 1 or 2 of these CWS on any day during hospitalization was associated with a 3 or 11-fold increased mortality risk compared with no signs, respectively. This study provides evidence for structured monitoring of daily CWS as recommended clinical practice as it improves prediction of inpatient mortality among sick children with complicated SAM. We propose a simple counting-tool to guide healthcare workers to assess treatment response for these children. NCT02246296.


Oxidatively damaged DNA in animals exposed to particles.
Exposure to combustion-derived particles, quartz and asbestos is associated with increased levels of oxidized and mutagenic DNA lesions. The aim of this survey was to critically assess the measurements of oxidatively damaged DNA as marker of particle-induced genotoxicity in animal tissues. Publications based on non-optimal assays of 8-oxo-7,8-dihydroguanine by antibodies and/or unrealistically high levels of 8-oxo-7,8-dihydroguanine (suggesting experimental problems due to spurious oxidation of DNA) reported more induction of DNA damage after exposure to particles than did the publications based on optimal methods. The majority of studies have used single intracavitary administration or inhalation with dose rates exceeding the pulmonary overload threshold, resulting in cytotoxicity and inflammation. It is unclear whether this is relevant for the much lower human exposure levels. Still, there was linear dose-response relationship for 8-oxo-7,8-dihydroguanine in lung tissue without obvious signs of a threshold. The dose-response function was also dependent on chemical composition and other characteristics of the administered particles, whereas dependence on species and strain could not be equivocally determined. Roles of cytotoxicity or inflammation for oxidatively induced DNA damage could not be documented or refuted. Studies on exposure to particles in the gastrointestinal tract showed consistently increased levels of 8-oxo-7,8-dihydroguanine in the liver. Collectively, there is evidence from animal experimental models that both pulmonary and gastrointestinal tract exposure to particles are associated with elevated levels of oxidatively damaged DNA in the lung and internal organs. However, there is a paucity of studies on pulmonary exposure to low doses of particles that are relevant for hazard/risk assessment.


Risk assessment of first-degree relatives of women with breast cancer: a feasibility study.
To measure psychological distress and test the feasibility of a psychological intervention to reduce distress in patients undergoing risk assessment. Descriptive. A comprehensive cancer center located in the southeastern United States. 20 first-degree relatives of women diagnosed with breast cancer (X age = 42; range = 21-70) completed the risk assessment process. Three were lost to follow-up at three months, leaving a total of 17 evaluable patients. Data collection was by means of family/medical history forms and questionnaires administered at baseline and one and three months. Participants were randomized to either a control group consisting of standard education about risk for breast cancer or to an intervention group consisting of standard education plus a psychological intervention designed to teach stress-management skills. Psychological distress, depressive symptoms, intrusive thoughts about breast cancer, and perceived risk for developing breast cancer. Delivery of a psychological intervention proved feasible. Although no statistically significant differences existed between the intervention and control groups on distress and depressive symptoms, the intervention group reported fewer intrusive thoughts about breast cancer at follow-up. Risk did not predict anxiety levels. A large majority (73%) of the women overestimated the risk of breast cancer at baseline. This study demonstrated the feasibility of a multidisciplinary team approach to breast cancer risk assessment and counseling and management of psychological distress in first-degree relatives of women with breast cancer. The data suggest that a psychological intervention may reduce cancer-specific psychological distress in women at increased risk for breast cancer. Oncology nurses can play an important role in the delivery of interventions to educate and reduce distress in women undergoing breast cancer risk assessment.


Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population.
Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis.


Propofol attenuates low-frequency fluctuations of resting-state fMRI BOLD signal in the anterior frontal cortex upon loss of consciousness.
Recent studies indicate that spontaneous low-frequency fluctuations (LFFs) of resting-state functional magnetic resonance imaging (rs-fMRI) blood oxygen level-dependent (BOLD) signals are driven by the slow (<0.1Hz) modulation of ongoing neuronal activity synchronized locally and across remote brain regions. How regional LFFs of the BOLD fMRI signal are altered during anesthetic-induced alteration of consciousness is not well understood. Using rs-fMRI in 15 healthy participants, we show that during administration of propofol to achieve loss of behavioral responsiveness indexing unconsciousness, the fractional amplitude of LFF (fALFF index) was reduced in comparison to wakeful baseline in the anterior frontal regions, temporal pole, hippocampus, parahippocampal gyrus, and amygdala. Such changes were absent in large areas of the motor, parietal, and sensory cortices. During light sedation characterized by the preservation of overt responsiveness and therefore consciousness, fALFF was reduced in the subcortical areas, temporal pole, medial orbital frontal cortex, cingulate cortex, and cerebellum. Between light sedation and deep sedation, fALFF was reduced primarily in the medial and dorsolateral frontal areas. The preferential reduction of LFFs in the anterior frontal regions is consistent with frontal to sensory-motor cortical disconnection and may contribute to the suppression of consciousness during general anesthesia.


Cell-surface markers on haemopoietic precursors. Reagents for the isolation and analysis of progenitor cell subpopulations.
Within the last decade, major advances have been made in the analysis of cell-surface marker expression on haemopoietic progenitor cells as a result of the development of multiparameter cell sorting and monoclonal antibody techniques. Although some controversy exists with regard to the actual identification of the stem cell, markers specific for CFU-s and for particular subsets of progenitor cells have not yet been identified. An analysis of cell-surface markers on haemopoietic progenitor cells is complicated by at least three factors. First, it appears that, in mice, the clonal assays do not adequately identify the haemopoietic stem cell. Complete repopulation of all haemopoietic cell compartments in vivo over an extended period of time appears to be the only reliable method for identifying such a cell. Secondly cell-surface marker distribution on haemopoietic progenitors from normal tissues may be indicative of the cycling status of cells. Thus, expression of markers on progenitors from bone marrow or foetal liver which have been perturbed by drugs or viruses may merely reflect a change in their cycling status following drug or viral insult. Thirdly, substantial loss of cells occurs during the purification of particular cell types. For most cell separation procedures, only a minor proportion of the progenitor cells of interest are recovered and these may not be representative of the progenitor population as a whole. During differentiation to mature cells, antigenic determinants present on early progenitor cells may either be progressively lost or amplified. This differential expression of cell-surface molecules has provided a useful tool for the substantial enrichment of haemopoietic subsets, particularly CFU-E and CFU-s. To date, however, most early haemopoietic progenitor cells detected by in vitro CFC assays (day 8 CFC) cannot be completely segregated from one another. The ability to distinguish between such progenitors during the early stages of lineage commitment would provide a more detailed understanding of the relationship between lymphoid precursors, myeloid precursors and stem cells, and would lead to significant advances in developmental biology. Separation of cells at different stages of differentiation within a given lineage would provide an opportunity for studying regulatory mechanisms involved in gene expression in normal cell populations.


Transcutaneous auricular vagus nerve stimulation (taVNS) for migraine: an fMRI study.
Dysfunction of the thalamocortical connectivity network is thought to underlie the pathophysiology of the migraine. This current study aimed to explore the thalamocortical connectivity changes during 4 weeks of continuous transcutaneous vagus nerve stimulation (taVNS) treatment on migraine patients. 70 migraine patients were recruited and randomized in an equal ratio to receive real taVNS or sham taVNS treatments for 4 weeks. Resting-state functional MRI was collected before and after treatment. The thalamus was parceled into functional regions of interest (ROIs) on the basis of six priori-defined cortical ROIs covering the entire cortex. Seed-based functional connectivity analysis between each thalamic subregion and the whole brain was further compared across groups after treatment. Of the 59 patients that finished the study, those in the taVNS group had significantly reduced number of migraine days, pain intensity and migraine attack times after 4 weeks of treatment compared with the sham taVNS. Functional connectivity analysis revealed that taVNS can increase the connectivity between the motor-related thalamus subregion and anterior cingulate cortex/medial prefrontal cortex, and decrease the connectivity between occipital cortex-related thalamus subregion and postcentral gyrus/precuneus. Our findings suggest that taVNS can relieve the symptoms of headache as well as modulate the thalamocortical circuits in migraine patients. The results provide insights into the neural mechanism of taVNS and reveal potential therapeutic targets for migraine patients.


Effects of age on ocular anterior segment dimensions measured by optical coherence tomography.
Older subjects tend to have smaller ocular anterior segment. The present study aimed to measure anterior segment dimensions with optical coherence tomography (OCT) and quantitatively assess the effect of age and other factors. Anterior segment OCT images were obtained in normal subjects residing in the greater Los Angeles area. Four line scans were acquired at the 90°, 45°, 0° and 135° meridians of each eye. Computer calipers acquired anterior segment dimensions of corneal diameter, anterior chamber width, corneal vault and anterior chamber depth on OCT images. Measurements from 4 meridians were averaged. Axial length and corneal power were measured by partial coherence interferometry. Univariate and multivariate analyses were performed to assess correlations. Sixty-six eyes of 33 normal subjects (aged 22 - 65 years, 19 Asians, 14 Caucasians) were enrolled. For every 1 year of age, corneal diameter was 0.033 mm narrower (P < 0.01), anterior chamber width was 0.031 mm narrower (P < 0.01), corneal vault was 0.016 mm lower (P < 0.01), and anterior chamber depth was 0.025 mm lower (P < 0.01). Asian eyes had smaller corneal diameter (P = 0.035) and anterior chamber width (P = 0.015) compared with those of Caucasian eyes. Body height showed positive correlation with corneal diameter (0.039 mm per centimeter of height, P < 0.01) and corneal vault (0.024 mm per centimetre of height, P < 0.01). Gender did not have an independent effect on anterior segment dimensions. Anterior segment dimensions were smaller in older subjects. Age-related changes may affect the tolerability of long-term implants such as phakic intraocular lens.


The role of imams in American Muslim health: perspectives of Muslim community leaders in Southeast Michigan.
American Muslims are a diverse and growing population, numbering nearly 200,000 in Southeast Michigan. Little empirical work exists on the influence of Islam upon the healthcare behaviors of American Muslims, and there is to date limited research on the roles that imams, Muslim religious leaders, play in the health of this community. Utilizing a community-based participatory research (CBPR) model through collaboration with four key community organizations, we conducted semi-structured interviews with 12 community leaders and explored their perceptions about the roles imams play in community health. Respondents identified four central roles for imams in healthcare: (1) encouraging healthy behaviors through scripture-based messages in sermons; (2) performing religious rituals around life events and illnesses; (3) advocating for Muslim patients and delivering cultural sensitivity training in hospitals; and (4) assisting in healthcare decisions for Muslims. Our analysis also suggests several challenges for imams stemming from medical uncertainty and ethical conflicts. Imams play key roles in framing concepts of health and disease and encouraging healthy lifestyles outside of the healthcare system, as well as advocating for Muslim patient needs and aiding in healthcare decisions within the hospital. Healthcare partnerships with these religious leaders and their institutions may be an important means to enhance the health of American Muslims.


Head injury in mixed martial arts: a review of epidemiology, affected brain structures and risks of cognitive decline.
Background: The popularity trend of mixed martial arts (MMA) is steeply increasing, especially in the very young population. Unfortunately, MMA carries an enormous risk of head trauma.Purpose: The aim of this article is to provide review of studies on the association between head injuries and cognitive functions in MMA fighters.Methods: A systematic literature review was performed. Web of Science, PubMed, Springer, and Scopus databases were used. A total of 30 studies were identified. The inclusion criteria were as follows: studies with MMA fighters and head injuries and/or TKO/KO and/or reduction of cognitive functions in these fighters.Results: The results indicate that the incidence of head traumas ranges between 58% and 78% of all injuries. The King-Devick test seems to be a suitable rapid tool used in the studies to assess the extent of cognitive impairment. Among the detected studies, the post-fighting scores were significantly worse for fighters with head trauma during the match. We also found anomalies in MMA fighters in different brain structures, but it seems that the thalamus and caudate are the most affected. The impaired performance in processing speed, verbal memory and psychomotor speed is regularly confirmed in studies with MMA fighters. In addition, head traumatization seems to be a risk factor for the development of neurodegenerative disorders and it may be one of the possible causes of chronic traumatic encephalopathy (CTE). Several global medical societies have identified MMA as a violent and dangerous sport and have called for its ban - but unsuccessfully.Conclusion: Therefore, possible recommendations should include increased medical supervision of the fighter (during his career, but also after it) and the introduction of practical safety instructions for fighters to reduce the risk of developing CTE. With the increasing popularity of MMA, the risk of CTE should not be underestimated.


Development of a Management Algorithm for Post-operative Pain (MAPP) after total knee and total hip replacement: study rationale and design.
Evidence from clinical practice and the extant literature suggests that post-operative pain assessment and treatment is often suboptimal. Poor pain management is likely to persist until pain management practices become consistent with guidelines developed from the best available scientific evidence. This work will address the priority in healthcare of improving the quality of pain management by standardising evidence-based care processes through the incorporation of an algorithm derived from best evidence into clinical practice. In this paper, the methodology for the creation and implementation of such an algorithm that will focus, in the first instance, on patients who have undergone total hip or knee replacement is described. In partnership with clinicians, and based on best available evidence, the aim of the Management Algorithm for Post-operative Pain (MAPP) project is to develop, implement, and evaluate an algorithm designed to support pain management decision-making for patients after orthopaedic surgery. The algorithm will provide guidance for the prescription and administration of multimodal analgesics in the post-operative period, and the treatment of breakthrough pain. The MAPP project is a multisite study with one coordinating hospital and two supporting (rollout) hospitals. The design of this project is a pre-implementation-post-implementation evaluation and will be conducted over three phases. The Promoting Action on Research Implementation in Health Services (PARiHS) framework will be used to guide implementation. Outcome measurements will be taken 10 weeks post-implementation of the MAPP. The primary outcomes are: proportion of patients prescribed multimodal analgesics in accordance with the MAPP; and proportion of patients with moderate to severe pain intensity at rest. These data will be compared to the pre-implementation analgesic prescribing practices and pain outcome measures. A secondary outcome, the efficacy of the MAPP, will be measured by comparing pain intensity scores of patients where the MAPP guidelines were or were not followed. The outcomes of this study have relevance for nursing and medical professionals as well as informing health service evaluation. In establishing a framework for the sustainable implementation and evaluation of a standardised approach to post-operative pain management, the findings have implications for clinicians and patients within multiple surgical contexts.


Soy Isoflavones and Osteoporotic Bone Loss: A Review with an Emphasis on Modulation of Bone Remodeling.
Osteoporosis is an age-related disorder that affects both women and men, although estrogen deficiency induced by menopause accelerates bone loss in older women. As the demographic shifts to a more aged population, a growing number of men and women will be afflicted with osteoporosis. Since the current drug therapies available have multiple side effects, including increased risk of developing certain types of cancer or complications, a search for potential nonpharmacologic alternative therapies for osteoporosis is of prime interest. Soy isoflavones (SI) have demonstrated potential bone-specific effects in a number of studies. This article provides a systematic review of studies on osteoporotic bone loss in relation to SI intake from diet or supplements to comprehensively explain how SI affect the modulation of bone remodeling. Evidence from epidemiologic studies supports that dietary SI attenuate menopause-induced osteoporotic bone loss by decreasing bone resorption and stimulating bone formation. Other studies have also illustrated that bone site-specific trophic and synergistic effects combined with exercise intervention might contribute to improve the bioavailability of SI or strengthen the bone-specific effects. To date, however, the effects of dietary SI on osteoporotic bone loss remain inconclusive, and study results vary from study to study. The current review will discuss the potential factors that result in the conflicting outcomes of these studies, including dosages, intervention materials, study duration, race, and genetic differences. Further well-designed studies are needed to fully understand the underlying mechanism and evaluate the effects of SI on osteoporosis in humans.