Household income, fetal size and birth weight: an analysis of eight populations.
The age at onset of the association between poverty and poor health is not understood. Our hypothesis was that individuals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth. Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage individual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis. The eight cohorts included 21 714 individuals. In the two-stage (cross-sectional) IPD analysis, individuals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for individuals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model. The association between HI, an index of poverty, and fetal size is already present in the second trimester.


Determination of Salicylic Acid in Feed Using LC-MS/MS.
Salicylic acid is a derivative of benzoic acid and occurs in nature. The main target of this study was to develop the liquid chromatography coupled with tandem mass spectrometry technique as a method for determination of salicylic acid in feed materials and compound feed. Salicylic acid was extracted from feed with 0.1% hydrochloric acid in methanol. Separation was achieved in 8 min in a gradient elution using 0.1% formic acid and acetonitrile. The analyte was detected using negative electrospray tandem mass spectrometry. The procedure was validated to the specifications of the European Commission Decision No. 2002/657/EC. The validation results showed the repeatability of the method, which was evaluated at three levels (0.25, 0.5, and 1.0 mg/kg). Calibration curves for the working ranges were linear (R2 0.9911 to 0.9936), and recoveries ranged from 98.3% to 101%. The LOD and LOQ for compound feed were 0.02 and 0.05 mg/kg, respectively. Salicylic acid was found mostly in corn, and its concentrations differed depending on whether it was young or fully grown (5.30-12.8 mg/kg and 0.13-1.01 mg/kg, respectively). A sensitive and reliable method for the determination of salicylic acid in feed and compound feed using LC-MS/MS was developed.


Prevalence of protein-energy wasting syndrome and its association with mortality in haemodialysis patients in a centre in Spain.
Malnutrition has been described in patients with chronic kidney disease as well as its association with cardiovascular risk and mortality in haemodialysis patients. Recently, the new term "protein energy wasting" has been proposed with new diagnostic criteria (biochemical and anthropometric markers) for early identification of patients at risk for protein energy wasting and mortality. The aim of this study was to examine the prevalence, evolution over time and prognostic significance of PEW in a Spanish dialysis centre for the first time in Spain. an observational study that included 122 prevalent haemodialysis patients at our centre. Between January 2010 and October 2012, three visits were carried out in which clinical, biochemical, anthropometric and body composition parameters were collected using BIS (bioelectrical impedance spectroscopy) along with their respective dialytic characteristics, in accordance with the criteria of the new definition. We analysed the prevalence of PEW in each visit, progression of the malnutrition parameters and factors potentially associated with PEW. After a mean follow-up period of 461 days, we analysed survival. Statistical analysis was performed using the R software. The prevalence of PEW remained constant over time: 37% at baseline visit, 40.5% at 12 months and 41.1% at 24 months. With the introduction of the dynamic variable muscle mass loss, included in the definition of PEW, prevalence increased to 50% at 24 months. The PEW situation is dynamic, as demonstrated by the fact that 26%-36% of patients without PEW develop it de novo each year and 12%-30% annually recover from this situation. The presence of PEW was associated with higher rates of resistance to erythropoietin (irEPO) and higher pulse pressure at the end of dialysis. In the multivariable regression model, PEW predictive clinical variables were over-hydration, irEPO, intracellular water and the extracellular water/intracellular water ratio. Twenty-six (21%) patients died. The Kaplan-Meier curve did not show any differences in mortality risk between patients with and those without PEW, but the loss of muscle mass was associated with increased mortality. The present observational study highlights the high prevalence of PEW, which has a dynamic nature in haemodialysis patients. Only the criterion of muscle mass loss (increased protein catabolism) was associated with increased mortality, while the other PEW criteria according to the ISRNM classification were not associated with increased mortality. We also observed a state of over-hydration in patients with PEW. This state of over-hydration (increased extracellular water due to occupation of muscle loss without an increase in total body water) cannot be evaluated by dry weight or the body mass index. Intervention studies are necessary in order to assess whether or not the prevention of sarcopaenia improves survival.


Influence of ankle joint plantarflexion and dorsiflexion on lateral ankle sprain: A computational study.
Understanding the mechanism of injury involved in lateral ankle sprain is essential to prevent injury, to establish surgical repair and reconstruction, and to plan reliable rehabilitation protocols. Most studies for lateral ankle sprain posit that ankle inversion, internal rotation, and plantarflexion are involved in the mechanism of injury. However, recent studies indicated that ankle dorsiflexion also plays an important role in the lateral ankle sprain mechanism. In this study, the contributions of ankle plantarflexion and dorsiflexion on the ankle joint were evaluated under complex combinations of internal and inversion moments. A multibody ankle joint model including 24 ligaments was developed and validated against two experimental cadaveric studies. The effects of ankle plantarflexion (up to 60°) and dorsiflexion (up to 30°) on the lateral ankle sprain mechanism under ankle inversion moment coupled with internal rotational moment were investigated using the validated model. Lateral ankle sprain injuries can occur during ankle dorsiflexion, in which the calcaneofibular ligament and anterior talofibular ligament tears may occur associated with excessive inversion and internal rotational moment, respectively. Various combinations of inversion and internal moment may lead to anterior talofibular ligament injuries at early ankle plantarflexion, while the inversion moment acts as a primary factor to tear the anterior talofibular ligament in early plantarflexion. It is better to consider inversion and internal rotation as primary factors of the lateral ankle sprain mechanism, while plantarflexion or dorsiflexion can be secondary factor. This information will help to clarify the lateral ankle sprain mechanism of injury.


A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial.
Atrial fibrillation (AF) is common and causes impaired quality of life, an increased risk of stroke and death as well as frequent hospital admissions. The majority of patients with AF require control of heart rate. In this article , we summarise the limited evidence from clinical trials that guides prescription, and present the rationale and protocol for a new randomised trial. As rate control has not yet been shown to reduce mortality, there is a clear need to compare the impact of therapy on quality of life, cardiac function and exercise capacity. Such a trial should concentrate on the long-term effects of treatment in the largest proportion of patients with AF, those with symptomatic permanent AF, with the aim of improving patient well-being. The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial will enrol 160 participants with a prospective, randomised, open-label, blinded end point design comparing initial rate control with digoxin or bisoprolol. This will be the first head-to-head randomised trial of digoxin and beta-blockers in AF. Recruited patients will be aged ≥60 years with permanent AF and symptoms of breathlessness (equivalent to New York Heart Association class II or above), with few exclusion criteria to maximise generalisability to routine clinical practice. The primary outcome is patient-reported quality of life, with secondary outcomes including echocardiographic ventricular function, exercise capacity and biomarkers of cellular and clinical response. Follow-up will occur at 6 and 12 months, with feasibility components to inform the design of a future trial powered to detect a difference in hospital admission. The RATE-AF trial will underpin an integrated approach to management including biomarkers, functions and symptoms that will guide future research into optimal, personalised rate control in patients with AF. East Midlands-Derby Research Ethics Committee (16/EM/0178); peer-reviewed publications. Clinicaltrials.gov: NCT02391337; ISRCTN: 95259705. Pre-results.


Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus).
Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior.


Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice.
We have already established human xenographic models for the effect of lysophosphatidic acid (LPA) on tumor metastasis in vivo. The purpose of this work is to establish a preclinical LPA effect model in immunocompetent mice. We first characterized the mouse epithelial ovarian cancer (EOC) cell line ID8 for its responsiveness to LPA in cell proliferation, migration, and invasion and compared these properties with those of human EOC. The signaling pathways related to cell migration were further investigated using pharmacologic and genetic approaches. The effects of LPA on the tumorigenesis of ID8 cells and mouse survival were then examined using two different mouse models (i.p. and orthotopic injections). LPA stimulated cell proliferation, migration, and invasion of mouse EOC ID8 cells in a manner closely resembling its activity in human EOC cells. The signaling pathways involved in LPA-induced cell migration in ID8 cells were also similar to those identified in human EOC cells. We have identified cyclooxygenase-1 and 15-lipoxygenase as two new signaling molecules involved in LPA-induced cell migration in both human and mouse EOC cells. In addition, LPA enhanced the tumorigenesis/metastasis of ID8 cell in vivo as assessed by increased tumor size, early onset of ascites formation, and reduced animal survival. We have established the first LPA-EOC preclinical model in immunocompetent mice. Because ID8 cells respond to LPA similar to human EOC cells, this model is very valuable in developing and testing therapeutic reagents targeting LPA in EOC.


Virulence of Staphylococcus aureus in a mouse mastitis model: studies of alpha hemolysin, coagulase, and protein A as possible virulence determinants with protoplast fusion and gene cloning.
Mutants of a genetically well-characterized strain of Staphylococcus aureus [SA113(83A)] were isolated after mutagenization. Alpha-hemolysin- (hla), coagulase- (coa), and protein A- (spa) negative mutants were characterized by more than 90 biochemical tests for production of extracellular proteins and biochemical profile to exclude pleiotropy. Protoplast fusion was then used to isolate double-defective (hla and coa) recombinants and recombinants with regained properties, i.e., production of alpha-hemolysin and coagulase. Studies of such mutants and recombinants in the mouse mastitis model showed that one alpha-hemolysin [SA113(83A) hla-5] and one coagulase-negative [SA113(83A) coa-147] mutant were lower in virulence compared with the wild-type strain SA113(83A). The double-negative mutant SA113(83A) hla-5 coa-147 showed a drastic decline in virulence and only induced very mild changes, as determined by microscopic examinations of infected mammary gland tissue. The recombinant with regained properties, however, was as virulent as the wild-type strain. This suggests that alpha-hemolysin and coagulase are virulence determinants of S. aureus. A high-level protein A-producing mutant (U300) showed the same virulence as the parent strain SA113(83A) in this model. One low virulence protein A-negative mutant (U320) did not markedly increase in virulence when a plasmid containing the cloned gene for protein A (pSPA15) was introduced into this mutant. By these and earlier observations, it seems likely that protein A is not an important virulence determinant in mastitis of mice. The reduced virulence of the protein A-negative mutant U320 compared with the wild-type SA113(83A) may be due to pleiotropic loss of some other unknown virulence determinant(s). Our data confirm earlier findings that pleiotropic changes are common in protein A-negative mutants.


Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial.
The phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). Patients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. Overall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus -3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of 'improvement' in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). HRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.


Noxious newts and their natural enemies: Experimental effects of tetrodotoxin exposure on trematode parasites and aquatic macroinvertebrates.
The dermal glands of many amphibian species secrete toxins or other noxious substances as a defense strategy against natural enemies. Newts in particular possess the potent neurotoxin tetrodotoxin (TTX), for which the highest concentrations are found in species within the genus Taricha. Adult Taricha are hypothesized to use TTX as a chemical defense against vertebrate predators such as garter snakes (Thamnophis spp.). However, less is known about how TTX functions to defend aquatic-developing newt larvae against natural enemies, including trematode parasites and aquatic macroinvertebrates. Here we experimentally investigated the effects of exogenous TTX exposure on survivorship of the infectious stages (cercariae) of five species of trematode parasites that infect larval amphibians. Specifically, we used dose-response curves to test the sensitivity of trematode cercariae to progressively increasing concentrations of TTX (0.0 [control], 0.63, 3.13, 6.26, 31.32, and 62.64 nmol L-1) and how this differed among parasite species. We further compared these results to the effects of TTX exposure (0 and 1000 nmolL-1) over 24 h on seven macroinvertebrate taxa commonly found in aquatic habitats with newt larvae. TTX significantly reduced the survivorship of trematode cercariae for all species, but the magnitude of such effects varied among species. Ribeiroia ondatrae - which causes mortality and limb malformations in amphibians - was the least sensitive to TTX, whereas the kidney-encysting Echinostoma trivolvis was the most sensitive. Among the macroinvertebrate taxa, only mayflies (Ephemeroptera) showed a significant increase in mortality following exogenous TTX exposure, despite the use of a concentration 16x higher than the maximum used for trematodes. Our results suggest that maternal investment of TTX into larval newts may provide protection against certain trematode infections and highlight the importance of future work assessing the effects of newt toxicity on both parasite infection success and the palatability of larval newts to invertebrate predators.


Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase.
Selenoprotein R (SelR) is a mammalian selenocysteine-containing protein with no known function. Here we report that cysteine homologs of SelR are present in all organisms except certain parasites and hyperthermophiles, and this pattern of occurrence closely matches that of only one protein, peptide methionine sulfoxide reductase (MsrA). Moreover, in several genomes, SelR and MsrA genes are fused or clustered, and their expression patterns suggest a role of both proteins in protection against oxidative stress. Consistent with these computational screens, growth of Saccharomyces cerevisiae SelR and MsrA mutant strains was inhibited, and the strain lacking both genes could not grow, in the presence of H2O2 and methionine sulfoxide. We found that the cysteine mutant of mouse SelR, as well as the Drosophila SelR homolog, contained zinc and reduced methionine-R-sulfoxide, but not methionine-S-sulfoxide, in in vitro assays, a function that is both distinct and complementary to the stereo-specific activity of MsrA. These findings identify a function of the conserved SelR enzyme family, define a pathway of methionine sulfoxide reduction, reveal a case of convergent evolution of similar function in structurally distinct enzymes, and suggest a previously uncharacterized redox regulatory role of selenium in mammals.


Molecular analysis of multiple isolates of the major serotypes of group B streptococci.
Serotyping of clinical isolates is a widely used technique for epidemiologic study of group B streptococcal infections. However, serotyping cannot definitively determine epidemiologically related or unrelated isolates. We investigated the use of restriction endonuclease analysis (REA) with both conventional agarose gel electrophoresis (AGE) and pulsed-field gel electrophoresis (PFGE) in 50 isolates of the major serotypes of group B streptococci. Single digestion with HindIII and HaeIII and double digestion with HindIII and then EcoRI were used for conventional AGE, and digestion with SmaI was used for PFGE. The molecular profile of one strain was compared with those of the strains within the same serotype as well as with the profiles from strains of different serotypes. Among 10 type Ia, Ia/alpha, Ia/alpha+beta, and Ia/R1 isolates and depending on the restriction enzyme used, we found between five and six REA patterns by conventional AGE and seven by PFGE; among 4 type Ib/alpha+beta isolates we found 2 to 4 REA patterns by conventional AGE and 4 by PFGE; among 21 type II, II/alpha, II/beta, II/alpha+beta, and II/R4 isolates, we found 11 REA patterns by both AGE and PFGE; and among 14 type III, III/R1, and III/R4 isolates, we found from 7 to 12 different REA patterns by AGE and 10 by PFGE. In total, among 13 serotypes and one nontypeable strain, we found 29 to 31 REA patterns by conventional AGE and 33 by PFGE. A particular REA pattern within a serotype was different from the patterns found in the other serotypes, suggesting that REA analysis by using conventional AGE or PFGE is a sensitive method for analyzing genetic relatedness and diversity in group B streptococci and has potential value in molecular epidemiologic studies.


Labour market conditions, labour force activity and prevalence of psychiatric disorders.
At a population level, the extent that labour market conditions influence labour force activity among people with psychiatric disorders, remains equivocal. Similarly equivocal is the hypothesised relationship between economic conditions and the reported prevalence of specific psychiatric disorders. We investigated these issues by examining the extent that labour market conditions were associated with change in labour force activity among people with anxiety disorders, affective disorders, and schizophrenia, in comparison to healthy working age adults. Data files were provided by the Australian Bureau of Statistics (ABS) from a population survey conducted in 1998 and replicated in 2003. Multi-stage probability samples were obtained in 1998 (N(1) = 37,580) and 2003 (N(2) = 36,088). Adults with schizophrenia, depression, and anxiety disorders were compared to healthy working age adults. Greater labour demand in 2003 was positively associated with increased labour force participation among healthy adults. The proportions actively looking for work declined among healthy adults and among those with anxiety disorders. Full-time employment significantly increased among healthy working age residents. The proportions employed part-time significantly increased in all groups except among people with schizophrenia. These results support policies which remove disincentives and increase access to the more intensive evidence-based employment programs even when labour market conditions are improving.


A molecular mechanism of nickel (II): reduction of nucleotide excision repair activity by structural and functional disruption of p53.
Nickel is a major carcinogen that is implicated in tumor development through occupational and environmental exposure. Although the exact molecular mechanisms of carcinogenesis by low-level nickel remain unclear, inhibition of DNA repair is frequently considered to be a critical mechanism of carcinogenesis. Here, we investigated whether low concentrations of nickel would affect p53-mediated DNA repair, especially nucleotide excision repair. Our results showed that nickel inhibited the promoter binding activity of p53 on the downstream gene GADD45A, as a result of the disturbance of p53 oligomerization by nickel. In addition, we demonstrated that nickel exposure trigger the reduction of GADD45A-mediated DNA repair by impairing the physical interactions between GADD45A and proliferating cell nuclear antigen or xeroderma pigmentosum G. Notably, in the GADD45A-knockdown system, the levels of unrepaired DNA photoproducts were higher than wild-type cells, elucidating the importance of GADD45A in the nickel-associated inhibition of DNA repair. These results imply that inhibition of p53-mediated DNA repair can be considered a potential carcinogenic mechanism of nickel at low concentrations.


Altered gene expression in three plant species in response to treatment with Nep1, a fungal protein that causes necrosis.
Nep1 is an extracellular fungal protein that causes necrosis when applied to many dicotyledonous plants, including invasive weed species. Using transmission electron microscopy, it was determined that application of Nep1 (1.0 micro g mL(-)(1), 0.1% [v/v] Silwet-L77) to Arabidopsis and two invasive weed species, spotted knapweed (Centaurea maculosa) and dandelion (Taraxacum officinale), caused a reduction in the thickness of the cuticle and a breakdown of chloroplasts 1 to 4 h after treatment. Membrane breakdown was most severe in cells closest to the surface of application. Differential display was used to isolate cDNA clones from the three species showing differential expression in response to Nep1 treatment. Differential gene expression was observed for a putative serpin (CmSER-1) and a calmodulin-like (CmCAL-1) protein from spotted knapweed, and a putative protein phosphatase 2C (ToPP2C-1) and cytochrome P-450 (ToCYP-1) protein from dandelion. In addition, differential expression was observed for genes coding for a putative protein kinase (AtPK-1), a homolog (AtWI-12) of wound-induced WI12, a homolog (AtLEA-1) of late embryogenesis abundant LEA-5, a WRKY-18 DNA-binding protein (AtWRKY-18), and a phospholipase D (AtPLD-1) from Arabidopsis. Genes showing elevated mRNA levels in Nep1-treated (5 micro g mL(-)(1), 0.1% [v/v] Silwet-L77) leaves 15 min after Nep1 treatment included CmSER-1 and CmCAL-1 for spotted knapweed, ToCYP-1 and CmCAL-1 for dandelion, and AtPK-1, AtWRKY-18, AtWI-12, and AtLEA-1 for Arabidopsis. Levels of mRNA for AtPLD-1 (Arabidopsis) and ToPP2C-1 (dandelion) decreased rapidly in Silwet-L77-treated plants between 15 min and 4 h of treatment, but were maintained or decreased more slowly over time in Nep1-treated (5 micro g mL(-)(1), 0.1% [v/v] Silwet-L77) leaves. In general, increases in mRNA band intensities were in the range of two to five times, with only ToCYP-1 in dandelion exceeding an increase of 10 times. The identified genes have been shown to be involved or are related to gene families that are involved in plant stress responses, including wounding, drought, senescence, and disease resistance.


Human exposure to PFOS and mercury through meat from baltic harbour seals (Phoca vitulina).
The overall aim of the present study was to assess human exposure to environmental contaminants from consumption of harbour seal (Phoca vitulina) meat in the southwestern Baltic Sea. For this purpose, muscle tissue from harbour seals (n = 27) was sampled from Danish locations in the period 2005-2015 and analysed for concentrations of total mercury (Hg), organochlorine contaminants such as polychlorinated biphenyls (PCBs) and organochlorine pesticides as well as perfluoroalkyl substances (PFAS) with particular focus on perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Hg, ∑PCB, PFOS and PFOA concentrations in the muscle tissue ranged between 0.27 and 4.76 μg g-1 wet weight (ww; mean: 1.38 μg g-1 ww, n = 27), 12.2-137 ng g-1 ww (mean: 47.5 ng g-1 ww, n = 10), 6.95-33.6 ng g-1 ww (mean: 15.8 ng g-1 ww, n = 10) and 0.16-0.55 ng g-1 ww (mean: 0.28 ng g-1 ww, n = 10), respectively. We compared the concentrations with literature-derived human tolerable weekly intake (TWI) values for mercury (1.3 μg kg-1 week-1), ∑PCB (2.1 μg kg-1 week-1), PFOS (0.013 μg kg-1 week-1) and PFOA (0.006 μg kg-1 week-1). The comparisons showed that the weekly consumption of harbour seal meat by children (weighing 30 kg), women (weighing 60 kg) and men (weighing 80 kg) should not exceed 28, 57 and 76 g (for Hg), 1.3, 2.7 and 3.5 kg (for ∑PCB), 25, 50 and 67 g (for PFOS) and 640, 1290 and 1720 g (for PFOA). In conclusion, Hg and PFOS are the contaminants of most importance in seal meat from this area with respect to existing tolerable intake rates and risks of adverse human health effects.


The basis of a suggested instrumental approach to the surveying of neutron fields and the measurement of personal dose from neutrons.
The basis of a two-component neutron monitoring system that could be applied to both survey instruments and personal dosemeters is considered. Neutrons with energies below 10 keV are detected by a thermal neutron detector which, in the survey instrument, is located inside a small moderating sphere, whereas in the personal dosemeter it is positioned behind a thermal neutron shield located on an individual's body. Neutrons above 10 keV are detected by counting pulses produced by protons ejected from a thin hydrogenous foil. By judicious choice of the characteristics of the detection elements, it is possible to ensure that the sum of the sensitivities of the elements of both survey instrument and personal dosemeter vary with neutron energy in a way close to that required for radiological protection purposes throughout the range thermal-10 MeV. The realisation of the elements sensitive below 10 keV presents few fundamental problems and appropriate devices have been reported in the literature. Those sensitive above 10 keV have proved to be more difficult to realise in practice.


99mTc-HYNIC Annexin-V imaging of primary head and neck carcinoma.
In this study, the potential of 99mTc-HYNIC Annexin-V scintigraphy to visualize primary head and neck carcinoma was assessed and compared with computed tomography (CT) findings and histology. Eighteen patients suspected of having primary head and neck carcinoma underwent a spiral CT scan and 99mTc-HYNIC Annexin-V scintigraphy within 1 week of each other, followed by resection of the suspected lesion. Results obtained by CT and scintigraphy were compared vs. histopathology. The diagnosis was primary head and neck carcinoma in 18 patients, accompanied by lymph node involvement in seven patients. 99mTc-HYNIC Annexin-V uptake was identified in five patients on planar images and in 17 patients on tomographic images (single-photon emission computed tomography, SPECT), corresponding to the pathological regions identified by CT. In the remaining patient, CT and 99mTc-HYNIC Annexin-V scintigraphy were false negative. In 11 patients, SPECT and CT scan were concordant, identifying all primary lesions and two sites of lymph node involvement. In the six remaining patients, CT and SPECT accurately identified the primary lesion, but were discordant with regard to the existence of lymph node involvement. In five of six patients, SPECT failed to identify lymph node involvement, whereas CT scan did not. In the remaining patient, CT scan was false positive for lymph node involvement, whereas SPECT was not. In this series, 99mTc-HYNIC Annexin-V allowed for the visualization of all primary head and neck tumours identified by CT scan, but failed to identify most of the sites of lymph node involvement.


A recurrent network model of somatosensory parametric working memory in the prefrontal cortex.
A parametric working memory network stores the information of an analog stimulus in the form of persistent neural activity that is monotonically tuned to the stimulus. The family of persistent firing patterns with a continuous range of firing rates must all be realizable under exactly the same external conditions (during the delay when the transient stimulus is withdrawn). How this can be accomplished by neural mechanisms remains an unresolved question. Here we present a recurrent cortical network model of irregularly spiking neurons that was designed to simulate a somatosensory working memory experiment with behaving monkeys. Our model reproduces the observed positively and negatively monotonic persistent activity, and heterogeneous tuning curves of memory activity. We show that fine-tuning mathematically corresponds to a precise alignment of cusps in the bifurcation diagram of the network. Moreover, we show that the fine-tuned network can integrate stimulus inputs over several seconds. Assuming that such time integration occurs in neural populations downstream from a tonically persistent neural population, our model is able to account for the slow ramping-up and ramping-down behaviors of neurons observed in prefrontal cortex.


Cytogenetic and fluorescence in situ hybridization characterization of chromosome 1 rearrangements in head and neck carcinomas delineate a target region for deletions within 1p11-1p13.
Cytogenetic analyses have revealed structural rearrangements of chromosome 1 in a large fraction of head and neck carcinomas (HNCA). These aberrations frequently affect chromosomal band 1p13 and the centromeric region, the latter often in the form of isochromosome i(1q) and whole-arm translocations. To delineate the critical region involved in rearrangements of proximal 1p, we have undertaken a more precise breakpoint mapping in 13 HNCAs, using metaphase fluorescence in situ hybridization with 11 yeast artificial chromosome (YAC) clones spanning 1p. All of the tumors had chromosome 1 changes at G-banding analyses. Fluorescence in situ hybridization showed that in almost all of the cases, at least one copy of chromosome 1 was affected by centromeric rearrangement. By the use of YAC clones mapped to juxtacentromeric regions and a centromere-specific alpha-satellite probe, we detected variable breakpoints in the whole-arm translocations. At the cytogenetic level, 1p13 rearrangements were frequent. However, molecular breakpoints within this band varied among the HNCAs tested. The lack of consistently rearranged chromosome segments indicates that the pathogenetically important consequence of 1p rearrangements in HNCAs is loss and/or gain of genes outside the breakpoint regions. In an assessment of the genomic imbalances, partial or complete overrepresentation of 1q was seen in eight cases. Loss of 1p material was also identified in eight cases; and in four of them, the deleted segments were too small to be discovered by G-banding analysis. The minimal overlapping deleted region was in the interval between YAC 959C4 (band p11-p12) and the centromere (p10). Our findings indicate that a target region potentially harboring tumor suppressor gene(s) crucial for HNCA is located within chromosomal bands 1p11-p13.


Lithium-induced male sexual impairment: two case reports.
Two cases of male sexual dysfunction associated with lithium therapy for major affective disorder, bipolar type I, are reported. One patient received a blind placebo substitution, with rapid disappearance of dysfunction. The second patient presented similar symptoms, which remitted spontaneously on continued lithium therapy. Since lithium is among the most effective and frequently used treatments for affective illness, such side effects, previously considered rare, may be expected to increase in frequency.


An analysis of global asymptotic stability of delayed cellular neural networks.
In this paper, a new sufficient condition is given for the uniqueness and global asymptotic stability of the equilibrium point for delayed cellular neural networks (DCNNs). This condition imposes constraints on the feedback and delayed feedback matrices of a DCNN independently of the delay parameter. This result is also compared with the previous results derived in the literature.


Autologous bone marrow-derived cells in the treatment of liver disease patients.
Liver transplantation is universally accepted as a "cure" procedure, and yet is not universally applicable for the treatment of end-stage liver diseases (ESLD) because of the shortage of donors, operative complications, risk of rejection, and high cost. Bioartificial liver device is an option to temporarily improve the liver function and to bridge the patients to liver transplantation. However, bioartificial liver device has many problems in clinical application, such as hepatocyte allograft rejection and maintenance of hepatocyte viability and function. Another therapeutic option is stem cell transplantation. There are two broad types of stem cells: Embryonic stem cells and adult stem cells. The latter are sourced from bone marrow (BM), adipose tissue, and blood. This review will concentrate on BM-derived cells. BM-derived cell transplantation, although not ideal, is theoretically an optimal modality for the treatment of ESLD. Autologous BM-derived cells have no graft rejection, have the capability of regeneration and self-renewal, and are multipotent stem cells that can differentiate into a variety of cell types which include hepatocytes. The pathway from BM-derived cell to hepatocyte is well documented. The present review summarizes the delivery routes of BM-derived cells to the liver, the evidences of engraftment of BM-derived cells in the liver, and the possible mechanisms of BM-derived cells in liver repair and regeneration, and finally, updates the clinical applications.


The protein oxidation product 3,4-dihydroxyphenylalanine (DOPA) mediates oxidative DNA damage.
A major product of hydroxy-radical addition to tyrosine is 3, 4-dihydroxyphenylalanine (DOPA) which has reducing properties. Protein-bound DOPA (PB-DOPA) has been shown to be a major component of the stable reducing species formed during protein oxidation under several conditions. The aim of the present work was to investigate whether DOPA, and especially PB-DOPA, can mediate oxidative damage to DNA. We chose to generate PB-DOPA using mushroom tyrosinase, which catalyses the hydroxylation of tyrosine residues in protein. This permitted us to study the reactions of PB-DOPA in the virtual absence of other protein-bound oxidation products. The formation of two oxidation products of DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG) and 5-hydroxy-2'-deoxycytidine (5OHdC), were studied with a novel HPLC using gradient elution and an electrochemical detection method, which allowed the detection of both DNA modifications in a single experiment. We found that exposure of calf thymus DNA to DOPA or PB-DOPA resulted in the formation of 8oxodG and 5OHdC, with the former predominating. The formation of these DNA oxidation products by either DOPA or PB-DOPA depended on the presence of oxygen, and also on the presence and on the concentration of transition metal ions, with copper being more effective than iron. The yields of 8oxodG and 5OHdC increased with DOPA concentration in proteins. Thus PB-DOPA was able to promote further radical-generating events, which then transferred damage to other biomolecules such as DNA.


Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase.
Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of efficient DNA replication in unperturbed S phase. We found that loss of RNF168 leads to reduced replication fork progression and to reversed fork accumulation, particularly evident at repetitive sequences stalling replication. Slow fork progression depends on MRE11-dependent degradation of reversed forks, implicating RNF168 in reversed fork protection and restart. Consistent with regular nucleosomal organization of reversed forks, the replication function of RNF168 requires H2A ubiquitination. As this novel function is shared with the key DDR players ATM, γH2A.X, RNF8, and 53BP1, we propose that double-stranded ends at reversed forks engage classical DDR factors, suggesting an alternative function of this pathway in preventing genome instability and human disease.


Efficiency of Salmonella isolation from meat-and-bone meal of one 300-g sample versus ten 30-g samples.
Twenty-five meat-and-bone meal samples were analyzed for salmonellae, comparing a single 300-g to ten 30-g samples. Seventeen were positive using the larger sample; eighteen were positive with the smaller. The 300-g sample showed a significantly higher (P < 0.01) percentage of confirmed salmonellae at 2 days of incubation than at 1 day. The ten 30-g samples did not show changes at 2 days. At 2 days, the 30-g samples showed significantly fewer confirmed salmonellae than the 300-g sample; however, there was no difference at 1 day. Of 1,417 presumptive colonies picked, 1,215 (85.7%) were lysine decarboxylase-positive and 1,152 (81.3%) were agglutinated by one of the somatic antisera. There were no significant differences in diversity or total numbers of different somatic groups between the large and small samples.


Human Intestinal PEPT1 Transporter Expression and Localization in Preterm and Term Infants.
The intestinal influx oligopeptide transporter peptide transporter 1 (PEPT1) (SLC15A1) is best known for nutrient-derived di- and tripeptide transport. Its role in drug absorption is increasingly recognized. To better understand the disposition of PEPT1 substrate drugs in young infants, we studied intestinal PEPT1 mRNA expression and tissue localization across the pediatric age range. PEPT1 mRNA expression was determined using real-time reverse-transcription polymerase chain reaction in small intestinal tissues collected from surgical procedures (neonates and infants) or biopsies (older children and adolescents). PEPT1 mRNA relative to villin mRNA expression was compared between neonates/infants and older children/adolescents. PEPT1 was visualized in infant tissue using immunohistochemical staining. Other transporters [multidrug resistance protein 1 (MDR1), multidrug resistance-like protein 2 (MRP2), and organic anion transporter polypeptide 2B1 (OATP2B1)] were also stained to describe the localization in relation to PEPT1. Twenty-six intestinal samples (n = 20 neonates/infants, n = 2 pediatric, n = 4 adolescents) were analyzed. The young infant samples were collected at a median (range) gestational age at birth of 29.2 weeks (24.7-40) and postnatal age of 2.4 weeks (0-16.6). The PEPT1 mRNA expression of the neonates/infants was only marginally lower (0.8-fold) than the older children (P < 0.05). Similar and clear apical PEPT1 and MRP2 staining, apical and lateral MDR1 staining, and intraepithelial OATP2B1 staining at the basolateral membrane of the enterocyte were detected in 12 infant and 2 adolescent samples. Although small intestinal PEPT1 expression tended to be lower in neonates than in older children, this difference is small and tissue distribution is similar. This finding suggests similar oral absorption of PEPT1 substrates across the pediatric age range.


An fMRI study of cognitive control in problem gamers.
A small proportion of video game players develop uncontrolled gaming behavior. A dysfunctional cognitive control circuit may explain this excessive behavior. Therefore, the current study investigated whether problem gamers are characterized by deficits in various aspects of cognitive control (inhibitory control, error processing, attentional control) by measuring brain activation using functional magnetic resonance imaging during Go-NoGo and Stroop task performance. In addition, both impulsivity and attentional control were measured using self-reports. Participants comprised 18 problem gamers who were compared with 16 matched casual gaming controls. Results indicate significantly increased self-reported impulsivity levels and decreased inhibitory control accompanied by reduced brain activation in the left inferior frontal gyrus (IFG) and right inferior parietal lobe (IPL) in problem gamers relative to controls. Significant hypoactivation in the left IFG in problem gamers was also observed during Stroop task performance, but groups did not differ on behavioral and self-reported measures of attentional control. No evidence was found for reduced error processing in problem gamers. In conclusion, the current study provides evidence for reduced inhibitory control in problem gamers, while attentional control and error processing were mostly intact. These findings implicate that reduced inhibitory control and elevated impulsivity may constitute a neurocognitive weakness in problem gamers.


Immunohistochemical localization of gonadotropin-releasing hormone (GnRH) in the brain and infundibulum of the sheep.
The distribution of gonadotropin-releasing hormone (GnRH) was studied in the brain and infundibulum (INF) or median eminence of sheep utilizing a peroxidase-antiperoxidase immunohistochemical method. This procedure utilized a specific antiserum generated against GnRH conjugated to bovine serum albumin. In the rostral INF, the greatest concentration of GnRH positive axons was found in the medial region, mostly in the external layer dorsal to the hypophysial portal plexus. In the intermediate portion of the INF, the hormone was mainly observed in the external layer at the more dorsolateral areas ventral to the tuberoinfundibular sulcus. GnRH was generally located medially in the caudal portion of the INF and dorsomedially in the rostral infundibular stalk. Substantial amounts of reaction product were also noted in the internal layer throughout the entire rostrocaudal extent of the INF. The hormone was localized in axons throughout the brain from the septal and medial preoptic areas to the mammillary bodies. GnRH-positive perikarya were scattered in various regions of the infundibular (arcuate) and for the first time in the ventromedial nuclei of sheep hypothalamus. Preabsorption of the specific antiserum with synthetic GnRH abolished staining in both axons and perikarya, whereas preabsorption with thyrotropin-releasing hormone, oxytocin, arginine-vasopressin, and adrenocorticotrophic hormone did not affect staining intensity.


Simplified computational methods for the analysis of protein flexibility.
Conformational flexibility is an inherent property of the protein structure. Large scale changes in the protein conformation play a key role in a variety of fundamental biological activities and have been implicated in a number of diseases. The time scales of functionally relevant dynamic processes in proteins generally do not allow the researchers to study them by the means of detailed atomic level simulations. Therefore, less computationally demanding methods based on the coarse grained models of protein structure and bioinformatics approaches are particularly important for the flexibility-related studies. This review is focused on two broad categories of protein flexibility - protein disorder and conformational switches. In the case of protein disorder, a flexible protein segment or entire protein is structurally disordered, meaning that it does not have a well-defined folded 3D structure. In the case of conformational switches, the protein backbone of a flexible segment can change or "switch" from one specific folded 3D conformation to another. In this review, the relative strengths and limitations of the existing computational tools, mostly from the bioinformatics domain, used to study and predict protein disorder and conformational switches will be discussed and the main challenges will be highlighted.


Complex Interplay Between Aging and Cancer: Role of TGF-β Signaling.
Although cancer is known to be predominantly a disease of the elderly, it is also thought that aging and cancer may occur either via similar or opposing cellular mechanisms. Studies during the past decades were focused on understanding the molecular events underlying both processes, aiming to ultimately improve the quality of life and lifespan. However, these efforts were traditionally performed or viewed independently without considering the interplay between aging and cancer-promoting mechanisms. Transforming growth factor-beta (TGF-β) signaling is essential for embryonic development and physiological tissue homeostasis. Although the fundamental roles of TGF-β in cancer progression have been investigated extensively, recent reports also provide evidence for its direct or indirect links to aging-related processes such as cell proliferation, senescence, stem cell renewal, DNA damage, inflammation, and telomere length. In this review, we present the latest findings regarding the TGF-β-regulated convergent and divergent mechanisms controlling the balance between aging and cancer. Finally, the implications of these processes in developing strategies to prolong the cancer-free human lifespan are discussed.


Relationship between binding affinities to cellular retinoic acid-binding protein and in vivo and in vitro properties for 18 retinoids.
A new rapid assay has been developed for measurement of the binding of [3H]retinoic acid to cellular retinoic acid-binding protein. The assay, which uses activated charcoal for the separation of bound from unbound retinoic acid, was used to determine the concentration required to inhibit the binding of [3H]retinoic acid to cellular retinoic acid-binding protein by 50% for 18 retinoids with free carboxylic acid groups. Partially purified cellular retinoic acid-binding proteins isolated from rat testes and carcinogen-induced rat mammary tumors were used for these determinations. The following parameters were also determined for some or all of the retinoids: hypervitaminosis A doses; activity against carcinogen-induced mouse skin papillomas; inhibition of growth of a rat chondrosarcoma; inhibition of growth of 3T6 cells; and differentiation of the embryonal carcinoma cell line PCC4.azaIR. While all retinoids that are potent in these biological test systems bind tightly to cellular retinoic acid-binding protein, the converse is not true. The lack of a consistent quantitative correlation between 50% inhibitory concentration and biological activity is probably due to insufficient concentrations of the retinoid in the target tissue or celll, which is a consequence of factors such as absorbability, metabolism, tissue distribution, and pharmacokinetics.


A novel network-based approach for discovering dynamic metabolic biomarkers in cardiovascular disease.
Metabolic biomarkers may play an important role in the diagnosis, prognostication and assessment of response to pharmacological therapy in complex diseases. The process of discovering new metabolic biomarkers is a non-trivial task which involves a number of bioanalytical processing steps coupled with a computational approach for the search, prioritization and verification of new biomarker candidates. Kinetic analysis provides an additional dimension of complexity in time-series data, allowing for a more precise interpretation of biomarker dynamics in terms of molecular interaction and pathway modulation. A novel network-based computational strategy for the discovery of putative dynamic biomarker candidates is presented, enabling the identification and verification of unexpected metabolic signatures in complex diseases such as myocardial infarction. The novelty of the proposed method lies in combining metabolic time-series data into a superimposed graph representation, highlighting the strength of the underlying kinetic interaction of preselected analytes. Using this approach, we were able to confirm known metabolic signatures and also identify new candidates such as carnosine and glycocholic acid, and pathways that have been previously associated with cardiovascular or related diseases. This computational strategy may serve as a complementary tool for the discovery of dynamic metabolic or proteomic biomarkers in the field of clinical medicine.


Analysis of cardiac function by MRI and stereology.
Design-based stereology and phase contrast magnetic resonance imaging (MRI) were combined to monitor changes in the volume of the four chambers of the human heart during the cardiac cycle. The data set consisted of 18 adjacent slices (or 'scanning levels') of 0.5 cm thickness, perpendicular to the long axis of the body, and encompassing the whole heart of a healthy volunteer. At each scanning level, a cardiac gated MR image was obtained at each of 16 equally spaced time frames within the cardiac cycle. Given stationarity with respect to time, absence of image artefacts and appropriate definition of chamber boundaries, for each time frame unbiased estimates of total blood volume in the relevant heart chambers were efficiently obtained using the Cavalieri method and point counting. Combined with a proper MRI acquisition, modern stereological methods constitute an efficient and reliable tool to quantify cardiac function noninvasively.


Transduction of renal cells in vitro and in vivo by adeno-associated virus gene therapy vectors.
There has been an increasing interest recently in the possibility of treating renal diseases using gene therapy. The ability to pursue gene therapy for renal diseases has been limited by the availability of an adequate system for gene delivery to the kidney. Adeno-associated virus (AAV) is a defective virus of the parvovirus family that has a number of properties attractive for renal gene delivery: recombinant AAV contains no viral genes; expression of genes delivered by these vectors does not activate cell-mediated immunity; the virus is able to transduce nondividing as well as dividing cells; and both wild-type and recombinant AAV integrate into the host chromosome resulting in long-term gene expression. Studies were performed to determine whether AAV can deliver reporter genes to kidney cells in vitro and in vivo. These studies show that AAV can deliver reporter genes with approximately equal efficiency to human mesangial, proximal tubule, thick ascending limb, collecting tubule, and renal cell carcinoma cells in primary culture. Immortalized mouse mesangial cells are transduced at a much greater efficiency. Transduction can be enhanced by pharmaceutical agents up to sevenfold in primary cells (transducing up to 20% of primary cells per well) and as much as 400-fold in immortalized mesangial cells. AAV delivered in vivo by intraparenchymal injection results in at least 3 mo of reporter gene expression in tubular epithelial, but not glomerular or vascular, cells at the injection site. These data indicate that AAV can deliver genes to renal cells both in vitro and in vivo resulting in prolonged gene expression, and thus AAV can be a useful tool for renal gene delivery.


Interaction between typical sulfonamides and bacterial diversity in drinking water.
The abuse of antibiotics is becoming more serious as antibiotic use has increased. The sulfa antibiotics, sulfamerazine (SM1) and sulfamethoxazole (SMZ), are frequently detected in a wide range of environments. The interaction between SM1/SMZ and bacterial diversity in drinking water was investigated in this study. The results showed that after treatment with SM1 or SMZ at four different concentrations, the microbial community structure of the drinking water changed statistically significantly compared to the blank sample. At the genus level, the proportions of the different bacteria in drinking water may affect the degradation of the SM1/SMZ. The growth of bacteria in drinking water can be inhibited after the addition of SM1/SMZ, and bacterial community diversity in drinking water declined in this study. Furthermore, the resistance gene sul2 was induced by SM1 in the drinking water.


Innervated island pedicled anterolateral thigh flap for neo-phallic reconstruction in female-to-male transsexuals.
Many techniques have been described to create an aesthetic and functional neo-phallus after penile amputation or in female-to-male transsexuals. Microsurgical free-flap phalloplasty seems to be the preferred method of penile reconstruction. For many years the radial forearm free flap has been considered the best procedure, but other flaps have been attempted to minimize donor site morbidity and optimize outcome. Pedicled flaps are considered to be reliable and to decrease the risk of total failure. Recently, a one-stage non-microsurgical technique was described for phallic reconstruction in a young male patient. We report successful total phallic reconstruction in a female-to-male transsexual patient using an island pedicled anterolateral thigh (ALT) flap. Urethral reconstruction was left as a possible further procedure due to patient's preference. A malleable soft silicone penile prosthesis was inserted within the flap and the lateral cutaneous femoral nerve stump was sutured to the dorsal clitoris branch from the pudendal nerve for flap sensation. After 6 months, the patient demonstrated successful aesthetic and functional reconstruction referring to satisfactory sexual activity. To our knowledge, this is the first report of an innervated island pedicled ALT flap used for female-to-male penile reconstruction in a transsexual patient. The pedicled ALT flap may be a reliable option to avoid visible scarring at the donor site on exposed parts of the body, and reduce the risk of total flap failure from microsurgical procedures for reconstruction of a neo-phallus in this increasing population of patients.


Differential Modulation of Quorum Sensing Signaling through QslA in Pseudomonas aeruginosa Strains PAO1 and PA14.
Two clinical isolates of the opportunist pathogen Pseudomonas aeruginosa named PAO1 and PA14 are commonly studied in research laboratories. Despite the isolates being closely related, PA14 exhibits increased virulence compared to that of PAO1 in various models. To determine which players are responsible for the hypervirulence phenotype of the PA14 strain, we elected a transcriptomic approach through RNA sequencing. We found 2,029 genes that are differentially expressed between the two strains, including several genes that are involved with or regulated by quorum sensing (QS), known to control most of the virulence factors in P. aeruginosa Among them, we chose to focus our study on QslA, an antiactivator of QS whose expression was barely detectable in the PA14 strain according our data. We hypothesized that lack of expression of qslA in PA14 could be responsible for higher QS expression in the PA14 strain, possibly explaining its hypervirulence phenotype. After confirming that QslA protein was highly produced in PAO1 but not in the PA14 strain, we obtained evidence showing that a PAO1 deletion strain of qslA has faster QS gene expression kinetics than PA14. Moreover, known virulence factors activated by QS, such as (i) pyocyanin production, (ii) H2-T6SS (type VI secretion system) gene expression, and (iii) Xcp-T2SS (type II secretion system) machinery production and secretion, were all lower in PAO1 than in PA14, due to higher qslA expression. However, biofilm formation and cytotoxicity toward macrophages, although increased in PA14 compared to PAO1, were independent of QslA control. Together, our findings implicated differential qslA expression as a major determinant of virulence factor expression in P. aeruginosa strains PAO1 and PA14.IMPORTANCEPseudomonas aeruginosa is an opportunistic pathogen responsible for acute nosocomial infections and chronic pulmonary infections. P. aeruginosa strain PA14 is known to be hypervirulent in different hosts. Despite several studies in the field, the underlining molecular mechanisms sustaining this phenotype remain enigmatic. Here we provide evidence that the PA14 strain has faster quorum sensing (QS) kinetics than the PAO1 strain, due to the lack of QslA expression, an antiactivator of QS. QS is a major regulator of virulence factors in P. aeruginosa; therefore, we propose that the hypervirulent phenotype of the PA14 strain is, at least partially, due to the lack of QslA expression. This mechanism could be of great importance, as it could be conserved among other P. aeruginosa isolates.


Statin therapy in patients with community-acquired pneumonia.
Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. There is evidence of an association between improved survival from infection and statin use. The possible beneficial effects of statins are complicated by the common use of macrolide antibiotics for pneumonia, with current guidance suggesting that concurrent macrolide and statin use is contraindicated.We conducted an observational study of statin use in patients with CAP. Of 2,067 patients with CAP, 30.4% were on statin therapy at admission. Statin users were more likely to survive the admission (p<0.001). In addition, we conducted a survey of doctors and found that knowledge regarding concurrent macrolide and statin use was lacking.These data suggest a potential role of statins in the management of CAP. Further research using high-dose statins is required to assess their safe use in subjects with mild to moderate infections.


Combined diffusion-weighted and perfusion-weighted flow heterogeneity magnetic resonance imaging in acute stroke.
The heterogeneity of microvascular flows is known to be an important determinant of the efficacy of oxygen delivery to tissue. Studies in animals have demonstrated decreased flow heterogeneity (FH) in states of decreased perfusion pressure. The purpose of the present study was to assess microvascular FH changes in acute stroke with use of a novel perfusion-weighted MRI technique and to evaluate the ability of combined diffusion-weighted MRI and FH measurements to predict final infarct size. Cerebral blood flow, FH, and plasma mean transit time (MTT) were measured in 11 patients who presented with acute (<12 hours after symptom onset) stroke. Final infarct size was determined with follow-up MRI or CT scanning. In normal brain tissue, the distribution of relative flows was markedly skewed toward high capillary flow velocities. Within regions of decreased cerebral blood flow, plasma MTT was prolonged. Furthermore, subregions were identified with significant loss of the high-flow component of the flow distribution, thereby causing increased homogeneity of flow velocities. In parametric maps that quantify the acute deviation of FH from that of normal tissue, areas of extreme homogenization of capillary flows predicted final infarct size on follow-up scans of 10 of 11 patients. Flow heterogeneity and MTT can be rapidly assessed as part of a routine clinical MR examination and may provide a tool for planning of individual stroke treatment, as well as in targeting and evaluation of emerging therapeutic strategies.


Myocardial autophagic energy stress responses--macroautophagy, mitophagy, and glycophagy.
An understanding of the role of autophagic processes in the management of cardiac metabolic stress responses is advancing rapidly and progressing beyond a conceptualization of the autophagosome as a simple cell recycling depot. The importance of autophagy dysregulation in diabetic cardiomyopathy and in ischemic heart disease - both conditions comprising the majority of cardiac disease burden - has now become apparent. New findings have revealed that specific autophagic processes may operate in the cardiomyocyte, specialized for selective recognition and management of mitochondria and glycogen particles in addition to protein macromolecular structures. Thus mitophagy, glycophagy, and macroautophagy regulatory pathways have become the focus of intensive experimental effort, and delineating the signaling pathways involved in these processes offers potential for targeted therapeutic intervention. Chronically elevated macroautophagic activity in the diabetic myocardium is generally observed in association with structural and functional cardiomyopathy; yet there are also numerous reports of detrimental effect of autophagy suppression in diabetes. Autophagy induction has been identified as a key component of protective mechanisms that can be recruited to support the ischemic heart, but in this setting benefit may be mitigated by adverse downstream autophagic consequences. Recent report of glycophagy upregulation in diabetic cardiomyopathy opens up a novel area of investigation. Similarly, a role for glycogen management in ischemia protection through glycophagy initiation is an exciting prospect under investigation.


[Bowel habits: non-congruent views of patients and nursing staff].
The bowel movement pattern in hospitalised patients is an important aspect of nursing and therapeutic considerations. The aim of the study was to gather and compare the views patients and nursing personnel on the subject of bowel movement habits. The investigation was carried out by means of a questionnaire that should enable gathering data on demographic factors and bowel movement patterns (regularity, frequency, colour, form, problems, influence of external factors). Data obtained from the questionnaires completed by 122 nursing personnel and 168 patients were subject to statistical analysis. Data were analysed with the help of SPSS, and individually according to sample groups, using the Chi square test. Comparison (nursing personnel and patients) of the results showed significant differences between the two groups in their assessment of what was "normal" and what was "pathological" in bowel movement patterns. The two groups differed significantly in what they considered as normal bowel movement frequency namely, "several times daily", "every second day" and "twice a week". It is interesting to note that the nursing staff more often considered "irregular" bowel movements as "normal" in comparison to patients. Significant differences between the two groups were also observed in their assessment off "watery stools" and "formed stools". As far as the question of stool colour is concerned, patients more frequently than the nursing staff, looked upon "pathological" colour changes (yellow and reddish-brown to black) as being normal.


Malignant melanoma of the vulva.
During the years 1969 to 1982, 16 patients with primary malignant melanoma of the vulva were entered into the Tumor Registry at the University of Miami Jackson Memorial Medical Center. The mean age was 55, with a range of 18 to 89 years. Treatment was primarily by radial vulvectomy with bilateral groin and pelvic node dissection. Survival was correlated to FIGO staging, Clark and Breslow classifications, and lymph node involvement. Survival correlated best to tumor thickness and Clark levels. Patients with Clark level 2 or less and less than 1.5 mm depth of penetration had the best prognosis. Lymph node involvement was present in 25% of the patients, and there were no survivors in this group. There were no instances of positive pelvic nodes when the groin nodes were negative, and routine pelvic lymphadenectomy is not recommended.


Machine Learning Derived Lifting Technique in People without Low Back Pain.
This paper presents a method for determining the number of lifting techniques used by healthy individuals through the analysis of kinematic data collected from 115 participants utilizing an motion capture system. The technique utilizes a combination of feature extraction and Ward's method to analyse the range of motion in the sagittal plane of the knee, hip, and trunk. The findings identified five unique lifting techniques in people without low back pain. The multivariate analysis of variance statistical analysis reveals a significant difference in the range of motion in the trunk, hip and knee between each cluster for healthy people (F (12, 646) = 125.720, p < 0.0001).Clinical Relevance- This information can assist healthcare professionals in choosing effective treatments and interventions for those with occupational lower back pain by focusing rehabilitation on specific body parts associated with problematic lifting techniques, such as the trunk, hip, or knee, which may lead to improved pain and disability outcomes, exemplifying precision medicine.


Tissue plasminogen activator-based nanothrombolysis for ischemic stroke.
Thrombolysis with intravenous tissue plasminogen activator (tPA) is the only FDA approved treatment for patients with acute ischemic stroke, but its use is limited by narrow therapeutic window, selective efficacy, and hemorrhagic complication. In the past two decades, extensive efforts have been undertaken to extend its therapeutic time window and explore alternative thrombolytic agents, but both show little progress. Nanotechnology has emerged as a promising strategy to improve the efficacy and safety of tPA. We reviewed the biology, thrombolytic mechanism, and pleiotropic functions of tPA in the brain and discussed current applications of various nanocarriers intended for the delivery of tPA for treatment of ischemic stroke. Current challenges and potential further directions of t-PA-based nanothrombolysis in stroke therapy are also discussed. Using nanocarriers to deliver tPA offers many advantages to enhance the efficacy and safety of tPA therapy. Further research is needed to characterize the physicochemical characteristics and in vivo behavior of tPA-loaded nanocarriers. Combination of tPA based nanothrombolysis and neuroprotection represents a promising treatment strategy for acute ischemic stroke. Theranostic nanocarriers co-delivered with tPA and imaging agents are also promising for future stroke management.


Breast cancer: biological characteristics in postmenopausal type 2 diabetic women. Identification of therapeutic targets.
Epidemiological data have suggested a possible relationship between diabetes mellitus and cancer risk, particularly breast cancer. We set out to investigate the effect of diabetes mellitus on the expression of estrogen and progesteron receptors and on the proliferative activity of primary breast cancer. We selected 77 diabetic women and 578 control patients all in post-menopause and diagnosed with primary breast cancer. All patients underwent surgical excision of the tumor and on the specimens were performed an assessment of estrogen receptor and progesteron receptor and proliferative activity assay by (3)H-Thymidine incorporation. Diabetic women showed a decreased proliferative activity, while having the same estrogen receptor and progesteron receptor status and mean cytoplasmic concentration of their receptors than control group. Insulin treated women had a lower proliferative activity than non-insulin treated ones. Hyperinsulinemia and hyperglicemia influence in negative way the proliferative activity of diabetic women, likely inducing the expression of transforming growth factor beta, despite the high serum levels of Insulin-like growth factor and estrogen.


Acute colchicine intoxication complicated with extramedullary hematopoiesis due to filgrastim in a child.
Colchicine is a widely used alkaloid extract in children and adults for standard therapy and prophylaxis for amyloid deposition in different rheumatologic disorders. Colchicine intoxication is a rare but severe complication. The aim of this study was to report the extramedullary hematopoiesis as a complication of filgrastim usage in a child with acute colchicine intoxication. Herein, we report a 3-year-old boy with colchicine intoxication associated with neutropenia, disseminated intravascular coagulation, liver injury, and rhabdomyolysis without hepatosplenomegaly. Filgrastim was started at the fourth day of administration for severe neutropenia with fever; 3 days after the start of filgrastim, the patient experienced hepatosplenomegaly with severe leukocytosis (51,110/mm) and myeloid precursors at peripheral blood smear. Bone marrow aspiration was normal; the clinical outcome of the child was eventful without any complication. The clinicians managing colchicine intoxications must be vigilant about the possible side effect of extramedullary hematopoiesis caused by filgrastim used for neutropenia in colchicine intoxication.


A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.
This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.


Cerebral hemodynamic and oxygenation changes induced by inner and heard speech: a study combining functional near-infrared spectroscopy and capnography.
The aim of this study was to investigate the effects of inner and heard speech on cerebral hemodynamics and oxygenation in the anterior prefrontal cortex (PFC) using functional near-infrared spectroscopy and to test whether potential effects were caused by alterations in the arterial carbon dioxide pressure (PaCO2). Twenty-nine healthy adult volunteers performed six different tasks of inner and heard speech according to a randomized crossover design. During the tasks, we generally found a decrease in PaCO2 (only for inner speech), tissue oxygen saturation (StO2), oxyhemoglobin ([O2Hb]), total hemoglobin ([tHb]) concentration and an increase in deoxyhemoglobin concentration ([HHb]). Furthermore, we found significant relations between changes in [O2Hb], [HHb], [tHb], or StO2 and the participants' age, the baseline PETCO2, or certain speech tasks. We conclude that changes in breathing during the tasks led to lower PaCO2 (hypocapnia) for inner speech. During heard speech, no significant changes in PaCO2 occurred, but the decreases in StO2, [O2Hb], and [tHb] suggest that changes in PaCO2 were also involved here. Different verse types (hexameter and alliteration) led to different changes in [tHb], implying different brain activations. In conclusion, StO2, [O2Hb], [HHb], and [tHb] are affected by interplay of both PaCO2 reactivity and functional brain activity.


Cementless hemispheric porous-coated sockets implanted with press-fit technique without screws: average ten-year follow-up.
Press-fit implantation of a porous-coated hemispheric acetabular component without screws is an option for primary total hip replacement. The purpose of the present study was to evaluate the results of this technique after an average duration of follow-up of ten years to determine if there was any loss of fixation or increase in osteolysis over time. From June 1988 to November 1990, 132 primary total hip replacements were performed with a porous-coated socket that was implanted with use of a press-fit technique. Twenty-two hips were excluded because the patient had died or had been lost to follow-up, leaving 110 hips (103 patients) available for inclusion in the study after an average duration of follow-up of 10.2 +/- 1.0 years. The average age of the patients at the time of operation was 60.7 years (range, 23.7 to 86.2 years). Radiographs were evaluated with regard to initial gaps, radiolucent lines, migration, polyethylene wear, and osteolysis. Kaplan-Meier survivorship analysis was performed to calculate the rate of survival of the acetabular component. One hip (0.9%) had revision of the socket because of aseptic loosening, and four hips (4%) had revision of a stable socket. With the numbers available, the presence of gaps on the initial postoperative radiographs was not associated with the occurrence of radiolucent lines (p = 0.039). Pelvic osteolysis was seen in four hips, with an average time to radiographic appearance of six years. Increased wear was directly related to an abduction angle of >40 degrees. The twelve-year survival rate was 99.1% with revision because of failure of fixation of the metal shell as the end point, 95.3% with revision for any reason as the end point, and 79.6% with exchange of the liner as the end point. The fixation of this press-fit socket did not deteriorate over time and was associated with a low rate of osteolysis. The most common reasons for reoperation were wear and dissociation of the polyethylene insert.


Development and maintenance of donor-specific chimerism in semi-allogenic and fully major histocompatibility complex mismatched facial allograft transplants.
The clinical application of composite tissue allograft transplants opened the discussion on the restoration of facial deformities by allotransplantation. We introduce a hemifacial allograft transplant model to investigate the rationale for the development of operational tolerance across a major histocompatibility complex (MHC) barrier. Thirty rats were studied in five groups of six animals each. The composite hemiface isograft transplantations were performed in group 1. Allograft rejection controls included semi-allogenic transplantations from LBN (RT1(1+n) donors (group 2) and fully allogenic transplantations from ACI (RT1a) donors (group 3) to LEW (RT1(1)) recipients. In the allograft treatment groups, recipients of LBN (group 4) and ACI donors (group 5) were treated with cyclosporine A monotherapy (16 mg/kg/day, tapered to 2 mg/kg/day). Face allografts were evaluated clinically and histologically. Donor-specific chimerism for MHC class I RT1n and RT1a antigens was assessed by flow cytometry. Mixed lymphocyte reaction for donor-specific tolerance in vitro was tested at day 160 posttransplant. Isograft controls survived indefinitely. All nontreated allografts rejected within 5 to 8 days posttransplant. Long-term survival was achieved in 100% of LBN (up to 400 days) and ACI (up to 330 days) recipients. At day 160, posttransplant donor-specific chimerism was present in recipients of LBN (10.14% CD4/RT1n, 6.38% CD8/RT1n, 10.02% CD45RA/RT1n) and ACI (17.54% CD4/RT1a, 9.28% CD8/RT1a) transplants, and mixed lymphocyte reaction confirmed tolerance in recipients of LBN transplants and moderate reactivity in recipients of ACI allografts. Operational tolerance was induced in hemiface allograft transplants across an MHC barrier under cyclosporine A monotherapy protocol. It was associated directly with the presence of multilineage donor-specific chimerism.


Protective effects of rosmarinic acid against azoxymethane-induced colorectal cancer in rats.
Colorectal cancer (CRC) incidence is increasing gradually and has been become one of the most common cancers worldwide. Hence, it is important to discover cheap, naturally occurring compounds to be effective in suppressing the devastating effect of colon-related tumors. Rosmarinic acid (RA), one of the compounds of plant origin, possesses attractive features for use as an agent for cancer prevention and treatment. This study investigated the ability of RA to prevent azoxymethane (AOM)-induced rat colon carcinogenesis by evaluating the effect of RA on tumor formation and circulatory oxidant-antioxidant status. Moreover, plasma levels of adiponectin (APN) monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) were detected by enzyme linked immunosorbent assay. The animals were divided into three groups: Control, AOM, and AOM + RA. Rats were fed a modified pellet diet (15.8% peanut oil was added to the standard diet) during the experimental period. Colon cancer was formed by applying 15 mg/kg AOM intraperitoneal once a week for 4 weeks in both the CRC group and AOM + RA group. Besides AOM, AOM + RA group received 5 mg/kg body weight RA orally every day during the study. The results showed that adenocarcinoma rates formed 87.5% of the AOM group. With treatment of RA, a reduction in the incidence of adenocarcinoma was observed in the AOM + RA group. The plasma MCP-1, IL-6, and TO levels were significantly higher, APN and TAS levels were significantly lower in the AOM group with respect to controls. In addition, there was a significant increase in TAS levels in the RA treatment group compared to the AOM group. These findings suggested that RA may be beneficial in preventing AOM-induced colon carcinogenesis formation.


[Rehabilitation of stroke patients. Possibilities, duration and effect].
A close relationship exists between the severity of a stroke and the functional level that can be obtained after rehabilitation. The goal of rehabilitation, therefore, should be based on the severity of the stroke. Remission mainly takes place (more than 80 per cent) within the first three months post stroke. Remission after six months is very rare. Age and side of hemiparesis do not seem to influence the effect of rehabilitation significantly. It is not elucidated whether the severity of the stroke influence the effect of rehabilitation. Most of the controlled and the randomized studies indicate that rehabilitation of stroke patients, especially in rehabilitation units, accelerate remission, reduces length of stay and gives rise to a lasting improvement of function.


Formation and characterization of aurothioneins: Au,Zn,Cd-thionein, Au,Cd-thionein, and (thiomalato-Au)chi-thionein.
Three gold-containing thioneins (Au,Zn,Cd-Th, Au,Cd-Th, and (TmSAu)chi Th, where Th = thionein and TmS = thiomalate) have been prepared by the reactions of horse kidney Zn,Cd-thionein with gold thiomalate (AuSTm). When thionein was present in excess, the thiomalate ligand was displaced and the protein chelated the gold in a bidentate fashion. Primarily zinc but also some cadmium was displaced to form Au,Zn,Cd-Th or Au,Cd-Th. Excess AuSTm reacted to form (TmSAu)chi-thionein with monodentate coordination of the protein to each bound gold, retention of the thiomalate, loss of zinc and cadmium, and an increase in the Stokes radius of the product. EXAFS/XANES studies of Au,Zn,Cd-Th and (TmSAu)chi Th established that the oxidation states and coordination environments of gold were Au(I)S2 and that the gold-sulfur bond distances were 229 and 230 pm, respectively. Radioimmunoassay established that the aurothioneins retained their antigenicity to native metallothionein antibodies. Metal exchange reactions with gold were complete within 5-10 min when Zincon or 4-(2-pyridylazo) resorcinol was used to monitor Cd2+ and Zn2+ displacement.


[Retinolemia, vitamin A intake, and blood pressure in the elderly].
The objective of this study was to evaluate the retinolemia and consumption of vitamin A rich foods and their association with blood pressure levels in the elderly. This is a cross-sectional study, with a systematic sample of 297 elderly subjects enrolled at the Family Health Program of Camaragibe, Pernambuco, between November/December of 2003. Vitamin A status was assessed by retinolemia (HPLC) and by the consumption of vitamin A rich foods (food frequency questionnaire). Blood pressure levels were classified according to the V Brazilian Guidelines on Hypertension. A prevalence of inadequate retinolemia (< 1.05 micromol/L) of 26.3% (CI95% 21.4-31.9) was found. The frequency of preformed vitamin A intake (> 3x/week) was lower (p = 0.000) than the provitamin A intake. The prevalence of systemic arterial hypertension (SAH) was 58.6% (CI95% 52.7-64.3). Isolated systolic hypertension was more prevalent among subjects. There was no correlation between retinolemia and vitamin A rich-food intake (p > 0.05). In addition, there was no association between blood pressure levels and vitamin A rich-food intake (p > 0.05). However, retinolemia in the elderly classified in stage 1 of SAH was higher (p = 0.02) than in the elderly with great/normal blood pressure. The findings suggest a vulnerability of these subjects to hypovitaminosis A and SAH. Nevertheless, the role of vitamin A in the endothelial function modulation and inflammatory responses associated to SAH should be addressed in future studies.


Guanidine block of single channel currents activated by acetylcholine.
The acetylcholine-activated channel of chick myotube was studied using the patch-clamp method. Single channel current amplitudes were measured between -300 and +250 mV in solutions containing the permeant ions Cs+ and guanidine (G+). G+ has a relative permeability, PG/PCs, of 1.6, but carries no more than half the current that Cs+ does, with an equivalent electrochemical driving force. Experiments using G+ revealed an asymmetry of the acetylcholine-activated channel, with G+ being more effective at reducing Cs+ currents when added to the outside than when added to the inside. The block caused by outside, but not inside, G+ was evident for both inward and outward currents. The block caused by outside G+ was voltage dependent, first increasing and then being partially relieved when the driving force was made more negative. Experiments with mixtures of Cs+ and G+ revealed anomalously low magnitudes for reversal potentials, relative to predictions based on the Goldman-Hodgkin-Katz equation. These findings are consistent with a two-well, three-barrier Eyring rate model for ion flow, and demonstrate that a highly permeant ion, guanidine, can block asymmetrically by acting from within the voltage field of the acetylcholine-activated channel.


A generic framework for internet-based interactive applications of high-resolution 3-D medical image data.
With the advances in medical imaging devices, large volumes of high-resolution 3-D medical image data have been produced. These high-resolution 3-D data are very large in size, and severely stress storage systems and networks. Most existing Internet-based 3-D medical image interactive applications therefore deal with only low- or medium-resolution image data. While it is possible to download the whole 3-D high-resolution image data from the server and perform the image visualization and analysis at the client site, such an alternative is infeasible when the high-resolution data are very large, and many users concurrently access the server. In this paper, we propose a novel framework for Internet-based interactive applications of high-resolution 3-D medical image data. Specifically, we first partition the whole 3-D data into buckets, remove the duplicate buckets, and then, compress each bucket separately. We also propose an index structure for these buckets to efficiently support typical queries such as 3-D slicer and region of interest, and only the relevant buckets are transmitted instead of the whole high-resolution 3-D medical image data. Furthermore, in order to better support concurrent accesses and to improve the average response time, we also propose techniques for efficient query processing, incremental transmission, and client sharing. Our experimental study in simulated and realistic environments indicates that the proposed framework can significantly reduce storage and communication requirements, and can enable real-time interaction with remote high-resolution 3-D medical image data for many concurrent users.


Evaluating the impact of pre-hospital trauma team activation criteria.
Little evidence exists studying the benefits of pre-hospital trauma team activation. Our study measured the impact of pre-hospital trauma team activation on 24-h survival. Our secondary objectives assessed the effects of pre-hospital trauma team activation on time to emergency procedure, computed tomography, blood transfusion, and critical administration threshold, as well as emergency department length of stay. We conducted a 40-month health records review on all trauma team activations at The Ottawa Hospital, a Level 1 Trauma Center. Outcomes were compared between pre-hospital and in-hospital trauma team activations. We used logistic and linear regression models to assess outcomes, while controlling for injury severity score, age, systolic blood pressure, and anti-coagulation use. A P value < 0.05 was considered statistically significant. A sensitivity analysis was also used to validate the primary outcome results. Of the 1013 trauma team activations occurring during the study period, 762 patients were included. The mean age (41.3 vs. 43.8) and percentage of males (79.4% vs. 77.5%) for pre-hospital activations were similar to their counterparts. Pre-hospital activations did not have a statistically significant effect on 24-h mortality (14.4% vs. 4.5%; P = 0.30). However, pre-hospital activations did demonstrate a statistically significant reduction in time (minutes) to emergency procedure (18.0 vs. 27.0; P < 0.001), computed tomography (37.0 vs 42.0; P = 0.009), and blood transfusion (14.0 vs. 28.0; P < 0.001), as well as emergency department length of stay (101.0 vs. 171.0; P < 0.001). When controlling for key covariates, pre-hospital trauma team activation did not have a significant effect on 24-h mortality, but did result in a significant reduction in time to emergency procedure, computed tomography, and blood transfusion, as well as emergency department length of stay. Our study demonstrates that pre-hospital trauma team activation can expedite patient intervention and disposition.


The Index of Cognitive Activity as a Measure of Cognitive Processing Load in Dual Task Settings.
Increases in pupil size have long been used as an indicator of cognitive load. Recently, the Index of Cognitive Activity (ICA), a novel pupillometric measure has received increased attention. The ICA measures the frequency of rapid pupil dilations, and is an interesting complementary measure to overall pupil size because it disentangles the pupil response to cognitive activity from effects of light input. As such, it has been evaluated as a useful measure of processing load in dual task settings coordinating language comprehension and driving. However, the cognitive underpinnings of pupillometry, and any differences between rapid small dilations as measured by the ICA and overall effects on pupil size are still poorly understood. Earlier work has observed that the ICA and overall pupil size may not always behave in the same way, reporting an increase in overall pupil size but decrease in ICA in a dual task setting. To further investigate this, we systematically tested two new dual-task combinations, combining both language comprehension and simulated driving with a memory task. Our findings confirm that more difficult linguistic processing is reflected in a larger ICA. More importantly, however, the dual task settings did not result in an increase in the ICA as compared to the single task, and, consistent with earlier findings, showed a significant decrease with a more difficult secondary task. This contrasts with our findings for pupil size, which showed an increase with greater secondary task difficulty in both tasks. Our results are compatible with the idea that although both pupillometry measures are indicators of cognitive load, they reflect different cognitive and neuronal processes in dual task situations.


Peroxidase profiling reveals genetic linkage between peroxidase gene clusters and basal host and non-host resistance to rusts and mildew in barley.
Higher plants possess a large multigene family encoding secreted class III peroxidase (Prx) proteins. Peroxidases appear to be associated with plant disease resistance based on observations of induction during disease challenge and the presence or absence of isozymes in resistant vs susceptible varieties. Despite these associations, there is no evidence that allelic variation of peroxidases directly determines levels of disease resistance. The current study introduces a new strategy called Prx-Profiling. We showed that with this strategy a large number of peroxidase genes can be mapped on the barley genome. In order to obtain an estimate of the total number of Prx clusters we followed a re-sampling procedure, which indicated that the barley genome contains about 40 peroxidase gene clusters. We examined the association between the Prxs mapped and the QTLs for resistance of barley to homologous and heterologous rusts, and to the barley powdery mildew fungus. We report that 61% of the QTLs for partial resistance to P. hordei, 61% of the QTLs for resistance to B. graminis and 47% of the QTLs for non-host resistance to other Puccinia species co-localize with Prx based markers. We conclude that Prx-Profiling was effective in finding the genetic location of Prx genes on the barley genome. The finding that QTLs for basal resistance to rusts and powdery mildew fungi tend to co-locate with Prx clusters provides a base for exploring the functional role of Prx-related genes in determining natural differences in levels of basal resistance.


The effects of oxidative stress on mitochondrial transmembrane potential in retinal ganglion cells.
Retinal ganglion cells (RGCs) are central neurons that undergo apoptosis after axonal injury. As the relationship between mitochondrial and oxidative signaling of apoptosis in neuronal systems is unclear, we sought to achieve a better understanding of the interplay of these two pathways by investigating the effect of direct oxidative stress on mitochondrial membrane potential in cultured RGCs, as measured with the dual-emission probe JC-1. Treatment with hydrogen peroxide caused RGC mitochondrial depolarization. Several pharmacological treatments were used to define the mechanism. Whereas cycloheximide, tris(2-carboxyethyl)phosphine, and cyclosporin A were unable to prevent the depolarization, bongkrekic acid significantly reduced the severity of the depolarization. This suggests that the hydrogen peroxide-induced depolarization may act through mitochondrial permeability transition pore opening independent of thiol oxidation, and may be preventable under certain conditions.


The effectiveness of interventions aimed at reducing anxiety in health care waiting spaces: a systematic review of randomized and nonrandomized trials.
Reducing waiting anxiety is an important objective of patient-centered care. Anxiety is linked to negative health outcomes, including longer recovery periods, lowered pain thresholds, and for children in particular, resistance to treatment, nightmares, and separation anxiety. The goals of this study were (1) to systematically review published research aimed at reducing preprocedural waiting anxiety, and (2) to provide directions for future research and development of strategies to manage preprocedural waiting anxiety in health care environments. We performed a systematic review of the literature via ISI Web of Knowledge, PubMed, PsycINFO, EMBASE, CINAHL, and Medline. Included in this review were studies describing measurable outcomes in response to interventions specifically intended to improve the waiting experience of patients in health care settings. Primary outcomes of interest were stress and anxiety. Exclusion criteria included (a) studies aimed at reducing wait times and management of waiting lists only, (b) waiting in non-health care settings, (c) design of health care facilities with nonspecific strategies pertaining to waiting spaces, (d) strategies to reduce pain or anxiety during the course of medical procedures, and (e) interventions such as massage, acupuncture, or hypnosis that require dedicated staff and/or private waiting environments to administer. We identified 8690 studies. Forty-one articles met the inclusion criteria. In adult populations, 33 studies were identified, wherein the effects of music (n = 25), aromatherapy (n = 6), and interior design features (n = 2) were examined. Eight pediatric studies were identified investigating play opportunities (n = 2), media distractions (n = 2), combined play opportunities and media distractions (n = 3), and music (n = 1). Based on results from 1129 adult participants in the 14 studies that evaluated music and permitted meta-analysis, patients who listened to music before a medical procedure exhibited a lowered-state anxiety (-5.1 ± 0.53 points on the State Trait Anxiety Scale) than those who received standard care. The efficacy of aromatherapy was inconclusive. Studies reporting on the impact of improved interior design of waiting areas, while positive, are minimal and heterogeneous. For children, insufficient evidence is available to corroborate the effectiveness of play opportunities, media distractions, and music for mitigating anxiety in children awaiting medical procedures. Music is a well-established means of decreasing anxiety in adult patients awaiting medical interventions. The effect of music on children's anxiety is not known. Limited studies and heterogeneity of interventions and methods in the areas of aromatherapy, interior design, digital media, and play opportunities (for children) suggest the need for future research.