Algorithmic improvements to species delimitation and phylogeny estimation under the multispecies coalescent.
The focus of this article is a Bayesian method for inferring both species delimitations and species trees under the multispecies coalescent model using molecular sequences from multiple loci. The species delimitation requires no a priori assignment of individuals to species, and no guide tree. The method is implemented in a package called STACEY for BEAST2, and is a extension of the author's DISSECT package. Here we demonstrate considerable efficiency improvements by using three new operators for sampling from the posterior using the Markov chain Monte Carlo algorithm, and by using a model for the population size parameters along the branches of the species tree which allows these parameters to be integrated out. The correctness of the moves is demonstrated by tests of the implementation. The practice of using a pipeline approach to species delimitation under the multispecies coalescent, has been shown to have major problems on simulated data (Olave et al. in Syst Biol 63:263-271. doi: 10.1093/sysbio/syt106 , 2014). The same simulated data set is used to demonstrate the accuracy and improved convergence of the present method. We also compare performance with *BEAST for a fixed delimitation analysis on a large data set, and again show improved convergence.


Treatment of chronic duodenal ulceration. Effectiveness of colloidal bismuth subcitrate tablets compared with cimetidine.
Fifty-eight patients with chronic duodenal ulceration proven at endoscopy consented to enter a trial comparing the effect of colloidal bismuth subcitrate (CBS)tablets with that of cimetidine. Fifty-four patients completed the six-week trial. An endoscopic assessment of healing was made at four weeks. If healing had not occurred, the trial was continued for another two weeks and the endoscopy was repeated. At four weeks, healing at endoscopy was demonstrated in 82% of patients receiving CBS and in 58% of those receiving cimetidine. At six weeks, the healing rates were 93% and 81%, respectively. No side effects were noted in either group. Continued smoking was not found to have an adverse effect on the healing rate of ulcers in either treatment group.


Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin.
Most patients with multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps. Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood were measured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay. Smoking and diabetes were more prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in a multivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps. These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps.


ON THE EFFECT OF FOUNDER EVENTS ON EPISTATIC GENETIC VARIANCE.
Mayr (1963) proposed that small isolated propagules from a large panmictic population would occasionally undergo a genetic revolution due to loss of genetic variability. More recently Templeton (1980a) has suggested that founder events may be much more important in systems that have strong epistasis. Because of the work of these and other authors it becomes an interesting theoretical problem to study the distribution of epistatic variance in a population following a founder event. In the model presented here measures of coancestry (Cockerham, 1967, 1984; Cockerham and Weir, 1973; Weir and Cockerham, 1973, 1977; Tachida and Cockerham, unpubl.) are used to examine the effect of founder events on additive-by-additive epistasis. Using this approach, the coancestries, or intraclass correlations, within individuals and within demes, together with the genetic variance components in the ancestral population are used to obtain the variance within and among demes following a founder event. Examples are analyzed for single founder events of 1-25 individuals and multiple founder events of two individuals. Following a single founder event, the contribution of the additive variance to the variance within demes relative to the additive variance in the ancestral population is always less than one. However, the contribution of epistatic variance to the variance within demes relative to the epistatic variance in the ancestral population is always greater than one. Thus, while a founder event decreases the contribution of additive variance to the variance within demes, it increases the contribution of epistatic variance to the variance within demes. The contribution of epistatic variance to the variance among demes following a single founder event is not qualitatively different from the contribution of additive variance to the variance among demes. These results indicate that epistatic variance is less likely than additive variance to cause a genetic revolution following a single founder event. When populations undergo multiple founder events the situation changes considerably. Epistatic variance may contribute as much as four times its original value to the variance among demes, while additive variance can contribute maximally twice its original value to the variance among demes. Thus, epistasis, which is relatively unimportant following a single founder event, may have major evolutionary implications if drift is allowed to continue for several generations.


Effect of Panax ginseng on age-related changes in the spontaneous motor activity and dopaminergic nervous system in the rat.
Effects of Panax ginseng on the spontaneous motor activity and central dopaminergic systems in old rats were investigated and compared with those in young rats. Oral intake of a 1.8% water extract of Panax ginseng for four weeks produced an increase in spontaneous motor activity during the dark period in old rats, while it caused a decrease in the activity in young rats. After the intake of ginseng extract for five weeks, it caused a significantly low dopamine utilization in the daytime in the striatum of old rats, while it produced a high dopamine utilization in the structure of young rats. Concentrations of striatal dopamine D-2 receptors in old rats were significantly lower than that in young rats, although subchronic Panax ginseng did not affect the striatal D-1 and D-2 receptors of old rats. These results suggest that subchronic intake of ginseng extract inhibits the activity of nigro-striatal dopamine neurons in the daytime and activates spontaneous motor activity during the dark period in old rats, while it produces opposite effects in young rats.


Ultrastructural localization of carbonic anhydrase in the chorioallantoic membrane by immunocytochemistry.
Carbonic anhydrase was localized in the chick embryo chorionic ectoderm at the ultrastructural level by immuno-cytochemistry. Preembedding staining of whole tissue was performed. The enzyme was present in the cytoplasm, on the membranes of apical vesicles, and on the membranes of microvilli in villus cavity cells, cells that may be involved in acid secretion and subsequent dissolution of the egg shell. In sinus covering cells, the enzyme is solely in the cytoplasm. The location of the enzyme in the thin cytoplasmic arms of the sinus covering cells is consistent with the role in nonrespiratory CO2 release.


Influence of manual thrombus aspiration on left ventricular diastolic function in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention.
Data on effects of thrombus aspiration on left ventricular diastolic function in ST-elevation myocardial infarction (STEMI) population are scarce. We sought to compare echocardiographic indices of the diastolic function and outcomes in STEMI patients treated with and without manual thrombus aspiration, in an academic, high-volume percutaneous coronary intervention (PCI) center. A total of 433 consecutive patients who underwent primary PCI in 2011-2012 were enrolled in the study. Patients were not eligible for the study if they already suffered a myocardial infarction, had been previously revascularized, received thrombolytics, presented with cardiogenic shock, had significant valvular disease, atrial fibrillation or had previously implanted pacemaker. Comprehensive echocardiogram was performed within 48 hours. During follow-up patients'status was assessed by an office visit or telephone interview. Patients treated with thrombus aspiration (TA+, n=216) had similar baseline characteristics as those without thrombus aspiration (TA-, n = 217). Groups had similar total ischemic time (319 ± 276 vs. 333 ± 372 min; p = 0.665), but TA+ group had higher maximum values of troponin I (39.5 ± 30.5 vs. 27.6 ± 26.9 ng/ml; p < 0.001). The echocardiography revealed similar left ventricular volumes and systolic function, but TA+ group had significantly higher incidence of E/e' > 15, as a marker of severe diastolic dysfunction' (TA+ 23.1% vs. TA- 15.2%; p = 0.050). During average follow-up of 14 ± 5 months, major adverse cardiac/cerebral events occurred at the similar rate (log rank p = 0.867). Thrombus aspiration is associated with a greater incidence of severe diastolic dysfunction in unselected STEMI patients treated with primary PCI, but it doesn't influence the incidence of major adverse cardiovascular events.


Cervical shock: a complication of incomplete abortion.
A case of a 37-year-old female primagravida who attended the emergency department (ED) via ambulance in hypotensive shock. She was 10 weeks pregnant, but had an inevitable miscarriage confirmed in the local Early Pregnancy Unit 3 weeks previously. She was hypotension (90/60 mm Hg), bradycardic (45 bpm) and was peripherally shut down. A provisional diagnosis of haemorrhagic shock was made, but despite intravenous fluid challenges, she appeared to be deteriorating, so a major haemorrhage protocol was activated. On examination, there was some vaginal bleeding and a protruding sac noted. The gynaecology registrar was informed and performed an Evacuation of the Retained Products of Conception in the ED. This gave instant relief to the patient and her blood pressure and heart rate became normal over a few minutes. She went on to make a full recovery. This case provides useful learning points for doctors working in the ED and other urgent care settings.


Effect of 2-week postpartum check-ups on screening positive for postpartum depression: a population-based cohort study using instrumental variable estimation in Japan.
Postpartum depression is experienced by approximately 10% of women and affects the health and development of their children. Although it is recommended that all mothers have the opportunity for early detection and intervention for postpartum depression, it is unclear whether early postpartum check-ups help to reduce postpartum depression. The aim of this study was to assess the effect of 2-week postpartum check-ups on screening positive for postpartum depression in Japan. This was a population-based cohort study that used the administrative database of Tsuyama, Japan. Participants were women who received postpartum home visits from a public health nurse in Tsuyama during the fiscal years 2017-2019. Data were obtained on participant's attendance at a 2-week postpartum check-up and their responses on the Edinburgh Postpartum Depression Scale. Owing to the initiation of a publicly funded postpartum check-up programme, participants were pseudo-randomly assigned to receive/not receive a 2-week postpartum check-up. We conducted instrumental variable estimation to assess the causal effects of the check-up on screening positive for postpartum depression. The characteristics of the 1,382 participants did not differ by fiscal year of childbirth. We found a 6.7% (95% confidence interval 2.2-11.2) reduction in the prevalence of screening positive for postpartum depression as an effect of 2-week postpartum check-ups among women received 1-month postpartum home visits. The results suggest that 2-week postpartum check-ups are effective in reducing the prevalence of screening positive for postpartum depression among 1-month postpartum women. Despite some limitations, early postpartum care could reduce postpartum depression.


Analytical results for a minimalist thermal diode.
We consider a system consisting of two interacting classical particles, each one subject to an on-site potential and to a Langevin thermal bath. We analytically calculate the heat current that can be established through the system when the bath temperatures are different, for weak nonlinear forces. We explore the conditions under which the diode effect emerges when inverting the temperature difference. Despite the simplicity of this two-particle diode, an intricate dependence on the system parameters is put in evidence. Moreover, behaviors reported for long chains of particles can be extracted, for instance, the dependence of the flux with the interfacial stiffness and type of forces present, as well as the dependencies on the temperature required for rectification. These analytical results can be a tool to foresee the distinct role that diverse types of nonlinearity and asymmetry play in thermal conduction and rectification.


The differential diagnosis of routinely processed anaplastic tumors using monoclonal antibodies.
The value of immunohistological labeling with a panel of monoclonal antibodies in the diagnosis of routinely processed surgical biopsies has been assessed. The cases examined consisted of an unselected series of tumor biopsies referred during a 12-month period because of doubt as to the nature of the neoplasm and are representative of the type of diagnostic problem regularly encountered in routine surgical pathology. In 30 of the 38 cases studied, reactivity with monoclonal antileukocyte antibody (and nonreactivity with monoclonal antiepithelial antibodies) indicated that the tumor was a lymphoma. Seven of the remaining eight cases gave the reverse reaction pattern and therefore were classified as carcinomas, while one biopsy was unreactive with all antibodies. Review of the clinical details in each case showed that the clinical management in several instances was influenced by establishing the correct diagnosis and it therefore is suggested that immunohistologic examination should be used more widely in the study of tumors that give rise to diagnostic difficulty.


The Calcium Sensor CBL-CIPK Is Involved in Plant's Response to Abiotic Stresses.
Abiotic stress halts the physiological and developmental process of plant. During stress condition, CBL-CIPK complex is identified as a primary element of calcium sensor to perceive environmental signals. Recent studies established that this complex regulates downstream targets like ion channels and transporters in adverse stages conditions. Crosstalks between the CBL-CIPK complex and different abiotic stresses can extend our research area, which can improve and increase the production of genetically modified crops in response to abiotic stresses. How this complex links with environmental signals and creates adjustable circumstances under unfavorable conditions is now one of the burning issues. Diverse studies are already underway to delineate this signalling mechanism underlying different interactions. Therefore, up to date experimental results should be concisely published, thus paving the way for further research. The present review will concisely recapitulate the recent and ongoing research progress of positive ions (Mg(2+), Na(+), and K(+)), negative ions (NO3 (-), PO4 (-)), and hormonal signalling, which are evolving from accumulating results of analyses of CBL and CIPK loss- or gain-of-function experiments in different species along with some progress and perspectives of our works. In a word, this review will give one step forward direction for more functional studies in this area.


Monistic dualism and the body electric: An ontology of disease, patient and clinician for person-centred healthcare.
Ontology is involved in medical care, because what both doctors and patients think the disease, the patient and the doctor are affects the giving and receiving of care, and hence the definition of medical care as profession. Going back to ancient philosophical views of disease as 'bounded entity' or as 'relation' (still echoed in contemporary theories and mindsets), I propose a way to think ontologically about disease that places it in necessary connection with the patient as person. Drawing on Augustine's views on disease, bodily integrity, and the human person as mind-body unit, I speak of 'monistic dualism' as the view where the unit and health of the person is continuously and personally generated by the mind's attention to and action on the body, whether the body is impaired or not. Monistic dualism is identified as the ontological position of both patients who are (or can become) healthy within illness and clinicians who are 'healthy' in their profession. It is what guides both to create what their body is in a personal state of integrity or health. This 'metaphysical body' is termed 'the body electric' in patients, and I argue that clinicians can attend properly to the diseased body by attending to patients' metaphysical body. As clinicians offer metaphysical care to themselves, employing monistic dualism to create their metaphysical body, they should not deny it to patients. Ontology cannot be part of medical care without making metaphysical care a requirement.


Mercuric resistance genes in gram-positive oral bacteria.
Mercury-resistant bacteria isolated from the oral cavities of children carried one of two types of merA gene that appear to have evolved from a common ancestor. Streptococcus oralis, Streptococcus mitis and a few other species had merA genes that were very similar to merA of Bacillus cereus strain RC607. Unlike the B. cereus RC607 merA gene, however, the streptococcal merA genes were not carried on Tn5084-like transposons. Instead, comparisons with microbial genomic sequences suggest the merA gene is located on a novel type II transposon. Coagulase-negative staphylococci and Streptococcus parasanguis had identical merA genes that represent a new merA variant.


Efficacy and Safety of Treatment With Ferric Carboxymaltose in Patients With Cirrhosis and Gastrointestinal Bleeding.
Background: Patients with liver cirrhosis and gastrointestinal bleeding (GIB) often develop anemia. Ferric carboxymaltose (FCM) is an intravenous (i.v.) iron formulation approved for use in patients with iron deficiency with inadequate response to oral iron therapy or when oral iron cannot be used. Here we analyzed the efficacy and safety of FCM treatment in cirrhotic patients with anemia and GIB. Methods: Retrospective observational study of patients with cirrhosis and acute or chronic GIB treated with 1,000 mg FCM at the University Hospital Arnau de Vilanova (Lleida, Spain) that follows a restrictive-transfusion strategy. All data were obtained from the patients' medical records. We used the Wilcoxon test to evaluate statistical significance. Results: Patients with cirrhosis and GIB (n = 34) were treated with 1,000 mg FCM. Portal hypertension were present in 88.2% of the patients. For hospitalized patients (n = 21), median serum hemoglobin (s-Hb) levels increased by 3.0 g/dL (p < 0.02) and 3.9 g/dL (p < 0.07) for patients treated with FCM who had or had not received also a transfusion, respectively, compared to levels recorded upon admission. For outpatients (n = 13) the mean s-Hb levels was 9.8 ± 1.6 g/dL before FCM treatment and 11.3 ± 2.1 g/dL after treatment, demonstrating a mean increase of 1.5 g/dL (p < 0.001). No serious adverse reactions to FCM were observed. Conclusion: FCM administration achieved optimal s-Hb levels in most cirrhotic patients with acute or chronic GIB, suggesting that early FCM infusion improves and maintains optimal s-Hb levels in these patients and may be an appropriate first-line therapy to treat their anemia.


Triplet-state photoexcitation dipole-jump relaxation method to observe adsorption/desorption kinetics at a reversed-phase silica/solution interface.
Electronic excitation of a probe chromophore can lead to a change in dipole moment that influences its activity or solubility in solution and changes its relative affinity for partitioning between two phases. Photoexcitation of a probe molecule can, therefore, perturb a sorption equilibrium, and the relaxation kinetics of the probe to the new equilibrium conditions can be monitored in a time-resolved luminescence experiment. The adsorption/desorption kinetics of rose bengal, distributed between a C-18 derivatized porous-silica surface and a liquid mobile-phase solution, were investigated. These kinetics were determined by observing their effect on the phosphorescence decay of the triplet state of rose bengal and its quenching by ferricyanide. The methanol/water solvent compositions were varied to alter the fraction of adsorbed rose bengal. The adsorption rate constant for the triplet state was determined from the dependence of the phosphorescence relaxation rate on dye concentration in solution. The results indicate that the adsorption kinetics are diffusion controlled and that the relaxation is influenced by efficient triplet-energy transfer between excited- and ground-state rose bengal at the C-18 silica/solution interface.


Prediction of major clinical response (ACR50) to infliximab in psoriatic arthritis refractory to methotrexate.
To determine the predictive factors of clinical response to infliximab in patients with refractory psoriatic polyarthritis. A multicentre open study which included 69 patients with psoriatic polyarthritis refractory to methotrexate (15 mg/week at least for 8 weeks). Patients were treated with infliximab 5 mg/kg every 8 weeks in addition to their stable doses of methotrexate. A major clinical response was defined by the ACR50 at week 38. Logistic regression analysis was performed to analyse which of the following measures at the start of treatment were associated with an ACR50 response: demographic and clinical characteristics, duration of disease, tender and swollen joint counts, involvement of large joints (knee or hip, or both), erythrocyte sedimentation rate, C reactive protein (CRP), Health Assessment Questionnaire disability index, axial involvement, and the presence of erosions at baseline. In an intention to treat analysis 30/69 (44%) patients achieved an ACR50 response. In the univariate analysis both the presence of large joint involvement and severe disability were associated with a poor clinical response. In a multivariate logistic regression analysis high CRP values were independently associated with a good therapeutic response (odds ratio (OR)=18.7; 95% confidence interval (CI) 1.8 to 181.6; p=0.011). In contrast, large joint involvement and severe disability were associated with a poor response, which reached significance for large joint involvement (OR=29.3; 95% CI 3.2 to 266.3; p=0.003). A lower disability and, in particular, the absence of large joint involvement and higher CRP serum levels at the start of infliximab treatment are factors that seem to influence the probability of achieving a good therapeutic response in patients with psoriatic arthritis.


Polymer Dielectrics with Outstanding Dielectric Characteristics via Passivation with Oxygen Atoms through C-F Vacancy Carbonylation.
The development of advanced electrical equipment necessitates polymer dielectrics with a higher electric strength. Unfortunately, this bottleneck problem has yet to be solved because current material modification methods do not allow direct control of deep traps. Here, we propose a method for directly passivating deep traps. Measurements of nanoscale microregion charge characteristics and trap parameters reveal a significant reduction in the number of deep traps. The resulting polymer dielectric has an impressively high electrical strength, less surface charge accumulation, and a significantly increased flashover voltage and breakdown strength. In addition, the energy storage density is increased without sacrificing the charge-discharge efficiency. This reveals a new approach to increasing the energy storage density by reducing the trap energy levels at the electrode-dielectric interface. We further calculated and analyzed the microscopic physical mechanism of deep trap passivation based on density functional theory and characterized the contributions of orbital composition and orbital hybridization.


Nicotinic acetylcholine receptors induce c-Kit ligand/Stem Cell Factor and promote stemness in an ARRB1/ β-arrestin-1 dependent manner in NSCLC.
Lung cancer remains the leading cause of cancer-related deaths worldwide. β-arrestin-1 (ARRB1), a scaffolding protein involved in the desensitization of signals arising from activated G-protein-coupled receptors (GPCRs), has been shown to play a role in invasion and proliferation of cancer cells, including nicotine-induced proliferation of human non-small cell lung cancers (NSCLCs). In this study, we identified genes that are differentially regulated by nicotine in an ARRB1/β-arrestin-1 dependent manner in NSCLC cells by microarray analysis. Among the identified genes, SCF (Stem cell factor) strongly differentiated smokers from non-smokers in the Director's Challenge Set expression data and its high expression correlated with poor prognosis. SCF, a major cytokine is the ligand for the c-Kit proto-oncogene and was found to be over expressed in human lung adenocarcinomas, but not squamous cell carcinomas. Data presented here show that transcription factor E2F1 can induce SCF expression at the transcriptional level and depletion of E2F1 or ARRB1/β-arrestin-1 could not promote self-renewal of SP cells. These studies suggest that nicotine might be promoting NSCLC growth and metastasis by inducing the secretion of SCF, and raise the possibility that targeting signalling cascades that activate E2F1 might be an effective way to combat NSCLC.


Contact pressure and tension in anterior cruciate ligament grafts subjected to roof impingement during passive extension.
Contact between an anterior cruciate ligament graft and the intercondylar roof has been termed roof impingement. Grafts with impingement sustain permanent damage, and if the injury is extensive enough, then the graft may fail, causing recurrent instability. This study evaluated two mechanical factors that could be responsible for the graft injury associated with roof impingement: an increase in graft tension or elevated pressures between the graft and the roof, or both. An anterior cruciate ligament reconstruction was performed using an Achilles tendon graft in five fresh-frozen cadaveric knees. Using a six-degree-of-freedom load application system, the anterior displacement of the knee with the native anterior cruciate ligament was restored in the reconstructed knee at a flexion angle of 30 degrees and with an anterior force of 200 N applied. Pressure between the graft and intercondylar roof, graft tension, and flexion angle were measured during passive knee extension for three tibial tunnel placements (anterior, center, and posterior). Intercondylar roof impingement increased the contact pressure between the graft and the roof but had no significant effect on graft tension. Therefore, during passive knee extension, the contact pressure between the anterior cruciate ligament graft and the intercondylar roof is a more likely cause of graft damage than increased graft tension.


1H-NMR analysis of amino acid metabolism in aqueous humor of patients with cataract, according to diabetes status.
To investigate the differences in amino acid metabolism in aqueous humor of patients with cataract, according to diabetes status, using a 1H-nuclear magnetic resonance approach. Aqueous humor samples from patients with age-related cataract, with or without diabetes, were collected during cataract surgery. All samples underwent nuclear magnetic resonance spectra analysis to characterize their metabolic function. Potential metabolic pathways were analyzed via MetaboAnalyst 3.0. This study included eight aqueous humor samples from patients with cataract and diabetes and eight aqueous humor samples from age- and sex-matched patients with cataract alone. Four metabolites were found to significantly differ in the aqueous humor of patients with cataract and diabetes, relative to patients with cataract alone; these metabolites were glucose (higher in patients with diabetes), valine, lysine, and tyrosine (all lower in patients with diabetes). Aminoacyl-tRNA biosynthesis was presumed to be involved in the metabolic differences observed in patients with cataract, according to diabetes status. The amino acid metabolic profile in the aqueous humor differed among patients with cataract, according to diabetes status. Disturbance of amino acid metabolism in the aqueous humor may be related to cataract formation in patients with diabetes.


Complete trisomy 17p a relatively new syndrome.
A patient with a de novo duplication of 17p is described. A comparison with five other published cases indicates several features in common that seem characteristic of the syndrome. Primary features include, low birth weight, small size, severe mental and motor retardation, heart defect, failure to thrive and peculiar facial traits. The prominent facial features are, a tendency for round and flat mid face, small palpebral fissures, hypertelorism, microcephaly and low set prominent ears.


Accuracy of ultrasonography for the diagnosis of intussusception in infants in Vietnam.
Intussusception (IS) is the most common cause of acute bowel obstruction in infants and young children. Ultrasonography is being increasingly used as the primary investigation for the diagnosis of IS and to guide air or hydrostatic enema reduction. However the accuracy of ultrasonography outside tertiary care settings in developed countries has not been assessed, particularly in Asia where the incidence of IS based on sonographic diagnosis has been reported as the highest in the world. The aim of this study was to evaluate the accuracy of ultrasonography in the diagnosis of acute IS in infants less than 2 years of age in a paediatric hospital in Vietnam. A prospective study was conducted at the National Hospital for Paediatrics, Hanoi, Vietnam, over a 14-month period recruiting patients <2 years of age with IS. Abdominal ultrasonography was performed on each patient and the accuracy of the diagnosis was evaluated against the final diagnosis provided by air enema and/or surgery. A total of 640 infants <2 years of age presented with clinical symptoms and signs of IS. The diagnosis was confirmed in 533 patients via air enema or surgery. Abdominal ultrasonography was 97.5% (466/478) sensitive and 99% (106/107) specific in the detection of IS. Ultrasonography is an accurate, safe and valuable clinical tool in the diagnosis of IS. The use of ultrasonography as a primary investigation for patients with suspected IS prevents unnecessary radiological or surgical procedures being performed, and reduces radiation exposure while maintaining a high level of diagnostic accuracy. These results validate the use of ultrasonography for the diagnosis of IS in a developing country setting.


Replantation of 45 avulsed permanent teeth: a 1-year follow-up study.
Thirty-four patients with 45 avulsed and replanted permanent teeth were followed for 1 year. All teeth were soaked in tetracycline before replantation. In addition, enamel matrix derivative was used in teeth with dry storage times exceeding 30 min. Splinting was carried out with a non-rigid titanium splint and was limited to 7-10 days. Within that period, root canal treatment was begun in all teeth with a closed apex, whereas teeth with an open apex and ideal post-traumatic storage were not instrumented. All patients were given tetracycline systematically for 10 days. The survival rate of replanted avulsed permanent teeth was 95.6% at the 1-year follow-up. In 82.2%, root canal treatment was performed. Pulp survival was never observed, but three teeth had pulp canal obliteration. Normal periodontal healing was observed in 57.7% of teeth; 42.3% of teeth showed external root resorption (28.9% replacement resorption, 6.7% infection-related resorption, 6.7% surface resorption). The occurrence of replacement resorption correlated with the period of extraoral dry storage. Compared with other clinical studies on avulsed and replanted teeth, the present study reports a higher percentage of periodontal healing. The favorable treatment outcome may be associated with a strict protocol to enforce endodontic treatment, the use of topical and systemic tetracycline, and the relatively high number of ideally stored teeth following avulsion. In contrast, the present study has a follow-up period limited to 1 year.


Antioxidant defense and oxidative damage vary widely among high-altitude residents.
People living at high altitude experience unavoidable low oxygen levels (hypoxia). While acute hypoxia causes an increase in oxidative stress and damage despite higher antioxidant activity, the consequences of chronic hypoxia are poorly understood. The aim of the present study is to assess antioxidant activity and oxidative damage in high-altitude natives and upward migrants. Individuals from two indigenous high-altitude populations (Amhara, n = 39), (Sherpa, n = 34), one multigenerational high-altitude population (Oromo, n = 42), one upward migrant population (Nepali, n = 12), and two low-altitude reference populations (Amhara, n = 29; Oromo, n = 18) provided plasma for measurement of superoxide dismutase (SOD) activity as a marker of antioxidant capacity, and urine for measurement of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of DNA oxidative damage. High-altitude Amhara and Sherpa had the highest SOD activity, while highland Oromo and Nepalis had the lowest among high-altitude populations. High-altitude Amhara had the lowest DNA damage, Sherpa intermediate levels, and high-altitude Oromo had the highest. High-altitude residence alone does not associate with high antioxidant defenses; residence length appears to be influential. The single-generation upward migrant sample had the lowest defense and nearly the highest DNA damage. The two high-altitude resident samples with millennia of residence had higher defenses than the two with multiple or single generations of residence.


Directed evolution for soluble and active periplasmic expression of bovine enterokinase in Escherichia coli.
Bovine enterokinase light chain (EKL) is an industrially useful protease for accurate removal of affinity-purification tags from high-value biopharmaceuticals. However, recombinant expression in Escherichia coli produces insoluble inclusion bodies, requiring solubilisation, refolding, and autocatalytic activation to recover functional enzyme. Error-prone PCR and DNA shuffling of the EKL gene, T7 promoter, lac operon, ribosome binding site, and pelB leader sequence, yielded 321 unique variants after screening ~ 6500 colonies. The best variants had > 11,000-fold increased total activity in lysates, producing soluble enzyme that no longer needed refolding. Further characterisation identified the factors that improved total activity from an inactive and insoluble starting point. Stability was a major factor, whereby melting temperatures > 48.4 °C enabled good expression at 37 °C. Variants generally did not alter catalytic efficiency as measured by kcat/Km, which improved for only one variant. Codon optimisation improved the total activity in lysates produced at 37 °C. However, non-optimised codons and expression at 30 °C gave the highest activity through improved protein quality, with increased kcat and Tm values. The 321 variants were statistically analysed and mapped to protein structure. Mutations detrimental to total activity and stability clustered around the active site. By contrast, variants with increased total activity tended to combine stabilising mutations that did not disrupt the active site.


A syn-Selective Aza-Aldol Reaction of Boron Aza-Enolates Generated from N-Sulfonyl-1,2,3-Triazoles and 9-BBN-H.
A syn-selective aza-aldol reaction of boron aza-enolates, generated from N-sulfonyl-1,2,3-triazoles and 9-BBN-H, is reported. It provides a sequential one-pot procedure for the stereoselective construction of 1,3-amino alcohols, having contiguous stereocenters, starting from terminal alkynes.


Cardiopulmonary dysfunction during porcine endotoxin shock is effectively counteracted by the endothelin receptor antagonist bosentan.
In a porcine endotoxin shock model, the mixed nonpeptide endothelin receptor antagonist bosentan was administered 2 h after onset of endotoxemia (n = 8). Cardiopulmonary vascular changes, oxygen-related variables, and plasma levels of endothelin-1-like immunoreactivity were compared with a control group that received only endotoxin (n = 8). Bosentan abolished the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance seen in controls. Possible mechanisms include blockade of vasoconstrictive endothelin receptors, and a lesser degree of edema and inflammation indicated by less alveolar protein and a lower inflammatory cell count observed in bronchoalveolar lavage. Further, bosentan restored cardiac index to the pre-endotoxin level by an increase in stroke volume index, improved systemic oxygen delivery, and acid base balance. Because mean arterial blood pressure was unaffected, bosentan reduced systemic vascular resistance. Endotoxemia resulted in an increase in tumor necrosis factor-alpha and endothelin-1-like immunoreactivity plasma levels, the latter being further increased by bosentan. In conclusion, in porcine endotoxemia, treatment with the endothelin receptor antagonist bosentan, administered during fulminate shock, abolished pulmonary hypertension and restored cardiac index. These findings suggest that bosentan could be an effective treatment for reversing a deteriorated cardiopulmonary state during septic shock.


Understanding the Challenges of Improving Sanitation and Hygiene Outcomes in a Community Based Intervention: A Cross-Sectional Study in Rural Tanzania.
Good sanitation and clean water are basic human rights yet they remain elusive to many rural communities in Sub-Saharan Africa (SSA). We carried out a cross sectional study to examine the impact of a four-year intervention aimed at improving access to water and sanitation and reducing waterborne disease, especially diarrhea in children under five years old. The study was carried out in April and May 2015 in Busangi, Chela and Ntobo wards of Kahama District of Tanzania. The interventions included education campaigns and improved water supply, and sanitation. The percentage of households (HHs) with access to water within 30 min increased from 19.2 to 48.9 and 17.6 to 27.3 in the wet and dry seasons, respectively. The percentage of HHs with hand washing facilities at the latrine increased from 0% to 13.2%. However, the incidence of diarrhea among children under five years increased over the intervention period, RR 2.91 95% CI 2.71-3.11, p < 0.0001. Availability of water alone may not influence the incidence of waterborne diseases. Factors such as water storage and usage, safe excreta disposal and other hygiene practices are critical for interventions negating the spread of water borne diseases. A model that articulates the extent to which these factors are helpful for such interventions should be explored.


[Comparison between the terminal motor pudendal nerve terminal motor latency, the localization of the perineal neuralgia and the result of infiltrations. Analysis of 53 patients].
The aim is to study the value of the pudendal nerve terminal motor latency (PNTML) testing, in respect to the painful side in patients with pudenda neuralgia, and to determine whether a possible increased latency in the painful side is predictive of a good result with the infiltration. This retrospective study included 53 outpatients (42 women, mean age 62) with suffering from pudendal neuralgia, who were seen between 2000 and 2004. The mean duration of the pain was 30+/-47 months. The PNTMPNL was measured by the Saint-Mark hospital technique, by the same operator. The following criteria have been were defined: significant increased latency greater than above 6 ms, significant difference of 2 ms in latency between 2 sides from 2 ms, and side of the infiltration corresponding to the side of the neuralgia. The infiltrations were performed either by perineal (30 cases) or transgluteal (8 cases) way. The results on pain were have been considered as good when a substantial reduction of the pain was observed for 6 months or more. Statistical analysis involved was done by the exact Fischer's test to seek for a possible relation between variables. Of 53 patients (42 women, 11 men, mean age 62) suffered from a with perineal neuralgia. The duration of the neuralgia was 30+/-47 months. It was bilateral in 10 cases and unilateral in 43 cases. In 43 patients with When the pain was unilateral pain, PNTML we find that the MDLPN was increased in both sides in 39.5% of the population, in the painful side in 14% and in the side opposite side of the to pain in 11%. In 10 patients with the neuralgia was bilateral pain, in 10 patients. Among then, 4 had a bilateral increase of the latency, one patient had an increase only on the right side, and another one an increase only on the left side. We did not find any correlation between the increased of the PNTML TMPNL and, either neither the duration of the neuralgia nor the result of the infiltrations, whatever the method way of the infiltration. The PNTML can be increased whether it corresponds or not to an entrapment of the pudendal nerve. Thus, the management of perineal pain is based mainly, from us, on clinical findings.


The theory-practice relationship in nursing: an exploration of contemporary discourse.
The nature of nursing practice, the nature and origins of nursing theory and the issue of the relationship between theory and practice are matters which have and continue to generate extensive philosophical discourse within nursing. Despite the abundance of literature on these matters, to date there have been few attempts to bring together, to summarise and to characterise the various ways in which the theory-practice relationship is understood within nursing. This paper offers a description of the principal ways in which the theory-practice relationship is commonly understood within contemporary philosophical discourse. An exploration of contemporary, scholarly discourse within the nursing literature, using Carr's typology of theories of theory and practice, as a framework for analysis, points to evidence that the theory-practice relationship is understood in a number of different ways. Foremost among these is the tendency to think of nursing as an applied-science and there is a tendency to think of theory and practice as separate endeavours. The content of the discourse also points to a tendency to view the relationship as one in which the basis for practice lies in the collective 'common-sense' understandings of practitioners engaged in practice. The relationship is also understood in terms of nursing being an 'ethical' activity in which practical wisdom, deliberation, judgements and choices are required for the conduct of practice. There is, in more recent discourse, evidence of views which attempt to contextualise nursing within its social reality and thus to conceive of the theory-practice relationship in ways congruent with the recognition that nursing practice is a human and a social enterprise that is inherently 'problematic'. These contemporary conceptualizations of the theory-practice relationship would appear to have evolved through a process in which each new conception has been accommodated with and assimilated into the already existing understandings. Ways of viewing the theory-practice relationship are expressed either explicitly or, in many instances, are implicit in and recoverable from expressions of views, beliefs and assumptions. It would appear that the current state of thinking with respect to the theory-practice relationship is one of eclecticism and pluralism and there is a general openness to the contribution of different paradigms of knowing to epistemological development.


Use of trochanteric nail for proximal femoral extracapsular fractures.
Proximal femoral extracapsular fractures have shown a significantly high morbidity and mortality rate at 1 year in cases of nonoperative treatment. The standard gamma nail was originally designed to provide stable fixation and allow early mobilization and weight bearing for elderly patients. The design of the standard gamma nail, however, appears to be associated with intraoperative or postoperative femoral shaft fractures in < or = 17% of patients, compromising the outcome. The trochanteric nail was developed to overcome the problems encountered with the use of the standard gamma nail. Between July 2000 and January 2001, 88 consecutive proximal femoral extracapsular fractures were treated with a trochanteric nail, Seventy-five patients (76 fractures) were observed clinically and radiographically for 2 years.


[Effects of different soil types on the foliar δ13C values of common local plant species in karst rocky desertification area in central Guizhou Province].
By measuring the foliar δ13C values of common local plant species grown in different soil types in Wangjiazhai catchments, a typical karst desertification area in Qingzhen City, Central Guizhou, we studied the impact of soil type and rocky desertification grade on the foliar δ13C values. The results showed that the foliar δ13C values were more negative in yellow soil area than those in black calcareous area and there was no obvious difference in foliar δ13C values between these two soil types. The distribution interval of foliar δ13C values in yellow soil area was narrower than those in black calcareous area and the variation coefficient of foliar δ13C values in yellow soil area were smaller than those in black calcareous area. With increasing degree of karst rocky desertification, the foliar δ13C values of plant community in black calcareous area increased, whereas those in yellow soil area first increased and then decreased. The result of multiple comparison showed that the difference in foliar δ13C values of plant community among rocky desertification grade was not obvious in yellow soil area, but it was obvious in black calcareous area. Correlation analysis between the foliar δ13C values of plant species and the main environmental factors indicated that slope and soil thickness were the main factors which affected the foliar δ13C values of plants in yellow soil area and soil water contant was the main factor in black calcareous area. The impact of soil on the foliar δ13C values was realized by adjusting the soil moisture in study area.


Searching for viral antibodies and genome in intraocular fluids of patients with Fuchs uveitis and non-infectious uveitis.
To characterise the polyspecific intraocular antibody synthesis in aqueous humor of patients with Fuchs uveitis and other types of non-infectious uveitis. Aqueous and serum samples collected from 24 patients with Fuchs uveitis, 21 patients with non-infectious uveitis, and 27 healthy subjects undergoing elective cataract surgery (control group) were analysed. In addition, vitreous samples, collected from seven uveitis patients (five Fuchs and two panuveitis) during retinal surgery, were examined. Specific immunoglobulin G antibodies against cytomegalovirus (CMV), rubella virus, herpes simplex virus (HSV), and varicella zoster virus (VZV) were investigated, and Goldmann-Witmer coefficients (GWCs) were calculated. Real-time PCR was performed to detect viral genome for HSV, VZV, and CMV, while nested PCR was conducted to detect rubella RNA. None of the control samples tested positive for any of the viral antibodies investigated. Intraocular antibody production was found in eight samples of patients affected by Fuchs uveitis (6/8 positive for rubella virus and 2/8 positive for herpes virus). Among patients with non-infectious uveitis, three tested positive for intraocular antibody production (one RV, one HSV and one for VZV). PCR was positive for RV in two patients with Fuchs uveitis, in three patients with non-infectious uveitis (one for RV and two for HSV), and in three control subjects (one for CMV and one for HSV). Our series confirmed the presence of specific viral antibodies, especially against rubella virus, in the subgroup of patients affected by Fuchs uveitis, suggesting that this virus may be responsible for this chronic inflammatory condition. Rubella virus is probably the main causative agent of Fuchs uveitis, but other viruses may also be involved in the pathogenesis of this disease.


Impact of prosthetic rehabilitation type on satisfaction of completely edentulous patients. A 5-year prospective study.
The aim of this study was to evaluate the satisfaction of rehabilitated edentulous patients in relation to implant prosthetic type. This prospective cohort study included 40 completely edentulous patients wearing conventional prostheses. They were divided into two study groups: Group A contained 20 patients rehabilitated with implant-supported fixed prostheses and Group B contained 20 patients with overdentures. Subjects were evaluated by means of a specially designed questionnaire before treatment and after 1, 3 and 5 years. Group A exhibited better results in terms of esthetics, function and personal satisfaction, although without statistically significant differences. However, statistically significant differences were found within parameters of oral hygiene after 1 year in favor of Group B. Overall satisfaction was seen to increase after implant rehabilitation, regardless of the type of prosthesis used. The satisfaction of edentulous patients differs depending on prosthetic type. Patients rehabilitated with fixed prostheses obtain a generally higher level of satisfaction than patients wearing overdentures.


Same but different: pleiotropy in centrosome-related microcephaly.
An intimate link between centrosome function and neurogenesis is revealed by the identification of many genes with centrosome-associated functions that are mutated in microcephaly disorders. Consistent with the major role of the centrosome in mitosis, mutations in these centrosome-related microcephaly (CRM) genes are thought to affect neurogenesis by depleting the pool of neural progenitor cells, primarily through apoptosis as a consequence of mitotic failure or premature differentiation as a consequence of cell cycle delay and randomization of spindle orientation. However, as suggested by the wide range of microcephaly phenotypes and the multifunctional nature of many CRM proteins, this picture of CRM gene function is incomplete. Here, we explore several examples of CRM genes pointing to additional functions that contribute to microcephaly, including regulation of cell cycle signaling, actin cytoskeleton, and Hippo pathway proteins, as well as functions in postmitotic neurons and glia. As these examples are likely just the tip of the iceberg, further exploration of the roles of microcephaly-related genes are certain to reveal additional unforeseen functions important for neurodevelopment.


Alcohol and congenital heart defects: an experimental study in mice.
Pregnant mice were exposed to a single dose of alcohol (0.03 ml of 25% alcohol X g-1 mouse) or two doses (2 X 0.015 ml of 25% alcohol X g-1 mouse) 4 h apart, by intraperitoneal injection or by gavage, on days 7, 8, 9 or 10 of gestation. The mice were killed on the day before term and the fetuses examined for heart defects. Alcohol exposure on day 8, 9 or 10 of gestation caused a high incidence of ventricular septal defects (60%, 75% and 15% respectively). Defects of both the membranous and muscular parts of the septum were seen as well as more complex ventricular septal defects involving the great vessels. Day 7 was resistant to the induction of heart defects. This study has demonstrated that a relatively short exposure to high doses of alcohol during pregnancy in mice can cause congenital heart defects. This has important implications both as a possible cause of congenital heart anomalies in humans and for the counselling of mothers of affected children.


Acylation of Aryl Halides and α-Bromo Acetates with Aldehydes Enabled by Nickel/TBADT Cocatalysis.
In this protocol aryl halides and α-bromo acetates are efficiently cross-coupled with an array of (hetero)aromatic and aliphatic aldehydes under the cooperative catalysis of nickel and tetrabutylammonium decatungstate as a hydrogen-atom-transfer photocatalyst. This method provides a concise approach to a variety of ketones with high compatibility of various functional groups.


Body Roundness Index and Waist-Hip Ratio Result in Better Cardiovascular Disease Risk Stratification: Results From a Large Chinese Cross-Sectional Study.
The appropriate optimal anthropometric indices and their thresholds within each BMI category for predicting those at a high risk of cardiovascular disease risk factors (CVDRFs) among the Chinese are still under dispute. We aimed to identify the best indicators of CVDRFs and the optimal threshold within each BMI category among the Chinese. Between 2012 and 2020, a total of 500,090 participants were surveyed in Hunan, China. Six anthropometric indices including waist circumference (WC), a body shape index (ABSI), body roundness index (BRI), waist-hip ratio (WHR), hip circumference (HC), and waist-height ratio (WHtR) were evaluated in the present study. Considered CVDRFs included dyslipidaemia, hypertension, diabetes mellitus (DM), and chronic kidney disease (CKD). The associations of anthropometrics with CVDRFs within each BMI category were evaluated through logistic regression models. The area under the receiver operating characteristic curve (AUROC) was used to assess the predictive abilities. For the presence of at least one CVDRFs, the WHR had the highest AUROC in overweight [0.641 (95%CI:0.638, 0.644)] and obese [0.616 (95%CI:0.609, 0.623)] men. BRI had the highest AUROC in underweight [0.649 (95%CI:0.629, 0.670)] and normal weight [0.686 (95%CI:0.683, 0.690)] men. However, the BRI had the highest discrimination ability among women in all the BMI categories, with AUROC ranging from 0.641 to 0.727. In most cases, the discriminatory ability of WHtR was similar to BRI and was easier to calculate; therefore, thresholds of BRI, WHR, and WHtR for CVDRFs identification were all calculated. In men, BRI thresholds of 1.8, 3.0, 3.9, and 5.0, WHtR thresholds of 0.41, 0.48, 0.53, and 0.58, and WHR thresholds of 0.81, 0.88, 0.92, and 0.95 were identified as optimal thresholds across underweight, normal weight, overweight, and obese populations, respectively. The corresponding BRI values in women were 1.9, 2.9, 4.0, and 5.2, respectively, and WHtR were 0.41, 0.48, 0.54, and 0.59, while the WHR values were 0.77, 0.83, 0.88, and 0.90. The recommended BRI, WHtR, or WHR cut-offs could not statistically differentiate high-risk CKD or hypercholesterolemia populations. We found that BRI and WHR were superior to other indices for predicting CVD risk factors, except CKD or hypercholesterolemia, among the Chinese.


Duties to the patient and beyond: where is the line drawn?
The decisions in two recent Australian cases, emphasize the tendency for the Courts to place weight on the reliance of patients and others, to act on the advice provided by practitioners. In doing so, the duty of the practitioner to his or her patient has been extended to include third parties such as the patient's sexual partner and the patient's parents. Additionally, the decisions have shown that practitioners need to maintain a level of knowledge in the provision of advice expected of a professional as patients rely heavily on the information provided by the practitioners. This may include information that is available on the Internet.


Guggulsterone sensitized drug-resistant human hepatocarcinoma cells to doxorubicin through a Cox-2/P-gp dependent pathway.
Previous researches indicated that cyclooxygenase-2 (Cox-2) might be involved in P-glycoprotein (P-gp)-mediated multidrug resistance in hepatocellular carcinoma cells. Doxorubicin-resistant hepatocellular carcinoma PLC/PRF/5 cells (PLC/PRF/5R) and HepG2 (HepG2R) cells were developed in the present study. The modulatory effect of guggulsterone on Cox-2 and P-gp in PLC/PRF/5R and HepG2R cells was investigated. Cells proliferation, Cox-2 and P-gp expression, and prostaglandin E2 release were examined using MTT, flow cytometry, western blot and ELISA assays. Small interfering RNA (siRNA) targeted against Cox-2 and multidrug resistance protein (Mdr-1) was used to regulate the expression of Cox-2 and P-gp. The results showed that co-administration of guggulsterone resulted in a significant increase in chemo-sensitivity of PLC/PRF/5R cells to doxorubicin, as compared with doxorubicin treatment alone. When doxorubicin (10µM) was combined with guggulsterone (50µM), the mean apoptotic population of PLC/PRF/5R cells was 20.16%. It was increased by 1.5 times, as compared with doxorubicin (10µM) treatment alone. Furthermore, guggulsterone had significantly inhibitory effect on the levels of Cox-2, P-gp and prostaglandin E2. However, guggulsterone did not show significantly inhibitory effect on the expression of prostaglandin E receptors. In addition, Cox-2 siRNA simultaneously reduced the expression of Cox-2 and P-gp in PLC/PRF/5R cells. Mdr-1 siRNA had no influence on Cox-2, but inhibited P-gp expression. The present study suggested that guggulsterone might enhance the cytotoxic effect of doxorubicin to PLC/PRF/5R cells through a Cox-2/P-gp dependent pathway.


Extracolonic manifestations of familial polyposis coli.
The original concept of familial polyposis coli (FPC) that it is only a genetically determined premalignant disease of the colon changed in the 1950s, with the description of Gardner's syndrome. The extracolonic manifestations of osteoma and epidermoid cyst since have been shown to be only a small part of the spectrum of both benign and malignant extracolonic manifestations of the disease. The modern concept of this condition is that FPC is a genetically determined generalized growth disorder that gives rise to tumors in various parts of the body.


Comparison of sampling procedures for recovery of Listeria monocytogenes from stainless steel food contact surfaces.
A number of techniques exist for microbiological sampling of food processing environments in food industries. In the present study the efficacies of nine sampling procedures for the recovery of Listeria monocytogenes from food contact surfaces, including a new sampling device consisting of a miniroller, were evaluated and compared. A stainless steel table was inoculated with L. monocytogenes strain 935 (serovar 4b, human origin) and L. monocytogenes strain 437/07 (serovar 1/2b, food origin), at 10(5) CFU/100 cm(2). L. monocytogenes strain 935 was best recovered with the minirollers (recovery of up to 6.27%), while poor recoveries (<0.30%) were obtained with the towel (one-ply composite tissue), alginate swab, metallic swab, and Petrifilm methods. In the case of L. monocytogenes strain 437/07 the replicate organism detection and counting (RODAC) ALOA contact plates yielded the best recoveries (4.15%), followed by the minirollers (up to 1.52%). Overall, recovery percentages with the minirollers were higher with stomacher homogenization than with Vibromatic agitation. The recovery percentages obtained for the Listeria strain of human origin were higher than those obtained with the food strain for all sampling procedures except Petrifilm and RODAC ALOA. With the miniroller device coated with wool fiber, the recovery of L. monocytogenes can be improved from 2 to 17 times over recoveries obtained with the sponge and cotton swab. This is the first report of a miniroller device for microbiological sampling in the available literature. The novel sampling procedure is convenient to apply on surfaces, is cost-effective, and results in better recovery of L. monocytogenes than do the conventional methods.


Response to tilted magnetic fields in Bi(2)Sr(2)CaCu(2)O(8) with columnar defects: evidence for transverse Meissner effect.
The transverse Meissner effect (TME) in the highly layered superconductor Bi(2)Sr(2)CaCu(2)O(8+y) with columnar defects is investigated by transport measurements. We present evidence for the persistence of the Bose glass phase for H(perpendicular)<H(perpendicular c): (i) the variable-range vortex hopping process crosses over to the half-loop regime; (ii) near H(perpendicular c) the energy barriers vanish linearly with H(perpendicular); (iii) the transition temperature is governed by T(BG)(H(parallel),0)-T(BG)(H(parallel),H(perpendicular)) approximately /H( perpendicular)/(1/nu(perpendicular)) with nu(perpendicular) = 1.0 +/- 0.1. Furthermore, above the transition as H(perpendicular)-->H(+)(perpendicular c), moving kink chains consistent with a commensurate-incommensurate transition scenario are observed. These results show the existence of the TME for H(perpendicular)<H(perpendicular c).


Pretransplant antibodies and renal allograft survival.
Fc receptor blocking antibodies directed against autologous lymphocytes were present in pretransplant sera from only one of a group of 24 cadaver donor renal transplant recipients. Such antibodies were present in recipient sera against B lymphocytes from the donor in 11/24, against normal B lymphocytes in 12/24 and against leukaemic B lymphocytes in 15/24 cases. There was a significant correlation between EA inhibiting antibodies directed against donor (p less than 0.01), normal (p less than 0.05) and leukaemic B lymphocytes (p less than 0.001) and improved one year allograft survival. No autolymphocytotoxic antibodies were detected. Fc receptor blocking antibodies detected by the Erythrocyte Antibody Inhibition assay may thus have a beneficial effect on graft outcome but do not appear to be autoantibodies.


The fatty acid pattern of dietary fat influences the oral bioavailability of the flavonol quercetin in pigs.
We have shown recently that dietary fat content influences the bioavailability of the flavonol quercetin. In the present study, the influence of the fatty acid pattern of dietary fats on the oral bioavailability of quercetin was investigated. Quercetin (30 micromol/kg body weight) was administered to growing pigs (n 6) in test meals consisting either of 200 g of a standard pig diet (2% crude fat) or of the same diet supplemented with 15 g fat/100 g diet using either medium-chain (MCT) or long-chain fatty acid triacylglycerols (LCT). Blood samples were drawn repeatedly over a period of 24 h and analysed by HPLC. In addition, the influence of the different diets on gastric emptying was investigated in rats. In pigs, the bioavailability of quercetin was measured by quantifying its plasma metabolites with an intact flavonol structure. Bioavailability was enhanced by 38% (P<0.05) and 12% (P>0.05) after intake with the MCT and LCT diets, respectively, compared to the standard diet. Maximum plasma concentrations of quercetin were reached significantly later with the MCT diet than with the LCT or the standard diet (P<0.05). No differences in dry matter of the gastric content were observed 60 min after intake of the experimental diets in rats. Thus, administration of quercetin together with a diet containing MCT fat enhances the bioavailability of the flavonol. Absorption of quercetin was delayed significantly with this diet. However, this was probably not due to slower gastric emptying of the MCT diet.


Electromagnetic interference on pacemakers.
External sources, either within or outside the hospital environment, may interfere with the appropriate function of pacemakers which are being implanted all around the world in current medical practice. The patient and the physician who is responsible for follow-up of the pacing systems may be confronted with some specific problems regarding the various types of electromagnetic interference (EMI). To avoid these unwanted EMI effects one must be aware of this potential problem and need to take some precautions. The effects of EMI on pacemaker function and precautions to overcome some specific problems were discussed in this review article. There are many sources of EMI interacting with pacemakers. Magnetic resonance imaging creates real problem and should be avoided in pacemaker patients. Cellular phones might be responsible for EMI when they were held on the same side with the pacemaker. Otherwise they don't cause any specific type of interaction with pacemakers. Sale security systems are not a problem if one walks through it without lingering in or near it. Patients having unipolar pacemaker systems are prone to develop EMI because of pectoral muscle artifacts during vigorous active physical exercise.


Single-centre experience of 85 patients with a continuous-flow left ventricular assist device: clinical practice and outcome after extended support.
We evaluated our single-centre clinical experience with the HeartMate II (HM II) left ventricular assist device (LVAD) as a bridge to transplantation (BTT) in end-stage heart failure (HF) patients. Survival rates, echocardiographic parameters, laboratory values and adverse events of 85 consecutive patients supported with a HM II were evaluated. Overall, mean age was 45 ± 13 years, 62 (73%) were male and non-ischaemic dilatated cardiomyopathy was present in 60 (71%) patients. The median duration of mechanical support was 387 days (IQR 150-600), with a range of 1-1835 days. The 6-month, 1-, 2-, 3- and 4-year survival rates during HM II LVAD support were 85, 81, 76, 76 and 68%, respectively. Echocardiographic parameters demonstrated effective left ventricular unloading, while laboratory results reflected adequate organ perfusion. However, HM II support was associated with adverse events, such as infections in 42 patients (49%; 0.67 events/patient-year), cardiac arrhythmia in 44 (52%; 0.86 events/patient-year), bleeding complications in 32 (38%; 0.43 events/patient-year) and neurological dysfunction in 17 (20%; 0.19 events/patient-year). In view of the increasing shortage of donor hearts, HM II LVAD support may be considered a life-saving treatment in end-stage HF patients, with good survival. However, it is still associated with some serious adverse events, of which neurological complications are the most critical.


[Medicinal vesiculation combined with quick cupping at Shenque (CV 8) for allergic rhinitis with syndrome of yang deficiency: a randomized controlled trial].
To compare the clinical efficacy differences between medicinal vesiculation combined with quick cupping at Shenque (CV 8) and regular medication for allergic rhinitis with syndrome of yang deficiency. Eighty-two cases were randomly divided into an observation group (42 cases) and a control group (40 cases). The observation group was treated with medicinal vesiculation combined with quick cupping at Shenque (CV 8). The medicinal vesiculation was applied at Feishu (BL 13), Gaohuang (BL 43), Fengmen (BL 12), Mingmen (GV 4) on the dog days in the summer, one treatment on the 1st dog-day, 2nd dog-day and last dog-day respectively with an interval of 10 days between two treatments. Three treatments were taken as one course, and totally one course was given. The quick cupping was applied at Shenque (CV 8), once a day, ten treatments were taken as one course, and totally three courses was given. The control group was treated with oral administration of loratadine and nasal spray of budesonide. The loratadine was given 10 mg per time, once a day for continuous 14 days; budesonide was given once a day, ten treatments were taken as one course, and totally three courses was given. The clinical efficacy in two groups after treatment was observed, and the contents of immune globulin E (IgE), interleukin-4 (IL-4), interleukin-5 (IL-5) and tumor necrosis factor-α (TNF-α) in peripheral serum were measured before and after the treatments. Of all the 82 patients, 79 cases completed the treatment, and 1 patient in the observation group and 2 patients in the control group dropped out. The effective rate was 87.8% (36/41) in the observation group, which was superior to 78.9% (30/38) in the control group (P<0.05). After treatment, both groups effectively reduced the contents of IgE, IL-4, IL-5 and TNF-α, and the observation group had superior effect on reducing IgE and IL-4 to the control group (P<0.05). The medicinal vesiculation combined with quick cupping at Shenque (CV 8) have better effect for allergic rhinitis with syndrome of yang deficiency than oral administration of loratadine and nasal spray of budesonide.


Hemophagocytic syndrome: a dilemma chasing the intensivists.
Hemophagocytic lymphohistiocytosis or hemophagocytic syndrome is represented by an uncontrolled inflammatory response characterized by marked histiocyte activation and a cytokine storm. The entity may present a primary or genetic type, and the secondary type is usually triggered by infectious diseases of any kind, autoimmune disease, or neoplasia. This entity, although well described and with definite diagnostic criteria, still remains misdiagnosed because of the overlap presentation with other inflammatory processes. The authors present the case of a 13-year-old girl who was submitted to an appendicectomy complicated with a pericolic abscess, which required a second operation in order to be drained surgically. During the postoperative period of this second surgical procedure, the patient remained febrile, developing cytopenias, and multiple organ failure. Unfortunately, she died despite the efforts of the intensive care staff. The autopsy findings were characteristic of hemophagocytic syndrome. The authors report the case to call attention to this diagnosis whenever unexpected outcomes of infections are experienced.


Effects of apocynin, an NADPH oxidase inhibitor, on levels of ADMA, MPO, iNOS and TLR4 induced by myocardial ischemia reperfusion.
In this study, the effects of apocynin, an NADPH oxidase inhibitor, on the levels of inducible nitric oxide synthase (iNOS) and the toll-like receptor 4 (TLR4), which are inflammatory mediators in myocardial ischemia-reperfusion (MIR) injury, and myeloperoxidase (MPO), which is the indicator of neutrophil infiltration and the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) increasing with oxidative stress were investigated. MIR injury was accomplished by the application of occlusion for 30 minutes and reperfusion for 120 minutes in the left anterior descending artery (LAD). In the study, 21 Sprague-Dawley male rats were divided into three groups: a sham group (n = 7); a MIR group (n = 7); and a MIR + apocynin treatment group (n = 7, before the procedure, an intraperitoneal administration of 10 mg/kg of apocynin for 15 days). After reperfusion, iNOS, TLR4, MPO and ADMA levels in myocardial tissue were measured by ELISA. While myocardial TLR4, MPO and ADMA levels increased in the MIR group, these parameters were found to be decreased significantly in the group treated with apocynin. Although iNOS levels showed an increase in the MIR group compared to the sham group and a reduction in the MIR+apocynin group, there was no statistically significant difference between the groups. In our study, the effect of the treatment of apocynin in MIR on ADMA, MPO, iNOS and TLR4 levels in myocardial tissue was shown for the first time. It is thought that apocynin treatment may show a protective effect in MIR injury by affecting oxidative stress (ADMA) and inflammatory parameters (iNOS, MPO).


A generalized gradient projection method based on a new working set for minimax optimization problems with inequality constraints.
Combining the techniques of the working set identification and generalized gradient projection, we present a new generalized gradient projection algorithm for minimax optimization problems with inequality constraints. In this paper, we propose a new optimal identification function, from which we provide a new working set. At each iteration, the improved search direction is generated by only one generalized gradient projection explicit formula, which is simple and could reduce the computational cost. Under some mild assumptions, the algorithm possesses the global and strong convergence. Finally, the numerical results show that the proposed algorithm is promising.


A simple inexpensive cryogenic storage device for microscopy specimens.
Cryogenic storage devices for microscopy specimens are costly and may require a particular size or type of dewar. Described here is a simple inexpensive storage container for small specimens (less than 5 mm in diameter) which can be constructed in less than 15 min from common laboratory materials. The unit is modular in design, can fit into any thermos type dewar and is reusable.


Pentacyclic antibiotics from a tidal mud flat-derived actinomycete.
The combination of investigating a unique source of chemically prolific bacterium with an LC/MS-based bacterial strain selection approach resulted in the discovery of two new secondary metabolites, buanmycin (1) and buanquinone (2), from the culture of a marine Streptomyces strain, which was isolated from a tidal mudflat in Buan, Republic of Korea. The carbon backbone of buanmycin (1), comprising 20 quaternary carbons out of 30 total carbons, was determined via (13)C-(13)C COSY NMR analysis after labeling 1 with (13)C by culturing the bacterium with (13)C-glucose. The complete structure of 1 was confidently elucidated, primarily based on 1D and 2D NMR spectroscopic and X-ray crystallographic analysis, as that of a new pentacyclic xanthone. The absolute configuration of the α-methyl serine unit in 1 was established by applying the advanced Marfey's method. The structure of buanquinone (2) was determined to be a new pentacyclic quinone based on NMR and MS spectroscopic data. Buanmycin exhibited potent cytotoxicity against colorectal carcinoma cells (HCT-116) and gastric carcinoma cells (SNU-638) with submicromolar IC50 values and strongly inhibited the pathogenic Gram-negative bacterium Salmonella enterica (MIC = 0.7 μM). In particular, buanmycin demonstrated inhibition of sortase A, which is a promising target for antibiotic discovery.


Performance evaluation of the Abbott Cell-Dyn 1800 automated hematology analyzer.
The Cell-Dyn 1800 is a new automated hematology analyzer that provides an 18-parameter blood count and operates at a throughput of 60 specimens per hour. (Clinical significance has not been established for plateletcrit and platelet distribution width; therefore these parameters are not reportable in the United States.) The instrument is smaller than its predecessor and offers a variety of enhanced features, including increased patient data storage, availability of a bar code reader, and a cyanide-free reagent system. Our study comprehensively assessed the analytical characteristics of the instrument in a variety of areas. When applicable the requirements of appropriate NCCLS guideline documents were followed. Instrument background and carryover were shown to be consistent with the performance specification. Accuracy was demonstrated by linearity studies and by comparison of results from the automated blood count parameters of the Cell-Dyn 1700 and from the manual differential method. The instrument-generated results and morphology flags were found to be effective in screening for abnormalities demonstrated by manual morphological assessment. Precision of the Cell-Dyn 1800 instrument was studied over the short term (with fresh blood) as well as the long term with stabilized quality control material. In either case, the instrument exhibited satisfactory performance. The blood count parameters showed acceptable stability during storage experiments, although in the case of mean platelet volume, the Cell-Dyn 1800 results increased during the first 6 hours of storage, reflecting the morphological changes expected of platelets from EDTA-anticoagulated specimens.


Wide variation in the multiplicity of HIV-1 infection among injection drug users.
Recent studies indicate that sexual transmission of human immunodeficiency virus type 1 (HIV-1) generally results from productive infection by only one virus, a finding attributable to the mucosal barrier. Surprisingly, a recent study of injection drug users (IDUs) from St. Petersburg, Russia, also found most subjects to be acutely infected by a single virus. Here, we show by single-genome amplification and sequencing in a different IDU cohort that 60% of IDU subjects were infected by more than one virus, including one subject who was acutely infected by at least 16 viruses. Multivariant transmission was more common in IDUs than in heterosexuals (60% versus 19%; odds ratio, 6.14; 95% confidence interval [CI], 1.37 to 31.27; P = 0.008). These findings highlight the diversity in HIV-1 infection risks among different IDU cohorts and the challenges faced by vaccines in protecting against this mode of infection.


Functional Mechanisms of Health Behavior Change Techniques: A Conceptual Review.
Health behavior change is among the top recommendations for improving health of patients with lifestyle-related chronic diseases. An array of behavior change techniques (BCTs) have been developed to support behavior change initiation and maintenance. These BCTs often show limited success when they are not informed by theory, leading to a mismatch between the intention of the BCT and patients' needs or expectations. Previous studies have identified a number of resources (domains) which patients may require to initiate and maintain health behavior change. Indeed, not yet well established is how BCTs address these resources, i.e., the functional mechanisms of BCTs. Provide a theoretical framework of the functional mechanisms of BCTs for developing and implementing successful interventions for health behavior change. Conceptual review, including literature analysis and synthesis as well as conceptualization of a new model based on the synthesis. Through the integration of dual-process models as well as reward and motivation proceeding, i.e., affective, emotional, or intuitive neurobiological cues, into the rational framework of rather linear cognitive or task-related decision progress, we categorize previously identified resources into three distinct sets: external, internal reflective, and internal affective resources. Based on this triad, we classify BCTs according to their functional mechanisms into facilitating (=providing external resources), boosting (=strengthening internal reflective resources), and nudging (=activating internal affective resources). Consequently, we present a simplified Behavior Change Resource Model (BCRM) that is centered on patients' resources. The model can be applied to develop health behavior change interventions, which promote engagement and empowerment. Future studies should aim at testing the applicability and practicality of the BCRM.


[Macromolecular complex of cardiac troponin I: differences of reactivity with DPC and Dade-Behring assays].
We have recently identified a macromolecular 440-kDa cardiac troponin I (cTnI) complex after successful percutaneous transluminal coronary angioplasty (PTCA) (Clin Chem 2003; 49: 505-7). The aim of the work was to confirm the existence of such a complex by using another cTnI assay (Dimension RXL, Dade-Behring). We have first studied the correlation between the two assays by using heparinized samples [cTnI(Immulite) = 2.00 cTnI(Dimension) - 0.01 (n = 176; r = 0,987)]. Then, cTnI taken 120 minutes after PTCA for two patients was measured with the two assays after fractionation by FPLC. The obtained results confirmed the existence of the 440-kDa cTnI complex and showed that the reactivity between the assays (DPC/Dade-Behring ratio) depended on the nature of the complex: the ratio increased from 0.7 (440-kDa cTnI complex) to 3 (80-kDa cTnI complex) therefore suggesting caution in the comparison between the different cTnI assays in the context of reperfusion therapy.


The Effects of Cellulose on AOM/DSS-Treated C57BL/6 Colorectal Cancer Mice by Changing Intestinal Flora Composition and Inflammatory Factors.
Chronic intestinal inflammation is a key risk factor of colorectal cancer (CRC). It is known that microbial dysbiosis induces increased inflammatory factors which promote tumorigenesis and cellulose can be beneficial to CRC. In the present study, we investigated the regulatory effects of cellulose on intestinal flora composition and colorectal carcinogenesis in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mouse model. Supplementation of cellulose significantly attenuated inflammation and tumor formation in AOM/DSS-treated CRC mice. The survival rate and the tumor inhibition rate were higher in the medium-dose cellulose group (MCEG) and high-dose cellulose group (HCEG) than in the model group (MG; P < 0.05). Cellulose supplementation stimulated shifts in the intestinal flora in AOM/DSS-treated CRC mice. Additionally, levels of inflammatory mediators involved in colorectal carcinogenesis, such as IL-6, IL-1β, and TNF-α, were lower in the serum of the low-dose cellulose group, MCEG, and HCEG when compared with the MG (P < 0.05). Whereas the abundance of differential bacteria was correlated with the concentration of IL-6, IL-1β, and TNF-α. These results showed cellulose changed the composition of intestinal flora and inhibited colon inflammation and neoplasm formation caused by the AOM/DSS treatment.


[Critical study of radiculomedullary and neuromuscular complications of ankylosing spondylitis].
Medullo-radicular and neuro-muscular involvements of ankylosing spondylarthritis, often reported in an analytic fashion in the literature, deserve to be the subject of a critical study. Various neurological manifestations secondary to exceptional atlo-occipital and sometimes axis-atlas subluxations and medullary lesions as well as syndromes of the cauda equina. The medullary lesions have an epidural origin (3 cases in the literature, 2 cases from the authors) or are secondary to a spondylodiscitis (4 cases in the literature) or secondary to both (1 case reported by the authors). As for syndromes of the cauda equina the authors report 3 cases to be added to the 55 published previously. It concerns always old spondylarthritis. The lesions combine posterior diverticula and lesions of the lamina. The treatment is usually ineffective. A special case is represented by forms with trophic disorders. More debatable are the radicular lesions, which, except for intercostal pain, should be linked to local pain. Electromyographic abnormalities are of no significance. Alterations of the paravertebral muscles viewed on the scanner X have, for now, an uncertain significance. Finally, various associations, without significance such as multiple sclerosis, diffuse muscular lesions and the classic spondylotic pseudo-tabes, should be rejected.


Comparison of clinical parameters, bronchoalveolar lavage, gallium-67 lung uptake, and serum angiotensin converting enzyme in assessing the activity of sarcoidosis.
A major problem in pulmonary sarcoidosis is the assessment of disease activity. We established a clinical score system composed of degree of dyspnea, chest radiographic stage, forced vital capacity, and clinical assessment of disease activity (normal = 0, maximum = 16). We evaluated this score in 50 patients with sarcoidosis along with other proposed measures of disease activity: bronchoalveolar lavage percent lymphocytes (% lymphs), Gallium-67 lung uptake measured as total lung to background ratio (TL/B ratio), and serum angiotensin converting enzyme (SACE) levels. The patients we studied had an average clinical score of 5.6 +/- 2.7 (+/- SD). Though bronchoalveolar lavage % lymphs (32 +/- 20%), TL/B ratio (192 +/- 73), and SACE (137 +/- 66) were all significantly elevated in these patients, Gallium-67 uptake was most frequently abnormal (80% of patients). However, the TL/B ratio was higher in smokers (231 +/- 91) than nonsmokers (178 +/- 64, p less than 0.05). There was no correlation between our clinical score, or any part of the clinical score, and other laboratory measures of alveolitis. Bronchoalveolar lavage % lymphs and TL/B ratio correlated weakly (n = 50, r = 0.36, p less than 0.02), while % lymphs and SACE correlated less well (n = 29, r = 0.36, p = 0.051). There was no correlation between TB/L ratio and SACE.(ABSTRACT TRUNCATED AT 250 WORDS)


Discovery of N-(Naphthalen-1-yl)-N'-alkyl Oxalamide Ligands Enables Cu-Catalyzed Aryl Amination with High Turnovers.
A class of N-(naphthalen-1-yl)-N'-alkyl oxalamides have been proven to be powerful ligands, making a coupling reaction of (hetero)aryl iodides with primary amines proceed at 50 °C with only 0.01 mol % of Cu2O and ligand as well as a coupling reaction of (hetero)aryl bromides with primary amines and ammonia at 80 °C with only 0.1 mol % of Cu2O and ligand. A wide range of coupling partners work well under these conditions, thereby providing an easy to operate method for preparing (hetero)aryl amines.


[Psychology in contemporary medicine].
In the last few decades we can observe a significant increase of the interest in psychology in medicine. There are several reasons behind it. Most importantly, there has been a drastic shift in the characteristics of illnesses as well as the leading causes of deaths. In the past, contagious diseases used to dominate, often in the form of an epidemic. In the second part of the twentieth century the so-called civilizational diseases appeared and currently have become the leading causes of deaths. In these types of diseases the psychosocial elements are key, which naturally raises the importance of psychology. Rapid progress in medicine apart from helping to fight disease has also introduced some negative issues, including dehumanization of medicine. It created an urgent need to reinforce the importance of the patient, who is above all a sick person needing help. And this is an important task for psychology in medicine. Contemporary medicine increasingly helps to save human life. However, there is also a question of the quality of life, which is another key issue for psychology. While medicine saves people from dying it also creates huge costs of hospitalization and rehabilitation. In this respect, there is a role for psychology to encourage healthy behaviors among young people, which can serve as disease prevention. Promotion of healthy lifestyles has a potential to reduce the risk of long-term diseases and bring down their social costs. There are also two more general reasons, which have increased the importance of psychology in today's medicine. One of them is the shift towards a more holistic approach in medicine. This approach stresses the importance of all the spheres of a person in the healing process; apart from the biological sphere, the focus is also on psychological, social and spiritual spheres. A natural consequence of such an approach is including psychology next to medicine in the healing process. A second reason has to do with the appearance of a new salutogenic model in medicine, as compared to the traditional pathogenetical model. This new model draws from the theory of stress and the theory of copying, which naturally includes references to psychology The issues of stress as well as copying are key in this model of health and illness.


Aging and feature binding in visual working memory.
Older adults have reduced performance in visual working memory tasks in comparison to young adults, but the precipitators of the age-related impairment are not fully understood. The most common interpretation of this difference is that older adults are incapable of maintaining the same amount of object representations as young adults over short intervals (in line with the fixed-slot model of working memory). However, it has remained largely unexplored whether the age-related decline is only due to the number of representations that older individuals can retain in visual working memory, or whether the content of the representation(s) may have an effect as well (in line with the flexible-resource model of working memory). Feature binding studies represent an interesting research line to examine the content of older adults' representations. In this mini-review, we present the main results across feature binding studies in aging, as well as highlight the importance of manipulating both the representation content and number to have a stress test of the various models of working memory and their contribution to aging. Overall, feature binding studies, together with the simultaneous manipulation of set size, will allow us to better understand the nature of the age-related decline of visual working memory.


Estrogen receptor α-mediated signaling inhibits type I interferon response to promote breast cancer.
Estrogen receptor α (ERα) is an important driver and therapeutic target in approximately 70% of breast cancers. How ERα drives breast carcinogenesis is not fully understood. In this study, we show that ERα is a negative regulator of type I interferon (IFN) response, which is critical for breast carcinogenesis. Activation of ERα by its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes (ISGs), whereas deficiency of ERα or stimulation with its antagonist fulvestrant has opposite effects. Mechanistically, ERα inhibits type I IFN response by two distinct mechanisms. ERα induces expression of the histone 2A variant H2A.Z, which restricts engagement of the IFN-stimulated gene factor 3 (ISGF3) complex at the ISG promoters. ERα also interacts with STAT2, which leads to disruption of the ISGF3 complex. These two events mutually lead to transcriptional inhibition of ISGs induced by type I IFNs. In a xenograft mouse tumor model, fulvestrant enhances the ability of IFN-β to suppress ERα+ breast tumor growth. Consistently, clinical data suggests that ERα+ breast cancer patients with higher levels of ISGs exhibit an increased survival rate. Our findings suggest that ERα inhibits type I IFN response via two distinct mechanisms to promote breast cancer.


Requirements for induction and maintenance of peripheral tolerance in stringent allograft models.
Peripheral tolerance can be achieved in many but not all murine allograft models. The requirements for controlling more aggressive immune responsiveness and generating peripheral tolerance in stringent allograft models are unknown. Understanding these requirements will provide insight toward ultimately achieving tolerance in humans, which are also resistant. We now demonstrate that the combination of donor-specific transfusion, anti-CD45RB, and anti-CD154 uniformly achieves >90-d survival of BALB/c skin allografts on C57BL/6 recipients. Recipients exhibit marked hyporesponsiveness to alloantigen in vitro. In distinct contrast to less rigorous models, engraftment remains absolutely dependent on cytotoxic T lymphocyte antigen 4 signaling, even after grafts are healed, suggesting that prolonged engraftment cannot simply be attributed to more effective depletion of alloreactive T cells but is actively maintained by regulation. Concordantly, we show that both CD4 and CD8 regulatory cells are required and can transfer donor-specific tolerance to naïve recipients. Nonetheless, most recipients ultimately develop gradual graft loss (median survival time = 140 d), suggesting that alloreactive cells emerging from the thymus eventually overwhelm regulatory capacity. In agreement, adding thymectomy to the regimen results in permanent engraftment (>250 d) and donor-specific tolerance not observed previously in this model. These results highlight the potency of both CD4 and CD8 regulatory cells but also suggest that in stringent settings, regulatory T cell longevity and capacity for infectious tolerance compete with prolonged graft immunogenicity and thymic output. These results provide insight into the mechanisms of tolerance in stringent models and provide a rational basis for innovative tolerogenic strategies in humans.


Serum LH and FSH responses to synthetic gonadotropin-releasing hormone in normal men.
The effects of dose and of age on the serum LH and FSH responses to synthetic gonadotropin-releasing hormone (GnRH) were determined in normal men. GnRH was given as in iv bolus in doses from 2 to 500 mug to each of nine normal men, 20-39 years old. The mean (+/- SE) maximum delta LH (maximum increment above the basal concentration) in response to each dose of GnRH was 2 mug, 7.2 +/- 1.7 mIU/ml; 10 mug, 15.7 +/- 3.4 mIU/ml; 50 mug, 37.7 +/- 9.6 mIU/ml; 250 mug, 47.8 +/- 11.2 mIU/ml; and 500 mug, 49.3 +/- 11.2 mIU/ml. The mean delta FSH in response to each dose was 2 mug, 0.5 +/- 0.2 mIU/ml; 10 mug, 0.8 +/- 0.2 mIU/ml; 50 mug, 1.2 +/- 0.3 mIU/ml; 250 mug, 2.0 +/- 0.3 mIU/ml; and 500 mug, 2.4 +/- 0.4 mIU/ml. Since both the LH and FSH responses to the 250 mug dose were significantly greater than those to smaller doses, but the responses to the 500 mug dose were not still larger, 250 mug was used as the standard test done for subsequent studies. The effect of age was tested by administering a 250 mug dose of GnRH as an iv bolus to 42 carefully selected normal men, 14 in each of three age groups, 20-39, 40-59, and 60-79 years old. Dialyzable serum testosterone levels decreased with increasing age, from 21.7 +/- 4.6 to 16.0 +/- 4.9 to 14.3 +/- 3.8 ng/dl (mean +/- SD), and the basal serum LH levels increased slightly, from 7.4 +/- 3.4 to 9.6 +/- 3.1 to 10.8 +/- 3.2 mIU/ml, suggesting that a slight degree of primary Leydig cell failure occurs with increasing age. There was no corresponding increase in mean maximum delta LH in response to GnRH with increasing age, despite the elevation in mean basal LH levels. The maximum delta LH/basal LH ratio, in fact, declined from 6.8 to 5.1 to 3.3 in the three age groups. The basal serum FSH levels did not change with increasing age, but the mean delta FSH values decreased from 3.0 +/- 0.5 to 2.9 +/- 1.1 +/- 0.3 mIU/ml. These data demonstrate decreased LH and FSH responses to synthetic GnRH, as well as some primary Leydig cell failure, in the male senescence.


Distinct, genome-wide, gene-specific selectivity patterns of four glucocorticoid receptor coregulators.
Glucocorticoids are a class of steroid hormones that bind to and activate the glucocorticoid receptor (GR), which then positively or negatively regulates transcription of many genes that govern multiple important physiological pathways such as inflammation and metabolism of glucose, fat and bone. The remodeling of chromatin and regulated assembly or disassembly of active transcription complexes by GR and other DNA-binding transcription factors is mediated and modulated by several hundred transcriptional coregulator proteins. Previous studies focusing on single coregulators demonstrated that each coregulator is required for regulation of only a subset of all the genes regulated by a steroid hormone. We hypothesized that the gene-specific patterns of coregulators may correspond to specific physiological pathways such that different coregulators modulate the pathway-specificity of hormone action, thereby providing a mechanism for fine tuning of the hormone response. We tested this by direct comparison of multiple coregulators, using siRNA to deplete the products of four steroid hormone receptor coregulator genes (CCAR1, CCAR2, CALCOCO1 and ZNF282). Global analysis of glucocorticoid-regulated gene expression after siRNA mediated depletion of coregulators confirmed that each coregulator acted in a selective and gene-specific manner and demonstrated both positive and negative effects on glucocorticoid-regulated expression of different genes. We identified several classes of hormone-regulated genes based on the effects of coregulator depletion. Each coregulator supported hormonal regulation of some genes and opposed hormonal regulation of other genes (coregulator-modulated genes), blocked hormonal regulation of a second class of genes (coregulator-blocked genes), and had no effect on hormonal regulation of a third gene class (coregulator-independent genes). In spite of previously demonstrated physical and functional interactions among these four coregulators, the majority of the several hundred modulated and blocked genes for each of the four coregulators tested were unique to that coregulator. Finally, pathway analysis on coregulator-modulated genes supported the hypothesis that individual coregulators may regulate only a subset of the many physiological pathways controlled by glucocorticoids. We conclude that gene-specific actions of coregulators correspond to specific physiological pathways, suggesting that coregulators provide a potential mechanism for physiological fine tuning in vivo and may thus represent attractive targets for therapeutic intervention.