Ocean color remote sensing: choosing the correct depth weighting function.
Values of reflectance and remote sensing reflectance are proportional to the ratio of sea water backscattering to absorption. However, in vertically non-homogeneous waters, this fraction needs to be depth weighted. The usual practice uses normalized vertical transmittance profiles as the weighting function. Recently, it was shown that the correct approach is to use, instead of transmittance, its first derivative. We used both approaches to calculate spectral reflectance and remote sensing reflectance over a submerged bubble cloud and chlorophyll rich layer and compared the results with a radiative transfer Monte Carlo code. We also compared several methods of approximating diffuse attenuation (not measured directly) to estimate the effect on calculating reflectance. Our results show that the traditional method of IOP weighting is inadequate in the presence of bubble clouds and/or chlorophyll rich layers. This is relevant for both "ground truth" studies and inverse methods of remote sensing (including lidar ones) for vertically inhomogeneous ocean sea waters.


A radical approach to minimally invasive total hip replacement: surgical technique and pre-clinical test data.
Currently total hip replacement surgery using minimally invasive techniques is a fast developing field. However, all reports concern adaptations of surgical techniques with adapted instruments using conventional implants. These conventional implants limit the minimal invasiveness to some extent. In this paper a new system is reported featuring a new surgical approach, new instrumentation and a new implant design. The purpose of this study was to introduce the system and to assess the feasibility of the system in terms of stability, range of motion and wear characteristics. The pre-clinical tests indicated that the factor of safety for this type of design is smaller than for conventional implants. However, the results show adequate performance of the system, which suggests that further development and testing is justified to advance the system for clinical use.


Inappropriate elevation of serum leptin levels in children with chronic renal failure. European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood.
Decreased spontaneous nutrient intake is a frequent clinical problem in patients with chronic renal failure (CRF). Leptin, the recently characterized gene product of the obese gene, is produced by adipocytes and is thought to act as an afferent satiety signal on the appetite and satiety centers of the brain. Serum leptin levels were investigated in 134 pediatric patients in different stages of CRF to evaluate a possible relationship between leptin, GFR, and spontaneous energy intake. Serum leptin levels, measured by a specific RIA, were elevated above the 50th percentile of the normal range in 78% of CRF patients and above the 95th percentile in 45% of patients. Gel chromatography of CRF sera yielded only one single immunoreactive peak at 16 kD, indicating that the increase of immunoreactive leptin levels in CRF serum was not due to accumulation of leptin degradation products. Multiple stepwise regression analysis revealed the percentage of body fat as assessed from skinfold measurements (r = 0.79, P < 0.0001) and GFR (r = -0.17, P < 0.005) as independent predictors of serum leptin levels, accounting for 66% of total statistical variability. There was an inverse linear correlation between standardized leptin levels (leptin z-score) and the spontaneous energy intake quantified from written dietary diaries (r = -0.36, P < 0.001). These data suggest that the percentage of body fat remains the main determinant of serum leptin in CRF patients, but their levels increase with declining GFR, presumably by reduced renal clearance. Leptin levels in CRF serum that are inappropriately elevated in relation to the percentage of body fat might lead to a dysregulation of the normal peripheral-central leptin feedback loop, thereby contributing to decreased nutrient intake in uremia.


Multi-Amplified Sensing of MicroRNA by a Small DNA Fragment-Driven Enzymatic Cascade Reaction.
Combining technological developments such as nanomaterials, DNA nanotechnology, and functional enzymes has great potential to facilitate next generation high performance molecular diagnostic systems. In this work, we describe a microRNA (miRNA) detection assay that combines target recycling and isothermal amplification in an elegantly designed enzyme-mediated cascade reaction. Target recycling is driven by the action of duplex-specific nuclease (DSN), resulting in highly amplified translation of input miRNA to short output DNA fragments. These fragments act as highly specific initiators of rolling circle amplification (RCA), an isothermal reaction that outputs a large volume of polymeric DNAzymes per initiator, and finally a fluorogenic output signal. Based on careful electrophoretic analysis we observed that the DSN produces ca. 10 nt DNA fragments from DNA/miRNA duplexes, regardless of the length of DNA strands. Target recycling yielded ca. 5 orders of magnitude amplification through the DSN-assisted recycling system on magnetic particles, and the RCA yielded a further 2 orders of magnitude. The final assay exhibited a limit of detection of 1.8 fM of miRNA spiked into 20% human serum, and showed excellent selectivity for miR-21 versus single base-mismatched sequences and other cancer-related miRNAs. The developed assay was further employed to determine accurate amounts of miR-21 in total RNA samples extracted from human cancer cell lines and normal cells, confirming the applicability of the assay for direct and absolute quantification of mature specific miRNA in real biological samples.


Comorbid Mental Disorders in Fetal Alcohol Spectrum Disorders: A Systematic Review.
A systematic review of published literature to estimate prevalence of comorbid mental disorders in fetal alcohol spectrum disorders (FASDs) and compare with general population prevalence estimates. A PubMed search was used to locate articles reporting on FASD and mental disorders published through June 2015. Next, lists of published studies from all issues of the National Organisation for Foetal Alcohol Syndrome-UK publication Fetal Alcohol Forum-were searched. Weighted average prevalence was estimated for the comorbid mental disorders with sufficient data for analysis. We then compared prevalence of mental disorders in the FASD population with rates in the mental health literature. We identified 26 articles reporting 5984 cases of FASD. Of the 15 comorbid mental disorders, 11 had sufficient data for inclusion in the analysis. Attention-deficit/hyperactivity disorder occurred in 50% of persons with FASD (10 times the expected rate). Intellectual disability occurred at 23 times the expected rate. In 5 of the 12 disorders, rates in the FASD population significantly exceeded expected rates by 10% to 45%. Increased rates of mental disorders in people with FASD are commonly reported. Mental health providers should routinely consider FASD in the diagnosis and management of mental illness and developmental disorders. The quality of the research and precision of comorbidity estimates would be improved by additional studies including people with FASD and non-FASD comparison subjects. Until these studies are available, this review provides the best available estimates of comorbid mental disorders in people with FASD.


Optical imaging of the ventral medullary surface across sleep-wake states.
We hypothesized that spontaneous activity declines over widespread areas of the cat ventral medullary surface (VMS) during rapid eye movement (REM) sleep. We assessed neural and hemodynamic activity, measured as changes in reflected 660- and 560-nm wavelength light, from the VMS during sleep and waking states in five adult, unrestrained cats and in two control cats. Relative to quiet sleep, overall activity declined, and variability, assessed by standard deviation, increased by 25% during REM sleep. Variability in activity during waking also increased by 45% over quiet sleep, but mean activity was unchanged. REM sleep onset was preceded by a reduction in the hemodynamic signal from 5 to 60 s before neural activity decline. The activity decline during REM sleep, previously noted in the goat rostral VMS, extends to intermediate VMS areas of the cat and differs from most neural sites, such as the cortex, hippocampus, and thalamus, which increase activity during REM sleep. The activity decline during REM sleep has the potential to modify VMS responsiveness to baroreceptor and chemoreceptor challenges during the REM state.


Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis.
The pathologic features of invasion such as stromal disruption and pleural/vascular involvement have been shown to be of prognostic value in adenocarcinoma. However, the relationship between the degree of invasion, histologic subtype of adenocarcinoma, and prognosis remains unclear. We retrospectively studied 380 peripheral adenocarcinomas of < or = 2.0 cm in diameter with regard to histology and clinical profiles. Their degree of invasive growth was classified into four grades as follows according to the structural deformity and its location in the adenocarcinoma lesion: Grade 0 had a pure bronchioloalveolar growth pattern and no evidence of stromal invasion. Grade 1 had stromal invasion in the area of bronchioloalveolar growth. Grade 2 had stromal invasion localized on the periphery of a fibrotic focus. Grade 3 had stromal invasion into the center of a fibrotic focus. The clinicopathological data were obtained from medical records. The distribution of the histologic grade of invasion was as follows: grade 0 in 85 tumors (22%), grade 1 in 37 (10%), grade 2 in 46 (12%), and grade 3 in 212 (56%). This histologic grade of invasion was closely related to other indicators of tumor spread. Vascular/lymphatic permeation was seen in none of grade 0, in 1 lesion each of grade 1 and grade 2, and 144 (68%) of grade 3. Lymph node metastasis was seen in 57 (27%) lesions of grade 3 but not in grades 0, 1, or 2. The 5-year disease-free survival rates were 100%, 100%, 100%, and 59.6% for tumors with grade 0, grade 1, grade 2, and grade 3 invasion, respectively. Tumors with grade 1 and grade 2 invasion, like tumors with grade 0 invasion (bronchioloalveolar carcinoma), showed an excellent prognosis. Therefore, tumors with grade 1 and grade 2 invasion could be considered "minimally invasive" or "early" adenocarcinomas.


Inverse determination of the penalty parameter in penalized weighted least-squares algorithm for noise reduction of low-dose CBCT.
A statistical projection restoration algorithm based on the penalized weighted least-squares (PWLS) criterion can substantially improve the image quality of low-dose CBCT images. The performance of PWLS is largely dependent on the choice of the penalty parameter. Previously, the penalty parameter was chosen empirically by trial and error. In this work, the authors developed an inverse technique to calculate the penalty parameter in PWLS for noise suppression of low-dose CBCT in image guided radiotherapy (IGRT). In IGRT, a daily CBCT is acquired for the same patient during a treatment course. In this work, the authors acquired the CBCT with a high-mAs protocol for the first session and then a lower mAs protocol for the subsequent sessions. The high-mAs projections served as the goal (ideal) toward, which the low-mAs projections were to be smoothed by minimizing the PWLS objective function. The penalty parameter was determined through an inverse calculation of the derivative of the objective function incorporating both the high and low-mAs projections. Then the parameter obtained can be used for PWLS to smooth the noise in low-dose projections. CBCT projections for a CatPhan 600 and an anthropomorphic head phantom, as well as for a brain patient, were used to evaluate the performance of the proposed technique. The penalty parameter in PWLS was obtained for each CBCT projection using the proposed strategy. The noise in the low-dose CBCT images reconstructed from the smoothed projections was greatly suppressed. Image quality in PWLS-processed low-dose CBCT was comparable to its corresponding high-dose CBCT. A technique was proposed to estimate the penalty parameter for PWLS algorithm. It provides an objective and efficient way to obtain the penalty parameter for image restoration algorithms that require predefined smoothing parameters.


Clinical trials and evaluation of a mobile, robotic tele-ultrasound system.
We have developed a robotic tele-ultrasound system (OTELO) that allows an expert to examine a distant patient by ultrasound. At the expert station, a sonographer controls a virtual probe. Movements are reproduced at the patient station, which may be several kilometres away, on a real probe held by a lightweight robot, which is positioned on the patient by a paramedic. Two medical teams tested the tele-ultrasound system at two different hospitals on a total of 52 patients. Except for some difficulties caused by particular conditions, the diagnosis obtained with the remote scanning system agreed in at least 80% of the cases with the diagnosis made by conventional scanning. The results demonstrate the feasibility and efficiency of the device.


Long-Term Consequence of Non-neurotropic H3N2 Influenza A Virus Infection for the Progression of Alzheimer's Disease Symptoms.
Influenza viruses until today are a leading cause of worldwide severe pandemics and represent a major threat to human and animal health. Although the primary target of influenza viruses is the lung, infection may manifest with acute and even chronic neurological complications (e.g., status epilepticus, encephalopathies, and encephalitis) potentially increasing the long-term risk for neurodegenerative diseases. We previously described that a peripheral influenza A virus (IAV) infection caused by non-neurotropic H3N2 (maHK68) variant leads to long-term neuroinflammation and synapse loss together with impaired memory formation in young adult mice. Processes of neuroinflammation have been associated with neurodegenerative diseases such as Alzheimer's disease (AD) and prolonged or excessive innate immune responses are considered a risk factor for AD. Here, the role of purely peripheral IAV infection for the development and progression of AD in a transgenic mouse model (APP/PS1) was investigated. At 2 months of age, mice were infected with H3N2 IAV and the detailed analysis of microglia morphology revealed neuroinflammation in the hippocampus already of 6 months old non-infected APP/PS1 mice together with impaired spatial learning, however, microglia activation, amyloid-β plaques load and cognitive impairments were even more pronounced in APP/PS1 mice upon H3N2 infection. Moreover, CA1 hippocampal dendritic spine density was reduced even at 120 dpi compared to wild-type and also to non-infected APP/PS1 mice, whereas neuronal cells number was not altered. These findings demonstrate that non-neurotropic H3N2 IAV infection as a peripheral immune stimulation may exacerbate AD symptoms possibly by triggering microglial hyperactivation.


Telemetry and genetics reveal asymmetric dispersal of a lake-feeding salmonid between inflow and outflow spawning streams at a microgeographic scale.
The degree of natal philopatry relative to natal dispersal in animal populations has important demographic and genetic consequences and often varies substantially within species. In salmonid fishes, lakes have been shown to have a strong influence on dispersal and gene flow within catchments; for example, populations spawning in inflow streams are often reproductively isolated and genetically distinct from those spawning in relatively distant outflow streams. Less is known, however, regarding the level of philopatry and genetic differentiation occurring at microgeographic scales, for example, where inflow and outflow streams are separated by very small expanses of lake habitat. Here, we investigated the interplay between genetic differentiation and fine-scale spawning movements of brown trout between their lake-feeding habitat and two spawning streams (one inflow, one outflow, separated by <100 m of lake habitat). Most (69.2%) of the lake-tagged trout subsequently detected during the spawning period were recorded in just one of the two streams, consistent with natal fidelity, while the remainder were detected in both streams, creating an opportunity for these individuals to spawn in both natal and non-natal streams. The latter behavior was supported by genetic sibship analysis, which revealed several half-sibling dyads containing one individual that was sampled as a fry in the outflow and another that was sampled as fry in the inflow. Genetic clustering analyses in conjunction with telemetry data suggested that asymmetrical dispersal patterns were occurring, with natal fidelity being more common among individuals originating from the outflow than the inflow stream. This was corroborated by Bayesian analysis of gene flow, which indicated significantly higher rates of gene flow from the inflow into the outflow than vice versa. Collectively, these results reveal how a combination of telemetry and genetics can identify distinct reproductive behaviors and associated asymmetries in natal dispersal that produce subtle, but nonetheless biologically relevant, population structuring at microgeographic scales.


Postfracture care for older women: gaps between optimal care and actual care.
To investigate rates of assessment and treatment of osteoporosis among older women during the year after they have had fractures. Observational, historical, population-based cohort study. Manitoba, which maintains a comprehensive population-based repository of health care services provided and has a publicly funded health care system. Women 50 years old and older who had suffered fractures between 1997 and 2002. These women were chosen from among approximately 175,000 women of this age in Manitoba. We examined each woman's annual medical record between April 1, 1997, and March 31, 2002, to find any International Classification of Diseases fracture codes that have been consistently associated with osteoporosis. We looked for postfracture care during the first 12 months after fractures: bone mineral density (BMD) testing or treated with osteoporosis pharmacotherapy. Analysis was stratified by type of fracture: designated type 1 fractures (spine or hip) and type 2 fractures (not spine or hip). Use of BMD testing or osteoporosis pharmacotherapy during the first 12 months following fractures. For type 1 fractures, BMD assessment during the first year after fracture increased from 2.6% in 1997-1998 to 4.6% in 2001-2002 (P for trend .0004). Rates of therapy with osteoporosis medication increased from 4.9% in 1997-1998 to 17.6% in 2001-2002 (P for trend < .0001). Results were similar for type 2 fractures. In the final year of the study, only 20.5% of women with either type of fracture underwent any identifiable intervention (BMD assessment or osteoporosis pharmacotherapy). The intervention rate was substantially higher among women 50 to 64 years old (26.4%) than among those 75 years old or older (17.9%, P for trend < .0001). Women at highest risk of future fractures are assessed infrequently for osteoporosis with BMD testing and given pharmacotherapy to prevent future fractures just as infrequently. This gap in care was particularly striking for BMD testing despite the fact that testing is free in Manitoba's publicly funded system. Data from this study could be educational for physicians treating osteoporosis and should encourage them to improve their practice patterns and optimize patient care.


The sensitivity of human mesenchymal stem cells to ionizing radiation.
Recent studies have shown that mesenchymal stem cells (MSCs) obtained from bone marrow transplantation patients originate from the host. This clinical observation suggests that MSCs in their niches could be resistant to irradiation. However, the biologic responses of bone marrow MSCs to irradiation have rarely been described in the literature. In this study, human bone marrow-derived, clonally expanded MSCs were used to investigate their sensitivity to irradiation in vitro, and the cellular mechanisms that may facilitate resistance to irradiation. The human lung cancer cell line A549 and the breast cancer cell line HCC1937 were used as controls for radiosensitivity; the former line has been shown to be radioresistant and the latter radiosensitive. We then examined their in vitro biologic changes and sensitivities to radiation therapy. Our results suggest that MSCs are characterized as resistant to irradiation. Several cellular mechanisms were demonstrated that may facilitate resistance to irradiation: ATM protein phosphorylation, activation of cell-cycle checkpoints, double-strand break repair by homologous recombination and nonhomologous end joining (NHEJ), and the antioxidant capacity for scavenging reactive oxygen species. As demonstrated, MSCs possess a better antioxidant reactive oxygen species-scavenging capacity and active double-strand break repair to facilitate their radioresistance. These findings provide a better understanding of radiation-induced biologic responses in MSCs and may lead to the development of better strategies for stem cell treatment and cancer therapy.


[The effect of occupational exposure to heavy metals and arsenic on serum concentrations of carotenoids in copper foundry workers].
The aim of the project was to analyze the effect of occupational exposure to heavy metals on the efficiency of antioxidative defensive mechanisms, represented by the concentration of carotenoids (KTND) in serum. The study involved 96 workers exposed to heavy metals in a copper foundry. Two subgroups of workers--those exposed only to lead and those to the combination of lead and arsenic--were analyzed. The control group consisted of 81 subjects not exposed to heavy metals. We measured concentrations of lead and cadmium in whole blood, selenium, manganese, copper, zinc, calcium, magnesium and carotenoids in serum, arsenic in urine and free erythrocyte protoporphyrin (FEP). Serum carotenoids concentration was significantly lower in workers exposed to heavy metals than in the control group (48.76 +/- 15.32 vs. 68.36 +/- 21.46 microg/dl; p < 0.001). There were no significant differences between serum concentrations of carotenoids in the subgroup exposed only to lead and the subgroup exposed to both lead and arsenic ((48.62 +/- 16.64 vs. 48.86 +/- 14.41 microg/dl). We found significant positive correlation between blood cadmium levels and serum carotenoids in the control group (r = -0.3406, p < 0.05). In the multiple regression analysis (optimal model), there was significant negative influence of blood lead on serum KTND levels and positive influence of blood cadmium on serum KTND concentrations in the subgroup of workers exposed only to lead (R(2) A = 0.9102; p < 0.001). In smelters exposed to both lead and arsenic, we observed significant negative influence of FEP and positive influence of arsenic on KTND concentrations in serum in the optimal model of multiple regression (R(2) A = 0.9249; p < 0.001). Occupational exposure to lead and arsenic in moderate doses affects serum carotenoids concentration in exposed humans.


[The patient record of the use of hormonal contraceptives--a possibility for better monitoring].
A card is introduced, which in addition to essential anamnestic data permits registration of entry of diseases, side effects, smoking habits, additional drug intake and results of examinations during steroid medication. The card to be presented whenever a physician is consulted is intended to convey better pill-taking information to other specialists, while also ensuring follow-up of such patients.


Artesunate tolerance in transgenic Plasmodium falciparum parasites overexpressing a tryptophan-rich protein.
Due to their rapid, potent action on young and mature intraerythrocytic stages, artemisinin derivatives are central to drug combination therapies for Plasmodium falciparum malaria. However, the evidence for emerging parasite resistance/tolerance to artemisinins in southeast Asia is of great concern. A better understanding of artemisinin-related drug activity and resistance mechanisms is urgently needed. A recent transcriptome study of parasites exposed to artesunate led us to identify a series of genes with modified levels of expression in the presence of the drug. The gene presenting the largest mRNA level increase, Pf10_0026 (PArt), encoding a hypothetical protein of unknown function, was chosen for further study. Immunodetection with PArt-specific sera showed that artesunate induced a dose-dependent increase of the protein level. Bioinformatic analysis showed that PArt belongs to a Plasmodium-specific gene family characterized by the presence of a tryptophan-rich domain with a novel hidden Markov model (HMM) profile. Gene disruption could not be achieved, suggesting an essential function. Transgenic parasites overexpressing PArt protein were generated and exhibited tolerance to a spike exposure to high doses of artesunate, with increased survival and reduced growth retardation compared to that of wild-type-treated controls. These data indicate the involvement of PArt in parasite defense mechanisms against artesunate. This is the first report of genetically manipulated parasites displaying a stable and reproducible decreased susceptibility to artesunate, providing new possibilities to investigate the parasite response to artemisinins.


Geriatric assessment in older patients with breast cancer.
Most cases of breast cancer are diagnosed in older adults. Older women have an increased risk for breast cancer-specific mortality and are at higher risk for treatment-associated morbidity than younger women. However, they are also less likely to be offered preventive care or adjuvant therapy for this disease. Major gaps in evidence exist regarding the optimal evaluation and treatment of older women with breast cancer because of significant underrepresentation in clinical trials. Chronologic age alone is an inadequate predictor of treatment tolerance and benefit in this heterogeneous population. Multiple issues uniquely associated with aging impact cancer care, including functional impairment, comorbidity, social support, cognitive function, psychological state, and financial stress. Applying geriatric principles and assessment to this older adult population would inform decision making by providing estimates of life expectancy and identifying individuals most vulnerable to morbidity. Ongoing research is seeking to identify which assessment tools can best predict outcomes in this population, and thus guide experts in tailoring treatments to maximize benefits in older adults with breast cancer.


The Effect That Induced Rider Asymmetry Has on Equine Locomotion and the Range of Motion of the Thoracolumbar Spine When Ridden in Rising Trot.
There is a paucity of evidence on the effect that rider asymmetry has on equine locomotion. The aim of this study was to evaluate the effect of rider asymmetry on equine locomotion by using a novel approach to induce rider asymmetry. Ten nonlame horses were recruited for this study. Joint center markers were used to capture 2D kinematics (Quintic Biomechanics) of the horse and rider and horses were equipped with seven inertial sensors positioned at the fifth (T5) and eighteenth (T18) thoracic vertebrae, third lumbar (L3) vertebra, tubera sacrale (TS), and left and right tubera coxae. Rider asymmetry was induced by shortening the ventral aspect of one stirrup by 5 cm. Kinematic data were compared between conditions using a mixed model with the horse defined as a random factor and stirrup condition (symmetrical stirrups and asymmetrical stirrups) and direction (inside and outside) defined as fixed factors. Data from riders where the right stirrup was shortened were mirrored to reflect a left stirrup being shortened. To determine differences between conditions, a significance of P ≤ .05 was set. On the rein with the shortened stirrup on the outside: an increase in lateral bending range of motion (ROM) at T5 (P = .003), L3 (P = .04), and TS (P = .02), an increase in mediolateral displacement at T5 (P = .04), T18 (P = .04), and L3 (0.03) were found. An increase in maximum fetlock extension was apparent for both the front (P = .01) and hind limb (P = .04) on the contralateral side to the shortened stirrup; for the asymmetrical stirrup condition on the rein with the shortened stirrup on the inside: an increase in flexion-extension ROM at T5 (P = .03) and L3 (P = .04), axial rotation at T5 (P = .05), and lateral bending of T5 (P = .03), L3 (P = .04), and TS (P = .02). Asymmetric rider position appears to have an effect on the kinematics of the thoracolumbar spine. These findings warrant further investigation to understand the long-term impact this may have on equine locomotor health.


Impact of Operators' Height on Individual Radiation Exposure Measurements During Catheter-Based Cardiovascular Interventions.
This study is aimed to evaluate the impact of an operators' height on personal radiation exposure measurements during cardiovascular interventional procedures. Based upon both clinical data and phantom simulation, a new approach for monitoring an individual's exposure is proposed. The clinical component of this study was composed of the operators and staff in a single center full service cardiovascular laboratory being divided into 2 groups based upon their height: group A included all individuals whose height was <165 cm; group B included the individuals >165 cm. All operators wore a standard TLD dosimeter at all times with doses recorded for 12 months. To support these clinical findings, a second investigation was performed utilizing a phantom. Measurements were obtained at 100 and 135 cm from the radiation source during simulation of different cardiovascular interventional procedures. The radiation dose measured from the personal dosimeters identified that Group A, operators <165 cm, had significantly higher doses than those recorded in Group B, operators >165 cm, when compared among individuals performing similar tasks (physicians, technicians, and nurses): 4.55 ± 4.0 (Group A) versus 1.95 ± 1.0 (Group B) mSv (P < 0.01). During procedure simulation with the phantom, the doses measured were similarly significantly higher if measured at 100 cm than at 135 cm from the radiation source. This study suggests that the height from radiation source does impact the measured dose from an operator worn personal TLD. This was operator specific, consistent thought-out multiple procedures, and confined with phantom measurements.


A real-time analysis of intraoperative interruptions in relation to use of simple preventive measures including a sign on the door and a checklist-based team brief.
This study aimed to evaluate intraoperative interruptions by frequency, type, interference and source, and preventive measures. The interruptions in the operating theatre were evaluated for 52 surgical procedures based on real-time recordings and divided into routine operative procedures (ROP, n = 26, without intervention) and intervened operative procedures (IOP, n = 26, observed after team brief and placement of a warning sign for unnecessary door openings) groups. Intervened operative procedures vs. routine operative procedures was associated with a significantly lower number of interruptions (p = 0.014). Implementation of preventive measures was associated with a significantly lower number of entrances and exits (p = 0.001) and equipment issues (p = 0.003), interruptions that affected the circulating nurse or anaesthesia technician/associate (p = 0.003) and those caused by team members other than assisting surgeon and scrub nurse (p-value ranged from 0.015 to 0.009). Our findings revealed significantly reduced interruptions after a simple preventive measure including team brief and the placement of a warning sign for unnecessary door openings.


Chemokines, selectins and intracellular calcium flux: temporal and spatial cues for leukocyte arrest.
Leukocyte trafficking to acute sites of injury or infection requires spatial and temporal cues that fine tune precise sites of firm adhesion and guide migration to endothelial junctions where they undergo diapedesis to sites of insult. Many detailed studies on the location and gradient of chemokines such as IL-8 and other CXCR ligands reveal that their recognition shortly after selectin-mediated capture and rolling exerts acute effects on integrin activation and subsequent binding to their ligands on the endothelium, which directs firm adhesion, adhesion strengthening, and downstream migration. In this process, G-protein coupled receptor (GPCR) signaling has been found to play an integral role in activating and mobilizing intracellular stores of calcium, GTPases such as Rap-1 and Rho and cytokeletal proteins such as Talin and F-actin to facilitate cell polarity and directional pseudopod formation. A critical question remaining is how intracellular Ca(2+) flux from CRAC channels such as Orai1 synergizes with cytosolic stores to mediate a rapid flux which is critical to the onset of PMN arrest and polarization. Our review will highlight a specific role for calcium as a signaling messenger in activating focal clusters of integrins bound to the cytoskeleton which allows the cell to attain a migratory phenotype. The precise interplay between chemokines, selectins, and integrins binding under the ubiquitous presence of shear stress from blood flow provides an essential cooperative signaling mechanism for effective leukocyte recruitment.


Dok2 likely down-regulates Klf1 in mouse erythroleukemia cells.
Docking protein 2 (Dok2) is an adapter protein which is involved in hematopoiesis. However, it still remains unclear how Dok2 functions in regulation of transcription of hematopoietic genes. To address this issue, we knocked-down Dok2 mRNA in mouse erythroleukemia cells which highly express Dok2 intrinsically. Mouse erythroleukemia cells were transfected with Dok2 siRNA for 24 h and gene expression of erythroid differentiation-related genes, such as GATA binding protein 1 (Gata1), Krüppel-like factor 1 (Klf1), α-globin and β-globin were assessed by real-time polymerase chain reaction. Among the tested genes, expression of Klf1 exhibited a 1.94-fold increase when compared to the control 24 h after transfection. Immunocytochemistry and chromatin immunoprecipitation assays revealed that Dok2 protein localizes in the nucleus and binds to the promoter region of Klf1 gene. Dok2 is able to control Klf1 expression by transcriptional regulation through directly binding to its promoter region.


How we diagnose and treat systemic mastocytosis in adults.
Rapid advances in the understanding of the molecular biology, data from translational and clinical trials, and retrospective analyses has influenced the diagnosis and treatment of systemic mastocytosis (SM). Many options have existed for the symptomatic management of SM patients, but recent evolution in regards to the molecular underpinnings of this disease and our ability to distinguish clonal mastocytosis from mast cell activation syndrome has changed our treatment paradigm and opened new opportunities for understanding genetic risk, transformation to mast cell leukaemia, and treatment choices. Key to this change has been the discovery of the KIT mutation and the use of next generation sequencing to evaluate for co-existing molecular mutations that may define the disease course. Careful diagnosis, judicious symptom management and close surveillance of those who may have yet undiagnosed disease is paramount in providing optimal management. In this article, we review the diagnosis and provide a paradigm for the management of SM patients.


An efficient method for parallel CRC automatic generation.
The State Transition Equation (STE) based method to automatically generate the parallel CRC circuits for any generator polynomial or required amount of parallelism is presented. The parallel CRC circuit so generated is partially optimized before being fed to synthesis tools and works properly in our LAN transceiver. Compared with the cascading method, the proposed method gives better timing results and significantly reduces the synthesis time, in particular.


Catabolism of the Last Two Steroid Rings in Mycobacterium tuberculosis and Other Bacteria.
Most mycolic acid-containing actinobacteria and some proteobacteria use steroids as growth substrates, but the catabolism of the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis, this pathway includes virulence determinants and has been proposed to be encoded by the KstR2-regulated genes, which include a predicted coenzyme A (CoA) transferase gene (ipdAB) and an acyl-CoA reductase gene (ipdC). In the presence of cholesterol, ΔipdC and ΔipdAB mutants of either M. tuberculosis or Rhodococcus jostii strain RHA1 accumulated previously undescribed metabolites: 3aα-H-4α(carboxyl-CoA)-5-hydroxy-7aβ-methylhexahydro-1-indanone (5-OH HIC-CoA) and (R)-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA), respectively. A ΔfadE32 mutant of Mycobacterium smegmatis accumulated 4-methyl-5-oxo-octanedioic acid (MOODA). Incubation of synthetic 5-OH HIC-CoA with purified IpdF, IpdC, and enoyl-CoA hydratase 20 (EchA20), a crotonase superfamily member, yielded COCHEA-CoA and, upon further incubation with IpdAB and a CoA thiolase, yielded MOODA-CoA. Based on these studies, we propose a pathway for the final steps of steroid catabolism in which the 5-member ring is hydrolyzed by EchA20, followed by hydrolysis of the 6-member ring by IpdAB. Metabolites accumulated by ΔipdF and ΔechA20 mutants support the model. The conservation of these genes in known steroid-degrading bacteria suggests that the pathway is shared. This pathway further predicts that cholesterol catabolism yields four propionyl-CoAs, four acetyl-CoAs, one pyruvate, and one succinyl-CoA. Finally, a ΔipdAB M. tuberculosis mutant did not survive in macrophages and displayed severely depleted CoASH levels that correlated with a cholesterol-dependent toxicity. Our results together with the developed tools provide a basis for further elucidating bacterial steroid catabolism and virulence determinants in M. tuberculosis.IMPORTANCE Bacteria are the only known steroid degraders, but the pathway responsible for degrading the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis, this pathway includes virulence determinants. Using a series of mutants in M. tuberculosis and related bacteria, we identified a number of novel CoA thioesters as pathway intermediates. Analysis of the metabolites combined with enzymological studies establishes how the last two steroid rings are hydrolytically opened by enzymes encoded by the KstR2 regulon. Our results provide experimental evidence for novel ring-degrading enzymes, significantly advance our understanding of bacterial steroid catabolism, and identify a previously uncharacterized cholesterol-dependent toxicity that may facilitate the development of novel tuberculosis therapeutics.


Ketone-body metabolism after partial hepatectomy in the rat.
Fed or 24 h-starved rats were subjected to two-thirds partial hepatectomy or sham-operation and subsequently starved for 4, 14 or 24 h. Despite high plasma fatty acid concentrations, the partially hepatectomized rats failed to respond to post-operative starvation with increased blood and liver ketone-body concentrations or to maintain the high ketone-body concentrations associated with pre-operative starvation. Hypoglycaemia and hyperlactaemia were observed within 30 min of functional hepatectomy, but not partial hepatectomy, of 24 h-starved rats, and, even after a further 24 h starvation of partially hepatectomized rats, blood glucose concentrations were only slightly decreased. The results are discussed with reference to fat oxidation and gluconeogenesis in the liver remaining after partial hepatectomy.


The impact of non-dialysis-dependent renal dysfunction on outcome following cardiac surgery.
We evaluated the results of different types of cardiovascular surgery in patients with chronic renal failure (CRF) (serum creatinine ≥2 mg/dL) who were not dialysis-dependent. Eighty-two patients who presented with non-dialysis-dependent CRF were retrospectively evaluated. Patients in Group 1 (n = 12) underwent valvular surgery, those in Group 2 (n = 58) underwent coronary artery bypass grafting (CABG), and those in Group 3 (n = 12) underwent combined CABG and valvular surgery. The demographics were similar among the groups. Cardiopulmonary bypass and aortic cross-clamping times were shorter (P < .01), the use of blood and blood products was less, and the mechanical ventilation time and hospital stay were shorter in Group 2 in comparison to the other groups (P < .01). There were 4 (6.9%) early mortalities in Group 2. Late mortalities occurred in 4 (33.3%), 16 (27.6%), and 6 (50%) patients from Groups 1, 2, and 3, respectively. Cox regression analysis revealed that age, the presence of a preoperative cerebrovascular accident, the presence of a left main coronary lesion, preoperative blood urea nitrogen level, and the use of blood and blood products were independent risk factors for early mortality. High Euroscore, cerebrovascular accident, the use of platelet suspension, longer ventilation support times, and combined CABG and valvular surgery were independent risk factors for late mortality. Morbidity and survival seemed to be more dependent on preoperative patient characteristics than the type of surgery in this group of patients. Combined CABG and valvular surgery was a risk factor for late mortality.


High-affinity L-arabinose transport operon. Gene product expression and mRNAs.
Various portions of the "high-affinity" L-arabinose transport operon were cloned into the plasmid expression vector pKK223-3 and the operon-encoded protein products were identified. The results indicate that three proteins are encoded by this operon. The first is a 33,000 Mr protein that is the product of the promoter-proximal L-arabinose binding protein coding sequence, araF. A 52,000 Mr protein is encoded by sequence 3' to araF and has been assigned to the araG locus. The sequence 3' to araG encodes a 31,000 Mr protein that has been assigned to the araH locus. Both the araG and araH gene products are localized in the membrane fraction of the cell, implying a role in the membrane-associated complex of the high-affinity L-arabinose transport system. Nuclease S1 protection studies indicate that two operon message populations are present in the cell, a full-length operon transcript and a seven- to tenfold more abundant binding protein-specific message. The relative abundance of these two message populations correlates with the differential expression of the binding protein and the membrane-associated proteins of the transport system.


Chylous metrorrhea.
A nine-year-old girl with primary (idiopathic) chylous metrorrhea is described. Extravasation from retroperitoneal lymphatics into the vaginal vault was seen on dorsal pedal lymphangiography. Bony abnormalities were also present in the lumbosacral vertebrae. Nineteen months after transperitoneal lymphangiectomy she is asymptomatic.


P7C3-A20 treats traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.
Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain. 3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine (P7C3-A20) can be neuroprotective in various diseases, including ischemic stroke and neurodegenerative diseases. However, whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear. Therefore, in the present study, we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms. We established a traumatic brain injury rat model using a modified weight drop method. P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury. Severe neurological deficits were found in rats after traumatic brain injury, with deterioration in balance, walking function, and learning memory. Furthermore, hematoxylin and eosin staining showed significant neuronal cell damage, while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis. The presence of autolysosomes was observed using transmission electron microscope. P7C3-A20 treatment reversed these pathological features. Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-II (LC3-II) autophagy protein, apoptosis-related proteins (namely, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 [BNIP3], and Bcl-2 associated x protein [Bax]), and elevated ubiquitin-binding protein p62 (p62) autophagy protein expression. Thus, P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.


Vitamin E for Alzheimer's disease.
Vitamin E is a dietary compound that functions as an antioxidant scavenging toxic free radicals. Evidence that free radicals may contribute to the pathological processes in Alzheimer's disease has led to interest in the use of vitamin E in the treatment of this disorder. To examine the effects of vitamin E treatment for people with Alzheimer's disease. The Cochrane Dementia Group Register of Clinical Trials was searched with the following terms: vitamin E, Alzheimer's disease, dementia, alpha-tocopherol, cognitive impairment, cognitive function and controlled trials. The latest search was carried out in July 2000. All unconfounded, double blind, randomized trials in which treatment with vitamin E at any dose was compared with placebo for patients with Alzheimer's disease. Two reviewers independently applied the selection criteria an assessed study quality. One reviewer extracted and analysed the data. For each outcome measure data were sought on every patient randomized. Where such data were not available an analysis of patients who completed treatment was conducted. Only one study was identified which met the inclusion criteria (Sano 1997). The primary outcome used in this study of 341 participants was survival time to the first of 4 endpoints, death, institutionalisation, loss of 2 out of 3 basic activities of daily living, or severe dementia, defined as a global Clinical Dementia Rating of 3. The investigators reported the total numbers in each group who reached the primary endpoint within two years for participants completing the study ("completers"). There appeared to be some benefit from vitamin E with fewer participants reaching endpoint - 58% (45/77) of completers compared with 74% (58/78) - a Peto odds ratio of 0.49, 95% confidence interval 0.25 to 0.96. However, more participants taking vitamin E suffered a fall (12/77 compared with 4/78; odds ratio 3.07, 95% CI 1.09 to 8.62). It was not possible to interpret the reported results for specific endpoints or for secondary outcomes of cognition, dependence, behavioural disturbance and activities of daily living. There is insufficient evidence of efficacy of vitamin E in the treatment of people with with Alzheimer's disease. The one published trial of acceptable methodology (Sano 1997) was restricted to patients with moderate disease, and the published results are difficult to interpret. There is sufficient evidence of possible benefit to justify further studies. There was an excess of falls in the vitamin E group compared with placebo which requires further evaluation.


Role of Vitamin D in Athletes and Their Performance: Current Concepts and New Trends.
We are currently experiencing a vitamin D (VITD) deficiency pandemic across the world. Athletes have the same predisposition to low levels of vitamin D, the majority of its concentrations being below 20 ng/mL in a wide range of sports, especially in the winter months. Vitamin D is important in bone health, but recent research also points out its essential role in extraskeletal functions, including skeletal muscle growth, immune and cardiopulmonary functions and inflammatory modulation, which influence athletic performance. Vitamin D can also interact with extraskeletal tissues to modulate injury recovery and also influence the risk of infection. The data presented in this paper has triggered investigations in relation to the importance of maintaining adequate levels of vitamin D and to the possible positive influence supplementation has on immune and musculoskeletal functions in athletes, benefiting their performance and preventing future injuries. The objective of this review is to describe the latest research conducted on the epidemiology of vitamin D deficiency and its effects on sports performance and musculoskeletal health.


Cardiac ultrasound and abdominal compartment syndrome.
This review focuses on the available literature published about the evaluation of haemodynamic consequences of the abdominal compartment syndrome (ACS). Animal and clinical studies described decreased venous return, systemic vasoconstriction, systolic and diastolic dysfunction of left and right ventricles. Doppler echocardiography is a non-invasive bedside procedure which provides a complete haemodynamic evaluation of patients with ACS. Despite numerous evaluations in anesthesia during laparoscopic surgery, the use of echocardiography remains scarce in critically ill patients with ACS.


Circadian Clock Genes in Diabetic Kidney Disease (DKD).
The purpose of this review is to provide a brief summary about the current state of knowledge regarding the circadian rhythm in the regulation of normal renal function. There is a lack of information regarding how the circadian clock mechanisms may contribute to the development of diabetic kidney disease. We discuss recent findings regarding mechanisms that are established in diabetic kidney disease and are known to be linked to the circadian clock as possible connections between these two areas. Here, we hypothesize various mechanisms that may provide a link between the clock mechanism and kidney disease in diabetes based on available data from humans and rodent models.


Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition.
Epithelial to mesenchymal transition (EMT), implicated as a mechanism for tumor dissemination, is marked by loss of E-cadherin, disruption of cell adhesion, and induction of cell motility and invasion. In most intraductal breast carcinomas E-cadherin is regulated epigenetically via methylation of the promoter. E-cadherin expression is therefore dynamic and open to modulation by the microenvironment. In addition, it has been observed that metastatic foci commonly appear more differentiated than the primary tumor, suggesting that cancer cells may further undergo a mesenchymal to epithelial reverting transition (MErT) in the secondary organ environment following the EMT that allows for escape. We first examined E-cadherin expression in primary breast tumors and their corresponding metastases to liver, lung and brain and discovered that 62% (10/16) of cases showed increased E-cadherin expression in the metastases compared to the primaries. These observations led to the question of whether the positive metastatic foci arose from expansion of E-cadherin-positive cells or from MErT of originally E-cadherin-negative disseminated cells. Thus, we aimed to determine whether it was possible for the mesenchymal-like MDA-MB-231 breast cancer cells to undergo an MErT through the re-expression of E-cadherin, either through exogenous introduction or induction by the microenvironment. Ectopic expression of full-length E-cadherin in MDA-MB-231 cells resulted in a morphological and functional reversion of the epithelial phenotype, with even just the cytosolic domain of E-cadherin yielding a partial phenotype. Introduction of MDA-MB-231 cells or primary explants into a secondary organ environment simulated by a hepatocyte coculture system induced E-cadherin re-expression through passive loss of methylation of the promoter. Furthermore, detection of E-cadherin-positive metastatic foci following the spontaneous metastasis of MDA-MB-231 cells injected into the mammary fat pad of mice suggests that this re-expression is functional. Our clinical observations and experimental data indicate that the secondary organ microenvironment can induce the re-expression of E-cadherin and consequently MErT. This phenotypic change is reflected in altered cell behavior and thus may be a critical step in cell survival at metastatic sites.


Predicting perceived safety to drive the morning after drinking: The importance of hangover symptoms.
People driving the day after drinking are at risk of impaired performance and accidents due to continued intoxication or the effects of alcohol hangover. Drivers are poor at estimating their own blood alcohol concentration, and some drive despite believing they are over the legal limit. It is therefore important to identify other factors influencing perceived ability to drive 'the morning after'. This study tested how accurately participants estimated their legal driving status, and the contribution of beliefs and hangover symptoms to the prediction of perceived driving safety. This cross-sectional study involved 193 students completing a questionnaire and alcohol breath test the morning after heavy alcohol consumption. Indicators of subjective intoxication, severity of hangover symptoms, estimated legal status and perceived safety to drive were measured. A hierarchical linear regression analysis was conducted. No participants thought they were under the English legal limit when they were not, and 47% thought they were over the limit when they were in fact legally permissible to drive. However, 20% of those believing they were over the limit nevertheless rated themselves as safe to drive. Hangover symptoms added 17% variance to the prediction of perceived safety to drive, over and above objective and subjective measures of intoxication. Perceived severity of hangover symptoms influence beliefs about driving ability: When judging safety to drive, people experiencing less severe symptoms believe they are less impaired. If this finding is robust, health promotion campaigns should aim to correct this misapprehension. [Cameron E, French D. Predicting perceived safety to drive the morning after drinking: The importance of hangover symptoms. Drug Alcohol Rev 2016;35:442-446].


Repeated mobility testing for later artificial visual function evaluation.
The study investigates the utility of a newly designed mobility test for repeated testing of visual function in patients with severe visual impairment and future application in evaluating functional progress in patients with artificial vision. Ten subjects divided into three groups based on visual acuity (VA) ranging from light perception to 20/200 and reduced visual field (VF) were included in the study. The mobility test consisted of using a set of four different but structurally similar and relatively short mazes having a constant number of obstacles of various sizes. The subjects, divided into three groups by acuity, passed through each course several times. In general, the patients with better VA had a larger extent of VF. Average speed and number of contacts were recorded as measures of performance. The average passing times of the groups through the courses were significantly different (p = 0.03), which was influenced by VA and VF. There was no significant difference in average number of contacts between the groups (p = 0.15). The mobility test proved to be appropriate for gaining statistically relevant results in repeated individual testing of patients with severe vision impairment. Results show promise for use this mobility test as a tool for assessing visual function of patients undergoing implantation of a visual prosthesis for artificial vision.


Review: The role of antibodies, autoantigens and food allergens in canine atopic dermatitis.
Canine atopic dermatitis (AD) is considered to be an immunoglobulin E (IgE)-mediated hypersensitivity response to environmental allergens. The role of other antibody isotypes and nonenvironmental allergens in disease pathogenesis remains unclear. The objective of this review is to provide an update on advances in the understanding of the relevance of specific antibody isotypes, autoallergens and nonenvironmental allergens in the pathogenesis of canine AD. Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed. Where necessary, older articles were included for background information. Neither total nor allergen-specific IgE necessarily correlates with clinical disease in canine AD. Some dogs exhibit clinical signs that are indistinguishable from AD but have no demonstrable allergen-specific IgE (atopic-like dermatitis). Allergen-specific immunoglobulin G may be demonstrated in canine AD, but there is no evidence that this isotype plays a role in disease development. Although humans with AD may develop serum IgE against autoallergens, this finding has not been substantiated in the dog. In contrast, adverse food reactions are frequently co-associated with AD in the dog. Ingestion of food and environmental allergens may trigger exacerbations of AD. Determination of the role of IgE in the pathogenesis of canine AD still requires clarification. Clinical trials and research studies must distinguish atopic dogs with allergen-specific IgE or skin test reactivity from those without. There is no convincing evidence demonstrating a pathogenic role for either allergen-specific immunoglobulin G or autoallergens in canine AD, but food items may be triggers for disease flares in certain individuals.


Towards Climate Resilient and Environmentally Sustainable Health Care Facilities.
The aim of building climate resilient and environmentally sustainable health care facilities is: (a) to enhance their capacity to protect and improve the health of their target communities in an unstable and changing climate; and (b) to empower them to optimize the use of resources and minimize the release of pollutants and waste into the environment. Such health care facilities contribute to high quality of care and accessibility of services and, by helping reduce facility costs, also ensure better affordability. They are an important component of universal health coverage. Action is needed in at least four areas which are fundamental requirements for providing safe and quality care: having adequate numbers of skilled human resources, with decent working conditions, empowered and informed to respond to these environmental challenges; sustainable and safe management of water, sanitation and health care waste; sustainable energy services; and appropriate infrastructure and technologies, including all the operations that allow for the efficient functioning of a health care facility. Importantly, this work contributes to promoting actions to ensure that health care facilities are constantly and increasingly strengthened and continue to be efficient and responsive to improve health and contribute to reducing inequities and vulnerability within their local settings. To this end, we propose a framework to respond to these challenges.


Role of surgery in local treatment of Ewing's sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy.
Although more and more patients with Ewing's sarcoma of bone (ESB) are being treated by surgery, the relative role of surgery and radiotherapy in the local treatment of this tumor has yet to be determined. Because the outcome of ESB may differ according to the anatomical site of the tumor, results reported in the literature, which generally refer to series with tumors located in all sites, may be selection biased. Therefore, we have retrospectively evaluated patients with ESB exclusively in the extremity and locally treated by surgery or radiotherapy. Two hundred and sixty-eight patients treated at Rizzoli 1979-1996 for non-metastatic ES of the extremities were assessed. Chemotherapy was administered according to four sequentially activated protocols. One hundred and thirty-six patients were treated by surgery, 70 by surgery and radiotherapy, and 60 patients by radiotherapy. Two patients underwent only chemotherapy. The follow-up range was 5-23 years (mean 13 years). One hundred and fifty-two patients remained continuously free of disease, 108 relapsed, 2 died of chemotherapy toxicity and 6 developed a second malignancy. The 5-year event-free survival (EFS) and overall survival (OS) were respectively 62 and 69%. Although patients of all groups were matched for possible risk factors, the rates of 5-year EFS and local control were significantly lower in patients treated with radiotherapy compared to patients treated by surgery or surgery and radiotherapy (48% vs 66%, p=0.002; 80% vs 94%, p=0.0001). Furthermore, in group 3 there were 6 secondary malignancies. Our results indicate that surgery should always be considered in the local treatment of ES of the extremities. Postoperative radiation therapy must be added in case of inadequate surgical margins.


Combined beta 1-adrenoceptor blockade and/or beta 2- or beta 1/2 adrenoceptor stimulation as treatment of essential hypertension.
Single and combined therapy with terbutaline (10 mg/day) and metoprolol (200 mg/day) and single therapy with orciprenaline (30 mg/day) were assessed over 8 weeks in a total of 45 patients with essential hypertension. Blood pressure at rest was comparably reduced by metoprolol + terbutaline and metoprolol alone, but with terbutaline and orciprenaline only after 4 weeks. The responder rates (greater than or equal to 10% reduction in diastolic blood pressure) at rest were 58% (metoprolol + terbutaline), 63% (metoprolol) and significantly lower with terbutaline alone at 42% and orciprenaline alone at 45%. The heart rate was affected only by metoprolol monotherapy, which caused a significant decrease. The beta-adrenoceptor stimulators terbutaline and orciprenaline in the chosen doses slightly decreased blood pressure and did not increase the heart rate. Metoprolol was an effective antihypertensive agent but decreased the heart rate. Under combined therapy with terbutaline, there was no additional blood pressure decrease, but the heart rate remained unaffected.


Current treatment strategies in pediatric gastrointestinal stromal cell tumor.
Gastrointestinal stromal tumors (GIST) are exceedingly rare tumors in the pediatric population. As a result, many clinicians either may never see this diagnosis or will encounter it only a few times throughout their careers. Additionally, the more we discover about this disease, it becomes evident that it represents a distinct clinical entity from adult GIST. Many of the treatments and strategies used to combat the adult tumor are either ineffective or may be harmful to the pediatric population with this disease. The unique tumor biology found in pediatric GIST necessitates unique approaches and treatment strategies in order to achieve the best clinical outcome. This review aims to discuss the most recent data available on the different therapeutic modalities utilized in cases of Pediatric GIST.


The binding mode of vilazodone in the human serotonin transporter elucidated by ligand docking and molecular dynamics simulations.
Vilazodone is a novel antidepressant used for the treatment of major depressive disorder (MDD) with a primary action mechanism of inhibiting the human serotonin reuptake transporter (hSERT) and acting as a 5-HT1A receptor partial agonist. The interaction between vilazodone and the 5-HT1A receptor has been reported, however, the binding mode of vilazodone in the hSERT remains elusive. In the current study, to elucidate the molecular mechanism of vilazodone binding in the hSERT, the drug and its five analogs were docked into the hSERT crystal structure as initial conformations and were sampled by 400 ns molecular dynamics (MD) simulations. Through the analysis of the profiles of protein-ligand binding free energies, interaction fingerprints, and conformational rearrangements, the binding mode of vilazodone in the hSERT was revealed. As a result, unlike the classical antidepressants located in the S1 site of the hSERT, vilazodone adopted a linear pose in the binding pocket. Its arylpiperazine fragment occupies the central site (S1) and interacts with Y95, D98, I172, Y176, F335, F341, S438, and T439, while the indole fragment extends to the allosteric site (S2) via interacting with the ionic switch (R104/E403) between the two sites. The new insights obtained are not only helpful in understanding the binding mode of vilazodone in the hSERT, but also provide valuable guidance to the discovery of novel antidepressant drugs.


The effects of sleep deprivation on item and associative recognition memory.
Sleep deprivation adversely affects the ability to perform cognitive tasks, but theories range from predicting an overall decline in cognitive functioning because of reduced stability in attentional networks to specific deficits in various cognitive domains or processes. We measured the effects of sleep deprivation on two memory tasks, item recognition ("was this word in the list studied") and associative recognition ("were these two words studied in the same pair"). These tasks test memory for information encoded a few minutes earlier and so do not address effects of sleep deprivation on working memory or consolidation after sleep. A diffusion model was used to decompose accuracy and response time distributions to produce parameter estimates of components of cognitive processing. The model assumes that over time, noisy evidence from the task stimulus is accumulated to one of two decision criteria, and parameters governing this process are extracted and interpreted in terms of distinct cognitive processes. Results showed that sleep deprivation reduces drift rate (evidence used in the decision process), with little effect on the other components of the decision process. These results contrast with the effects of aging, which show little decline in item recognition but large declines in associative recognition. The results suggest that sleep deprivation degrades the quality of information stored in memory and that this may occur through degraded attentional processes. (PsycINFO Database Record


The effect of pericardium on the diastolic properties of the heart--experimental studies on volume load and on acute ischemia in open chest dogs.
We studied the effect of the pericardium on the end-diastolic pressure-segment length (P-L) relation in volume loading (Experiment I) and in acute ischemia (Experiment II). Experiment I: In 6 open chest dogs, segment length of left and right ventricles were measured using ultrasonic crystals during blood infusion. Drawing end-diastolic pressure (P, on ordinate) against segment length (L, on abscissa), the P-L curve with pericardium positioned upward compared to that without pericardium. The slopes (b) of the exponential curve (P = aebL) with pericardium were steeper than those without pericardium in both ventricles. The difference between the slopes with and without pericardium was significantly larger in the right ventricle (RV, 0.30 +/- 0.10, mean +/- SEM) than in the left ventricle (LV, 0.05 +/- 0.02, p less than 0.05). These results show that the pericardium inhibits the distensibility of the free wall more in RV than in LV, and enhances a mechanical coupling of both ventricles during volume over-load. Experiment II: In 8 open chest dogs, segment lengths of ischemic and non-ischemic regions in LV were measured after left circumflex coronary occlusion. When the segment lengths and LV pressure became stable, a pericardiectomy was performed. After the pericardiectomy, whereas heart rate and LV systolic pressure did not change, end-diastolic segment length in the ischemic region further lengthened (12.0 +/- 0.2 to 12.5 +/- 0.2 mm, p less than 0.01) and that in the non-ischemic region did not change despite the concomitant fall in LV end-diastolic pressure (EDP, 11.9 +/- 0.6 to 9.8 +/- 0.6 mmHg, p less than 0.01). These results suggest that the pericardium alters the LV end-diastolic pressure-volume relation and is one of the factors contributing to an increase in LVEDP during acute ischemia.


Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System.
The prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared with male rats. Here, we describe a novel within-session behavioral-economic paradigm that allows for the simultaneous measurement of the intake at null cost (Q0) and normalized demand elasticity (α) of 3 types of palatable food (low fat, high fat, and chocolate sucrose pellets) via demand curve analysis. In light of evidence that the orexin (hypocretin) system is critically involved in reward and feeding behaviors, we also examined the role of orexin function in sex differences of economic demand for palatable foods. The novel within-session behavioral-economic approach revealed that female rats have higher intake (demand) than males for all palatable foods at low cost (normalized to body weight) but no difference in intake at higher prices, indicating sex-dependent differences in the hedonic, but not motivational, aspects of palatable food. Immediately following behavioral-economic testing, we observed more orexin-expressing neurons and Fos expression (measure of recent neural activation) in these neurons in female rats compared with male rats. Moreover, the orexin-1 receptor antagonist SB334867 reduced both low- and high-cost intake for palatable food in both male and female rats. These findings provide evidence of higher demand at low prices for palatable food in females and indicate that these behavioral differences may be associated with sexual dimorphism in orexin system function.


Teaching acupuncture to medical students: the experience of Rio Preto Medical School (FAMERP), Brazil.
Complementary and alternative medicine, and in particular acupuncture, has been practised and taught in recent years in many universities in the Western world. Here, we relate our experiences since 1997 in teaching acupuncture to medical students at Rio Preto Medical School (Faculty of Medicine of São José do Rio Preto (FAMERP)), Brazil. Classes are given in the third and fifth years. The main goals of understanding the mechanisms of action and being able to recognise patients who may benefit from treatment and referring them have been well achieved, scoring 3.6 and 4.1, respectively, on a scale of 1-5. Also using that scale, medical students believe that acupuncture is important in the curriculum (4.6), course time is not sufficient (2.7) and they would like more information (4.6). To overcome these concerns, many students join an undergraduate study group (Acupuncture League) where they have more time to learn. We also describe the presence of foreign medical students who, since 2000, have enrolled in a course of 150 h in an exchange programme.


MRI-Based Deep Learning Segmentation and Radiomics of Sarcoma in Mice.
Small-animal imaging is an essential tool that provides noninvasive, longitudinal insight into novel cancer therapies. However, considerable variability in image analysis techniques can lead to inconsistent results. We have developed quantitative imaging for application in the preclinical arm of a coclinical trial by using a genetically engineered mouse model of soft tissue sarcoma. Magnetic resonance imaging (MRI) images were acquired 1 day before and 1 week after radiation therapy. After the second MRI, the primary tumor was surgically removed by amputating the tumor-bearing hind limb, and mice were followed for up to 6 months. An automatic analysis pipeline was used for multicontrast MRI data using a convolutional neural network for tumor segmentation followed by radiomics analysis. We then calculated radiomics features for the tumor, the peritumoral area, and the 2 combined. The first radiomics analysis focused on features most indicative of radiation therapy effects; the second radiomics analysis looked for features that might predict primary tumor recurrence. The segmentation results indicated that Dice scores were similar when using multicontrast versus single T2-weighted data (0.863 vs 0.861). One week post RT, larger tumor volumes were measured, and radiomics analysis showed greater heterogeneity. In the tumor and peritumoral area, radiomics features were predictive of primary tumor recurrence (AUC: 0.79). We have created an image processing pipeline for high-throughput, reduced-bias segmentation of multiparametric tumor MRI data and radiomics analysis, to better our understanding of preclinical imaging and the insights it provides when studying new cancer therapies.


Randomized trial of tourniquet vs blood pressure cuff for target vein dilation in ultrasound-guided peripheral intravenous access.
Ten percent of the time, peripheral intravenous access (PIV) is not obtained in 2 attempts in the emergency department. Typically, a tourniquet is used to dilate the target vein; but recent research showed that a blood pressure (BP) cuff improves dilation, which may translate to increased PIV success. We sought to determine if there is improved success in obtaining ultrasound-guided PIV using a BP cuff vs a tourniquet in "difficult stick" patients. This is a prospective, randomized, single-blinded trial. Adult patients requiring PIV with at least 2 prior failed attempts were enrolled. Patients were assigned to tourniquet or BP cuff for target vein dilation randomly. Nurses prepared the patient for PIV attempt by either placing a BP cuff inflated to 150 mm Hg or placing a tourniquet on the chosen extremity. The extremity was draped to blind the physician to assignment. Physicians then attempted ultrasound-guided PIV. Failures were defined as IVs requiring greater than 3 ultrasound-guided attempts or 30 minutes, or patient intolerance. If failure occurred, the physician was unblinded; and the patient could be crossed over and reattempted. Thirty-eight patients were enrolled. The success rate for the tourniquet group (n = 17) and BP cuff group (n = 21) was 82.4% and 47.6%, respectively (P = .04). There were no differences between groups for vessel depth, diameter, or procedure time. Six in the BP cuff group were crossed over and had successful PIV obtained with tourniquet. Tourniquet is superior to BP cuff for target vein dilation in ultrasound-guided PIV.


Innovative drug delivery nanosystems improve the anti-tumor activity in vitro and in vivo of anti-estrogens in human breast cancer and multiple myeloma.
Anticancer drug efficiency is governed by its bioavailability. In order to increase this parameter, we synthesized several injectable and biodegradable systems based on incorporation of anti-estrogens (AEs) in nanoparticles (NPs) and liposomes were synthesized. Both nanospheres (NS) and nanocapsules (NCs, polymers with an oily core in which AEs were solubilized) incorporated high amounts of 4-hydroxy-tamoxifen (4-HT) or RU 58668 (RU). Physico-chemical and biological parameters of these delivery systems, and coupling of polyethylene-glycol chains on the NP surface revealed to enhance the anti-tumoral activity of trapped AEs in a breast cancer MCF-7 cell xenograft model and to induce apoptosis. These features correlated with an augmentation of p21(Waf-1/Cip1) and of p27(Kip1) and a concomitant decrease of cyclin D1 and E in tumor extracts. Liposomes containing various ratios of lipids enhanced the apoptotic activity of RU in several multiple myeloma (MM) cell lines tested by flow cytometry. MM cell lines expressed both estrogen receptor alpha and beta subtypes except Karpas 620. Karpas 620 cells which did not respond to AEs became responsive following ER cDNA transfection. A new MM xenograft model was generated after s.c. injection of RPMI 8226 cells in nude mice. RU-loaded liposomes, administered i.v. in this model, at a dose of 12mgRU/kg/week, induced the arrest of tumor growth contrary to free RU or to empty liposomes. Thus, the drug delivery of anti-estrogens enhances their ability to arrest the growth of tumors which express estrogen receptors and are of particular interest for estrogen-dependent breast cancer treatment. In addition it represents a new potent therapeutic approach for multiple myeloma.


Production of diarrheal enterotoxins and other potential virulence factors by veterinary isolates of bacillus species associated with nongastrointestinal infections.
With the exceptions of Bacillus cereus and Bacillus anthracis, Bacillus species are generally perceived to be inconsequential. However, the relevance of other Bacillus species as food poisoning organisms and etiological agents in nongastrointestinal infections is being increasingly recognized. Eleven Bacillus species isolated from veterinary samples associated with severe nongastrointestinal infections were assessed for the presence and expression of diarrheagenic enterotoxins and other potential virulence factors. PCR studies revealed the presence of DNA sequences encoding hemolysin BL (HBL) enterotoxin complex and B. cereus enterotoxin T (BceT) in five B. cereus strains and in Bacillus coagulans NB11. Enterotoxin HBL was also harbored by Bacillus polymyxa NB6. After 18 h of growth in brain heart infusion broth, all seven Bacillus isolates carrying genes encoding enterotoxin HBL produced this toxin. Cell-free supernatant fluids from all 11 Bacillus isolates demonstrated cytotoxicity toward human HEp-2 cells; only one Bacillus licheniformis strain adhered to this test cell line, and none of the Bacillus isolates were invasive. This study constitutes the first demonstration that Bacillus spp. associated with serious nongastrointestinal infections in animals may harbor and express diarrheagenic enterotoxins traditionally linked to toxigenic B. cereus.


Construction and reconstruction of brain circuits: normal and pathological axon guidance.
Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.


Prion-associated dilated cardiomyopathy.
Creutzfeldt-Jakob disease is a spongiform encephalopathy affecting 1 individual per million population per year. We report on a previously healthy 43-year-old patient who presented with the simultaneous onset of a movement disorder, encephalopathy, cognitive decline, and dilated cardiomyopathy, and was found to have spongiform encephalopathy on brain biopsy. Although her neurological features could be explained by Creutzfeldt-Jakob disease, the etiology of the dilated cardiomyopathy could not be established. Finally, special staining of the endomyocardial biopsy specimen revealed the presence of abnormal prion, possibly infectious scrapie prion. As an exhaustive search for familial, ischemic, infectious, autoimmune, toxic, and metabolic causes of dilated cardiomyopathy was unrevealing, the presence of abnormal prion in the cardiac muscle suggested the possibility of prion-induced dilated cardiomyopathy in our patient.


Does Social Support Moderate the Association between Adverse Childhood Experiences and Substance-Related Problems?
Background: More than half of individuals in the United States have had adverse childhood experiences (ACEs), which can result in physical and mental distress. ACEs has been linked with greater likelihood of harmful alcohol and drug use. Research has found that protective factors, such as social support, may potentially buffer against harmful substance use engagement among those who have experienced ACEs. The purpose of this study was to examine associations between perceived social support, ACEs, and alcohol and cannabis-related problems. Moreover, this study aimed to examine if specific domains of perceived social support (family, friends, and significant other) moderated the relationship between ACEs and alcohol and cannabis-related problems. Method: Validated measures of ACEs, perceived social support, and alcohol and cannabis problems were collected in a sample of 401 emerging adults via Prolific Academic (an online data collection platform). Results: Overall perceived social support and domains such as perceived family and friend social support moderated the relationship between ACEs and alcohol-related problems but not ACEs and cannabis-related problems. The association between ACEs and alcohol-related problems was strongest at low levels of perceived family and friend social support. Perceived social support was not associated with cannabis-related problems. Conclusions: Lack of social support is a potential risk factor for alcohol-related problems among emerging adults. Bolstering perceived social support from family and friends among those who have experienced ACEs may be beneficial in intervention and treatment efforts aiming to reduce harmful substance use in this population.


[Profile of the over-user of a health center].
To find the sociodemographic and family characteristics of our Health Centre's over-user, along with the connection between psychological malaise, family dysfunction and greater or lesser attendance. We carried out a descriptive crossover study, after a prior simple random sampling. La Felguera Health Centre (Asturias) in 1993. We studied 276 over-users, defining as such someone who consulted 6 or more times during the year of the study (percentage > 75), with bureaucratic and scheduled visits being excluded. We used personal interviews with questionnaires to find: Family function (applying the family Apgar Test); psychological malaise (using the Goldberg General Health questionnaire in its reduced 28-item version); and sociodemographic characteristics (with a test composed by ourselves). Average age of the over-user was 54 +/- 19. They were mainly women (72.1%). 51.1% were house-wives and only 25.75% had more than a primary education. 67.8% belonged to nuclear families and 8.3% to dysfunctional families. We found psychological malaise in 40.7%, with a statistically significant relationship between this and women (p < 0.05). The profile of the over-user of our health centre is a middle-aged housewife with a low level of education, who is part of a nuclear family. A high proportion suffer psychological malaise, but family dysfunction is not determinant.


Somatostatin analogs for the treatment of neuroendocrine tumors.
Somatostatin is an important regulator of endocrine and exocrine secretion, affecting the release of many hormones. The effects of somatostatin are mediated through its interaction with one of five somatostatin receptors. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express multiple somatostatin receptors, making them excellent potential therapeutic targets. Many trials have shown that treatment with somatostatin analogs is associated with disease stabilization and prolonged survival. More recently, somatostatin analogs have been shown to have antiproliferative effects, thus broadening the scope of their uses. In this review, we update the current data on the treatment of GEP-NETs with somatostatin analogs, with particular emphasis on the results of the PROMID study. In addition, we discuss the current state of knowledge of novel therapies against GEP-NETs, including the use of somatostatin analogs with broader receptor binding profiles, chimeric somatostatin-dopamine molecules, combinations of somatostatin analogs with other active chemotherapy agents, and peptide receptor-targeted radionuclide therapy.


Vitamin K antagonism of coumarin intoxication in the rat.
An in vitro system which expresses all enzyme activities related to vitamin K-dependent carboxylation of blood clotting factors was prepared from livers of rats overdosed with warfarin, difenacoum and dicumarol respectively. In this system, the activities of the two pathways that are known to produce active reduced vitamin K1 cofactor for the carboxylation reaction were measured. Also the ability of high concentrations of vitamin K1 to overcome inhibition of clotting factor synthesis was studied. In the systems prepared from livers of warfarin and difenacoum intoxicated rats, pathway I was inactive. Vitamin K epoxide reductase was also inactive which strongly suggests that this enzyme catalyzes the activity of pathway I in vivo. Reduction of vitamin K1 by pathway II bypassed the inactive pathway I and resulted in carboxylation activity. This pathway therefore mediates the antidotic effect of vitamin K1 in the coumarin intoxicated liver. In the in vitro system prepared from dicumarol intoxicated livers the activity of pathway I was not significantly affected. Dicumarol however was a strong inhibitor when added to liver microsomes in vitro.


[Pareto-optimal alignment of biological sequences].
The problem of alignment of two symbol sequences is considered. The validity of the available algorithms for constructing optimal alignment depends on the weighting coefficients which are frequently difficult to choose. A new approach to the problem is proposed, which is based on the use of vector weighting functions (instead of tradionally used scalar ones) and Pareto-optimal alignment (an alignment that is optimal at any choice of weighting coefficient will always be Pareto-optimal). An efficient algorithm for constructing all Pareto-optimal alignments of two sequences is proposed. An approach to choosing a "biologically correct" alignment among all Pareto-optimal alignments is suggested.


School-based youth health nurses and adolescent decision-making concerning reproductive and sexual health advice: How can the law guide healthcare practitioners in this context?
Abstract School-Based Youth Health Nurses (SBYHNs) work in Queensland high schools, providing sexual and reproductive health care/advice (amongst other things) to adolescents. SBYHNs are often responsible for referring high school students to other health care practitioners or external health services/community agencies. One of the difficulties faced in this context is how to assess the issue of capacity in terms of the adolescent's ability to provide consent to his or her own health care without parental involvement. This is important because it enables SBYHNs to maintain confidentiality with adolescents, which encourages adolescents to obtain sexual health advice. In this paper we outline the key legal principles relevant to nurses working in this field. We provide some practical examples of issues faced by SBYHNs and consider how the issue of Gillick competency is relevant to these examples. We demonstrate that the law seeks to prioritise the concept of confidentiality and aims to avoid exposing adolescents to harm that may result from unsafe sexual practices. Importantly, the issues discussed in this paper are relevant to nurses working within this field in all Australian jurisdictions.


Removal of the inferior olive abolishes myoclonic seizures associated with a loss of olivary serotonin.
Several lines of clinical evidence suggest that myoclonus is caused by a reduction of serotonin in the brain and hyperactivity of the inferior olive. We determined whether a change in serotonin content within the olivocerebellar system accompanied a predisposition to myoclonus and investigated the necessity of the inferior olive for a myoclonic seizure. The experiments employed the genetically epilepsy-prone rat that exhibits a profound myoclonic seizure in response to an auditory stimulus. We found that these animals demonstrated a significant reduction in the serotonergic innervation of the inferior olive without a significant change in the serotonergic innervation at any other level of the olivocerebellar circuit. The deficit in olivary serotonin was verified physiologically and pharmacologically by a reduced sensitivity of the genetically epilepsy-prone rat to the tremorogenic effect of harmaline, which is known to produce tremor through a mechanism that requires serotonergic innervation of the inferior olive. We quantified the timing of the myoclonic seizure of the genetically epilepsy-prone rat and found that its large amplitude 2-6 Hz clonus was always preceded by 9-10 Hz tremor that was synchronized among limbs. Ablation of the inferior olive by 3-acetylpyridine abolished the myoclonic seizure. The specificity of the deficit in olivary serotonin, the timing of the seizure, and the demonstration of the necessity of the inferior olive for myoclonus suggest that pathological inferior olivary activity contributes to the genesis of a myoclonic seizure.


Ultraviolet radiation oxidative stress affects eye health.
In the eye, ultraviolet radiation (UVR) is not known to contribute to visual perception but to mainly damage multiple structures. UVR carries higher energy than visible light and high dose exposure to UVR causes direct cellular damage, which has an important role in the development of cancer. This review provides an overview on the most recent knowledge on the role of UVR in oxidative stress (OS) in relation to noncancer ocular pathologies: various corneal pathologies, cataract, glaucoma and age-related macular degeneration. Possible OS signaling streams and mechanisms in the aging eye are discussed. Excessive exposure to UVR through live may seriously contribute to increase in OS of various eye tissues and thus lead to the advancement of serious ocular pathologies. Children are especially vulnerable to UVR because of their larger pupils and more transparent ocular media: up to 80% of a person's lifetime exposure to UVR is reached before the age of 18. Therefore, efficient everyday protection of the sensitive tissues of the eye by wearing of sunglasses, clear UVR-blocking spectacles or contact lenses should be considered from early age on. Many initiatives are taken worldwide to inform and raise the population's awareness about these possible UVR hazards to the eye.


Penicillamine-induced pemphigus.
Penicillamine therapy has been associated with a variety of autoimmune disorders, including pemphigus vulgaris and pemphigus foliaceus. The "late scaling rash" or oral ulcerations associated with penicillamine may represent the superficial erosions of early pemphigus. We describe four patients with pemphigus induced by penicillamine therapy and emphasize the "seborrhea-like" characteristics of this eruption that may obscure the diagnosis. A high prevalence (71%) of HLA-B15 is noted in the seven patients on whom HLA data are available. Early recognition is important because of the potentially fatal nature of pemphigus. The mechanism by which penicillamine induces or unmasks pemphigus and other immunologic syndromes remains to be elucidated.


Physiological characterization of Saccharomyces cerevisiae mutants supersensitive to G1 arrest by a factor and alpha factor pheromones.
Saccharomyces cerevisiae MATa cells carrying mutations in either sst1 or sst2 are supersensitive to the G1 arrest induced by alpha factor pheromone. When sst1 mutants were mixed with normal SST+ cells, the entire population recovered together from alpha factor arrest, suggesting that SST+ cells helped sst1 mutants to recover. Complementation tests and linkage analysis showed that sst1 and bar1, a mutation which eliminates the ability of MATa cells to act as a "barrier" to the diffusion of alpha factor, were lesions in the same genes. These findings suggest that sst1 mutants, are defective in recovery from alpha factor arrest because they are unable to degrade the pheromone. In contrast, recovery of sst2 mutants was not potentiated by the presence of SST+ cells in mixing experiments. When either normal MATa cells or mutant cells carrying defects in sst1 or sst2 were exposed to alpha factor for 1 h and then washed free of the pheromone, the sst2 cells subsequently remained arrested in the absence of alpha factor for a much longer time than SST+ or sst1 cells. These observations suggest that the defect in sst2 mutants is intrinsic to the cell and is involved in the mechanism of alpha factor action at some step after the initial interaction of the pheromone with the cell. The presence of an sst2 mutation appears to cause a growth debility, since repeated serial subculture of haploid sst2-1 strains led to the accumulation of faster-growing revertants that were pheromone resistant and were mating defective ("sterile").


Genome Reduction and Microbe-Host Interactions Drive Adaptation of a Sulfur-Oxidizing Bacterium Associated with a Cold Seep Sponge.
As the most ancient metazoan, sponges have established close relationships with particular microbial symbionts. However, the characteristics and physiology of thioautotrophic symbionts in deep-sea sponges are largely unknown. Using a tailored "differential coverage binning" method on 22-Gb metagenomic sequences, we recovered the nearly complete genome of a sulfur-oxidizing bacterium (SOB) that dominates the microbiota of the cold seep sponge Suberites sp. Phylogenetic analyses suggested that this bacterium (an unclassified gammaproteobacterium termed "Gsub") may represent a new deep-sea SOB group. Microscopic observations suggest that Gsub is probably an extracellular symbiont. Gsub has complete sulfide oxidation and carbon fixation pathways, suggesting a chemoautotrophic lifestyle. Comparative genomics with other sponge-associated SOB and free-living SOB revealed significant genome reduction in Gsub, characterized by the loss of genes for carbohydrate metabolism, motility, DNA repair, and osmotic stress response. Intriguingly, this scenario of genome reduction is highly similar to those of the endosymbionts in deep-sea clams. However, Gsub has retained genes for phage defense and protein secretion, with the latter potentially playing a role in interactions with the sponge host. In addition, we recovered the genome of an ammonia-oxidizing archaeon (AOA), which may carry out ammonia oxidation and carbon fixation within the sponge body. IMPORTANCE Sponges and their symbionts are important players in the biogeochemical cycles of marine environments. As a unique habitat within marine ecosystems, cold seeps have received considerable interest in recent years. This study explores the lifestyle of a new symbiotic SOB in a cold seep sponge. The results demonstrate that both this sponge symbiont and endosymbionts in deep-sea clams employ similar strategies of genome reduction. However, this bacterium has retained unique functions for immunity and defense. Thus, the functional features are determined by both the symbiotic relationship and host type. Moreover, analyses of the genome of an AOA suggest that microbes play different roles in biochemical cycles in the sponge body. Our findings provide new insights into invertebrate-associated bacteria in cold seep environments.


Introduction to the special section: More than measurement error: Discovering meaning behind informant discrepancies in clinical assessments of children and adolescents.
Discrepancies often arise among multiple informants' reports of child and adolescent psychopathology and related constructs (e.g., parenting, family relationship quality and functioning, parental monitoring). Recently, studies using various designs (laboratory, longitudinal, randomized controlled trial, meta-analysis) have revealed that discrepancies among informants' reports (a) yield important information regarding where children express behaviors (time course, features of the context[s] of behavioral expression) and about the informants who observe their expression, (b) demonstrate stability over time in both community and clinic settings, (c) predict poor child and adolescent outcomes in ways that the individual informants' reports do not, and (d) can be used to identify meaningful treatment outcomes patterns within randomized controlled trials. Using existing data sources, the articles in this special section expand upon this emerging body of research. In particular, the articles illustrate how clinical science and practice can use informant discrepancies to increase understanding of the causes and consequences of, as well as treatments for, child and adolescent psychopathology.