Identification by primary care clinicians of patients with obstructive sleep apnea: a practice-based research network (PBRN) study.
Obstructive sleep apnea (OSA) is a reasonably common disorder that is associated with daytime tiredness and a host of medical conditions. Little is known about how primary care clinicians (PCCs) detect, diagnose, and manage patients who have OSA. We gathered information from 44 randomly selected practices in 5 regional practice-based research networks. This included interviews with PCCs and sleep consultants, medical records abstraction, and patient surveys. Descriptive analyses of the quantitative data were used to describe the prevalence of sleep symptoms, the proportion of primary care patients at high risk for OSA, and the methods used by PCCs to detect and diagnose patients with OSA. More than 90% of adult patients visiting a PCC on any given day are experiencing sleep-related symptoms. Based on their Berlin Questionnaire scores, more than one third are at high risk of having sleep apnea. However, most patients have not discussed their sleep-related symptoms with their PCC, and fewer than one third have sleep-related symptoms documented in their medical records. Very few PCCs routinely screen for OSA, and, despite using billing records, problem lists, clinician and staff recall, and prospective logs enhanced by waiting room posters, PCCs were generally unable to identify 25 patients with OSA in their practices. A substantial proportion of patients who see PCCs regularly are at high risk for OSA. Very few of them are being diagnosed or treated. Clearer guidelines and a systematic approach are needed if this is indeed a problem that should be addressed.


A somatic TSHR mutation in a patient with lung adenocarcinoma with bronchioloalveolar carcinoma, coronary artery disease and severe chronic obstructive pulmonary disease.
In a screen for thoracic malignancy-associated markers, thyroid stimulating hormone receptor (TSHR) was identified as a candidate as it binds to the previously-characterized lung cancer marker NKX2-1. We screened for mutations in all coding regions of the TSHR gene in 96 lung adenocarcinoma samples and their matched adjacent normal lung samples. We found one patient with a somatic mutation at codon 458 (exon 10), which is located at the transmembrane domain where most TSHR mutations have been found in thyroid-related diseases. This patient had lung adenocarcinoma with BAC (bronchioloalveolar carcinoma) features in the setting of a prior medical history significant for carotid stenosis and severe chronic obstructive pulmonary disease (COPD). In order to characterize the genetic features of TSHR in lung cancer, we checked for TSHR expression and copy number in the 96 lung cancer tissues. TSHR protein expression was generally overexpressed in multiple thoracic malignancies (adenocarcinoma, squamous cell carcinoma and malignant pleural mesothelioma) by immunohistochemistry. Our data suggest that aberrant TSHR function may contribute to lung cancer development or a subgroup of lung cancer with specific clinical phenotypes.


ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells.
The chromatin structure of DNA determines genome compaction and activity in the nucleus. On the basis of in vitro structures and electron microscopy (EM) studies, the hierarchical model is that 11-nanometer DNA-nucleosome polymers fold into 30- and subsequently into 120- and 300- to 700-nanometer fibers and mitotic chromosomes. To visualize chromatin in situ, we identified a fluorescent dye that stains DNA with an osmiophilic polymer and selectively enhances its contrast in EM. Using ChromEMT (ChromEM tomography), we reveal the ultrastructure and three-dimensional (3D) organization of individual chromatin polymers, megabase domains, and mitotic chromosomes. We show that chromatin is a disordered 5- to 24-nanometer-diameter curvilinear chain that is packed together at different 3D concentration distributions in interphase and mitosis. Chromatin chains have many different particle arrangements and bend at various lengths to achieve structural compaction and high packing densities.


Characterization of an Epstein-Barr virus-related gammaherpesvirus from common marmoset (Callithrix jacchus).
A gammaherpesvirus related to Epstein-Barr virus (EBV; Human herpesvirus 4) infects otherwise healthy common marmosets (Callithrix jacchus). Long-term culture of common marmoset peripheral blood lymphocytes resulted in outgrowth of spontaneously immortalized lymphoblastoid cell lines, primarily of B cell lineage. Electron microscopy of cells and supernatants showed herpesvirus particles. There were high rates of serological cross-reactivity to other herpesviruses (68-86%), but with very low geometric mean antibody titres [1:12 to human herpesvirus 6 and 1:14 to Herpesvirus papio (Cercopithecine herpesvirus 12)]. Sequence analysis of the conserved herpesvirus DNA polymerase gene showed that the virus is a member of the lymphocryptovirus subgroup and is most closely related to a lymphocryptovirus from rhesus macaques and is closely related to EBV and Herpesvirus papio. High seroprevalence (79%, with geometric mean antibody titre of 1:110) among 28 common marmosets from two geographically distinct colonies indicated that the virus is likely present in many common marmosets in captivity. A New World primate harbouring a lymphocryptovirus suggests that this subgroup arose much earlier than previously thought.


Optimum BMI cut points to screen asian americans for type 2 diabetes.
Asian Americans manifest type 2 diabetes at low BMI levels but may not undergo diagnostic testing for diabetes if the currently recommended BMI screening cut point of ≥25 kg/m(2) is followed. We aimed to ascertain an appropriate lower BMI cut point among Asian-American adults without a prior diabetes diagnosis. We consolidated data from 1,663 participants, ages ≥45 years, without a prior diabetes diagnosis, from population- and community-based studies, including the Mediators of Atherosclerosis in South Asians Living in America study, the North Kohala Study, the Seattle Japanese American Community Diabetes Study, and the University of California San Diego Filipino Health Study. Clinical measures included a 2-h 75-g oral glucose tolerance test, BMI, and glycosylated hemoglobin (HbA1c). Mean age was 59.7 years, mean BMI was 25.4 kg/m(2), 58% were women, and type 2 diabetes prevalence (American Diabetes Association 2010 criteria) was 16.9%. At BMI ≥25 kg/m(2), sensitivity (63.7%), specificity (52.8%), and Youden index (0.16) values were low; limiting screening to BMI ≥25 kg/m(2) would miss 36% of Asian Americans with type 2 diabetes. For screening purposes, higher sensitivity is desirable to minimize missing cases, especially if the diagnostic test is relatively simple and inexpensive. At BMI ≥23 kg/m(2), sensitivity (84.7%) was high in the total sample and by sex and Asian-American subgroup and would miss only ∼15% of Asian Americans with diabetes. The BMI cut point for identifying Asian Americans who should be screened for undiagnosed type 2 diabetes should be <25 kg/m(2), and ≥23 kg/m(2) may be the most practical.


Variation of Forehead Temperature during Routine Working Shift in Hospital Laboratory Personnel: Implications for SARS-CoV-2 Screening.
Scarce information is available on circadian body temperature fluctuation in healthy healthcare workers. Forehead temperature was measured with an infrared thermometer in 33 ostensibly healthy laboratory professionals (mean age, 43 ± 13 years; 76% females) throughout a regular working shift, from 800 AM to 300 PM, at 1-hour intervals. A significant difference was found at different times of the day by 1-way analysis of variance (F statistics, 13.79; p < 0.001). The lowest mean forehead temperature was 36.2 ± 0.3℃, recorded at 100 PM, whilst the highest was 36.7 ± 0.3℃, at 900 AM. The mean difference between forehead temperature at acrophase and nadir was 0.5℃ (95% CI, 0.3-0.6℃; p < 0.001). The forehead temperature measured between 900-1200 AM was also significantly higher than that measured between 100-300 PM (0.3℃; 95% CI, 0.2-0.4℃; p < 0.001). The mean intra-individual variation of forehead temperature was higher but not significantly different in men (1.0 ± 0.2%) compared to women (0.8 ± 0.3%; p = 0.112). Fever screening protocols for purposes of coronavirus disease 2019 (COVID-19) and other infectious diseases monitoring should consider normal daily fluctuations in forehead temperature.


Limb salvage after delayed diagnosis for blunt traumatic infrapopliteal occlusion.
Infrapopliteal occlusion is uncommon after blunt trauma, and limb salvage after delayed diagnosis is even rarer. We present the case of a 56-year-old man who had complex lower leg orthopedic fractures along with a reportedly normal pulse examination with an 11-day diagnostic delay of limb-threatening ischemia requiring distal revascularization. This case illustrates an incidence of delayed infrapopliteal three-vessel occlusion with successful revascularization and subsequent endovascular management to maintain patency. We describe the workup and treatment of delayed infrapopliteal occlusion and a review of the current literature on this topic.


Dengue virus type 2 infects human endothelial cells through binding of the viral envelope glycoprotein to cell surface polypeptides.
The endothelial cell line ECV304, derived from human umbilical cord and identified to be susceptible to dengue virus type 2 (DEN-2) infection, was used to study the molecular mechanism of DEN-2 binding to endothelial cells. DEN-2 was found by virus overlay protein-binding assays (VOPBAs) to bind to three ECV304 cell membrane proteins with molecular masses of 29, 34 and 43 kDa. Only a single protein of 29 kDa was observed when VOPBAs were carried out using preparations of trypsin-treated ECV304 cells. Pre-incubation of live ECV304 cells in culture or cell membrane proteins in modified VOPBAs with the recombinant DEN-2 envelope glycoprotein (rEgp) inhibited DEN-2 infection and blocked virus binding to the three proteins identified. These results indicate that DEN-2 rEgp could bind to three proteins on the surface of ECV304 cells. This virus-cell interaction may be associated with the receptor complex specific for DEN-2 infection of endothelial cells.


The impact of pulmonary hypertension on outcomes of transcatheter mitral valve replacement in mitral annular calcification.
To assess the impact of pulmonary hypertension (PH) on outcomes of patients with severe mitral annular calcification (MAC) undergoing transcatheter mitral valve replacement (TMVR). PH is associated with poor outcomes after mitral valve surgery. Whether the presence of PH in patients with MAC undergoing (TMVR) is associated with poor outcomes, is unknown. Retrospective evaluation of 116 patients from 51 centers in 11 countries who underwent TMVR with valve in mitral annular calcification (ViMAC) using balloon-expandable aortic transcatheter valves (THVs) from September 2012 to March 2017. Pulmonary artery systolic blood pressure (PASP) by echocardiogram was available in 90 patients. The subjects were stratified based on PASP: No PH = PASP ≤35 mmHg (n = 11); mild to moderate PH = PASP 36-49 mmHg (n = 21) and severe PH = PASP ≥50 mmHg (n = 58). Clinical, procedural, and echocardiographic outcomes were assessed. Mean age was 72.7 (±12.8) years, 59 (65.6%) were female, Society of Thoracic Surgeons score was 15.8 + 11.8% and 90.0% where in New York Heart Association (NYHA) class III-IV. There was no significant difference in all-cause mortality at 30 days (no PH = 27.3%, mild-moderate PH = 19.0%, severe PH = 31.6%; p = 0.55) or at 1 year (no PH = 54.5%, mild-moderate PH = 38.1%, severe PH = 56.1%; p = 0.36). No difference in adverse events, NYHA class or amount of residual mitral regurgitation at 1 year were observed between the groups. This study suggests that the presence of PH in patients with predominantly mitral stenosis with MAC undergoing TMVR does not impact mortality or adverse events. Further studies are needed to fully understand the effect of PH in this group of patients.


Assessing the effects of climate change on aquatic invasive species.
Different components of global environmental change are typically studied and managed independently, although there is a growing recognition that multiple drivers often interact in complex and nonadditive ways. We present a conceptual framework and empirical review of the interactive effects of climate change and invasive species in freshwater ecosystems. Climate change is expected to result in warmer water temperatures, shorter duration of ice cover, altered streamflow patterns, increased salinization, and increased demand for water storage and conveyance structures. These changes will alter the pathways by which non-native species enter aquatic systems by expanding fish-culture facilities and water gardens to new areas and by facilitating the spread of species during floods. Climate change will influence the likelihood of new species becoming established by eliminating cold temperatures or winter hypoxia that currently prevent survival and by increasing the construction of reservoirs that serve as hotspots for invasive species. Climate change will modify the ecological impacts of invasive species by enhancing their competitive and predatory effects on native species and by increasing the virulence of some diseases. As a result of climate change, new prevention and control strategies such as barrier construction or removal efforts may be needed to control invasive species that currently have only moderate effects or that are limited by seasonally unfavorable conditions. Although most researchers focus on how climate change will increase the number and severity of invasions, some invasive coldwater species may be unable to persist under the new climate conditions. Our findings highlight the complex interactions between climate change and invasive species that will influence how aquatic ecosystems and their biota will respond to novel environmental conditions.


Identification of three redundant segments responsible for herpes simplex virus 1 ICP0 to fuse with ND10 nuclear bodies.
Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is a key regulator in both lytic and latent infections. In lytic infection, an important early event is the colocalization of ICP0 to nuclear domain 10 (ND10), the discrete nuclear bodies that impose restrictions on viral expression. ICP0 contains an E3 ubiquitin ligase that degrades promyelocytic leukemia protein (PML) and Sp100, two major components of ND10, and disperses ND10 to alleviate repression. We previously reported that the association between ICP0 and ND10 is a dynamic process that includes three steps: adhesion, fusion, and retention. ICP0 residues 245 to 474, defined as ND10 entry signal (ND10-ES), is a region required for the fusion step. Without ND10-ES, ICP0 adheres at the ND10 surface but fails to enter. In the present study, we focus on characterizing ND10-ES. Here we report the following. (i) Fusion of ICP0 with ND10 relies on specific sequences located within ND10-ES. Replacement of ND10-ES by the corresponding region from ORF61 of varicella-zoster virus did not rescue ND10 fusion. (ii) Three tandem ND10 fusion segments (ND10-FS1, ND10-FS2, and ND10-FS3), encompassing 200 amino acids within ND10-ES, redundantly facilitate fusion. Each of the three segments is sufficient to independently drive the fusion process, but none of the segments by themselves are necessary for ND10 fusion. Only when all three segments are deleted is fusion blocked. (iii) The SUMO interaction motif located within ND10-FS2 is not required for ND10 fusion but is required for the complete degradation of PML, suggesting that PML degradation and ND10 fusion are regulated by different molecular mechanisms. ND10 nuclear bodies are part of the cell-intrinsic antiviral defenses that restrict viral gene expression upon virus infection. As a countermeasure, infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) localizes to ND10s, degrades the ND10 organizer, and disperses ND10 components in order to alleviate repression. We studied the ICP0-ND10 association to delineate elements important for this dynamic interaction and to understand its role in viral replication and host defense. In this work, we show that ICP0 contains three redundant segments to ensure an effective mergence of ICP0 with ND10 nuclear bodies. This is the first study to systematically investigate ICP0 elements that are important for ICP0-ND10 fusion.


Reversible binding of water, methanol, and ethanol to a five-coordinate ruthenium(II) complex.
The known green, five-coordinate, square-pyramidal trans-RuCl(2)(P-N)(PPh(3)) complex reversibly binds water, MeOH and EtOH in the vacant coordination site in the solid state and in CH(2)Cl(2) solution to give pink adducts (P-N = o-diphenylphosphino-N,N'-dimethylaniline). The adducts are well characterized, including X-ray analysis of the aqua complex, trans-RuCl(2)(P-N)(PPh(3))(H(2)O), which crystallizes in two different benzene-solvated forms. Comparison of the structural data with those determined previously for the binding of H(2)S, thiols, and H(2), which form cis-RuX(2)(P-N)(PPh(3))L products (X = Cl, Br; L = a S-ligand or H(2)) reveals the trans-influence trend P > H(2)S ~ thiols > H(2) > Cl ~ Br > H(2)O. Thermodynamic data for the binding of water were estimated in solution by UV-Vis spectroscopy, and ΔH(o) data for the aqua and alcohol adducts in the solid state were obtained by differential scanning calorimetry. Inclusion of published data for the S-ligand adducts reveals the thermal stability trend of the solid complexes as MeSH > MeOH > H(2)S > H(2)O > EtSH > EtOH.


Plasma vitamin concentrations and incidence of mesothelioma and lung cancer in individuals exposed to crocidolite at Wittenoom, Western Australia.
Increased rates of death from asbestos-related diseases have been reported in former workers and residents exposed to crocidolite (blue asbestos) at Wittenoom (Western Australia). The relationships between plasma concentrations of retinol, carotene and vitamin E and incidence of mesothelioma and lung cancer in a cohort of people from this town were examined. The relationships were evaluated by survival analyses using data obtained at the first visit, at each visit and with the rate of change of each vitamin during the period of follow-up. Of 1953 study participants, 65 developed mesothelioma during the follow-up, and 47 developed lung cancer. A lower incidence of mesothelioma was related to plasma concentrations of retinol at the first visit [hazard ratio (HR)=0.63, 95% confidence interval=0.41-0.99], and to measurements at each visit (HR=0.71, 95% confidence interval=0.50-1.00). Plasma carotene concentrations at the first measurement, but not during the follow-up period, were associated with lower incidence of lung cancer in men and in workers. No significant associations were found between carotene concentrations and incidence of mesothelioma. Vitamin E concentrations were not significantly associated with mesothelioma or lung cancer incidence. These findings suggest that people with chronically low plasma levels of retinol have increased risk of developing mesothelioma and lung cancer.


Meteorological and hydrological influences on the spatial and temporal prevalence of West Nile virus in Culex mosquitoes, Suffolk County, New York.
The factors determining the spatial and temporal distribution of West Nile virus (family Flaviviridae, genus Flavivirus, WNV) activity are not well understood. Here, we explore the effects of hydrological and meteorological conditions on WNV infection among Culex genus mosquitoes collected during 2001-2009 in Suffolk County, Long Island, NY. We show that WNV infection rates in assayed pools of Culex mosquitoes are associated in both space and time with hydrological and meteorological variability. Specifically, wet winter, warm and wet spring conditions, and dry summer conditions are associated with the increased local prevalence of WNV among Culex mosquitoes during summer and fall. These findings indicate that within Suffolk County, and for a given year, areas at risk for heightened WNV activity may be identified in advance by using hydrology model estimates of land surface wetness and observed meteorological conditions.


Characteristics of multicomponent, nonpharmacological interventions to reduce or avoid sleep disturbances in nursing home residents: a systematic review.
Dementia guidelines propose the use of nonpharmacological interventions for sleep disturbances for older people. Based on available reviews, it seems most likely that multicomponent interventions have the strongest potential to be effective in improving sleep. However, a detailed description of multicomponent interventions is missing. This systematic review aims to identify, describe, and summarize multicomponent, nonpharmacological interventions to reduce or avoid sleep disturbances in nursing home residents. This review followed established methodological frameworks for systematic evidence syntheses. A computerized search was conducted in December 2018, using the databases PubMed, CINAHL, Scopus, and Cochrane Library. Two independent reviewers assessed all search results to identify eligible studies and assessed studies' methodological quality following the Cochrane Risk of Bias methodology for randomized controlled trials and the CASP Appraisal Checklist for controlled trials.Evaluation studies of any design investigating multicomponent interventions were included, except case studies. Components of included intervention programs were analyzed applying the TIDieR and CReDECI 2 criteria. A total of 2056 studies were identified through the database search; ten publications about nine interventions met the inclusion criteria and were included in the review. The identified interventions can be summarized assigned to the categories "daytime activities," "nighttime activities," "staff training," and "light exposure." The approaches showed similarities and differences in procedures, materials, modes of delivery, intervention provider, and intervention period. None of the studies described any intended interactions between components or considered context characteristics in intervention modeling as well as internal and external facilitators or barriers influencing delivery of intervention. We identified positive or mixed positive effects for sleep-related outcomes for the mentioned categories. The analysis of included interventions demonstrates somehow promising results, although findings are difficult to interpret as interventions were not well described, and the challenges of developing and evaluating complex interventions were not sufficiently acknowledged.


[Etidronic acid therapy in Paget's disease of bone].
Treatment of Paget's disease of bone was done in 32 patients using monotherapy with disodium etidronate (Diphos). A further 19 patients underwent combined treatment with etidronate and human calcitonin. Both monotherapy and combined treatment led to marked regression of disease activity in most patients as measured be decreased activity of alkaline phosphatase. In most cases this coincided with improvement of complaints. In two cases with initial monotherapy and in six with combined treatment success of treatment remained unsatisfactory. The latter group comprised patients with very serious illness. Our experience suggests that etidronic acid is an effective and well tolerated drug relatively free of side-effects for the treatment of Paget's disease of bone.


Factors associated with change in exacerbation frequency in COPD.
Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent (FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or zero exacerbations per year. Although most patients do not change category from year to year, some will, and the factors associated with this behaviour have not been examined. 1832 patients completing two year follow-up in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study were examined at baseline and then yearly. Exacerbations were defined by health care utilisation. Patient characteristics compared between those patients who did or did not change exacerbation category from year 1 to year 2. Between years 1 and 2, 221 patients (17%) changed from IE to FE and 210 patients (39%) from FE to IE. More severe disease was associated with changing from IE to FE and less severe disease from FE to IE. Over the preceding year, small falls in FEV1 and 6-minute walking distance were associated with changing from IE to FE, and small falls in platelet count associated with changing from FE to IE. No parameter clearly predicts an imminent change in exacerbation frequency category. SCO104960, clinicaltrials.gov identifier NCT00292552.


Projected Iterative Soft-Thresholding Algorithm for Tight Frames in Compressed Sensing Magnetic Resonance Imaging.
Compressed sensing (CS) has exhibited great potential for accelerating magnetic resonance imaging (MRI). In CS-MRI, we want to reconstruct a high-quality image from very few samples in a short time. In this paper, we propose a fast algorithm, called projected iterative soft-thresholding algorithm (pISTA), and its acceleration pFISTA for CS-MRI image reconstruction. The proposed algorithms exploit sparsity of the magnetic resonance (MR) images under the redundant representation of tight frames. We prove that pISTA and pFISTA converge to a minimizer of a convex function with a balanced tight frame sparsity formulation. The pFISTA introduces only one adjustable parameter, the step size, and we provide an explicit rule to set this parameter. Numerical experiment results demonstrate that pFISTA leads to faster convergence speeds than the state-of-art counterpart does, while achieving comparable reconstruction errors. Moreover, reconstruction errors incurred by pFISTA appear insensitive to the step size.


Moving beyond the descriptive in psychotherapy research.
There are challenges to conducting randomised controlled trials in psychotherapy. This article therefore discusses methodological advances in applying this design to the field. The application of evidence-based practice to psychotherapy means that people with psychological problems, clinicians, health services and any third-party payers can confidently choose from a range of effective treatments that are best suited to an individual's needs.


Surface Charge Measurements with Scanning Ion Conductance Microscopy Provide Insights into Nitrous Acid Speciation at the Kaolin Mineral-Air Interface.
Unique surface properties of aluminosilicate clay minerals arise from anisotropic distribution of surface charge across their layered structures. Yet, a molecular-level understanding of clay mineral surfaces has been hampered by the lack of analytical techniques capable of measuring surface charges at the nanoscale. This is important for understanding the reactivity, colloidal stability, and ion-exchange capacity properties of clay minerals, which constitute a major fraction of global soils. In this work, scanning ion conductance microscopy (SICM) is used for the first time to visualize the surface charge and topography of dickite, a well-ordered member of the kaolin subgroup of clay minerals. Dickite displayed a pH-independent negative charge on basal surfaces whereas the positive charge on edges increased from pH 6 to 3. Surface charges responded to malonate addition, which promoted dissolution/precipitation reactions. Results from SICM were used to interpret heterogeneous reactivity studies showing that gas-phase nitrous acid (HONO) is released from the protonation of nitrite at Al-OH2+ groups on dickite edges at pH well above the aqueous pKa of HONO. This study provides nanoscale insights into mineral surface processes that affect environmental processes on the local and global scale.


Androgen priming and response to chemotherapy in advanced prostatic cancer.
A total of 67 patients with progressive stage D2 prostatic cancer refractory to orchiectomy was entered in a controlled clinical trial to test whether androgen priming enhances the efficacy of cytotoxic drugs. All patients were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion and were given cyclic intravenous chemotherapy. In addition, the 34 patients randomized to the stimulation arm received fluoxymesterone for 3 days before and on the day of chemotherapy. There was 33 controls. The median duration of followup was 24 months. A modestly higher response rate (objective remission plus disease stabilization) was observed in the stimulation arm (85 versus 72 per cent, p less than 0.05) when the analysis was restricted to the evaluable patients. However, a larger fraction of unevaluable patients was present in the stimulation group (41 versus 16 per cent), mostly as a result of toxicity from fluoxymesterone, which prompted early discontinuation of treatment. Thus, when data analysis included all patients the response rate actually was slightly higher in the control than in the stimulation arm (60 versus 50 per cent, p not significant). No difference was observed in median duration of response (9 months in both groups) or over-all survival. Our data suggest that at least in those patients with advanced disease androgen priming does not seem to enhance significantly the antitumor effect of the combination of amino-glutethimide and chemotherapy, and is associated with significant toxicity. These largely negative results may be explained by the large number of hormone-resistant cells present in tumors that have become refractory to orchiectomy.


N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/- mice.
Major aspects of neuronal function are regulated by Ca(2+) including neurotransmitter release, excitability, developmental plasticity, and gene expression. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited both greater excitability and evoked release of neuropeptides compared to wildtype mice. Furthermore, augmented voltage-dependent sodium currents but not potassium currents contribute to the enhanced excitability. To determine the mechanisms giving rise to the enhanced release of substance P and calcitonin gene-related peptide in the Nf1+/- sensory neurons, the potential differences in the total voltage-dependent calcium current (ICa) as well as the contributions of individual Ca(2+) channel subtypes were assessed. Whole-cell patch-clamp recordings from small-diameter capsaicin-sensitive sensory neurons demonstrated that the average peak ICa densities were not different between the two genotypes. However, by using selective blockers of channel subtypes, the current density of N-type (Cav2.2) ICa was significantly larger in Nf1+/- neurons compared to wildtype neurons. In contrast, there were no significant differences in L-, P/Q- and R-type currents between the two genotypes. Quantitative real-time polymerase chain reaction measurements made from the isolated but intact dorsal root ganglia indicated that N-type (Cav2.2) and P/Q-type (Cav2.1) Ca(2+) channels exhibited the highest mRNA expression levels although there were no significant differences in the levels of mRNA expression between the genotypes. These results suggest that the augmented N-type (Cav2.2) ICa observed in the Nf1+/- sensory neurons does not result from genomic differences but may reflect post-translational or some other non-genomic modifications. Thus, our results demonstrate that sensory neurons from Nf1+/- mice, exhibit increased N-type ICa and likely account for the increased release of substance P and calcitonin gene-related peptide that occurs in Nf1+/- sensory neurons.


Human platelet alphaIIbeta3 integrin binding affinity and specificity of SJ874: antiplatelet efficacy versus aspirin.
To define the affinity and specificity of SJ874, a nonpeptide antiplatelet agent for platelet glycoprotein Ilb/IIIa integrin, and to determine the antiplatelet efficacy of SJ874 relative to those of glycoprotein IIbIIIa antagonists and aspirin. Binding affinity and specificity of SJ874 for platelet glycoprotein IIb/IIIa integrin were determined using integrin-mediated binding and adhesion assays with human cells. Additionally, the antiplatelet efficacy of SJ874 was determined and compared with those of other glycoprotein IIb/IIIa antagonists and aspirin using light-transmittance and laser-scattering aggregometry. SJ874 inhibited aggregation of human platelets induced by 10 micromol/l adenosine diphosphate (ADP) with a concentration for half-maximal effect of 0.046 +/- 0.005 micromol/l using light-transmittance aggregometry. Using laser-scattering aggregometry, SJ874 was found to totally inhibit formation both of micro-aggregates and of macro-aggregates induced either by ADP or by epinephrine. In contrast, administration of 325 mg aspirin to normal healthy volunteers attenuated formation of macro-aggregates but not micro-aggregates. SJ874 inhibited binding of [125I]-fibrinogen to activated (by ADP, epinephrine, and arachidonic acid at concentrations of 100 micromol/l each) gel-filtered human platelets with a concentration for half-maximal effect of 0.0012 +/- 0.0005 micromol/l. SJ874 was demonstrated to associate more tightly with resting human platelets than did DMP754 [1] and slightly less tightly than did DMP802 [2]. SJ874 was demonstrated to exhibit a high degree of specificity for platelet glycoprotein IIb/IIIa (alphaIIb/beta3) integrin compared with other known integrins, including alphavbeta3, alphavbeta5, and alpha5beta1 (concentration for half-maximal effect > 100 micromol/l). SJ874 is a potent and specific platelet glycoprotein IIb/IIIa antagonist with high affinity for and tight association with human platelets. These data suggest that SJ874 might have good antiplatelet utility for inhibiting formation both of platelet micro-aggregates and of macro-aggregates of platelets and a long duration of action in humans due to its slow dissociation from human platelets.


[Endosonography: a review of applications in gastroenterology].
Endosonography is a very important method of investigation in several specialties. It allows the gastroenterologist to reach organs and structures, that may not be seen by percutaneous ultrasound performing a closer imaging of them. Endoscopic ultrasound was initially introduced as a pure diagnostic tool. Nowadays there are many therapeutic interventions that can be done endosonographically. This publication reviews the last development of this method.


Inversion of in situ synthesized oligonucleotides: improved reagents for hybridization and primer extension in DNA microarrays.
Oligonucleotides synthesized in array format suffer from contamination by truncated species. We have developed a method to invert DNA molecules in situ after completed synthesis. Reactive functions at the 5'-ends of the oligonucleotides are permitted to react with functions on the support before the 3'-ends are released, in effect reversing the orientation of full-length oligonucleotides, while any 5'-truncated molecules are lost. This strategy serves both to purify in situ synthesized reagents and to reorient the oligonucleotides, causing them to expose free 3'-hydroxyls. In situ inverted oligonucleotides can be used in assays based on DNA polymerase-assisted extension of immobilized primers, and we demonstrate their utility in minisequencing and in pyrosequencing.


Personality traits, cognitive states, and mortality in older adulthood.
Research suggests that personality traits are associated with mild cognitive impairment (MCI), dementia, and mortality risk, but the timing of when traits are most important in the progression to dementia and the extent to which they are associated with years of cognitive health span are unclear. This project applied secondary data analysis to the Rush Memory and Aging Project (N = 1954; baseline Mage = 80 years; 74% female) over up to 23 annual assessments. Multistate survival modeling examined the extent to which conscientiousness, neuroticism, and extraversion, assessed using the NEO Five Factor Inventory, were associated with transitions between cognitive status categories and death. Additionally, multinomial regression models estimated cognitive health span and total survival based on standard deviation units of personality traits. Adjusting for demographics, depressive symptoms, and apolipoprotein (APOE) ε4, personality traits were most important in the transition from no cognitive impairment (NCI) to MCI. For instance, higher conscientiousness was associated with a decreased risk of transitioning from NCI to MCI, hazard ratio (HR) = 0.78, 95% CI [0.72, 0.85] and higher neuroticism was associated with an increased risk of transitioning from NCI to MCI, HR = 1.12, 95% CI [1.04, 1.21]. Additional significant and nonsignificant results are discussed in the context of the existing literature. While personality traits were not associated with total longevity, individuals higher in conscientiousness and extraversion, and lower in neuroticism, had more years of cognitive health span, particularly female participants. These findings provide novel understanding of the simultaneous associations between personality traits and transitions between cognitive status categories and death, as well as cognitive health span and total longevity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


3-Weeks of Exercise Training Increases Ischemic-Tolerance in Hearts From High-Fat Diet Fed Mice.
Physical activity is an efficient strategy to delay development of obesity and insulin resistance, and thus the progression of obesity/diabetes-related cardiomyopathy. In support of this, experimental studies using animal models of obesity show that chronic exercise prevents the development of obesity-induced cardiac dysfunction (cardiomyopathy). Whether exercise also improves the tolerance to ischemia-reperfusion in these models is less clear, and may depend on the type of exercise procedure as well as time of initiation. We have previously shown a reduction in ischemic-injury in diet-induced obese mice, when the exercise was started prior to the development of cardiac dysfunction in this model. In the present study, we aimed to explore the effect of exercise on ischemic-tolerance when exercise was initiated after the development obesity-mediated. Male C57BL/6J mice were fed a high-fat diet (HFD) for 20-22 weeks, where they were subjected to high-intensity interval training (HIT) during the last 3 weeks of the feeding period. Sedentary HFD fed and chow fed mice served as controls. Left-ventricular (LV) post-ischemic functional recovery and infarct size were measured in isolated perfused hearts. We also assessed the effect of 3-week HIT on mitochondrial function and myocardial oxygen consumption (MVO2). Sedentary HFD fed mice developed marked obesity and insulin resistance, and demonstrated reduced post-ischemic cardiac functional recovery and increased infarct size. Three weeks of HIT did not induce cardiac hypertrophy and only had a mild effect on obesity and insulin resistance. Despite this, HIT improved post-ischemic LV functional recovery and reduced infarct size. This increase in ischemic-tolerance was accompanied by an improved mitochondrial function as well as reduced MVO2. The present study highlights the beneficial effects of exercise training with regard to improving the ischemic-tolerance in hearts with cardiomyopathy following obesity and insulin resistance. This study also emphasizes the exercise-induced improvement of cardiac energetics and mitochondrial function in obesity/diabetes.


Survival from methicillin-sensitive Staphylococcus aureus bloodstream infections over 20 years: a cohort of 1328 patients.
Staphylococcus aureus bloodstream infections (SA BSI) are associated with substantial mortality. The rapid emergence of methicillin-resistant S. aureus (MRSA), known to be associated with worse outcome, may blur advances made regarding mortality attributed to SA BSI caused by methicillin-sensitive S. aureus (MSSA) strains. In the unusual setting of a very low MRSA prevalence institution, we investigated incidence, mortality and trends of BSI caused by MSSA over the last 20 years. To evaluate and demonstrate trends in incidence and mortality of MSSA BSI as well as risk factors for mortality. Retrospective, observational analysis of the prospective bloodstream infection cohort at the University Hospital Basel between January 1993 and December 2013. All patients with blood cultures positive for MSSA were included. All patients were analysed regarding pertinent demographic, clinical and antimicrobial treatment data. We calculated incidence, temporal trends and mortality of MSSA BSI. 1328 episodes of MSSA BSI were identified, accounting for a yearly incidence ranging from 2.1 to 4.5 per 10 000 patient-days (p = 0.2 for trend). Overall mortality was 19.3% and did not improve over time. Community-acquired MSSA BSI significantly increased over time, while nosocomial cases decreased (p <0.05). Mortality related to MSSA BSI remains high and unchanged over the last 20 years. Despite advances in treatment and supportive care in medicine during the last 20 years survival did not improve and, therefore, new approaches are required to lower mortality in MSSA BSI.


Acute effect of triiodothyronine on the dynamics of thyrotropin release from superfused anterior pituitary cells.
The effects of triiodothyronine (T3) on the dynamics of thyrotropin (TSH) release induced by TSH-releasing hormone (TRH) were examined in the presence or absence of a protein synthesis inhibitor, cycloheximide (CX), in a superfusion system using primarily cultured cells of the rat anterior pituitary gland on microcarrier beads. When the cells were continuously stimulated with TRH (10 nM, 180 min), TSH release occurred in a biphasic manner and the profile of TSH release was characterized by an initial sharp peak (phase I), followed by a lower plateau form phase (phase II). Both phase-I and phase-II releases were significantly suppressed in the presence of T3 (1 ng/ml), which was added to the superfusion medium 1 h before initiation of TRH stimulation. The biphasic nature of the release profile was maintained in the presence of T3, suggesting that the site of the T3 action may be common between phase-I and phase-II release. We have already suggested that phase-I release is protein synthesis-independent and phase-II release protein synthesis-dependent using CX in TRH-stimulated cells. In the presence of CX, phase-I release was not suppressed by T3, while phase-II release was still suppressed by T3. The inability of CX to reverse the T3-induced suppression of phase-II release may be masked by the direct CX effect on phase-II release of TSH. The present study indicates that each component (phase I and phase II) of the biphasic release of TSH induced by TRH stimulation was acutely suppressed by T3 and suggests that the T3 action is mediated through protein synthesis.


Simultaneous Measurement of In vivo and Transit Mid-Plane Doses with Ionization Chambers in Gynecological Malignancy Patients Undergoing Three-Dimensional Conformal Radiotherapy.
The aim of this study is to estimate delivered radiation doses inside planning tumor volume (PTV) using the in vivo (mid-plane dose) measurement and transit measurement methods in gynecological malignancy patients undergoing three-dimensional conformal radiotherapy (3DCRT) using calibrated ionization chambers. Six patients with histopathologically proven carcinoma of the cervix or endometrium were planned with four-field 3DCRT to the pelvic site. Isocenter was at the geometric mid-plane of PTV with a dose prescription of 50 Gy in 25 fractions. Clinical mid-plane dose (D iso, Transit) estimates were done in one method (transit) using the FC-65 positioned at electronic portal imaging device level. In another method, a repeat computerized tomography scan was performed (at the 11th fraction) using CC-13 having a protective cap in the vaginal cavity for in vivo measurements (D in vivo ). Simultaneous measurements were performed with the two chambers from the 11th fraction onward at least 3-4 times during the remaining course of treatment. The agreement of mean doses from these two described methods and treatment planning system reference doses was in the range of -4.4 ± 1.1% (minimum) to -0.3 ± 2.0% (maximum) and -4.0 ± 1.7% (minimum) to 1.9 ± 2.4% for D in vivo and D iso, Transit , respectively, which are an acceptable range of daily radiation dose delivery. The fundamental importance of this study lies in simultaneous validation of delivered dose in real time with two methods. A study in this small number of patients has given the confidence to apply transit measurements for quality assurance on a routine basis as an accepted clinical dosimetry for the selected patients.


New European guidelines for cardiovascular disease prevention in clinical practice.
In 2007, the Fourth Joint European Societies' Task Force on cardiovascular disease (CVD) prevention in clinical practice issued an update of the guidelines on how to prevent CVD. These guidelines are endorsed by 10 international societies interested in the subject. Particular attention is given to lifestyle changes, risk factor management, and the use of cardioprotective drugs. In this paper, the content of the guidelines is summarized with emphasis on what is new compared to the previous version and on what could be of particular interest to clinical chemists. For those who would like to read more on this, please refer to the full document (112 pages including 1105 references).


Confinement Effects and Charge Dynamics in Zn3N2 Colloidal Quantum Dots: Implications for QD-LED Displays.
Zinc nitride (Zn3N2) colloidal quantum dots are composed of nontoxic, low-cost, and earth-abundant elements. The effects of quantum confinement on the optical properties and charge dynamics of these dots are studied using steady-state optical characterization and ultrafast fluence-dependent transient absorption. The absorption and emission energies are observed to be size-tunable, with the optical band gap increasing from 1.5 to 3.2 eV as the dot diameter decreased from 8.9 to 2.7 nm. Size-dependent absorption cross sections (σ = 1.22 ± 0.02 × 10-15 to 2.04 ± 0.03 × 10-15 cm2), single exciton lifetimes (0.36 ± 0.02 to 0.65 ± 0.03 ns), as well as Auger recombination lifetimes of biexcitons (3.2 ± 0.4 to 5.0 ± 0.1 ps) and trions (20.8 ± 1.8 to 46.3 ± 1.3 ps) are also measured. The degeneracy of the conduction band minimum (g = 2) is determined from the analysis of the transient absorption spectra at different excitation fluences. The performance of Zn3N2 colloidal quantum dots thus broadly matches that of established visible light emitting quantum dots based on toxic or rare elements, making them a viable alternative for QD-LED displays.


Chapter 17: Occupational immunologic lung disease.
Occupational immunologic lung disease is characterized by an immunologic response in the lung to an airborne agent inhaled in the work environment and can be subdivided into immunologically mediated occupational asthma (OA) and hypersensitivity pneumonitis (HP). Irritant-induced OA, a separate nonimmunologic entity, can be caused by chronic exposure to inhaled irritants or reactive airways dysfunction syndrome, defined as an asthma-like syndrome that persists for >3 months and occurs abruptly after a single exposure to a high concentration of an irritating industrial agent. High-risk fields for OA include farmers, printers, woodworkers, painters, plastic workers, cleaners, spray painters, electrical workers, and health care workers. OA can be triggered by high molecular weight (HMW) proteins that act as complete allergens or low molecular weight (LMW) sensitizers that act as haptens. HMW proteins (>10 kDa) are generally derived from microorganisms (such as molds and bacteria, including thermophilic actinomycetes), plants (such as latex antigens and flour proteins), or animals (such as animal dander, avian proteins, and insect scales) and are not specifically regulated by the Occupational Safety and Health Administration (OSHA). LMW haptens that bind to proteins in the respiratory mucosa include some OSHA-regulated substances such as isocyanates, anhydrides, and platinum. HP can present in an acute, a chronic, or a subacute form. The acute, subacute, and early chronic form is characterized by a CD4(+) T(H)1 and CD8(+) lymphocyte alveolitis. Classically, the bronchoalveolar lavage will show a CD4/CD8 ratio of <1.


Etanercept increases tumor necrosis factor-alpha level but not sFas level in patients with rheumatoid arthritis.
Targeted anti-tumor necrosis factor-alpha (TNFα) therapy in patients with rheumatoid arthritis (RA) has resulted in dramatic improvement in the disease course and prognosis. One of the features of RA is hyperplasia of synovial cells, particularly RA synovial fibroblasts (RA-SF), caused partially by impaired apoptosis of RA-SF cells. It has been shown that TNFα may inhibit apoptosis in RA-SF cells and this process may be reversed by the use of TNFα antagonists. To determine the influence of etanercept, an anti-TNFα agent, on sFas (CD 95) receptor. We analyzed serum levels of sFaS and TNFα in a group of 26 patients with high RA disease activity who were selected to start treatment with etanercept. Assessment of sFas receptor and TNFα levels was performed before and 6 months after treatment with etanercept. Treatment with etanercept resulted in increased TNFα levels (log TNFα 0.602 vs. 1.17, P < 0.05) but no change in sFas levels (log sFas 3.17 vs. 3.11, P = 0.37). As expected, treatment resulted in significant reduction in both disease activity and levels of inflammatory markers. Etanercept may increase TNFα levels in patients with RA. We also speculate that the Fas pathway is not the main apoptotic pathway in patients with RA treated with etenercept, since sFas, a marker of apoptotic activity, remained unchanged and was not influenced by disease activity and concomitant treatment.


Placebo effect of saline in pain management: compared study with hemodialysis and non-hemodialysis nurses' experiences.
objectives: To identify and compare hemodialysis and non-hemodialysis nurses' experiences about the placebo effect of intravenous saline injection in pain management. This descriptive study design was carried out between January 22nd - February 4th, 2012 with 202 voluntary nurses who work in hemodialysis and medical-surgical clinics. An online survey system was used for data collecting. Cookie and IP logging prevented multiple voting. The survey contained 21 questions. Data were evaluated by descriptive statistics and Chi-Square test. The mean age of the nurses was 31.13 ± 6.03 years. Fifty-two point five percent (n=106) of the nurses were working in a hemodialysis unit while the others (45.5%) were from other clinics such as medical and surgical units. While 68.4% of the hemodialysis nurses stated that they "sometimes" use placebo, 62.7% of the non-hemodialysis nurses stated that they "rarely" use placebo. In hemodialysis nurses, "always" believing the patient's pain was significantly lower than expected count. This ratio was found more than expected in non-hemodialysis nurses (p=0.006). Hemodialysis nurses stated that "the use of placebo is not necessary to be recorded". However, non-hemodialysis nurses stated more than expected that "the placebo usage should be recorded" (p=0.006). Hemodialysis nurses are more likely to use saline injection as a placebo in pain management rather than non-hemodialysis nurses. However, non-hemodialysis nurses believe the patient's pain more than hemodialysis nurses do. This makes placebo usage for the first step choice among hemodialysis nurses.


The responses of normal an athymic mice to infections by togaviruses: strain differentiation in active and adoptive immunization.
Strains of yellow fever virus (YFV), Venezuelan equine encephalomyelitis virus (VEEV) and Semliki Forest virus (SFV) have been used to compare the stimulations of regulatory immunity (pre-challenge), antibody synthesis and protective immunity (post-challenge) in athymic-nude and normal mice. Similarly, direct assessments have been extended to athymic recipients of normal spleen cells and to adoptively immunized mice. The results indicate that the responses of mice to different togaviruses or strains of togaviruses may be differentially T-lymphocyte dependent at any one or more of the above three stages of host response. T-cell reconstitution or adoptive immunization may be effective only for the virus strains of highest immunogenicity. These results suggest a resolution of T-lymphocytes dependence at three levels of host response to virus infections. This approach may be of value in the similarly direct in vivo differentiation of other virus strains and as a practical framework for the consideration of the in vivo significance of the variety of in vitro lymphocytes markers.


A cross-sectional serosurvey of SARS-CoV-2 and co-infections in stray cats from the second wave to the sixth wave of COVID-19 outbreaks in Spain.
Severe Acute Respiratory Syndrome Coronavirus 2 is the causative agent of Coronavirus Disease 2019 in humans. Among domestic animals, cats are more susceptible to SARS-CoV-2 than dogs. The detection of anti-SARS-CoV-2 antibodies in seemingly healthy cats and/or infected cats which are in close contact with infected humans has been described. The presence of animals that tested positive by serology or molecular techniques could represent a potential transmission pathway of SARS-CoV-2 that can spill over into urban wildlife. This study analyses the seroprevalence variation of SARS-CoV-2 in stray cats from different waves of outbreaks in a geographical area where previous seroepidemiological information of SARS-CoV-2 was available and investigate if SARS-CoV-2-seropositive cats were exposed to other co-infections causing an immunosuppressive status and/or a chronic disease that could lead to a SARS-CoV-2 susceptibility. For this purpose, a total of 254 stray cats from Zaragoza (Spain) were included. This analysis was carried out by the enzyme-linked immunosorbent assay using the receptor binding domain of Spike antigen and confirmed by serum virus neutralization assay. The presence of co-infections including Toxoplasma gondii, Leishmania infantum, Dirofilaria immitis, feline calicivirus, feline herpesvirus type 1, feline leukemia virus and feline immunodeficiency virus, was evaluated using different serological methods. A seropositivity of 1.57% was observed for SARS-CoV-2 including the presence of neutralizing antibodies in three cats. None of the seropositive to SARS-CoV-2 cats were positive to feline coronavirus, however, four SARS-CoV-2-seropositive cats were also seropositive to other pathogens such as L. infantum, D. immitis and FIV (n = 1), L. infantum and D. immitis (n = 1) and L. infantum alone (n = 1).Considering other pathogens, a seroprevalence of 16.54% was detected for L. infantum, 30.31% for D. immitis, 13.78%, for T. gondii, 83.86% for feline calicivirus, 42.52% for feline herpesvirus type 1, 3.15% for FeLV and 7.87% for FIV.Our findings suggest that the epidemiological role of stray cats in SARS-CoV-2 transmission is scarce, and there is no increase in seropositivity during the different waves of COVID-19 outbreaks in this group of animals. Further epidemiological surveillances are necessary to determine the risk that other animals might possess even though stray cats do not seem to play a role in transmission.


Preliminary biological studies of certain amino acid analogues.
Among four amino acid analogues and their corresponding hydantoins prepared synthetically, two of the amino acids, 2-amino-2-methyl-5-hexenoic acid and 2-ethylphenylalanine, were found at moderately high concentrations to inhibit growth of Escherichia coli 9723 and the growth inhibition is prevented by methionine and phenylalanine, respectively. Mammalian studies showed no toxic effects in albino male mice, and the analogues were excreted unchanged primarily in the urine.


Thermotropic behavior of binary mixtures of dipalmitoylphosphatidylcholine and glycosphingolipids in aqueous dispersions.
The thermotropic behavior of mixtures of dipalmitoylphosphatidylcholine (DPPC) with natural glycosphingolipids (galactosylceramide, phrenosine, kerasine, glucosylceramide, lactosylceramide, asialo-GM1, sulfatide, GM3, GM1, GD1a, GT1b) in dilute aqueous dispersions were studied by high sensitivity differential scanning calorimetry over the entire composition range. The pretransition of DPPC is abolished and the cooperativity of the main transition decreases sharply at mole fractions of glycosphingolipids below 0.2. All systems exhibit non-ideal temperature-composition phase diagrams. The mono- and di-hexosylceramides are easily miscible with DPPC when the proportion of glycosphingolipids in the system is high. A limited quantity (1-6 molecules of DPPC per molecule of glycosphingolipid (GSL) can be incorporated into a homogeneously mixed lipid phase. Domains of DPPC, immiscible with the rest of a mixed GSL-DPPC phase that shows no cooperative phase transition, are established as DPPC exceeds a certain proportion in the system. One negative charge (sulfatide) or four neutral carbohydrate residues (asialo-GM1) in the oligosaccharide chain of the glycosphingolipids results in phase diagrams exhibiting coexistence of gel and liquid phases over a broad temperature-composition range. Systems containing gangliosides show complex phase diagrams, with more than one phase transition. However, no evidence for phase-separated domains of pure ganglioside species is found. The thermotropic behavior of systems containing DPPC and glycosphingolipids correlates well with their interactions in mixed monolayers at the air/water interface.


Melanoma incidence, stage, and survival after solid organ transplant: A population-based cohort study in Ontario, Canada.
Risk of melanoma is increased with potentially worse outcomes after solid organ transplant. To estimate the incidence, stage, and survival in transplant recipients with melanoma. Population-based, retrospective, observational study using linked administrative databases. Adults receiving their first solid organ transplant from 1991 through 2012 were followed to December 2013. We identified 51 transplant recipients with melanoma, 11 369 recipients without melanoma, and 255 matched patients with melanoma from the nontransplant population. Transplant recipients were at increased risk of melanoma (standardized incidence ratio, 2.29; 95% confidence interval [CI], 2.07-2.49) and more likely to be diagnosed at stages II through IV (adjusted odds ratio, 4.29; 95% CI, 2.04-9.00) compared with the nontransplant population. Melanoma-specific mortality was increased in transplant recipients compared with the nontransplant population (adjusted hazard ratio, 1.93; 95% CI, 1.03-3.63). Among transplant recipients, all-cause mortality was increased after melanoma compared with those without melanoma (stage T1/T2: adjusted hazard ratio, 2.18; 95% CI, 1.13-4.21; T3/T4: adjusted hazard ratio, 4.07; 95% CI, 2.36-7.04; III/IV: adjusted hazard ratio, 7.92; 95% CI, 3.76-16.70). The databases did not contain data on immunosuppressive drugs; ascertainment of melanoma metastasis relied on pathology reports. Melanoma after solid organ transplant is more often diagnosed at a later stage and leads to increased mortality, even for early-stage tumors.


Primary site of action of ketoconazole on Candida albicans.
Ketoconazole, an antifungal drug, completely inhibited the growth of Candida albicans 7N at concentrations of greater than or equal to 50 microgram/ml (94 microM). However, ketoconazole incompletely inhibited the growth of this opportunistic yeast at concentrations of 25 to 0.2 microgram/ml (47 to 0.4 microM). At these lower concentrations, 2,3,5-triphenyl tetrazolium chloride, an electron acceptor, was reduced by several strains of C. albicans. This effect resulted in red coloration of colonies. Concomitantly, this phenomenon was not antagonized in the presence of ergosterol. Furthermore, neither ketoconazole nor antimycin A inhibited the growth of C. albicans under anaerobic conditions, as revealed by a paper disk method. Ketoconazole at the concentrations stated above inhibited endogenous and exogenous respiration immediately after it was added to a system containing log phase C. albicans cells, as determined polarographically. At the same time, ketoconazole inhibited the activity of NADH oxidase at the mitochondrial level. In contrast, higher concentrations of ketoconazole (greater than 100 microM) were required to inhibit the activity of succinate oxidase from rat liver mitochondria. In addition, concentrations of ketoconazole greater than 100 microM were required to impair the uptake of labeled leucine and adenine and, subsequently, the incorporation of the former into protein and the latter into DNA and RNA in intact cells. On the other hand, ketoconazole at concentrations of 10, 1.0, and 0.4 microM had no effect on either membrane permeability or macromolecular synthesis.


Bioinspired Superhydrophobic Fibrous Materials.
Natural fibers with robust water repellency play an important role in adapting organisms to various environments, which has inspired the development of artificial superhydrophobic fibrous materials with applications in self-cleaning, antifogging, water harvesting, heat exchanging, catalytic reactions, and microrobots. However, these highly textured surfaces (micro/nanotextured) suffer from frequent liquid penetration in high humidity and abrasion-induced destruction of the local environment. Herein, bioinspired superhydrophobic fibrous materials are reviewed from the perspective of the dimension scale of fibers. First, the fibrous dimension characteristics of several representative natural superhydrophobic fibrous systems are summarized, along with the mechanisms involved. Then, artificial superhydrophobic fibers are summarized, along with their various applications. Nanometer-scale fibers enable superhydrophobicity by minimizing the liquid-solid contact area. Micrometer-scale fibers are advantageous for enhancing the mechanical stability of superhydrophobicity. Micrometer-scale conical fibrous structures endow a Laplace force with a particular magnitude for self-removing condensed tiny dewdrops in highly humid air and stably trapping large air pockets underwater. Furthermore, several representative surface modification strategies for constructing superhydrophobic fibers are presented. In addition, several conventional applications of superhydrophobic systems are presented. It is anticipated that the review will inspire the design and fabrication of superhydrophobic fibrous systems.


Effect of intestinal microflora on digestible energy and fiber digestion in chickens fed a high-fiber diet.
The effect of intestinal microflora on digestible energy (DE) value and fiber digestion was studied in single-comb White Leghorn chickens fed a low-fiber diet (experiment 1) or a high-fiber diet with low or adequate metabolizable energy (ME) value (experiment 2). Fecal energy excretion was calculated from the difference between total energy excretion in urinary and fecal droppings and urinary energy excretion, which was estimated from the energy values for individual urinary nitrogenous compounds extracted with Li2CO3. When the birds were fed the low-fiber diet, no differences in growth, DE, or ME were observed between germ-free and conventional environments. Of birds fed the high-fiber diet, growth of those in the conventional environment was similar to that of the birds in the germ-free environment at the adequate ME value, whereas birds in the conventional environment grew faster than the birds in the germ-free environment at the low ME value. Changes in observed dietary ME values of the high-fiber diets, being higher in birds in the conventional environment than in birds in the germ-free environment (experiment 2), were almost entirely accounted for by those in dietary DE values, most of which was contributed by crude fiber digestion. It was concluded, therefore, that by means of fiber digestion, the intestinal microflora may benefit the host bird by supplying extra energy, which would result in growth promotion, particularly when the bird is deficient in energy.


Effect of puboprostatic ligament reconstruction on continence recovery after robot-assisted laparoscopic prostatectomy: our initial experience.
Prostate cancer represents a serious health problem worldwide. Radical prostatectomy is the gold standard for management of localized prostate cancer. Urinary incontinence is among the most common complications affecting robot-assisted laparoscopic prostatectomy (RALP) patients' postoperative quality of life. Several surgical modifications were introduced to overcome this problem including the puboprostatic ligament reconstruction. In this study, we discuss our technique of anterior reconstruction of the puboprostatic ligament during RALP and its effect on the continence outcome postoperatively. In this retrospective study, the data of 95 consecutive patients were analyzed and the patients were divided in two groups; the control group "group A" (47 patients) and the anterior reconstruction group "group B" (48 patients). The primary endpoint of this study was to compare both groups as regards the postoperative continence rates. Complete continence (no pads) rates were reported at time of catheter removal (T0), 1 month (T1), 4 months (T4), 6 months (T6) and 12 months (T12) postoperatively. Moreover, the social continence (0-1 security pad) was reported at 12 months postoperatively. Complete continence was significantly different between both groups at T0 and T6 (P=0.022, and P=0.035 respectively). The social continence was not significantly different between both groups (85.1% vs. 89.6% in group A vs. group B). Despite anterior reconstruction of the puboprostatic ligament showed no significant effect on the overall continence, it showed earlier return to continence up to 6 months, which supports the theory that anterior puboprostatic reconstruction may provide better immediate continence and shorten the time to continence for RALP patients. However, most of the published literature showed better continence rates with the total anatomical reconstruction (combined anterior and posterior). Therefore, we started to offer patients in our center total anatomical reconstruction during RALP.


Clinical and Ultrasound Characteristics of the Microcystic Elongated and Fragmented (MELF) Pattern in Endometrial Cancer According to the International Endometrial Tumor Analysis (IETA) criteria.
To describe sonographic features of the microcystic elongated and fragmented (MELF) pattern of myometrial invasion (MI) using the International Endometrial Tumor Analysis (IETA) criteria; to assess the effect of the MELF pattern on preoperative ultrasound evaluation of MI; and to determine the relationship of the MELF pattern to more advanced stage (≥ IB) and lymph node metastases in women with endometrioid endometrial cancer. We included 850 women with endometrioid endometrial cancer from the prospective IETA 4 study. Ultrasound experts performed all ultrasound examinations, according to the IETA protocol. Reference pathologists assessed the presence or absence of the MELF pattern. Sonographic features and accuracy of ultrasound assessment of MI were compared in cases with the presence and the absence of the MELF pattern. The MELF pattern was correlated to more advanced stage (≥IB) and lymph node metastases. The MELF pattern was present in 197 (23.2%) women. On preoperative ultrasound imaging the endometrium was thicker (p = 0.031), more richly vascularized (p = 0.003) with the multiple multifocal vessel pattern (p < 0.001) and the assessment of adenomyosis was more often uncertain (p < 0.001). The presence or the absence of the MELF pattern did not affect the accuracy of the assessment of MI. The MELF pattern was associated with deep myometrial invasion (≥ 50%) (p < 0.001), cervical stromal invasion (p = 0.037), more advanced stage (≥ IB) (p < 0.001) and lymph node metastases (p = 0.011). Tumors with the MELF pattern were slightly larger, more richly vascularized with multiple multifocal vessels and assessment of adenomyosis was more uncertain on ultrasound imaging. The MELF pattern did not increase the risk of underestimating MI in preoperative ultrasound staging. Tumors with the MELF pattern were more than twice as likely to have more advanced stage (≥ IB) and lymph node metastases.


Reduced basal forebrain and hippocampal activation during memory encoding in girls with fragile X syndrome.
Fragile X syndrome (FraX), the most common heritable cause of developmental disability, is associated with IQ, memory, and visuospatial processing deficits. The fragile X gene (FMR1) is prominently transcribed in two regions critical to memory encoding and attention: the hippocampus and the basal forebrain. To probe functional MRI activation abnormalities associated with the disorder, girls with FraX and age-matched, normally-developing girls were scanned during a test of visual memory encoding. While there were considerable similarities in activation patterns between the two groups, the girls with FraX showed significantly less activation in the hippocampus and the basal forebrain. This is the first study, to our knowledge, demonstrating functional deficits in FraX subjects in brain regions known to have the highest FMR1 transcription.


Platelet pool inventory management: theory meets practice.
The shelf life of platelet concentrates (PCs) is a matter of days. Simultaneously, the demand is highly variable, shortages are not allowed, and producing too many results in outdating. Concurrently, younger PCs, implying an extended time till outdating (TTO), are preferred. Common PC inventory management relies on experience-based order-up-to rules. This study aimed at minimizing outdating and shortages, while extending the TTO through a theoretical approach. It focuses on PCs processed from whole blood donations. A combined approach of stochastic dynamic programming and simulation techniques (SDP/S), from the mathematical discipline operations research, has been implemented. This approach included the design of the dedicated software tool thrombocyte inventory management optimizer (TIMO). Based on the 2007 data, an optimal order-up-to rule was calculated. Outdating percentages and TTOs have been collected from August 2005 to July 2010. The resulting order-up-to rule has been applied and adjusted from summer 2007 onward. Over the study period, the results of the practical implementation showed significant improvements. The median weekly outdating percentage dropped to less than 1% and a gain in TTO of 0.48 day was reached. The results and the additional computer simulations brought confidence to the personnel to apply and adopt the "theoretical" approach and TIMO. Applying theory may help a blood bank to improve its PC inventory management and may help to identify to what extent practical limits can approach theoretical limits. The application of the theory has led to both a significant improvement and a more structured and less panic-driven PC inventory management.


Implementation of a three-tiered approach to identify and characterize anti-drug antibodies raised against HIV-specific broadly neutralizing antibodies.
The ability to detect, quantify, and interrogate the properties of immune responses raised against biological therapeutics is not only important to our understanding of these molecules, but also to their success in the clinic. A tiered assay approach to identify the presence, specificity, and titer of anti-drug antibody (ADA) responses has been adopted as a gold standard by industry leaders, the FDA, and the EMA. In order to support pre-clinical and clinical trials, these assays must be standardized, and their performance sufficiently characterized to ensure the accuracy and reproducibility of results under relevant testing conditions. Here we present implementation of electrochemiluminiscence assays that fit into the tiered paradigm of ADA testing for five HIV broadly neutralizing antibodies (3BNC117, 3BNC117-LS, 10-1074, PGT121, and PGDM1400) in compliance with Good Clinical Laboratory practices. Assay sensitivities and matrix effects were evaluated and used to inform the development of positivity cut points. Once cut points were established, assay precision, specificity, free-drug tolerance, and robustness were defined. In all cases, assay characteristics met or surpassed recommendations set forth by the FDA. To further evaluate the performance of these assays and the tiered approach, samples from non-human primates that had received a subset of the five therapeutics were evaluated. In sum, this study reports qualification of a set of ADA assays available to the scientific community as pre-clinical and clinical trials of broadly HIV-neutralizing antibodies proceed, and a framework that is easily adapted as new drug products are advanced in the clinic.


Value Frameworks in Oncology: Comparative Analysis and Implications to the Pharmaceutical Industry.
As the cost of oncology care continues to rise, composite value models that variably capture the diverse concerns of patients, physicians, payers, policymakers, and the pharmaceutical industry have begun to take shape. To review the capabilities and limitations of 5 of the most notable value frameworks in oncology that have emerged in recent years and to compare their relative value and application among the intended stakeholders. We compared the methodology of the American Society of Clinical Oncology (ASCO) Value Framework (version 2.0), the National Comprehensive Cancer Network Evidence Blocks, Memorial Sloan Kettering Cancer Center DrugAbacus, the Institute for Clinical and Economic Review Value Assessment Framework, and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale, using a side-by-side comparative approach in terms of the input, scoring methodology, and output of each framework. In addition, we gleaned stakeholder insights about these frameworks and their potential real-world applications through dialogues with physicians and payers, as well as through secondary research and an aggregate analysis of previously published survey results. The analysis identified several framework-specific themes in their respective focus on clinical trial elements, breadth of evidence, evidence weighting, scoring methodology, and value to stakeholders. Our dialogues with physicians and our aggregate analysis of previous surveys revealed a varying level of awareness of, and use of, each of the value frameworks in clinical practice. For example, although the ASCO Value Framework appears nascent in clinical practice, physicians believe that the frameworks will be more useful in practice in the future as they become more established and as their outputs are more widely accepted. Along with patients and payers, who bear the burden of treatment costs, physicians and policymakers have waded into the discussion of defining value in oncology care, as well as pharmaceutical companies that seek to understand the impact of these value frameworks on each stakeholder, as they model the value and financial threshold of innovative, high-cost drugs.


The Glostavent: evolution of an anaesthetic machine for developing countries.
The sophisticated anaesthetic machines designed for use in modem hospitals are not appropriate for many parts of the developing world, as they are reliant on regular servicing by skilled engineers and an uninterrupted supply of electricity and compressed gases, which are not always available. The Glostavent has been designed specifically to meet the challenges faced by anaesthetists working in these countries. It is robust, simple to use, economical, easy to service and will continue to run during an interruption of the supply of oxygen or electricity. Feedback from widespread use throughout the developing world over the last 10 years has led to significant improvements to the original design. This article describes the basic components of the original version and the modifications which have been introduced as a result of practical experience in the developing world.


Black cohosh (Cimicifuga racemosa) in tamoxifen-treated breast cancer patients with climacteric complaints - a prospective observational study.
The antihormonal therapy of breast cancer patients with the antiestrogen tamoxifen often induces or aggravates menopausal complaints. As estrogen substitution is contraindicated, herbal alternatives, e.g. extracts of black cohosh are often used. A prospective observational study was carried out in 50 breast cancer patients with tamoxifen treatment. All patients had had surgery, most of them had undergone radiation therapy (87%) and approximately 50% had received chemotherapy. Every patient was treated with an isopropanolic extract of black cohosh (1-4 tablets, 2.5 mg) for 6 months. Patients recorded their complaints before therapy and after 1, 3, and 6 months of therapy using the menopause rating scale (MRS II). The reduction of the total MRS II score under black cohosh treatment from 17.6 to 13.6 was statistically significant. Hot flashes, sweating, sleep problems, and anxiety improved, whereas urogenital and musculoskeletal complaints did not change. In all, 22 patients reported adverse events, none of which were linked with the study medication; 90% reported the tolerability of the black cohosh extract as very good or good. Black cohosh extract seems to be a reasonable treatment approach in tamoxifen treated breast cancer patients with predominantly psychovegetative symptoms.


Asymptomatic tonsillar herniation in a neonate with cleidocranial dysplasia.
A male neonate was antenatally diagnosed with cleidocranial dysplasia on the basis of prenatal ultrasound findings and molecular testing of the RUNX2 gene. The patient presented with urosepsis at 24 days of life and subsequently developed apneas after endoscopic examination of the vocal cords. Computed tomography and MRI studies of the head revealed crowding of the posterior fossa with tonsillar and uncal herniation. Apneas were initially thought to be related to brainstem compression; however, the patient responded immediately to caffeine and subsequently stabilized with antibiotic therapy. To our knowledge, this is the first published MRI study of the brain of a neonate with cleidocranial dysplasia to demonstrate the striking posterior fossa findings seen secondary to the reduced bony skull structures. However, despite the dramatic herniation, brainstem function was not compromised.


B-1 and B-2 cell-derived immunoglobulin M antibodies are nonredundant components of the protective response to influenza virus infection.
We have studied the role of secreted immunoglobulin (Ig)M in protection from infection with influenza virus and delineated the relative contributions of B-1 versus B-2 cell-derived IgM in this process. Mice deficient in secreted IgM but capable of expressing surface IgM and secreting other Ig classes show significantly reduced virus clearance and survival rates compared with wild-type controls. Irradiation chimeras in which only either B-1 or B-2 cells lack the ability to secrete IgM show mortality rates similar to those of mice in which neither B-1 nor B-2 cells secrete IgM. Dependence on both sources of IgM for survival is partially explained by findings in allotype chimeras that broadly cross-reactive B-1 cell-derived natural IgM is present before infection, whereas virus strain-specific, B-2 cell-derived IgM appears only after infection. Furthermore, lack of IgM secreted from one or both sources significantly impairs the antiviral IgG response. Reconstitution of chimeras lacking B-1 cell-derived IgM only with IgM-containing serum from noninfected mice improved both survival rates and serum levels of virus-specific IgG. Thus, virus-induced IgM must be secreted in the presence of natural IgM for efficient induction of specific IgG and for immune protection, identifying B-1 and B-2 cell-derived IgM antibodies as nonredundant components of the antiviral response.


[A study of the efficacy and safety of valdoxan in the treatment of a depressive episode].
An open non-randomized controlled prospective study was conducted to investigate the efficacy and safety of valdoxan in the treatment of depression as monotherapy and in the combination with other drugs. Based on the clinical and psychometric measures, author confirmed the high efficacy of valdoxan. The drug can be combined with other antidepressants, no adverse effects are observed in these cases. Positive changes in sleep patterns during the treatment with valdoxan were found. The high tolerability and minimal risk of serious adverse effects were observed. Preliminary data revealed that the age of the patient and scores on some HAMD items were predictors of treatment efficacy. The authors developed a computer program for express-assessment of probability of remission and response to treatment.


Toward a complete human genome sequence.
We have begun a joint program as part of a coordinated international effort to determine a complete human genome sequence. Our strategy is to map large-insert bacterial clones and to sequence each clone by a random shotgun approach followed by directed finishing. As of September 1998, we have identified the map positions of bacterial clones covering approximately 860 Mb for sequencing and completed >98 Mb ( approximately 3.3%) of the human genome sequence. Our progress and sequencing data can be accessed via the World Wide Web (http://webace.sanger.ac.uk/HGP/ or http://genome.wustl.edu/gsc/).


Myristoylation-dependent N-terminal cleavage of the myristoylated alanine-rich C kinase substrate (MARCKS) by cellular extracts.
The myristoylated alanine-rich C kinase substrate (MARCKS) has been proposed to regulate the plasticity of the actin cytoskeleton at its site of attachment to membranes. In macrophages, MARCKS is implicated in various cellular events including motility, adhesion and phagocytosis. In this report we show that macrophage extracts contain a protease which specifically cleaves human MARCKS, expressed in a cell-free system or in E. coli, between Lys-6 and Thr-7. Cleavage of MARCKS decreases its affinity for macrophage membranes by ca. one order of magnitude, highlighting the contribution of the myristoyl moiety of MARCKS to membrane binding. Importantly, cleavage requires myristoylation of MARCKS. Furthermore, MARCKS-related protein (MRP), the second member of the MARCKS family, is not digested. Since Thr-7 is lacking in MRP this suggests that Thr-7 at the P1 position is important for the recognition of lipid-modified substrates. A different product is observed when MARCKS is incubated with a calf brain cytosolic extract. This product can be remyristoylated in the presence of myristoyl-CoA and N-myristoyl transferase, demonstrating that cycles of myristoylation/demyristoylation of MARCKS can be achieved in vitro. Although the physiological relevance of these enzymes still needs to be demonstrated, our results reveal the presence of a new class of cleaving enzymes recognizing lipid-modified protein substrates.


Transformer fault diagnosis research based on LIF technology and IAO optimization of LightGBM.
Transformer fault diagnosis is a necessary operation to ensure the stable operation of a power system. In view of the problems of the low diagnostic rate and long time needed in traditional methods, such as the dissolved gas in oil method, a laser-induced fluorescence (LIF) spectral technology is proposed in this paper, which incorporated an improved aquila optimizer (IAO) and light gradient boosting machine (LightGBM), to predict the types of transformer faults. The original AO was improved using the Nelder Mead (NM) simple search method and opposition-based learning (OBL) mechanism, which could improve the parameter optimization ability of the model. Normal oil, thermal fault oil, local moisture oil, and electrical fault oil were selected as experimental samples. First, the spectral images of the four oil samples were obtained by LIF technology, and the fluorescence spectral curves obtained were preprocessed by multivariate scattering correction (MSC) and normalization (normalize), while kernel-based principle component analysis (KPCA) was used for dimensional reduction. The dimensionality-reduced data were then imported into the LightGBM model for training, and the IAO algorithm was used to optimize the parameters of the LightGBM. Finally, the experiment showed that the LIF technology demonstrated good recognition of the fault types for transformer fault diagnosis; the data purity after MSC preprocessing was higher than that of other processing methods; the prediction effect of the LightGBM model was superior to other prediction models; the LightGBM model optimized by IAO had better convergence, parameter optimization ability, and prediction accuracy than the LightGBM model optimized by the original AO and particle swarm optimization (PSO). Among the models, the MSC-IAO-LightGBM model had the best effect on fault prediction, with the mean square error (MSE) reaching 9.0643 × 10-7, mean absolute error (MAE) reaching 8.7439 × 10-4, and goodness of fit (R2) approaching 1. It can be implemented as a new diagnostic method in transformer fault detection, which is of great significance to ensure the stable and safe operation of power systems.


Amphetamine-Type-Stimulants (ATS) Use and Homosexuality-Related Enacted Stigma Are Associated With Depression Among Men Who Have Sex With Men (MSM) in Two Major Cities in Vietnam in 2014.
Men who have sex with men (MSM) are disproportionately affected by mental health concerns, including depression. Amphetamine-type-stimulants (ATS) use and homosexuality-related stigma and discrimination have been found associated with depression among MSM. To assess the prevalence of depression and its associations with ATS use and homosexuality-related stigma and discrimination among MSM in Vietnam. 622 MSM were conveniently recruited in Hanoi and Ho Chi Minh city, Vietnam, from September to December 2014. We collected information on demographic characteristics, ATS, alcohol and other drug use, sexual behaviors, homosexuality-related and discrimination stigma, and sexual sensation-seeking. Depression and suicidal thoughts were assessed by the Patient Health Questionnaire (PHQ-9). We assessed associations of depression with ATS use and homosexuality-related stigma and discrimination using logistic regression. Of 622 sampled MSM, 11.3% were classified as having major depression, 9.8% reported any suicidal thoughts in the last two weeks, 30.4% ever had used any ATS, 88.8% ever ad drank alcohol and 21.5% had ever used any other drugs. In multivariate analysis, depression was significantly associated with ATS use (Adjusted Odds Ratio [AOR: 2.20; (95% Confidence Interval (CI): 1.32-3.67], younger age of sexual debut with another man (AOR: 0.09; 95% CI: 0.02-0.50), and greater enacted homosexuality-related stigma (AOR: 1.97; 95% CI: 1.19-3.26). We found a moderate prevalence of depression among sampled MSM, which was associated with ATS use and enacted homosexuality-related stigma. We recommend integrating assessment and interventions regarding depression and methamphetamine use into gay-friendly, culturally adapted holistic HIV prevention for MSM in Vietnam.


Multiparametric comparison of chromogenic-based culture methods used to assess the microbiological quality of drinking water and the mFC method combined with a molecular confirmation procedure.
MI agar and Colilert(®), as well as mFC agar combined with an Escherichia coli-specific molecular assay (mFC + E. coli rtPCR), were compared in terms of their sensitivity, ease of use, time to result and affordability. The three methods yielded a positive E. coli signal for 11.5, 10.8, and 11.5% of the 968 well water samples tested, respectively. One hundred and thirty-six (136) samples gave blue colonies on mFC agar and required confirmation. E. coli-specific rtPCR showed false-positive results in 23.5% (32/136) of cases. In terms of ease of use, Colilert was the simplest method to use while the MI method provided ease of use comparable to all membrane filtration methods. However, the mFC + E. coli rtPCR assay required highly trained employees for confirmation purposes. In terms of affordability, and considering contamination rate of well water samples tested, the Colilert method and the mFC + E. coli rtPCR assay were at least five times more costly than the MI agar method. Overall, compared with the other two methods tested, the MI agar method offers the most advantages to assess drinking water quality.


Actual 3-year survival after laparoscopy-assisted gastrectomy for gastric cancer.
To analyze 3-year actual disease-free survival after laparoscopy-assisted gastrectomy for gastric cancer on the assumption that 3-year disease-free survival may represent 5-year overall survival. Retrospective analysis. Department of surgery of a university hospital. A total of 197 patients who underwent laparoscopy-assisted gastrectomy for gastric cancer from May 1998 to September 2007 and who were followed up for more than 3 years. Feasibility and long-term survival rate with survival analysis by the Kaplan-Meier method. Subtotal and total gastrectomies were performed in 178 and 19 patients, respectively. The scope of the lymph node dissections were D1 + beta (n = 152) and D2 (n = 45). There were 153, 28, 8, 6, 1, and 1 patients in stages Ia, Ib, II, IIIa, IIIb, and IV, respectively. The median follow-up was 45 months (range, 1-113 months), and there were 7 recurrences. Multivariate analysis of disease-specific survival showed that depth of invasion and lymph node metastasis influenced the prognosis independently. The actual 3-year disease-free survival rate for all patients was 96.9%. The 173 patients with early gastric cancer and 24 with advanced gastric cancer showed 98.8% and 79.1% actual 3-year disease-free survival rates, respectively. Laparoscopy-assisted gastrectomy is acceptable oncologically in early gastric cancer if 3-year disease-free survival represents 5-year overall survival. Laparoscopy-assisted gastrectomy may also play an important role in the treatment of advanced gastric cancer.


Pharmacology of ciliated protozoa--drug (in)sensitivity and experimental drug (ab)use.
Most data on the effects of drugs as inhibitors, modulators, or stimulators have been collected with higher eukaryotic, mainly mammalian cells. Although in cell biological experiments with lower eukaryotes, including ciliates, the same drugs have frequently been applied, many results remained questionable for several reasons. Most drugs had to be used in unusually high concentrations. Moreover, drug effects have rarely been verified at the biochemical or molecular level. Data steadily emerging from genomics of ciliates, mainly Paramecium tetraurelia and Tetrahymena thermophila, show that drug-binding sites have only occasionally been conserved during evolution. They may vary or be totally absent in ciliate orthologs or specifically in certain paralogs. We here try to evaluate data available so far on the pharmacology of ciliates. In the future, domain analysis and drug screenings may detect compounds specifically effective in specific ciliated protozoa, including pathogenic forms, and, thus, yield an important basis not only for cell biology but also for ecotoxicology.


Pericardiocentesis versus pericardiotomy for malignant pericardial effusion: a retrospective comparison.
Treatment of malignant pericardial effusion remains controversial, because no randomized controlled trials have been conducted to determine the best approach, and results of retrospective studies have been inconsistent. The objective of the present study was to compare pericardiocentesis and pericardiotomy with respect to efficacy for preventing recurrence, and to determine, for those two procedures, diagnostic yields, complication rates, and effects on survival. We also aimed to identify clinical and procedural factors that could predict effusion recurrence. We retrospectively assessed 61 patients who underwent a procedure for treatment of a malignant pericardial effusion at the Institut universitaire de cardiologie et de pneumologie de Québec between February 2004 and September 2013. Pericardiocentesis was performed in 42 patients, and pericardiotomy, in 19 patients. The effusion recurrence rate was significantly higher in patients treated with pericardiocentesis than with pericardiotomy (31.0% vs. 5.3%, p = 0.046). The diagnostic yield of the procedures was not significantly different (92.9% vs. 86.7%, p = 0.6). The overall rate of complications was similar in the two groups, as was the median overall survival (2.4 months vs. 2.6 months, p = 0.5). In univariate analyses, the procedure type was the only predictor of recurrence that approached statistical significance. Age, sex, type of cancer, presence of effusion at the time of cancer diagnosis, prior chest irradiation, tamponade upon presentation, and total volume of fluid removed did not influence the recurrence rate. Compared with pericardiocentesis, pericardiotomy had higher success rate in preventing recurrence of malignant pericardial effusion, with similar diagnostic yields, complication rates, and overall survival.


Evaluation of farm-level parameters derived from animal movements for use in risk-based surveillance programmes of cattle in Switzerland.
This study focused on the descriptive analysis of cattle movements and farm-level parameters derived from cattle movements, which are considered to be generically suitable for risk-based surveillance systems in Switzerland for diseases where animal movements constitute an important risk pathway. A framework was developed to select farms for surveillance based on a risk score summarizing 5 parameters. The proposed framework was validated using data from the bovine viral diarrhoea (BVD) surveillance programme in 2013. A cumulative score was calculated per farm, including the following parameters; the maximum monthly ingoing contact chain (in 2012), the average number of animals per incoming movement, use of mixed alpine pastures and the number of weeks in 2012 a farm had movements registered. The final score for the farm depended on the distribution of the parameters. Different cut offs; 50, 90, 95 and 99%, were explored. The final scores ranged between 0 and 5. Validation of the scores against results from the BVD surveillance programme 2013 gave promising results for setting the cut off for each of the five selected farm level criteria at the 50th percentile. Restricting testing to farms with a score ≥ 2 would have resulted in the same number of detected BVD positive farms as testing all farms, i.e., the outcome of the 2013 surveillance programme could have been reached with a smaller survey. The seasonality and time dependency of the activity of single farms in the networks requires a careful assessment of the actual time period included to determine farm level criteria. However, selecting farms in the sample for risk-based surveillance can be optimized with the proposed scoring system. The system was validated using data from the BVD eradication program. The proposed method is a promising framework for the selection of farms according to the risk of infection based on animal movements.


Modulation of microsomal benzo[a]pyrene metabolism by DNA.
Inclusion of calf thymus DNA during microsomal benzo[a]pyrene (BP) metabolism increases product formation by decreasing the accessibility of microsomal enzymes to inhibitory BP quinones. The relief of product inhibition of BP metabolism, the stimulation of the formation of BP 7,8-dihydrodiol-9,10-oxides (DE), and the corresponding DNA adducts were all dependent to varying extents on DNA concentration. The role of BP quinones was evidenced by effects of DNA on all aspects of quinone reactivity: (a) inhibition of microsomal reduction of quinones, (b) inhibition of quinone glucuronidation, (c) inhibition of quinone monooxygenation, (d) a substantial reduction of the inhibition of BP metabolism and diol epoxide (DE) formation by added BP 6,12-quinone, and (e) a stimulation of BP metabolism even though quinine levels were also increased. DNA inhibited the reduction of 1,6- and 3,6-quinone to a similar degree under both oxygen-depleted and aerobic conditions. Other effects of DNA were very selective; glucuronidation of added 1,6- and 6,12-quinone was inhibited less than glucuronidation of 3,6-quinone (35% and 50% versus over 80%). However, monooxygenation of 3,6-quinone was not inhibited, whereas monooxygenation of 1,6-quinone was reduced by 60-70%. There was no measurable monooxygenation of 6,12-quinone. This specificity may indicate that DNA exerts its effect not simply by sequestering BP quinones. The interaction with DNA produced a distinct 25-nm red shift in the visible spectra of 1,6- and 3,6-quinone, while the change in the 6,12-quinone spectrum was less pronounced. RNA induced a similar red shift in the 1,6-quinone spectrum. Spectral measurements indicated binding of one molecule of 1,6-quinone per 50 DNA base pairs, while binding to RNA was 10-fold less extensive. The binding of 1,6-quinone to DNA was decreased by Mg2+, suggesting that 1,6-quinone binds by intercalation. DNA perturbs BP metabolism in a second way by increasing the ratio of 9-phenol to 9,10-dihydrodiol 4-fold. This is probably due to a DNA-catalyzed rearrangement of 9,10-oxide to 9-phenol. This effect contributes substantially to the greater sensitivity of the formation of 9-phenol 4,5-oxide-DNA adducts to the DNA concentration. It is evident from these data that, in addition to binding carcinogens covalently, DNA can affect the kinetics and product distribution of carcinogen metabolism. The high capacity of DNA to sequester BP quinones from cellular membranes is likely to be associated with additional DNA damage which may contribute to carcinogenesis.