BRCA1 status in Pakistani breast cancer patients with moderate family history.
To determine BRCA1 status in breast carcinoma patients of Pakistani origin. Observational study. The Oncology Clinics of the Aga Khan University Hospital, Karachi, between May 2005 and December 2009. Fifty three breast cancer patients based on clinical and laboratory diagnosis were recruited for this study. Moderate family history was defined as having a close relative (mother, daughter, sister) diagnosed with breast cancer under 45 years. Peripheral blood samples were collected from each patient in a 5 ml tube containing EDTA as anticoagulant. Subsequent to DNA extraction, mutational analysis of BRCA1 exons 2, 5, 6, 16, 20 and 22 was carried out using single strand conformation polymorphism (SSCP) assay while protein truncation test (PTT) was used to examine mutations in exon 11. All BRCA1 sequence variants were confirmed by DNA sequencing. Twenty-three patients were diagnosed with early onset breast cancer, 30 patients had moderate family history. At the time of diagnosis, the median age of enrolled patients was 39 years (range 24-65 years). Out of 53 patients, analyzed by SSCP assay, mobility shift was detected in exon 6, 16 and 20 of three patients, whereas one patient was tested positive for mutation in exon 11 by PTT assays. All patients with BRCA1 mutations were further confirmed by DNA sequencing analysis. In exon 16 c.4837A > G was confirmed, which is a common polymorphism reported in several populations including Asians. Moreover, mutations in exon 6 (c.271T > G), exon 20 (c.5231 delG) and exon 11 (c.1123 T > G) were reported first time in the Pakistani population. Several BRCA1 mutations were observed in Pakistani breast cancer patients with moderate family history. Therefore, mutation-based genetic counselling for patients with moderate family history can facilitate management, if one first or second degree relative or early onset disease is apparent.


The degradation of two mitotic cyclins contributes to the timing of cytokinesis.
Cytokinesis occurs just as chromosomes complete segregation and reform nuclei. It has been proposed that cyclin/Cdk kinase inhibits cytokinesis until exit from mitosis; however, the timer of cytokinesis has not been experimentally defined. Whereas expression of a stable version of Drosophila cyclin B blocks cytokinesis along with numerous events of mitotic exit, stable cyclin B3 allows cytokinesis even though it blocks late events of mitotic exit. We examined the interface between mitotic cyclin destruction and the timing of cytokinesis. In embryonic mitosis 14, the cytokinesis furrow appeared 60 s after the metaphase/anaphase transition and closed 90 s later during telophase. In cyclin B or cyclin B3 mutant cells, the cytokinesis furrow appeared at an earlier stage of mitosis. Expression of stable cyclin B3 delayed and prolonged furrow invagination; nonetheless, cytokinesis completed during the extended mitosis. Reduced function of Pebble, a Rho GEF required for cytokinesis, also delayed and slowed furrow invagination, but incomplete furrows were aborted at the time of mitotic exit. In functional and genetic tests, cyclin B and cyclin B3 inhibited Pebble contributions to cytokinesis. Temporal coordination of mitotic events involves inhibition of cytokinesis by cyclin B and cyclin B3 and punctual relief of the inhibition by destruction of these cyclins. Both cyclins inhibit Pebble-dependent activation of cytokinesis, whereas cyclin B can inhibit cytokinesis by additional modes. Stable cyclin B3 also blocks the later return to interphase that otherwise appears to impose a deadline for the completion of cytokinesis.


Common polymorphic variation in the genetically diverse African insulin gene and its association with size at birth.
The insulin variable number of tandem repeats (INS VNTR) has been variably associated with size at birth in non-African populations. Small size at birth is a major determinant of neonatal mortality, so the INS VNTR may influence survival. We tested the hypothesis, therefore, that genetic variation around the INS VNTR in a rural Gambian population, who experience seasonal variation in nutrition and subsequently birth weight, may be associated with foetal and early growth. Six polymorphisms flanking the INS VNTR were genotyped in over 2,500 people. Significant associations were detected between the maternally inherited SNP 27 (rs689) allele and birth length [effect size 17.5 (5.2-29.8) mm; P = 0.004; n = 361]. Significant associations were also found between the maternally inherited African-specific SNP 28 (rs5506) allele and post-natal weight gain [effect size 0.19 (0.05-0.32) z score points/year; P = 0.005; n = 728). These results suggest that in the Gambian population studied there are associations between polymorphic variation in the genetically diverse INS gene and foetal and early growth characteristics, which contribute to overall polygenic associations with these traits.


Hospital-reported medical errors in children.
Medical errors are an important problem for hospitalized adult inpatients. However, medical errors in children remain comparatively understudied, and published research has been relatively limited. To investigate the national rates of hospital-reported medical errors in pediatric inpatients over the period 1988-1997; and to determine the association of patient and hospital characteristics with the occurrence of hospital-reported medical errors in children. A nonconcurrent cohort study of hospitalized nonnewborn pediatric patients in the United States <or=18 years of age. Data from the Healthcare Cost and Utilization Project for the years 1988, 1991, 1994, and 1997 were used for these analyses. The occurrence of hospital-reported medical errors. The national rate of hospital-reported medical errors in hospitalized children ranged from 1.81 to 2.96 per 100 discharges. These medical error rates were statistically lower in 1988, with the years 1991, 1994, and 1997 not being statistically different from each other. There were no consistent differences in the rates of medical errors when stratified by gender, race, payor status, or median household income of the patient's zip code across years. There was, however, a statistically significant relationship between higher median household income and increasing medical error rates; this trend was consistent across all 4 years. Similarly, children with special medical needs or dependence on a medical technology also had significantly higher rates of hospital-reported medical errors. Although hospital size did not seem to be related to the rate of medical errors, private for-profit hospitals consistently reported lower rates, whereas urban teaching hospitals in all years but 1997 reported higher rates of medical errors. These data highlight both the strengths and limitations of administrative data in the investigation of medical errors. Substantively, they suggest fruitful areas for additional and more detailed study, notably children with special medical needs.


In vitro ultraviolet-induced damage in human corneal, lens, and retinal pigment epithelial cells.
The purpose was to develop suitable in vitro methods to detect ocular epithelial cell damage when exposed to UV radiation, in an effort to evaluate UV-absorbing ophthalmic biomaterials. Human corneal epithelial cells (HCEC), lens epithelial cells (HLEC), and retinal pigment epithelial cells (ARPE-19) were cultured and Ultraviolet A/Ultraviolet B (UVA/UVB) blocking filters and UVB-only blocking filters were placed between the cells and a UV light source. Cells were irradiated with UV radiations at various energy levels with and without filter protections. Cell viability after exposure was determined using the metabolic dye alamarBlue and by evaluating for changes in the nuclei, mitochondria, membrane permeability, and cell membranes of the cells using the fluorescent dyes Hoechst 33342, rhodamine 123, calcein AM, ethidium homodimer-1, and annexin V. High-resolution images of the cells were taken with a Zeiss 510 confocal laser scanning microscope. The alamarBlue assay results of UV-exposed cells without filters showed energy level-dependent decreases in cellular viability. However, UV treated cells with 400 nm LP filter protection showed the equivalent viability to untreated control cells at all energy levels. Also, UV irradiated cells with 320 nm LP filter showed lower cell viability than the unexposed control cells, yet higher viability than UV-exposed cells without filters in an energy level-dependent manner. The confocal microscopy results also showed that UV radiation can cause significant dose-dependent degradations of nuclei and mitochondria in ocular cells. The annexin V staining also showed an increased number of apoptotic cells after UV irradiation. The findings suggest that UV-induced HCEC, HLEC, and ARPE-19 cell damage can be evaluated by bioassays that measure changes in the cell nuclei, mitochondria, cell membranes, and cell metabolism, and these assay methods provide a valuable in vitro model for evaluating the effectiveness of UV-absorbing ophthalmic biomaterials, including contact lenses and intraocular lenses.


A prospective study of acceptance of pain and patient functioning with chronic pain.
Acceptance of chronic pain is emerging as an important concept in understanding ways that chronic pain sufferers can remain engaged with valued aspects of life. Recent studies have relied heavily on cross-sectional investigations at a single time point. The present study sought to prospectively investigate relations between acceptance of chronic pain and patient functioning. A sample of adults referred for interdisciplinary treatment of severe and disabling chronic pain was assessed twice, an average of 3.9 months apart. Results showed that pain and acceptance were largely unrelated. Pain at Time 2 was weakly related to measures of functioning at Time 2. On the other hand, acceptance at Time 1 was consistently related to patient functioning at Time 2. Those patients who reported greater acceptance at Time 1 reported better emotional, social, and physical functioning, less medication consumption, and better work status at Time 2. These data suggest that willingness to have pain, and to engage in activity regardless of pain, can lead to healthy functioning for patients with chronic pain. Treatment outcome and process studies may demonstrate the potential for acceptance-based clinical methods for chronic pain management.


Remoteness from emission sources explains the fractionation pattern of polychlorinated biphenyls in the northern hemisphere.
The global distillation hypothesis states that fractionation patterns of persistent semivolatile chemicals in the environment are determined by the effect of spatially varying environmental temperature on the temperature-dependent phase partitioning coefficients of chemicals. Here, we use a model experiment and an analysis of monitoring data for polychlorinated biphenyls (PCBs) to explore an alternative hypothesis, the differential removal hypothesis, which proposes that fractionation results from different loss rates from the atmosphere, acting along a gradient of remoteness from emission sources. Model calculations for a range of PCB congeners demonstrate that fractionation occurs with distance from sources, regardless of the temperature gradient. We have assembled two independent data sets of PCB concentrations in European air that show fractionation, and quantified the remoteness of monitoring sites from PCB sources using the remoteness index, RI. Regression analysis of these empirical data against RI and temperature demonstrates that RI determines fractionation patterns. Based on this result, we calculate empirical effective residence times in air for a set of PCB congeners from the relationship between measured concentrations and RI. These empirical effective residence times agree well with values calculated by a multimedia mass balance model. Our conclusion from the model experiment and analysis of monitoring data is that temperature is not a driver of the fractionation of PCBs currently observed in European air, but rather that fractionation reflects differential removal from the atmosphere.


The ring nerve of the box jellyfish Tripedalia cystophora.
Box jellyfish have the most elaborate sensory system and behavioural repertoire of all cnidarians. Sensory input largely comes from 24 eyes situated on four club-shaped sensory structures, the rhopalia, and behaviour includes obstacle avoidance, light shaft attractance and mating. To process the sensory input and convert it into the appropriate behaviour, the box jellyfish have a central nervous system (CNS) but this is still poorly understood. The CNS has two major components: the rhopalial nervous system and the ring nerve. The rhopalial nervous system is situated within the rhopalia in close connection with the eyes, whereas the ring nerve encircles the bell. We describe the morphology of the ring nerve of the box jellyfish Tripedalia cystophora as ascertained by normal histological techniques, immunohistochemistry and transmission electron microscopy. By light microscopy, we have estimated the number of cells in the ring nerve by counting their nuclei. In cross sections at the ultrastructural level, the ring nerve appears to have three types of neurites: (1) small "normal"-looking neurites, (2) medium-sized neurites almost completely filled by electron-lucent vacuoles and (3) giant neurites. In general, only one giant neurite is seen on each section; this type displays the most synapses. Epithelial cells divide the ring nerve into compartments, each having a tendency to contain neurites of similar morphology. The number and arrangement of the compartments vary along the length of the ring nerve.


Limited reverse transcriptase activity of phi29 DNA polymerase.
Phi29 (Φ29) DNA polymerase is an enzyme commonly used in DNA amplification methods such as rolling circle amplification (RCA) and multiple strand displacement amplification (MDA), as well as in DNA sequencing methods such as single molecule real time (SMRT) sequencing. Here, we report the ability of phi29 DNA polymerase to amplify RNA-containing circular substrates during RCA. We found that circular substrates with single RNA substitutions are amplified at a similar amplification rate as non-chimeric DNA substrates, and that consecutive RNA pyrimidines were generally preferred over purines. We observed RCA suppression with higher number of ribonucleotide substitutions, which was partially restored by interspacing RNA bases with DNA. We show that supplementing manganese ions as cofactor supports replication of RNAs during RCA. Sequencing of the RCA products demonstrated accurate base incorporation at the RNA base with both Mn2+ and Mg2+ as cofactors during replication, proving reverse transcriptase activity of the phi29 DNA polymerase. In summary, the ability of phi29 DNA polymerase to accept RNA-containing substrates broadens the spectrum of applications for phi29 DNA polymerase-mediated RCA. These include amplification of chimeric circular probes, such as padlock probes and molecular inversion probes.


Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival.
Cancer stem cells are thought to be responsible for rapid tumor growth, metastasis, and enhanced tumor survival following drug treatment. For this reason, there is a major emphasis on identifying proteins that can be targeted to kill cancer stem cells or control their growth, and transglutaminase type II (TGM2/TG2) is such a target in epidermal squamous cell carcinoma. TG2 was originally described as a transamidase in the extracellular matrix that crosslinks proteins by catalyzing ε-(γ-glutamyl)lysine bonds. However, subsequent studies have shown that TG2 is a GTP-binding protein that plays an important role in cell signaling and survival. In the present study, TG2 shows promise as a target for anticancer stem cell therapy in human squamous cell carcinoma. TG2 was determined to be highly elevated in epidermal cancer stem cells (ECS cells), and TG2 knockdown or suppression of TG2 function with inhibitors reduced ECS cell survival, spheroid formation, Matrigel invasion, and migration. The reduction in survival is associated with activation of apoptosis. Mechanistic studies, using TG2 mutants, revealed that the GTP-binding activity is required for maintenance of ECS cell growth and survival, and that the action of TG2 in ECS cells is not mediated by NF-κB signaling. This study suggests that TG2 has an important role in maintaining cancer stem cell survival, invasive, and metastatic behavior and is an important therapeutic target to reduce survival of cancer stem cells in epidermal squamous cell carcinoma.


Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.
Based on past studies of an experimental model of severe intrauterine pulmonary hypertension, we hypothesized that endothelin-1 (ET-1) contributes to high pulmonary vascular resistance (PVR), hypertensive lung structural changes, and right ventricular hypertrophy (RVH) caused by prolonged closure of the ductus arteriosus. To test this hypothesis, we studied the effects of BQ 123, a selective ET(A) receptor antagonist, after ligation of the ductus arteriosus in utero. In 19 late gestation fetal lambs (126+/-3 d; 147 d, term) we ligated the ductus arteriosus at surgery, and treated animals with either BQ 123 (1 mg/d) or vehicle (0.1% DMSO, HTN) in the pulmonary artery for 8 d. Chronic BQ 123 treatment attenuated the rise in mean pulmonary artery pressure (PAP) 8 d after ductus arteriosus ligation (78+/-2, HTN vs. 70+/-4 mmHg, BQ 123, P < 0.05). To study the effects of ET(A) blockade at birth, 15 animals were delivered by cesarean section and ventilated with 10% oxygen (O2), 100% O2 and inhaled nitric oxide (NO). Lambs treated with BQ 123 had lower PVR after delivery during ventilation with 10% O2, 100% O2, and inhaled NO (HTN vs. BQ 123, P < 0.05 for each intervention). Acute BQ 123 treatment (2 mg/30 min) lowered PVR in three HTN animals ventilated with 100% O2 and inhaled NO (P < 0.05). Chronic BQ 123 treatment prevented the development of RVH as determined by the ratio of the right ventricle/left ventricle + septum (0.79+/-0.03, HTN vs. 0.57+/-0.06, BQ 123, P < 0.05) and attenuated the increase in wall thickness of small pulmonary arteries (61+/-2, HTN vs. 50+/-2%, BQ 123, P < 0.05). In summary, chronic intrauterine ET(A) receptor blockade decreased PAP in utero, decreased RVH and distal muscularization of small pulmonary arteries, and increased the fall in PVR at delivery. We conclude that ET(A) receptor stimulation contributes to the pathogenesis and pathophysiology of experimental perinatal pulmonary hypertension.


Perioperative Management of Antithrombotic Therapy in Common Otolaryngologic Surgical Procedures: State of the Art Review.
The perioperative management of patients undergoing otolaryngologic procedures is increasingly complicated by the use of newer antithrombotic agents. Furthermore, with advances in anesthesia and surgical technique, otolaryngologists are presented with the challenge of operating on patients with advanced comorbid diseases. The objective of this review is to provide evidence-based recommendations on perioperative antithrombotic management for common otolaryngologic procedures. PubMed/MEDLINE. Selected literature on patient-specific thromboembolic risk, rate of bleeding complications in otolaryngologic procedures, and the interruption of antithrombotic therapy is reviewed and interpreted by expert opinion. By stratifying patients into either low thromboembolic risk (≤ 5%) or high thromboembolic risk (> 5%) and interpreting this in the context of procedural bleed risk and potential clinical consequences in the event of a bleed, otolaryngologists can make evidence-based decisions to determine the appropriate perioperative management of antithrombotic therapy. When the perioperative management of antithrombotic therapy is being decided, 3 critical factors must be considered systematically: the patient's inherent thromboembolic risk, the risk and potential consequences of bleeding related to the procedure, and the timing of interruption of thromboembolic therapy.


Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial.
Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist memantine, but further data are needed. Therefore, the efficacy and safety of memantine were investigated in patients with mild to moderate Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB). Patients (≥50 years of age) with mild to moderate PDD or DLB were recruited from 30 specialist centres in Austria, France, Germany, the UK, Greece, Italy, Spain, and Turkey. They were randomly assigned to placebo or memantine (20 mg per day) according to a computer-generated list. Patients and all physicians who had contact with them were masked to treatment assignment. No primary endpoint was defined. Safety analyses were done for all patients who took at least one dose of memantine or placebo, and efficacy analyses were done for all patients who had at least one valid postbaseline assessment. This trial is registered with ClinicalTrials.gov, number NCT00855686. Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given memantine, and 41 with DLB and 58 with PDD were given placebo. 159 (80%) patients completed the study: 80 in the memantine group and 79 in the placebo group. 93 patients treated with memantine and 97 patients treated with placebo were included in the efficacy analysis. At week 24, patients with DLB who received memantine showed greater improvement according to Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores than did those who received placebo (mean change from baseline 3·3 vs 3·9, respectively, difference -0·6 [95% CI -1·2 to -0·1]; p=0·023). No significant differences were noted between the two treatments in patients with PDD (3·6 with memantine vs 3·8 with placebo, -0·1 [-0·6 to 0·3]; p=0·576) or in the total population (3·5 with memantine vs 3·8 with placebo, -0·3 [-0·7 to 0·1]; p=0·120). Neuropsychiatric-inventory scores showed significantly greater improvement in the memantine group than in the placebo group (-4·3 vs 1·7, respectively, -5·9 [-11·6 to -0·2]; p=0·041) in patients with DLB, but not in those with PDD (-1·6 vs -0·1, respectively, -1·4 [-5·9 to 3·0]; p=0·522) or in the total patient population (-2·6 vs 0·4, respectively, -2·9 [-6·3 to 0·5]; p=0·092). In most of the cognitive test scores, ADCS-activities of daily living, and Zarit caregiver burden scores, there were no significant differences between the two treatment groups in any of the study populations. The incidence of adverse events and number of discontinuations due to adverse events were similar in the two groups. The most common serious adverse events were stroke (n=3 in memantine group), falls (n=2 in memantine group; n=1 in placebo group), and worsening of dementia (n=2 in memantine group). Memantine seems to improve global clinical status and behavioural symptoms of patients with mild to moderate DLB, and might be an option for treatment of these patients. Lundbeck.


Signal detectability in diffusive media using phased arrays in conjunction with detector arrays.
We investigate Hotelling observer performance (i.e., signal detectability) of a phased array system for tasks of detecting small inhomogeneities and distinguishing adjacent abnormalities in uniform diffusive media. Unlike conventional phased array systems where a single detector is located on the interface between two sources, we consider a detector array, such as a CCD, on a phantom exit surface for calculating the Hotelling observer detectability. The signal detectability for adjacent small abnormalities (2 mm displacement) for the CCD-based phased array is related to the resolution of reconstructed images. Simulations show that acquiring high-dimensional data from a detector array in a phased array system dramatically improves the detectability for both tasks when compared to conventional single detector measurements, especially at low modulation frequencies. It is also observed in all studied cases that there exists the modulation frequency optimizing CCD-based phased array systems, where detectability for both tasks is consistently high. These results imply that the CCD-based phased array has the potential to achieve high resolution and signal detectability in tomographic diffusive imaging while operating at a very low modulation frequency. The effect of other configuration parameters, such as a detector pixel size, on the observer performance is also discussed.


Release of small bioactive molecules from physical gels.
Pharmaceutical drugs with low water solubility have always received great attention within the scientific community. The reduced bioavailability and the need of frequent administrations have motivated the investigation of new drug delivery systems. Within this context, drug carriers that release their payload in a sustained way and hence reduce the administration rate are highly demanded. One interesting strategy to meet these requirements is the entrapment of the drugs into gels. So far, the most investigated materials for such drug-loaded gels are derived from polymers and based on covalent linkages. However, over the last decade the use of physical (or supramolecular) gels derived from low molecular weight compounds has experienced strong growth in this field, mainly due to important properties such as injectability, stimuli responsiveness and ease of synthesis. This review summarizes the use of supramolecular gels for the encapsulation and controlled release of small therapeutic molecules.


Review of the use of NMR spectroscopy to investigate structure, reactivity, and dynamics of lead soap formation in paintings.
Heavy metal carboxylate or soap formation is a widespread deterioration problem affecting oil paintings and other works of art bearing oil-based media. Lead soaps are prevalent in traditional oil paintings because lead white was the white pigment most frequently chosen by old masters for the paints and in some cases for the ground preparations, until the development of other white pigments from approximately the middle of the 18th century on, and because of the wide use of lead-tin yellow. In the latter part of the 19th century, lead white began to be replaced by zinc white. The factors that influence soap formation have been the focus of intense study starting in the late 1990s. Since 2014, nuclear magnetic resonance (NMR) studies have contributed a unique perspective on the issue by providing chemical, structural, and dynamic information about the species involved in the process, as well as the effects of environmental conditions such as relative humidity and temperature on the kinetics of the reaction(s). In this review, we explore recent insights into soap formation gained through solid-state NMR and single-sided NMR techniques.


Gold-silver alloy semi-nanoshell arrays for label-free plasmonic biosensors.
Nanosphere lithography coupled with reactive ion etching has been used to synthesize hexagonal ordered arrays of Au-Ag bimetallic semi-nanoshells to be used as plasmonic biosensors. The degree of lateral interaction between adjacent semi-nanoshells can be controlled by tailoring the reactive ion etching time in order to boost the global plasmonic properties through the formation of near-field hot-spots, which in turn can improve the sensitivity of the biosensors. To test the efficiency of the proposed system as a biosensor, we used an established protocol for the detection of biomolecules (local sensitivity), based on the receptor-ligand approach and using the biotin-streptavidin model system. We also tested the sensitivity to a homogeneous change in the refractive index of the buffer over the sensor (bulk sensitivity). Comparing the obtained results to those of an array of nanoprisms, chosen as a benchmark, significantly higher performances both in local and bulk sensitivities have been found, in agreement with electrodynamics simulations based on finite-element methods.


The development of palliative care knowledge in care homes for older people: the place of action research.
Action research in health care is a relatively new research approach, which is adopted when one aim of the research is to bring about change in practice and to research the process of that change. This paper describes the way action research, as a research methodology, can be used to develop palliative care knowledge in generalist care settings. An overview of action research is presented and its relationship to more conventional research paradigms. Two action research projects, undertaken to develop knowledge about end-of-life care for older people in care homes, are used to illustrate the key principles of action research, methods of data collection and data analysis. Finally, the challenges of such, utilising an action research approach and its strengths, are discussed.


Anticoagulation and bleeding risk in patients with COVID-19.
There is no current standardized approach to anticoagulation in patients with Coronavirus Disease 2019 (COVID-19) while potential bleeding risks remain. Our study characterizes the patterns of anticoagulation use in COVID-19 patients and the risk of related bleeding. This is a single center retrospective analysis of 355 adult patients with confirmed diagnosis of COVID-19 from March 1 to May 31, 2020. Chi-square was used to analyze the relationship between degree of anticoagulant dose and bleeding events by site. Multivariable logistic regression was used to look at factors associated with inpatient death. 61% of patients were being treated with prophylactic doses of anticoagulation, while 7% and 29% were being treated with sub-therapeutic and therapeutic anticoagulation (TA) doses respectively. In 44% of patients, we found that the decision to escalate the dose of anticoagulation was based on laboratory values characterizing the severity of COVID-19 such as rising D-dimer levels. There were significantly higher rates of bleeding from non-CNS/non-GI sites (p = 0.039) and from any bleeding site overall (p = 0.019) with TA. TA was associated with significantly higher rates of inpatient death (41.6% vs 15.3% p < 0.0001) compared to those without. All patients who developed CNS hemorrhage died p = 0.011. After multivariable logistic regression, only age OR 1.04 95% CI (1.01 to 1.07) p = 0.008 and therapeutic anticoagulation was associated with inpatient mortality OR 6.16 95% CI (2.96 to 12.83) p ≤ 0.0001. The use of TA was significantly associated with increased risk of bleeding. Bleeding in turn exhibited trends towards higher inpatient death among patients with COVID-19. These findings should be interpreted with caution and larger more controlled studies are needed to verify the net effects of anticoagulation in patients with COVID-19.


Basic and acidic fibroblast growth factors have trophic effects on neurons from multiple CNS regions.
Basic fibroblast growth factor (bFGF) supports the survival of neurons from many regions of the E18 fetal rat brain. Survival was significantly increased for neurons derived from the hippocampus, entorhinal cortex (EC), frontal cortex, parietal cortex (PC), occipital cortex, striatum, septum, and thalamus, but not from the subiculum (Sb). The proportion of neurons rescued by bFGF varied among brain regions, suggesting the existence of subpopulations of responsive neurons. Like hippocampal neurons, neurons from the EC and PC required about 1 pM bFGF (10-20 pg/ml) for half-maximal response; striatal neurons, in contrast, required about 3 pM bFGF. Neurite outgrowth after 24 hr exposure was significantly increased for neurons from the hippocampus, EC, and PC, while striatal neurons had only a marginal response. Although bFGF stimulated some astrocytic proliferation in the cultures, glial contamination was maintained at 2% or less. Acidic FGF (aFGF) supported smaller numbers of neurons from each region, although it significantly increased survival of neurons from hippocampus, EC, PC, striatum, and Sb. The concentration required for half-maximal survival was around 100-300 pM (2-5 ng/ml). It appears that bFGF and aFGF are potent trophic factors for many populations of CNS neurons and could potentially play a significant role in nervous system development.


Supporting Simultaneous Air Revitalization and Thermal Control in a Crewed Habitat With Temperate Chlorella vulgaris and Eurythermic Antarctic Chlorophyta.
Including a multifunctional, bioregenerative algal photobioreactor for simultaneous air revitalization and thermal control may aid in carbon loop closure for long-duration surface habitats. However, using water-based algal media as a cabin heat sink may expose the contained culture to a dynamic, low temperature environment. Including psychrotolerant microalgae, native to these temperature regimes, in the photobioreactor may contribute to system stability. This paper assesses the impact of a cycled temperature environment, reflective of spacecraft thermal loops, to the oxygen provision capability of temperate Chlorella vulgaris and eurythermic Antarctic Chlorophyta. The tested 28-min temperature cycles reflected the internal thermal control loops of the International Space Station (C. vulgaris, 9-27°C; Chlorophyta-Ant, 4-14°C) and included a constant temperature control (10°C). Both sample types of the cycled temperature condition concluded with increased oxygen production rates (C. vulgaris; initial: 0.013 mgO2 L-1, final: 3.15 mgO2 L-1 and Chlorophyta-Ant; initial: 0.653 mgO2 L-1, final: 1.03 mgO2 L-1) and culture growth, suggesting environmental acclimation. Antarctic sample conditions exhibited increases or sustainment of oxygen production rates normalized by biomass dry weight, while both C. vulgaris sample conditions decreased oxygen production per biomass. However, even with the temperature-induced reduction, cycled temperature C. vulgaris had a significantly higher normalized oxygen production rate than Antarctic Chlorophyta. Chlorophyll fluorometry measurements showed that the cycled temperature conditions did not overly stress both sample types (FV/FM: 0.6-0.75), but the Antarctic Chlorophyta sample had significantly higher fluorometry readings than its C. vulgaris counterpart (F = 6.26, P < 0.05). The steady state C. vulgaris condition had significantly lower fluorometry readings than all other conditions (FV/FM: 0.34), suggesting a stressed culture. This study compares the results to similar experiments conducted in steady state or diurnally cycled temperature conditions. Recommendations for surface system implementation are based off the presented results. The preliminary findings imply that both C. vulgaris and Antarctic Chlorophyta can withstand the dynamic temperature environment reflective of a thermal control loop and these data can be used for future design models.


Bassoon and the synaptic ribbon organize Ca²+ channels and vesicles to add release sites and promote refilling.
At the presynaptic active zone, Ca²+ influx triggers fusion of synaptic vesicles. It is not well understood how Ca²+ channel clustering and synaptic vesicle docking are organized. Here, we studied structure and function of hair cell ribbon synapses following genetic disruption of the presynaptic scaffold protein Bassoon. Mutant synapses--mostly lacking the ribbon--showed a reduction in membrane-proximal vesicles, with ribbonless synapses affected more than ribbon-occupied synapses. Ca²+ channels were also fewer at mutant synapses and appeared in abnormally shaped clusters. Ribbon absence reduced Ca²+ channel numbers at mutant and wild-type synapses. Fast and sustained exocytosis was reduced, notwithstanding normal coupling of the remaining Ca²+ channels to exocytosis. In vitro recordings revealed a slight impairment of vesicle replenishment. Mechanistic modeling of the in vivo data independently supported morphological and functional in vitro findings. We conclude that Bassoon and the ribbon (1) create a large number of release sites by organizing Ca²+ channels and vesicles, and (2) promote vesicle replenishment.


Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions.
New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.


Açai palm fruit (Euterpe oleracea Mart.) pulp improves survival of flies on a high fat diet.
Reducing oxidative damage is thought to be an effective aging intervention. Açai, a fruit indigenous to the Amazon, is rich in phytochemicals that possesses high anti-oxidant activities, and has anti-inflammatory, anti-cancer and anti-cardiovascular disease properties. However, little is known about its potential anti-aging properties especially at the organismal level. Here we evaluated the effect of açai pulp on modulating lifespan in Drosophila melanogaster. We found that açai supplementation at 2% in the food increased the lifespan of female flies fed a high fat diet compared to the non-supplemented control. We measured transcript changes induced by açai for age-related genes. Although transcript levels of most genes tested were not altered, açai increased the transcript level of l(2)efl, a small heat-shock-related protein, and two detoxification genes, GstD1 and MtnA, while decreasing the transcript level of phosphoenolpyruvate carboxykinase (Pepck), a key gene involved in gluconeogenesis. Furthermore, açai increased the lifespan of oxidative stressed females caused by sod1 RNAi. This suggests that açai improves survival of flies fed a high fat diet through activation of stress response pathways and suppression of Pepck expression. Açai has the potential to antagonize the detrimental effect of fat in the diet and alleviate oxidative stress in aging.


Judith Balkányi-Lepintre (1912-1982): first woman neurosurgeon, first woman war neurosurgeon, and first woman pediatric neurosurgeon in France.
Recently, a series of historical reports portrayed the first women neurosurgeons in various countries. One such woman, a pioneer on many levels, remained unrecognized: Judith Balkányi-Lepintre. She was the first woman neurosurgeon in France, the first woman war neurosurgeon for the French Army, and the first woman pediatric neurosurgeon in France. Born in 1912 to a Hungarian Jewish family, she graduated with honors from medical school in Budapest in 1935, then moved to Paris where she started neurosurgical training in 1937 at L'Hôpital de la Pitié under the mentorship of Clovis Vincent, the founder of French neurosurgery. Shortly after marrying a French colleague in 1940, she had to escape the Geheime Staatspolizei (Gestapo) in Paris and ended up in Algeria, where she joined the French Army of De Gaulle. As a neurosurgeon, she participated in the campaigns of Italy and France between 1943 and 1945. After the war, she returned to work at La Pitié Hospital. In 1947, she defended her doctoral thesis, "Treatment of cranio-cerebral wounds by projectiles and their early complications." Soon thereafter, she joined Europe's first dedicated children's hospital, Hôpital Necker-Enfants Malades in Paris, and contributed to the establishment of pediatric neurosurgery in France. She remained clinically and academically active at Necker until her death in 1982 but was never promoted.


Lactococcus lactis subsp. lactis as a natural anti-listerial agent in the mushroom industry.
Mushroom growth substrates from different commercial producers of mushrooms (Agaricus bisporus) were screened for the presence of bacteria with potential for use as biocontrol agents for controlling Listeria monocytogenes in the mushroom production environment. Eight anti-listerial strains were isolated from different sources and all were identified using 16s rRNA gene sequencing as Lactococcus lactis subsp. lactis. Whole-genome sequencing of the Lc. lactis isolates indicated that strains from different sites and substrate types were highly similar. Colony MALDI-TOF mass spectrometry found that these strains were Nisin Z producers but inhibitory activity was highly influenced by the incubation conditions and was strain dependant. The biofilm forming ability of these strains was tested using a crystal violet assay and all were found to be strong biofilm formers. Growth of Lc. lactis subsp. lactis using mixed-biofilm conditions with L. monocytogenes on stainless steel resulted in a 4-log reduction of L. monocytogenes cell numbers. Additional sampling of mushroom producers showed that these anti-listerial Lc. lactis strains are commonly present in the mushroom production environment. Lc. lactis has a generally regarded as safe (GRAS) status and therefore has potential for use as an environmentally benign solution to control L. monocytogenes in order to prevent product contamination and to enhance consumer confidence in the mushroom industry.


Detection of previous proximal venous thrombosis with Doppler ultrasonography and photoplethysmography.
To evaluate the reliability of two noninvasive tests, the photoplethysmograph (PPG) and venous Doppler ultrasound, in determining the presence or absence of previous proximal deep vein thrombosis (DVT), we performed a blinded retrospective cohort study of patients with objectively confirmed (DVT+) or refuted (DVT-) previous episodes of suspected DVT. Twenty-nine of 33 DVT+ patients had abnormal PPG and/or reflux by venous Doppler ultrasound, whereas 39 of 49 DVT- patients had normal PPG and no Doppler reflux (sensitivity, 88%; specificity, 80%). Of 33 DVT+ patients, 20 had abnormal Doppler results (sensitivity, 61%), in contrast to 46 of 49 DVT- patients with normal results (specificity, 94%). Moreover, 23 of 33 DVT+ patients showed abnormal PPG results (sensitivity, 70%), whereas 40 of 49 DVT- patients had normal PPG (specificity, 82%). Based on our findings, the presence of Doppler reflux is specific for previous proximal DVT, whereas a combination of normal PPG and Doppler ultrasound is reliable for excluding previous proximal DVT. Abnormal PPG with normal Doppler ultrasound does not reliably predict the presence or absence of previous DVT. However, this occurred in only 16 of 82 patients. Therefore, the combination of PPG and venous Doppler ultrasound can reliably predict the presence or absence of previous proximal DVT in most patients.


Characteristics of the old and homeless: identifying distinct service needs.
Research suggests that being older and homeless is associated with unique characteristics and potential barriers to improved living conditions. Additional research is needed to better understand the vulnerabilities associated with this population. The purpose of this study was to identify characteristics related to aging and homelessness. It was hypothesized that older adults would exhibit more vulnerability compared to other age groups related to health, social support proximity, occupational perceptions, and recent living conditions prior to seeking assistance at an emergency shelter. It was also hypothesized that these age-related characteristics would predict the amount of time that individuals resided in the emergency shelter. A cross-sectional sample of young, middle-aged, and older homeless adults seeking shelter at two emergency homeless shelters was utilized for this study. Data included information obtained during a structured interview after participants arrived at the shelter and the number of days that were spent at the shelter. Older adults were more likely to exhibit several characteristics (i.e., poorer health, being further from social support, longer durations of homelessness, lack of employment area, prior residence types, and mental health treatment) potentially contributing to and/or recovering from homelessness. Duration of homelessness, reports of having no career area, and age were predictive of the amount of time spent at the shelter. The various characteristics that differentiate older homeless populations (e.g., health, social support, homelessness duration, and employment) could create potential barriers to overcoming homelessness that should be considered when serving this population.


STEP trial and HIV-1 vaccines inducing T-cell responses.
Recombinant, nonreplicating, human adenovirus serotype 5-vectored vaccine, known as MRKAd5, expressing three HIV-1 clade B-derived internal proteins when used in a homologous immunization regimen, did not decrease HIV-1 infection rate nor postinfection virus load in the first Phase IIb proof-of-concept trial. However, the vaccine did not reach the limits of vaccine T-cell induction and its design can be improved both from the point of the HIV-1-derived immunogens and their delivery. Therefore, failure of the first experimental HIV-1 vaccine focusing on induction of T-cell responses cannot be a reason for dismissal of the whole T-cell vaccine concept, nor for losing a positive attitude toward systematic HIV-1 vaccine development.


Use of chloride blockers: a novel approach for cardioprotection against ischemia-reperfusion damage.
We examined whether the chloride channel blockers anthracene-9-carboxylic acid (9-AC) and 4-acetamide-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) exert protective effects against myocardial ischemia-reperfusion damage. In isolated guinea pig ventricular cells, 9-AC (200 microM), but not SITS (100 microM), inhibited the chloride current induced by isoproterenol. Electrical and mechanical activities and intracellular pH of arterially perfused guinea pig right ventricular preparations were recorded with an intracellular microelectrode, a force transducer and a pH-sensitive fluorescent probe, respectively. The preparations were subjected to 30 min of no-flow ischemia, with or without 9-AC (100 microM) or SITS (10 microM), followed by reperfusion. No-flow ischemia produced decreases in action potential amplitude and duration, and the contractile force was completely abolished. Although the changes in electrical parameters were reversed upon reperfusion, the contractile force recovered only to about 50% of preischemic values. 9-AC and SITS had no inhibitory effect on contractile force under normal conditions and during ischemia but significantly improved the recovery of contractile force upon reperfusion to about 80% of preischemic values. Both 9-AC and SITS showed significant inhibition of the ischemia-induced abbreviation of action potential duration. Other parameters were not affected by 9-AC or SITS. During ischemia, intracellular pH showed a transient small increase followed by a sustained decrease, which was completely recovered upon reperfusion. The decrease in pH during ischemia was attenuated by 80% in SITS- but not 9-AC-treated preparations. Thus, we demonstrated that the chloride channel blockers 9-AC and SITS, which have no cardiosuppressive effects, exert protective effects against myocardial ischemia-reperfusion damage.


Blood transfusion, anesthesia, surgery and risk of non-Hodgkin lymphoma in a population-based case-control study.
The incidence of NHL has increased dramatically since at least the 1950s, and during this timeframe there has been a major increase in the use of blood transfusions, invasive surgical procedures and anesthesia, all of which can impact immune function. We evaluated these factors with NHL risk in a population-based study of 759 cases and 589 frequency-matched controls. Risk factor data were collected during in-person interviews. Unconditional logistic regression was used to estimate ORs and 95% CIs, adjusted for the matching factors. History of transfusion was associated with a 26% higher risk of NHL (95% CI 0.91-1.73), and the elevated risk was specific to transfusions first given 5-29 years before the reference date (OR = 1.69; 95% CI 1.08-2.62) and transfusions given for a medical condition (OR = 2.09; 95% CI 1.03-4.26). The total number of surgeries and dental procedures (OR = 1.53 for 26+ surgeries compared to 0-6; 95% CI 1.02-2.29) and to a lesser extent the total number of exposures to general or local/regional anesthesia (OR = 1.35 for 24+ times compared to 0-6; 95% CI 0.91-2.02) were positively associated with risk of NHL. Inclusion of transfusion and surgery or transfusion and anesthesia in the same model did not attenuate these associations. All results were broadly consistent for both DLBCL and follicular subtypes. Blood transfusions were associated with NHL risk, but appear to be a marker for underlying medical conditions. Multiple surgical procedures and/or repeated administration of anesthesia have not been previously reported to be associated with risk of NHL and these exposures warrant further evaluation.


Visualization of Cranial Nerves Using High-Definition Fiber Tractography.
Recent studies have demonstrated diffusion tensor imaging tractography of cranial nerves (CNs). Spatial and angular resolution, however, is limited with this modality. A substantial improvement in image resolution can be achieved with high-angle diffusion magnetic resonance imaging and atlas-based fiber tracking to provide detailed trajectories of CNs. To use high-definition fiber tractography to identify CNs in healthy subjects and patients with brain tumors. Five neurologically healthy adults and 3 patients with brain tumors were scanned with diffusion spectrum imaging that allowed high-angular-resolution fiber tracking. In addition, a 488-subject diffusion magnetic resonance imaging template constructed from the Human Connectome Project data was used to conduct atlas space fiber tracking of CNs. The cisternal portions of most CNs were tracked and visualized in each healthy subject and in atlas fiber tracking. The entire optic radiation, medial longitudinal fasciculus, spinal trigeminal nucleus/tract, petroclival portion of the abducens nerve, and intrabrainstem portion of the facial nerve from the root exit zone to the adjacent abducens nucleus were identified. This suggested that the high-angular-resolution fiber tracking was able to distinguish the facial nerve from the vestibulocochlear nerve complex. The tractography clearly visualized CNs displaced by brain tumors. These tractography findings were confirmed intraoperatively. Using high-angular-resolution fiber tracking and atlas-based fiber tracking, we were able to identify all CNs in unprecedented detail. This implies its potential in localization of CNs during surgical planning. CN, cranial nerveDSI, diffusion spectrum imagingDTI, diffusion tensor imagingHCP, Human Connectome ProjectHDFT, high-definition fiber tractographyMLF, medial longitudinal fasciculusODF, orientation distribution functionROI, region of interest.


Sedimentary records of sewage pollution using faecal markers in contrasting peri-urban shallow lakes.
Sewage contamination in shallow lake sediments is of concern because the pathogens, organic matter and nutrients contribute to the deterioration of the water-bodies' health and ecology. Sediment cores from three shallow lakes (Coneries, Church and Clifton Ponds) within Attenborough nature reserve located downstream of sewage treatment works were analysed for TOC, C/N, δ(13)C, δ(15)N, bacterial coliforms and faecal sterols. (210)Pb and (137)Cs activities were used to date the sediments. Elemental analysis suggests that the source of organic matter was algal and down profile changes in δ(13)C indicate a possible decrease in productivity with time which could be due to improvements in sewage treatment. δ(15)N for Coneries Pond are slightly higher than those observed in Church or Clifton and are consistent with a sewage-derived nitrate source which has been diluted by non-sewage sources of N. The similarity in δ(15)N values (+12 ‰ to +10 ‰) indicates that the three ponds were not entirely hydrologically isolated. Analysis by gas chromatography/mass spectrometry (GC/MS) reveals that Coneries Pond had sterol concentrations in the range 20 to 30 μg/g (dry wt.), whereas, those from Clifton and Church Ponds were lower. The highest concentrations of the human-sourced sewage marker 5β-coprostanol were observed in the top 40 cm of Coneries Pond with values up to 2.2 μg/g. In contrast, Church and Clifton Pond sediments contain only trace amounts throughout. Down-profile comparison of 5β-coprostanol/cholesterol, 5β-coprostanol/(5β-coprostanol+5α-cholestanol) and 5β-epicoprostanol/coprostanol as well as 5α-cholestanol/cholesterol suggests that Coneries Pond has received appreciable amounts of faecal contamination. Examination of 5β-stigmastanol (marker for herbivorous/ruminant animals) down core concentrations suggests a recent decrease in manure slurry input to Coneries Pond. The greater concentration of β-sitosterol in sediments from Church and Clifton Ponds as compared to Coneries is attributed in part to their greater diversity and extent of aquatic plants and avian faeces.


Amrinone in severe congestive heart failure: another look at an intriguing new cardioactive drug.
Seven patients with severe congestive heart failure received amrinone i.v. (continuous infusions of 10, 20 and 40 micrograms/kg/min) and orally (1.5, 3.0 and 4.5 mg/kg) in order to determine the comprehensive acute hemodynamic response of this agent. Standard hemodynamic, echocardiographic and systolic time interval measurements were made before and sequentially after amrinone administration. Intravenous amrinone significantly increased cardiac index and stroke volume index, did not alter heart rate and significantly decreased pulmonary capillary wedge pressure, mean systemic blood pressure and systemic and pulmonary vascular resistances. The determinants of left ventricular inotropy, delta P/delta t, pre-ejection period index and velocity of circumferential fiber shortening were not affected by amrinone; dobutamine (5 and 10 micrograms/kg/min), used as an internal standard for inotropy, significantly improved these determinants. Except for a significant reduction in pulmonary capillary wedge pressure, first-dose oral amrinone effected little change in central hemodynamic variables and indices of ventricular inotropy; no additional changes occurred after the fifth dose. In the setting of severe chronic congestive heart failure, short-term iv infusions and oral administration of amrinone elicit only mild to moderate hemodynamic changes. Furthermore, these changes are a result of vasodilation (preload and afterload reduction) rather than positive inotropy.


Childhood adversity and adolescent psychopathology: evidence for mediation in a national longitudinal cohort study.
Childhood adversity is a well-established risk factor for psychopathology; however, many who experience adversity do not go on to develop psychopathology. Poor self-concept and poor parental support are known risk factors for adolescent psychopathology, which may account for some of this mechanism. To investigate candidate mediators in the relationship between childhood adversity and psychopathology. We used data from the age 9 and 13 waves of the child-cohort of the Growing Up in Ireland study. We undertook mediation analysis by path decomposition of the relationship between childhood adversity and psychopathology (internalising and externalising problems) at age 13 and persistent psychopathology. Candidate mediators were self-concept, parent-child relationship and hobby participation at age 9. Childhood adversity was reported by 28.2% of participants, and was significantly associated with internalising and externalising problems. Parent-child conflict mediated the relationship between childhood adversity and both age 13 and persistent psychopathology, accounting for 52.4% of the relationship between childhood adversity and persistent externalising problems (indirect odds ratio, 1.30; 95% CI 1.19-1.43) and 19.2% for persistent internalising problems (indirect odds ratio, 1.24; 95% CI 1.15-1.34). There was a small mediating effect of self-concept. Hobby participation and positive parent-child relationship did not mediate these relationships. Parent-child conflict explains almost half the relationship between childhood adversity and persisting externalising problems in adolescence, and a fifth of the relationship with persisting internalising problems. This suggests parent-child conflict is a good target for interventions in childhood to prevent adolescent psychopathology. None.


Individual culture and atmospheric oxygen during culture affect mouse preimplantation embryo metabolism and post-implantation development.
Does single embryo culture under atmospheric or reduced oxygen alter preimplantation metabolism and post-implantation development compared with culture in groups? Mouse embryos were cultured under 5% or 20% oxygen, individually or in groups of 10. Spent media were analysed after 48, 72 and 96 h of culture. Blastocysts were assessed by outgrowth assay or transferred to pseudo-pregnant recipients, and fetal and placental weight, length and morphology were assessed. Compared with group culture, individually cultured blastocysts had lower net consumption of glucose and aspartate and higher glutamate production. Atmospheric oxygen reduced uptake of glucose and aspartate and increased production of glutamate and ornithine compared with 5% oxygen. Combining 20% oxygen and single culture resulted in further metabolic changes: decreased leucine, methionine and threonine consumption. Under 5% oxygen, individual culture decreased placental labyrinth area but had no other effects on fetal and placental development or outgrowth size compared with group culture. Under 20% oxygen, however, individual culture reduced outgrowth size and fetal and placental weight compared with group-cultured embryos. Preimplantation metabolism of glucose and amino acids is altered by both oxygen and individual culture, and fetal weight is reduced by individual culture under atmospheric oxygen but not 5% oxygen. This study raises concerns regarding the increasing prevalence of single embryo culture in human IVF and adds to the existing evidence regarding the detrimental effects of atmospheric oxygen during embryo culture. Furthermore, these data demonstrate the cumulative nature of stress during embryo culture and highlight the importance of optimizing each element of the culture system.


Experimental demonstration of spectral broadening in an all-silica Bragg fiber.
We present the first report on experimental observation of nonlinear spectral broadening in an all-solid photonic band gap Bragg fiber of relatively large mode area approximately 62 microm(2). The theoretically designed Bragg fiber for this specific application was fabricated by the well known MCVD technique. Nonlinear spectral broadening was observed by launching high power femtosecond pulses of 1067 nm pump wavelength. These first results indicate that fabrication of such Bragg fibers, once perfected, should potentially serve as an alternative route for realization of supercontinuum light.


Pest categorisation of Diabrotica undecimpunctata howardi.
The EFSA Panel on Plant Health performed a pest categorisation of Diabrotica undecimpunctata howardi (Coleoptera: Chrysomelidae) for the EU. This subspecies occurs in North and Central America. Adults oviposit on annual plants in the families Asteraceae, Chenopodiaceae, Cucurbitaceae, Fabaceae, Poaceae, Polygonaceae and Solanaceae. Adults feed on tender plant parts in hosts in 40 additional botanical families. Preimaginal development takes place on the roots of the host plant, where larvae feed and pupate. D. undecimpunctata howardi is a multivoltine species. Overwintering adults, which may enter a facultative diapause, abandon crops in autumn and reinvade them in spring. D. undecimpunctata howardi is not known to occur in the EU and is regulated in Annex IIA of Commission Implementing Regulation 2019/2072. This species is a competent vector of Erwinia tracheiphila (Smith) Bergey et al., which can cause bacterial wilt, a serious disease of cucurbits. The bacterium, which is restricted to temperate midwestern and eastern North America, is not regulated in the EU. Within Commission Implementing Regulation 2019/2072, potential entry pathways for D. undecimpunctata howardi, such as Asteraceae, Poaceae and Solanaceae plants for planting with foliage and soil/growing medium, and soil/growing media by themselves can be considered as closed. However, plants for planting of the families Chenopodiaceae, Cucurbitaceae, Fabaceae and Polygonaceae are not specifically regulated. Should D. undecimpunctata howardi arrive in the EU, climatic conditions and availability of susceptible hosts provide conditions suitable for establishment and further spread. Economic impact is anticipated in maize and outdoor cucurbit production. D. undecimpunctata howardi satisfies the criteria that are within the remit of EFSA to assess for this species to be regarded as a potential Union quarantine pest. This species does not meet the criteria of being present in the EU, nor plants for planting being the main pathway for spread, for it to be regarded as a potential regulated non-quarantine pest.


Induction of apoptosis in human myeloid leukemic cells by 1'-acetoxychavicol acetate through a mitochondrial- and Fas-mediated dual mechanism.
The purpose of this investigation was to determine the antileukemic effects of 1'-acetoxychavicol acetate (ACA) obtained from rhizomes of the commonly used ethno-medicinal plant Languas galanga (Zingiberaceae). We evaluated the effects of ACA on various myeloid leukemic cells in vitro and in vivo. We further examined the molecular mechanisms of ACA-induced apoptosis in myeloid leukemic cells. Low-dose ACA dramatically inhibited cellular growth of leukemic cells by inducing apoptosis. Because NB4 promyelocytic leukemic cells were most sensitive to ACA, we used NB4 cells for further analyses. Production of reactive oxygen species triggered ACA-induced apoptosis. ACA-induced apoptosis in NB4 cells was in association with the loss of mitochondrial transmembrane potential (DeltaPsim) and activation of caspase-9, suggesting that ACA-induced death signaling is mediated through a mitochondrial oxygen stress pathway. In addition, ACA activated Fas-mediated apoptosis by inducing of casapse-8 activity. Pretreatment with the thiol antioxidant N-acetyl-L-cysteine (NAC) did not inhibit caspase-8 activation, and the antagonistic anti-Fas antibody ZB4 did not block generation of reactive oxygen species, indicating that both pathways were involved independently in ACA-induced apoptosis. Furthermore, ACA had a survival advantage in vivo in a nonobese diabetic/severe combined immunodeficient mice leukemia model without any toxic effects. We conclude that ACA induces apoptosis in myeloid leukemic cells via independent dual pathways. In addition, ACA has potential as a novel therapeutic agent for the treatment of myeloid leukemia.


Prediction models for exacerbations in patients with COPD.
Personalised medicine aims to tailor medical decisions to the individual patient. A possible approach is to stratify patients according to the risk of adverse outcomes such as exacerbations in chronic obstructive pulmonary disease (COPD). Risk-stratified approaches are particularly attractive for drugs like inhaled corticosteroids or phosphodiesterase-4 inhibitors that reduce exacerbations but are associated with harms. However, it is currently not clear which models are best to predict exacerbations in patients with COPD. Therefore, our aim was to identify and critically appraise studies on models that predict exacerbations in COPD patients. Out of 1382 studies, 25 studies with 27 prediction models were included. The prediction models showed great heterogeneity in terms of number and type of predictors, time horizon, statistical methods and measures of prediction model performance. Only two out of 25 studies validated the developed model, and only one out of 27 models provided estimates of individual exacerbation risk, only three out of 27 prediction models used high-quality statistical approaches for model development and evaluation. Overall, none of the existing models fulfilled the requirements for risk-stratified treatment to personalise COPD care. A more harmonised approach to develop and validate high- quality prediction models is needed to move personalised COPD medicine forward.


Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes.
Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein-coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1-treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.


Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure.
Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) PH Registry. We characterized clinical and laboratory features of patients enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Spearman rank correlation and estimated renal survival using the Kaplan-Meier method. We determined factors associated with renal survival by Cox proportional hazard models. Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m(2) and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/1.73 m(2) per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This association remained even when adjusted for sex, age, and baseline eGFR (HR, 4.2; 95% CI, 1.6 to 10.8). Among patients with PH, higher urinary oxalate excretion is predictive of poor renal outcome.


The evolution of superstitious and superstition-like behaviour.
Superstitious behaviours, which arise through the incorrect assignment of cause and effect, receive considerable attention in psychology and popular culture. Perhaps owing to their seeming irrationality, however, they receive little attention in evolutionary biology. Here we develop a simple model to define the condition under which natural selection will favour assigning causality between two events. This leads to an intuitive inequality--akin to an amalgam of Hamilton's rule and Pascal's wager--that shows that natural selection can favour strategies that lead to frequent errors in assessment as long as the occasional correct response carries a large fitness benefit. It follows that incorrect responses are the most common when the probability that two events are really associated is low to moderate: very strong associations are rarely incorrect, while natural selection will rarely favour making very weak associations. Extending the model to include multiple events identifies conditions under which natural selection can favour associating events that are never causally related. Specifically, limitations on assigning causal probabilities to pairs of events can favour strategies that lump non-causal associations with causal ones. We conclude that behaviours which are, or appear, superstitious are an inevitable feature of adaptive behaviour in all organisms, including ourselves.


Tithonia diversifolia-derived orizabin suppresses cell adhesion, differentiation, and oxidized LDL accumulation by Akt signaling suppression via PTEN promotion in THP-1 cells.
As a Japanese folk medicine, Tithonia diversifolia is used for cardiovascular disease prevention and health maintenance. We isolated T. diversifolia-derived orizabin based on the nitric oxide production inhibitory effect. This study aimed to consider orizabin as a novel functional compound with anti-atherosclerotic activity. Orizabin significantly inhibited the adhesion of THP-1 cells to human umbilical vein endothelial cells (HUVECs) and suppressed the mRNA expression of adhesion molecules in HUVECs. In Phorbol 12-myristate 13-acetate stimulated THP-1 cells, orizabin suppressed macrophage differentiation, CD36 expression (1% at 10 μM), and NFκB transcriptional activity. Furthermore, orizabin suppressed oxidized low-density lipoprotein (oxLDL) uptake in macrophages and the Akt phosphorylation. On the contrary, we revealed that phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN) mRNA and protein expression were promoted significantly by orizabin (mRNA, 270-fold at 10 μM). Our study presented the possibility that T. diversifolia-derived orizabin is novel anti-atherosclerotic compound via the suppression of Akt phosphorylation, and T. diversifolia may be effective as a new crop for vascular health maintenance. PRACTICAL APPLICATIONS: In this study, the differentiation of monocytes was suppressed without any toxicity, it was obvious in the image, and the oxLDL uptake in monocytes was clearly suppressed by orizabin. Our findings presented that T. diversifolia-derived compound orizabin specifically contributes to the promotion of PTEN expression and suppression of Akt signal in cells, and acts to suppress inflammation by suppression of NFκB transcriptional activity. As a component derived from food, it has a strong function and can be used to maintain the health for blood vessels. It is also a finding that deserves to expand production currently being carried out on a small scale. Furthermore, the promoting effect of PTEN known as a cancer suppressor in orizabin may result in further use for pharmaceuticals research. Orizabin can be safely used as a food-derived compound for maintaining human health.


Comparison of high and moderate intensity of strength training on mood and anxiety in older adults.
This study was designed to examine the psychological benefits of anaerobic exercise for older adults. Specifically, strength training was employed to examine the effects on mood and anxiety in a group of healthy but sedentary older women. 36 women (mean age = 68.5 yr.) were randomly assigned to groups given high intensity or moderate intensity strength training or to a control group. Strength training was conducted three days a week for 12 weeks. After the training period, both high and moderate strength-training programs produced marked improvements in muscle strength and body composition compared to the control subjects. The average improvements in the high and moderate intensity strength-training groups for muscle strength were 40.5 and 35.5%, respectively, and for percent body fat 1.52 and 2.50%, respectively. As for psychological changes, both training groups significantly improved positive mood (vigor), and the moderate intensity group significantly reduced trait anxiety compared to means of the control group. Also, both training groups showed some decrease in tension and state anxiety after the training period. These findings provide evidence for the effectiveness of anaerobic training to enhance perception of psychological well-being in older women. A moderate intensity rather than high intensity of training regimen may be more beneficial for sedentary older women to improve psychological health.


Acid production potentials of massive sulfide minerals and lead-zinc mine tailings: a medium-term study.
Weathering of sulfide minerals is a principal source of acid generation. To determine acid-forming potentials of sulfide-bearing materials, two basic approaches named static and kinetic tests are available. Static tests are short-term, and easily undertaken within a few days and in a laboratory. In contrast, kinetic tests are long-term procedures and mostly carried out on site. In this study, experiments were conducted over a medium-term period of 2 months, not as short as static tests and also not as long as kinetic tests. As a result, pH and electrical conductivity oscillations as a function of time, acid-forming potentials and elemental contents of synthetically prepared rainwater leachates of massive sulfides and sulfide-bearing lead-zinc tailings from abandoned and currently used deposition areas have been determined. Although the lowest final pH of 2.70 was obtained in massive pyrite leachate, massive chalcopyrite leachate showed the highest titrable acidity of 1.764 g H2SO4/L. On the other hand, a composite of currently deposited mine tailings showed no acidic characteristic with a final pH of 7.77. The composite abandoned mine tailing leachate had a final pH of 6.70, close to the final pH of massive galena and sphalerite leachates, and produced a slight titrable acidity of 0.130 g H2SO4/L.


Changes of heart rate variability and prefrontal oxygenation during Tai Chi practice versus arm ergometer cycling.
[Purpose] Exercise has been shown to improve cardiovascular fitness and cognitive function. Whether the inclusion of mind over exercise would increase parasympathetic control of the heart and brain activities more than general exercise at a similar intensity is not known. The aim of this study was to compare the effects of Tai Chi (mind-body exercise) versus arm ergometer cycling (body-focused exercise) on the heart rate variability and prefrontal oxygenation level. [Subjects and Methods] A Tai Chi master was invited to perform Tai Chi and arm ergometer cycling with similar exercise intensity on two separate days. Heart rate variability and prefrontal oxyhemoglobin levels were measured continuously by a RR recorder and near-infrared spectroscopy, respectively. [Results] During Tai Chi exercise, spectral analysis of heart rate variability demonstrated a higher high-frequency power as well as a lower low-frequency/high-frequency ratio than during ergometer cycling, suggesting increased parasympathetic and decreased sympathetic control of the heart. Also, prefrontal oxyhemoglobin and total hemoglobin levels were higher than those during arm ergometer exercise. [Conclusion] These findings suggest that increased parasympathetic control of the heart and prefrontal activities may be associated with Tai Chi practice. Having a "mind" component in Tai Chi could be more beneficial for older adults' cardiac health and cognitive function than body-focused ergometer cycling.


Approximate analysis and design of rectangular-lattice photonic crystals.
We present a theoretical analysis of wave propagation in rectangular- and square-lattice photonic crystals by approximating the arbitrary refractive-index function with a staircase profile. This profile has a number of tunable parameters that allow one to fit the band structures of the staircase and the desired structure over a large frequency range. The staircase profile is such that its corresponding two-dimensional wave equation decomposes into two one-dimensional equations by means of a constant decoupling parameter. We show that basic features of the band structure and Bloch waves in photonic crystals can be analyzed theoretically through this simple approximation.


Total and specific IgE (house dust mite and intestinal helminths) in asthmatics and controls from Gondar, Ethiopia.
The role, if any, of parasitosis in the development of asthma remains incompletely understood; both 'protective' and 'predictive' associations have been reported. We report a study which examined immunoglobulin (Ig) E responses to two common helminths in asthmatics living in Ethiopia. To compare the frequencies of specific IgE antibodies to Ascaris and Necator species and to Der p 1 among 84 adult asthmatics and a referent group of nonasthmatics. A case-control analysis. Total IgE levels were not different between the two groups. The presence of specific IgE to Der p 1 was strongly associated with asthma (P = 0.001). Raised levels of Ascaris-(P = 0.010) and Necator- (P = 0.001) specific IgE antibodies were more common among referents; there were no associations between specific IgE production to Der p 1 and either of the two parasites. These findings confirm the association between Der p 1 sensitization and asthma among urban, adult Ethiopians. While they also indicate a negative relationship with two indicators of helminth infestation it appears that this is not mediated through the immunological response to common aeroallergens.


Automatic Generation of 3D Caricatures Based on Artistic Deformation Styles.
Caricatures are a form of humorous visual art, usually created by skilled artists for the intention of amusement and entertainment. In this paper, we present a novel approach for automatic generation of digital caricatures from facial photographs, which capture artistic deformation styles from hand-drawn caricatures. We introduced a pseudo stress-strain model to encode the parameters of an artistic deformation style using "virtual" physical and material properties. We have also developed a software system for performing the caricaturistic deformation in 3D which eliminates the undesirable artifacts in 2D caricaturization. We employed a Multilevel Free-Form Deformation (MFFD) technique to optimize a 3D head model reconstructed from an input facial photograph, and for controlling the caricaturistic deformation. Our results demonstrated the effectiveness and usability of the proposed approach, which allows ordinary users to apply the captured and stored deformation styles to a variety of facial photographs.


Using patients' experiences in e-learning design.
Design of the undergraduate and postgraduate medical curriculum is traditionally the task of medical professionals and educationalists, with regulating bodies approving curriculum content. Although this should ensure a thorough approach to a medical model of the curriculum, it may overlook the importance of the patient's perspective in medical education. The General Medical Council recently issued advice about patient and public involvement in all areas of medical education, including curricular design, but it is not immediately clear how this should be incorporated. This article describes and analyses an innovative approach to curriculum design, in which patients' experiences are placed at the centre of learning. Important themes identified from qualitative research with patients (and their carers) with autistic spectrum conditions were compared with a pre-established curriculum for an e-learning module by the Royal College of General Practitioners. Significant divergence was identified between the doctor-designed curriculum and the themes identified through patients' experiences. The divergence was analysed and patients' experiences were used to expand the proposed course. This research concerned e-learning about autistic spectrum conditions, but may have implications for other areas and modalities of medical education. Further research is needed to determine whether the inclusion in the curriculum of previously ignored themes, which are nevertheless important to patients, has an impact on the quality of the doctor-patient interaction and relationship.


Infection control interventions in small rural hospitals with limited resources: results of a cluster-randomized feasibility trial.
There are few reports on the feasibility of conducting successful infection control (IC) interventions in rural community hospitals. Ten small rural community hospitals in Idaho and Utah were recruited to participate in a cluster-randomized trial of multidimensional IC interventions to determine their feasibility in the setting of limited resources. Five hospitals were randomized to develop individualized campaigns to promote HH, isolation compliance, and outbreak control. Five hospitals were randomized to continue with current IC practices. Regular blinded observations of hand hygiene (HH) compliance were conducted in all hospitals as the primary outcome measure. Additionally, periodic prevalence studies of patient colonization with resistant pathogens were performed. The 5-months intervention time period was compared to a 4-months baseline period, using a multi-level logistic regression model. The intervention hospitals implemented a variety of strategies. The estimated average absolute change in "complete HH compliance" in intervention hospitals was 20.1% (range, 7.8% to 35.5%) compared to -3.1% (range -6.3% to 5.9%) in control hospitals (p = 0.001). There was an estimated average absolute change in "any HH compliance" of 28.4% (range 17.8% to 38.2%) in intervention hospitals compared to 0.7% (range -16.7 to 20.7%) in control hospitals (p = 0.010). Active surveillance culturing demonstrated an overall prevalence of MRSA carriage of 9.7%. A replicable intervention significantly improved hand hygiene as a primary outcome measure despite barriers of geographic distance and lack of experience with study protocols. Active surveillance culturing identified unsuspected reservoirs of MRSA colonization and further promoted IC activity.


Splice variants in the proteome: a promising and challenging field to targeted drug discovery.
The advent and improvement of high-throughput sequencing over the past decade leveraged the study of whole genomes and transcriptomes of different organisms at lower costs. In transcriptomics, RNA-Seq expands our capacity to understand gene expression in different tissues and pathologies, and how alternative splicing might affect the final protein sequence. Here, we discuss the association of using transcriptome and proteome high-throughput data to foster drug discovery. Using this innovative strategy, some research groups have already identified computationally predicted novel peptides derived from putative splice variants in experimental human proteome data. These discoveries provide new opportunities for targeted drug development.


A novel cytoskeletal structure involved in purse string wound closure and cell polarity maintenance.
The process of wound repair in monolayers of the intestinal epithelial cell line, Caco-2BBe, was analyzed by a combination of time-lapse differential interference contrast (DIC) video and immunofluorescence microscopy, and laser scanning confocal immunofluorescence microscopy (LSCIM). DIC video analysis revealed that stab wounds made in Caco-2BBe monolayers healed by two distinct processes: (a) Extension of lamellipodia into the wounds; and (b) Purse string closure of the wound by distinct arcs or rings formed by cells bordering the wound. The arcs and rings which effected purse string closure appeared sharp and sheer in DIC, spanned between two and eight individual cells along the wound border, and contracted in a concerted fashion. Immunofluorescence analysis of the wounds demonstrated that the arcs and rings contained striking accumulations of actin filaments, myosin-II, villin, and tropomyosin. In contrast, arcs and rings contained no apparent enrichment of microtubules, brush border myosin-I immunogens, or myosin-V. LSCIM analysis confirmed the localization of actin filaments, myosin-II, villin, and tropomyosin in arcs and rings at wound borders. ZO-1 (a tight junction protein), also accumulated in arcs and rings around wounds, despite the fact that cell-cell contacts are absent at wound borders. Sucrase-isomaltase, an apically-localized integral membrane protein, maintained an apical localization in cells where arcs or rings were formed, but was found in lamellipodia extending into wounds in cells where arcs failed to form. Time-course, LSCIM quantification of actin, myosin II, and ZO-1 revealed that accumulation of these proteins within arcs and rings at the wound edge began within 5 minutes and peaked within 30-60 minutes of wounding. Actin filaments, myosin-II, and ZO-1 achieved 10-, 3-, and 4-fold enrichments, respectively, relative to cell edges which did not border wounds. The results demonstrate that wounded Caco-2BBe monolayers assemble a novel cytoskeletal structure at the borders of wounds. The results further suggest that this structure plays at least two roles in wound repair; first, mediation of concerted, purse string movement of cells into the area of the wound and second, maintenance of apical/basolateral polarity in cells which border the wound.


Cost-Effectiveness Analysis of Percutaneous Vertebroplasty for Osteoporotic Compression Fractures.
Single-center, single-arm, prospective time-series study. To assess the cost-effectiveness and improvement in quality of life (QOL) of percutaneous vertebroplasty (PVP). PVP is known to relieve back pain and increase QOL for osteoporotic compression fractures. However, the economic value of PVP has never been evaluated in Japan where universal health care system is adopted. We prospectively followed up 163 patients with acute vertebral osteoporotic compression fractures, 44 males aged 76.4±6.0 years and 119 females aged 76.8±7.1 years, who underwent PVP. To measure health-related QOL and pain during 52 weeks observation, we used the European Quality of Life-5 Dimensions (EQ-5D), the Rolland-Morris Disability Questionnaire (RMD), the 8-item Short-Form health survey (SF-8), and visual analogue scale (VAS). Quality-adjusted life years (QALY) were calculated using the change of health utility of EQ-5D. The direct medical cost was calculated by accounting system of the hospital and Japanese health insurance system. Cost-effectiveness was analyzed using incremental cost-effectiveness ratio (ICER): Δ medical cost/Δ QALY. After PVP, improvement in EQ-5D, RMD, SF-8, and VAS scores were observed. The gain of QALY until 52 weeks was 0.162. The estimated lifetime gain of QALY reached 1.421. The direct medical cost for PVP was ¥286,740 (about 3061 US dollars). Cost-effectiveness analysis using ICER showed that lifetime medical cost for a gain of 1 QALY was ¥201,748 (about 2154 US dollars). Correlations between changes in EQ-5D scores and other parameters such as RMD, SF-8, and VAS were observed during most of the study period, which might support the reliability and applicability to measure health utilities by EQ-5D for osteoporotic compression fractures in Japan as well. PVP may improve QOL and ameliorate pain for acute osteoporotic compression fractures and be cost-effective in Japan.


Association between ambient particulate matter and disorders of vestibular function.
Exposure to environmental chemicals has been suggested to alter the physiologic state of the inner and middle ear. However, it is unknown if particulate matter exposure is associated with acute vestibular dysfunction. To estimate the effects of particulate matter exposure on the number of hospital visits related to three major diseases of vestibular dysfunction, Meniere's disease (MD), benign paroxysmal positional vertigo (BPPV), and vestibular neuronitis (VN). Our study subject is from Korean National Health Insurance Service-National Sample Cohort, which is dynamic cohort consist of 1 million participants representing the Korean population. Among total cohort participants, we used the hospital visit data of 210,000 individuals who resided in Seoul from 2007 to 2010. Time series analysis using the Poisson generalized additive model and case-crossover analysis using conditional logistic regression were used to investigate the association between daily particulate matter levels (PM2.5, particulate matter <2.5μg/m3; PM10, particulate matter <10μg/m3; PM10-2.5, PM10- PM2.5) and number of MD, BPPV, and VN hospital visits. Time series analysis showed that an interquartile range (IQR) increase in PM10 and PM10-2.5 on lag day 1 was associated with an increased risk of MD hospital visits [relative risk (RR), 95% confidence interval (CI), PM10: 1.09 (1.02-1.15); PM10-2.5: 1.06 (1.02-1.10)]. In addition, elderly individuals (≥60 years old) showed an increased risk of MD hospital visits after particulate matter exposure when compared to younger individuals. An IQR increase in particulate matter on lag day 1 was associated with a marginally significant increase in VN hospital visits [RR (95%CI), PM2.5: 1.11 (0.98-1.25); PM10: 1.07 (0.99-1.15); PM10-2.5: 1.04 (0.99-1.09)]. However, no association between particulate matter exposure and BPPV hospital visits was noted. Case-crossover analyses showed similar results to the time-series analysis across all three diseases. MD hospital visits were associated with ambient particulate matter exposure. Elderly individuals, in particular, were more susceptible to particulate matter exposure than younger individuals.


Individual differences in Zhong-Yong tendency and processing capacity.
The present study investigated how an individual's Zhong-Yong tendency is related to his/her perceptual processing capacity. In two experiments, participants completed a Zhong-Yong Thinking Style Scale and performed a redundant-target detection task. Processing capacity was assessed with a non-parametric approach (systems factorial technology, SFT) and a parametric (linear ballistic accumulator model, LBA) approach. Results converged to suggest a positive correlation between Zhong-Yong tendency and processing capacity. High middle-way thinkers had larger processing capacity in multiple-signal processing compared with low middle-way thinkers, indicating that they processed information more efficiently and in an integrated fashion. Zhong-Yong tendency positively correlates with the processing capacity. These findings suggest that the individual differences in processing capacity can account for the reasons why high middle-way thinkers tend to adopt a global and flexible processing strategy to deal with the external world. Furthermore, the influence of culturally dictated thinking style on cognition can be revealed in a perception task.


Assessment of long-term quality of life using the FACT-BL questionnaire in patients with an ileal conduit, continent reservoir, or orthotopic neobladder.
To assess and compare quality of life (QOL) of patients followed for a long time who underwent an ileal conduit (IC), continent reservoir (CR) or ileal neobladder (NB) using FACT-BL, a bladder-cancer-specific questionnaire. One hundred and forty-seven patients underwent radical cystectomy and urinary diversion for bladder cancer from 1987 to 2002 at our institution. Of them, 79 (54%) patients were asked to participate in this study. Forty-nine patients (20 IC, 14 CR and 15 NB) returned the answered questionnaire for a survey response rate of 62%. Mean follow-up was 83.0 months. Four categories (physical, social/familial, emotional and functional well-being) in FACT-G were equally favorable in these groups. Patients with IC had less trouble controlling urine but had a worse image on altered body appearance compared with NB patients. Interest in sex was extremely low in all patients and capability of maintaining an erection was also low in 39 male patients. The mean total value of FACT-BL in IC, CR and NB patients was 106.3+/-16.4, 104.0+/-14.2, and 110.9+/-18.0, respectively, showing no significant difference. Ten (77%) of 13 IC, seven (78%) of nine CR and six (86%) of seven NB patients answered that they would choose the same type of diversion if they had the choice again. The type of urinary diversion does not appear to be associated with a different QOL by general cancer-related assessment. Urinary function and body image are affected and related to the method used to reconstruct the urinary system.


Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3'-phosphate and 3'-phosphoglycolate ends.
Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-alpha, beta-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-alpha, beta-unsaturated aldehyde ends, and can act with DNA polymerase beta and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.


Rapid collapse into a molten globule is followed by simple two-state kinetics in the folding of lysozyme from bacteriophage λ.
Stopped-flow fluorescence and circular dichroism spectroscopy have been used in combination with quenched-flow hydrogen exchange labeling, monitored by two-dimensional NMR and electrospray ionization mass spectrometry, to investigate the folding kinetics of lysozyme from bacteriophage λ (λ lysozyme) at pH 5.6, 20 °C. The first step in the folding of λ lysozyme occurs very rapidly (τ < 1 ms) after refolding is initiated and involves both hydrophobic collapse and formation of a high content of secondary structure but only weak protection from (1)H/(2)H exchange and no fixed tertiary structure organization. This early folding step is reflected in the dead-time events observed in the far-UV CD and ANS fluorescence experiments. Following accumulation of this kinetic molten globule species, the secondary structural elements are stabilized and the majority (ca. 88%) of refolding molecules acquire native-like properties in a highly cooperative two-state process, with τ = 0.15 ± 0.03 s. This is accompanied by the acquisition of substantial native-like protection from hydrogen exchange. A double-mixing experiment and the absence of a denaturant effect reveal that slow (τ = 5 ± 1 s) folding of the remaining (ca. 12%) molecules is rate limited by the cis/trans isomerization of prolines that are trans in the folded enzyme. In addition, native state hydrogen exchange and classical denaturant unfolding experiments have been used to characterize the thermodynamic properties of the enzyme. In good agreement with previous crystallographic evidence, our results show that λ lysozyme is a highly dynamic protein, with relatively low conformational stability (ΔG°(N-U) = 25 ± 2 kJ·mol(-1)).