[Psychotherapeutic processes--regarding the difficulty in explaining psychotherapeutic changes].
Until now, there is no sufficient answer to the question how psychotherapy works. It is argued that progress will come from three areas. First, the understanding what the term "therapeutic process" means has to be improved. It will be useful to start from the three central phenomena of psychotherapy: (a) client changes within the therapeutic situation and his/her life context, (b) therapeutic procedures including personal characteristics of therapists, (c) the context of the institution of psychotherapy. Second, there is a need to define more carefully elements of the therapeutic process, e.g. there is an inflational (mis-) use of the term "therapeutic relationship". Referring to a model by LINSENHOFF, BASTINE & KOMMER (1982), two components of psychotherapy process (problem conceptualization and therapeutic relationship) were critically examined. Third, two different ways to analyse psychotherapeutic change were evaluated: In Type A-studies, therapeutic processes were characterized by stable features as interactional factors (e.g. age, gender, education of the participants; therapeutic maxims). In contrast, Type B-studies rely on a transactional view of the therapeutic process as a sequence of heterogeneous segments (therapeutic episodes; therapeutic strategies).


The effect of alternative prey on the dynamics of imperfect Batesian and Müllerian mimicries.
Both Batesian and Müllerian mimicries are considered classical evidence of natural selection where predation pressure has, at times, created a striking similarity between unrelated prey species. Batesian mimicry, in which palatable mimics resemble unpalatable aposematic species, is parasitic and only beneficial to the mimics. By contrast, in classical Müllerian mimicry the cost of predators' avoidance learning is shared between similar unpalatable co-mimics, and therefore mimicry benefits all parties. Recent studies using mathematical modeling have questioned the dynamics of Müllerian mimicry, suggesting that fitness benefits should be calculated in a way similar to Batesian mimicry; that is, according to the relative unpalatability difference between co-mimics. Batesian mimicry is very sensitive to the availability of alternative prey, but the effects of alternative prey for Müllerian dynamics are not known and experiments are rare. We designed two experiments to test the effect of alternative prey on imperfect Batesian and Müllerian mimicry complexes. When alternative prey were scarce, imperfect Batesian mimics were selected out from the population, but abundantly available alternative prey relaxed selection against imperfect mimics. Birds learned to avoid both Müllerian models and mimics irrespective of the availability of alternative prey. However, the rate of avoidance learning of models increased when alternative prey were abundant. This experiment suggests that the availability of alternative prey affects the dynamics of both Müllerian and Batesian mimicry, but in different ways.


A Machine Learning Approach to Predicting the Stability of Inpatient Lab Test Results.
A primary focus for reducing waste in healthcare expenditure is identifying and discouraging unnecessary repeat lab tests. A machine learning model which could reliably predict low information lab tests could provide personalized, real-time predictions to discourage over-testing. To this end, we apply six standard machine learning algorithms to six years (2008-2014) of inpatient data from a tertiary academic center, to predict when the next measurement of a lab test is likely to be the "same" as the previous one. Out of 13 common inpatient lab tests selected for this analysis, several are predictably stable in many cases. This points to potential areas where machine learning approaches may identify and prevent unneeded testing before it occurs, and a methodological framework for how these tasks can be accomplished.


Prevalence and age-dependent occurrence of intestinal protozoan infections in suckling piglets.
A cross-sectional survey was performed on 20 pig breeding farms in southern Hesse, central Germany, to evaluate the prevalence and age-dependent occurrence of intestinal protozoan parasites in unweaned piglets. Faecal samples of 514 clinically unaffected piglets of different age (< 1 to 5-7 weeks) were examined using the sodium acetate-acetic acid-formalin (SAF) concentration technique. Infections with the following protozoan species were detected: Balantidium coli (16 of 20 farms), Entamoeba sp. (15), Jodamoeba sp. (14), Isospora (I.) suis (9), Chilomastix sp. (6) and Eimeria spp. (6). The protozoan species differed in the start and course of (oo)cyst excretion. I. suis oocysts and Jodamoeba cysts were detected already in the first week of life whereas shedding of the other parasites started later on. The prevalence of Isospora oocyst excretion increased to a maximum (18%) in 2-3 weeks old animals followed by a sharp decline. The proportion of Balantidium, Entamoeba or Jodamoeba positive suckling piglets continously increased until the age of 5-7 weeks to 60%, 52% and 22%, respectively, whereas that of Chilomastix positive animals remained on a low level of 8-12% independent of the age. Eimeria oocysts were found transiently in the faeces of 1-4 weeks old piglets.


Template-directed ligation on repetitive DNA sequences: a chemical method to probe the length of Huntington DNA.
Several genomic disorders are caused by an excessive number of DNA triplet repeats. We developed a DNA-templated reaction in which product formation occurs only when the number of repeats exceeds a threshold indicative for the outbreak of Chorea Huntington. The combined use of native chemical PNA ligation and auxiliary DNA probes enabled reactions on templates obtained from human genomic DNA.


Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development.
Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1(-/-) mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras(V12) oncoproteins developed bigger tumors than TP53INP1(+/+) transformed MEFs or TP53INP1(-/-) transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.


The role of radiotherapy in the treatment of hepatocellular carcinoma with portal vein tumor thrombus.
The aim of this study was to evaluate the role of radiotherapy in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVT) and to determine the prognostic factors for overall survival. Altogether, 106 patients with HCC and PVT referred for radiotherapy between 2004 and 2009 were retrospectively reviewed. A total of 60 Gy in 30 daily fractions was delivered with intensity-modulated radiotherapy techniques. Patient-related and treatment-related factors were analyzed to evaluate their prognostic significance for the overall survival rate. Complete response was noted in 10 patients and partial response in 55 patients. The liver lesions had become resectable after the completion of radiotherapy in 12 patients, and surgery was subsequently performed. One or two courses of transarterial chemoembolization (TACE) were administered to 19 patients following radiotherapy. The 1-year and 2-year overall survival rates were 34.7% and 11%, respectively, and the median survival was 7 months for the entire cohort of patients. Post-radiotherapy treatment modality, response to radiotherapy and JIS score were demonstrated as independent prognostic factors for overall survival (P = 0.003, P < 0.001, P < 0.001, respectively). For patients who received surgical intervention after radiotherapy, the median survival was 30 months and the 2-year overall survival rate was 67%. Radiotherapy achieved a 61.5% objective response rate and prolonged survival in patients with PVT. The liver tumors had become resectable after radiotherapy in 11% of patients. Our results suggested that radiotherapy could offer survival benefits and should be considered as a treatment option for patients with PVT. Radiotherapy could also be considered as a preoperative treatment modality in patients with HCC and PVT.


Traveling concentric-roll patterns in Rayleigh-Bénard convection with modulated rotation.
We present experimental results for pattern formation in Rayleigh-Bénard convection with modulated rotation about a vertical axis. The dimensionless rotation rate Omega was varied as Omega(m)=Omega[1+delta cos(phi Omega t)] (time is scaled by the vertical viscous diffusion time of the cell). We used a cylindrical cell of aspect ratio (radius/height) Gamma=11.8 and varied Omega, delta, phi, and epsilon identical with R/R(c)(Omega)-1 (R is the Rayleigh number). The fluid was water with a Prandtl number of 4.5. Sufficiently far above onset even a small delta greater than approximately 0.02 stabilized a concentric-roll (target) pattern. Multiarmed spirals were observed close to onset. The rolls of the target patterns traveled radially inward independent of the sense of rotation. The radial speed v was nearly independent of epsilon for fixed Omega, delta, and phi. However, v increased with any one of Omega, delta, and phi when all the other parameters were held fixed.


Complex craniosynostosis in the context of Carpenter's syndrome.
Carpenter's syndrome or acrocephalopolysyndactyly type II is a rare genetic autosomal recessive disease, with an incidence estimated at 1 per 1 million births. Common findings of a brachydactyly, polysyndactyly, and a trefoil-like skull with extreme brachycephaly due to fusion of the bilateral coronal, sagittal and lambdoid sutures. We report a 12-month-old male who was referred to our care for evaluation of a craniofacial deformity-a trefoil-like skull, flattened and receding forehead, bulging of temporal bones, hypertelorism, exorbitism, and polysyndactyly in the upper and lower limbs and psychomotor delay. Head computed tomography (CT) with 3D reconstruction revealed craniosynostosis with fusion of the coronal, metopic, and sagittal sutures. Correction of the craniofacial deformity was performed with satisfactory aesthesis of the craniofacial bones at 2 years of follow-up. Early correction of craniofacial deformity in Carpenter's syndrome is usually safe within 6 to 12 months. Venous drainage abnormalities and ectatic emissary veins can lead to significant bleeding and may be detected on MR angiography. Significant skull weakening may lead to bony fragmentation while creating cranial flaps and is best evaluated with 3D CT imaging. Taking these pitfalls into consideration decreases the chances of aborting the surgery and may lead to better overall outcomes.


Suction diathermy adenoid ablation.
Adenoidectomy is a surgical procedure frequently carried out in otolaryngological practice, traditionally undertaken blindly with curettage using an adenotome following palpation of the adenoid bed. While a number of alternative methods have been described for surgical removal of the adenoid pad (power-assisted/microdebrider, transnasal adenoid ablation, suction coagulation and liquefaction/aspiration) none has become the definitive procedure. Suction diathermy adenoidectomy has been known and used for some time; it has gained in popularity over recent years and is established as an alternative to conventional curettage, particularly in children. We describe several techniques which improve the view of the surgical field while performing suction diathermy adenoid ablation.


Structure and function of 6,7-dicarboxyheme-substituted myoglobin.
Myoglobin was reconstituted with 6,7-dicarboxy-1,2,3,4,5, 8-hexamethylheme, a compact synthetic heme with the shortest acid side chains, to pursue the structural and functional consequences after intensive disruption of the heme propionate-apoglobin linkages in the native protein. The electron-withdrawing carboxylate groups directly attached to the porphyrin ring lowered the oxygen affinity by 3-fold as compared with native myoglobin. Autoxidation of the oxy derivative to the ferric protein proceeded with 1.6 x 10(-)2 min-1 at pH 7.0 and 30 degrees C. The crystallographic structure of the cyanomet myoglobin with 1.9 A resolution shows that the heme adopts a unique orientation in the protein pocket to extend the two carboxylates toward solvent sphere. The native globin fold is conserved, and the conformations of globin side chains are almost intact except for those located nearby the heme 6,7-carboxylates. The 7-carboxylate only weakly interacts with Ser92 and His97 through two mediating water molecules. The 6-carboxylate, on the other hand, forms a novel salt bridge with Arg45 owing to conformational flexibility of the guanidinium side chain. The proton NMR shows that the small heme does not fluctuate about the iron-histidine bond even at 55 degreesC, suggesting that the salt bridge between Arg45 and heme 6-carboxylate is of critical importance to recognize and fix the heme in myoglobin.


Direct fabrication of highly nanoporous polystyrene fibers via electrospinning.
A direct approach for fabricating nanoporous polymer fibers via electrospinning has been demonstrated. Polystyrene (PS) fibers with micro- and nanoporous structures both in the core and/or on the fiber surfaces were electrospun in a single process by varying solvent compositions and solution concentrations of the PS solutions. The porous structures of the fibrous mats were characterized by field emission scanning electron microscopy and Brunauer-Emmett-Teller measurements to confirm that they could be accurately controlled by tuning vapor pressure of tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) solvent mixtures and PS concentrations in the solutions. As the solution concentration decreased, the average fiber diameter decreased, whereas the bead density increased dramatically to show a beads-on-string morphology. Both the specific surface area and pore volume of the fibrous mats showed a unimodal distributions centered at 1/3 THF /DMF mix ratio. Fibers formed from 5 wt % PS in the 1/3 THF and DMF mixtures had the largest specific surface area of 54.92 m(2) g(-1) and a pore volume of 0.318 cm(3)g(-1), respectively.


Beta-adrenergic blockade alone does not decrease renal perfusion in black hypertensives.
We assessed the effects on renal haemodynamics in 18 black patients with essential hypertension of acute and chronic beta-adrenergic blockade with three agents having different properties: atenolol, nadolol or propranolol. Six patients received each drug. In our patients the antihypertensive response to beta-blockers was minimal or nonexistent. This permitted us to analyse the effects on renal haemodynamics of 'pure' beta-blockade, as opposed to the combined effects of beta-blockade and decreased systemic perfusion pressure. In this setting, neither acute nor chronic administration (two months) of each of these agents decreased renal perfusion. We conclude, therefore, that beta-blockade per se has no deleterious effect on renal function and previous observations are most probably accounted for by the blood pressure lowering effect of these drugs, either alone or coupled with beta-blockade of the renal vasculature allowing unopposed alpha-sympathetically mediated vasoconstriction.


Changes in plasma glucagon, pancreatic polypeptide and insulin during development of alloxan diabetes mellitus in dog.
Changes in canine plasma glucose, immunoreactive glucagon (IRG), pancreatic polypeptide (PP) and insulin (IRI) were studied during the acute development of diabetes mellitus after iv alloxan injection. 100 mg or 75 mg/kg body weight of alloxan was injected iv and blood was taken successively till one or two days later. Plasma glucose showed four phases: first immediate and moderate decrease appeared 30 min after injection, second initial hyperglycemic phase, third hypoglycemic and fourth diabetic ones. Plasma IRI had already increased to 182 +/- 60 microU/ml 10 min after injection and again began to increase after about 6 h, peaking to 134 +/- 49 microU/ml at 18 h. Plasma IRG began increasing gradually soon after alloxan injection. The initial value was 196 +/- 26 pg/ml and it increased to 534 +/- 144 pg/ml at 4 h during the initial hyperglycemic phase, then reached a higher level through the hypoglycemic and diabetic phases. The change in plasma PP was similar to that in IRG. The initial value was 256 +/- 95 pg/ml at 12 h after injection, peaking to 840 +/- 100 pg/ml in the hypoglycemic phase. Similar blunted values were obtained following 75 mg/kg alloxan injection. Thus not only plasma IRI but also plasma IRG and PP varied greatly during the acute development of alloxan diabetes and some contribution of IRG to the initial hyperglycemic phase was suggested.


Transition metal ligands as novel DNA-base substitutes.
The base modified nucleoside dBP, carrying a non-hydrogen-bonding non-shape complementary base was incorporated into oligonucleotides (Brotschi, C.; Häberli, A.; Leumann C.J. Angew. Chem. Int. Ed. 2001, 40, 3012-3014). This base was designed to coordinate transition metal ions into well defined positions within a DNA double helix. Melting experiments revealed that the stability of a dBP:dBP base couple in a DNA duplex is similar to a dG:dC base pair even in the absence of transition metal ions. In the presence of transition metal ions, melting experiments revealed a decrease in duplex stability which is on a similar order for all metal ions (Mn2+, Cu2+, Zn2+, Ni2+) tested.


GM1 ganglioside-bound amyloid beta-protein in Alzheimer's disease brain.
The central question related to beta-amyloidogenesis is how amyloid beta-protein (Abeta) is generated and deposited. To address this issue, we investigated the early stage of beta-amyloidogenesis using cerebral cortices from Alzheimer's disease and Down's syndrome patients and normal aged individuals with BC05, a specific monoclonal antibody for Abeta42(43), which is believed to be an initially deposited Abeta species, as a probe. In that study, we found that Abeta42 is bound to membranes in brains with abundant diffuse plaques, and that the bound lipid is likely GM1 ganglioside. To further characterize this novel Abeta species, we investigated its reactivity to cholera toxin, and performed immunoprecipitation experiments using several anti-Abeta monoclonal antibodies. The immunoprecipitates obtained with BAN052 (specific for the N-terminus of Abeta), but not BC05 and 4G8 (specific for Abeta17-24), showed significant Abeta immunoreactivity and cholera toxin reactivity. The present results strongly suggest that Abeta binds to a GM1 ganglioside in such a way that the bound Abeta is only recognized by BAN052, of the monoclonal antibodies used in this study.


Advanced review on type II collagen and peptide: preparation, functional activities and food industry application.
Type II collagen is a homologous super-helical structure consisting of three identical α1(II) chains. It is a major component of animal cartilage, and is widely used in the food industry. Type II collagen can be extracted by acids, salts, enzymes, and via auxiliary methods and can be further hydrolyzed chemically and enzymatically to produce collagen peptides. Recent studies have shown that type II collagen and its polypeptides have good self-assembly properties and important biological activities, such as maintaining cartilage tissue integrity, inducing immune tolerance, stimulating chondrocyte growth and redifferentiation, and providing antioxidant benefits. This review focuses specifically on type II collagen and describes its structure, extraction, and purification, as well as the preparation of type II collagen peptides. In particular, the self-assembly properties and functional activities of type II collagen and collagen peptides are reviewed. In addition, recent research advances in the application of type II collagen and collagen peptides in functional foods, food additives, food coating materials, edible films, and carriers for the food industry are presented. This paper provides more detailed and comprehensive information on type II collagen and peptide for their application.


[Antibiotic resistance factors and "jumping" genes (author's transl)].
Antibiotics are natural products inhibiting the growth of bacteria. In research they play an important role in studying the details of bacterial macromolecular synthesis. However, their major importance lies in application, i.e., in treatment of infectious bacterial diseases and as additives to livestock feed. The application of antibiotics, however, presents serious problems: the development and spread of antibiotic-resistant bacterial strains which impede therapy.


The effects of respiratory inhaled drugs on the prevention of acute mountain sickness.
Acute mountain sickness (AMS) is common in high-altitude travelers, and may lead to life-threatening high-altitude cerebral edema (HACE) or high-altitude pulmonary edema (HAPE). The inhaled drugs have a much lower peak serum concentrations and a shorter half-life period than oral drugs, which give them a special character, greater local effects in the lung. Meanwhile, short-term administration of inhaled drugs results in almost no adverse reactions. We chose inhaled ipratropium bromide/salbutamol sulfate (combivent, COM), budesonide (pulmicortrespules, BUD), and salbutamol sulfate (ventolin, VEN) in our study to investigate their prophylactic efficacy against AMS. Since COM is a compound drug of ipratropium bromide and salbutamol sulfate, to verify which part of COM plays a role in the prevention of AMS, we also tested VEN in our experiment. In our study, Lake Louise scores (LLS) in the COM (1.14 ± 0.89 vs 1.91 ± 1.23, P < .05) and BUD (1.35 ± 0.94 vs 1.91 ± 1.23, P < .05) groups were both significantly lower than the placebo group at 72 hours. There were no significant differences in LLS scores among the 4 groups at 120 hours. The incidence of AMS in the COM group was significantly reduced at 72 hours (16.7% in COM group vs 43.4% in placebo group, P < .05) after exposure to high-altitude. There were no significant differences in AMS incidences at 120 hours among the 4 groups. The prophylactic use of COM could prevent AMS in young Chinese male at 72 hours after high-altitude exposure. BUD also could reduce LLS but not prevent AMS at 72 hours. Ipratropium bromide maybe the effective drug in COM work on the prevention of AMS alone.


Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial, or peritoneal lining. Although surgery, chemotherapy, radiotherapy, and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there are no published reports regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant antibody-dependent cellular cytotoxicity activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients.


DNA nanopores as artificial membrane channels for bioprotonics.
Biological membrane channels mediate information exchange between cells and facilitate molecular recognition. While tuning the shape and function of membrane channels for precision molecular sensing via de-novo routes is complex, an even more significant challenge is interfacing membrane channels with electronic devices for signal readout, which results in low efficiency of information transfer - one of the major barriers to the continued development of high-performance bioelectronic devices. To this end, we integrate membrane spanning DNA nanopores with bioprotonic contacts to create programmable, modular, and efficient artificial ion-channel interfaces. Here we show that cholesterol modified DNA nanopores spontaneously and with remarkable affinity span the lipid bilayer formed over the planar bio-protonic electrode surface and mediate proton transport across the bilayer. Using the ability to easily modify DNA nanostructures, we illustrate that this bioprotonic device can be programmed for electronic recognition of biomolecular signals such as presence of Streptavidin and the cardiac biomarker B-type natriuretic peptide, without modifying the biomolecules. We anticipate this robust interface will allow facile electronic measurement and quantification of biomolecules in a multiplexed manner.


Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study).
Purpose: Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy.Experimental Design: This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line.Results: Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemotherapy were included. Patients with a high (>10 ng/mL) versus low (≤0.1 ng/mL) ctDNA concentration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C0 and C2 or C1 (C2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n = 58) versus "bad ctDNA responder" (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001).Conclusions: This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. Clin Cancer Res; 23(18); 5416-25. ©2017 AACR.


A case-control study of lung cancer mortality in four rural Arizona smelter towns.
To investigate factors related to lung cancer mortality in four Arizona copper-smelter towns, the authors identified 142 lung cancer cases and 2 matched controls per case from decedent residents during 1979-1990. The authors obtained detailed information on lifetime residential, occupational, and smoking histories via structured telephone interviews with knowledgeable informants. The authors linked estimated historical environmental exposures to smelter emissions (based on atmospheric diffusion modeling of measured sulfur dioxide concentrations) with residential histories to derive individual profiles of residential exposure. The results of this study provided little evidence of a positive association between lung cancer and residential exposure to smelter emissions. Conditional logistic regression analysis revealed a statistically significant positive association between lung cancer and reported employment in copper mines and/or smelters, although specific factors associated with the apparently increased risk among these workers could not be identified in this community-based study.


Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale.
Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial cardiometabolic disorder. Almost half of adults with diabetes fail to achieve their recommended glucose control target. This has prompted some clinicians to advocate the use of more intensive initial therapy, including the use of combination therapy to target multiple physiologic defects in diabetes with the goal of achieving and sustaining glucose control. Numerous options exist for combining the various classes of glucose-lowering agents in the treatment of T2DM. This report reviews the mechanism, rationale, and evidence from clinical trials for combining two of the newer drug classes, namely, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors, and considers the possible role of such dual therapy in the management of T2DM.


Injustice in Mobile Leisure: A Conceptual Exploration of Pokémon Go.
In augmented reality, video games and the physical world converge as individuals participate in digital leisure overlaid on physical spaces. In Pokémon Go, game play in the physical world is impacted by constraints that limit access and play of marginalized groups. Global popularity of Pokémon Go created an opportunity to explore experiences of marginalized groups participating in augmented reality game play. Grey literature surrounding Pokémon Go is rich with accounts of constraints experienced by marginalized groups, particularly individuals self-identifying as White women, Black women, or Black men. Their experiences with Pokémon Go illustrate the need for social justice in digital leisure. Because the lifespan of mobile applications is limited, the gradual process from research to social change may be insufficient in addressing ever evolving digital platforms. Researchers need to strategically work with industry partners to identify needs for social justice during the planning and designing stages.


Cardiovascular adaptation to chronic anemia in the elderly: an echocardiographic study.
To study the effects of chronic severe anemia on the aging heart. We studied 41 elderly patients (mean age 69.8 yr, standard deviation [SD] 3.9 yr) suffering from chronic severe anemia (mean hemoglobin 6.3, SD 0.5 g/dL) with no history of cardiac disease, along with 63 healthy age- and sex-matched controls. Assessment included physical examination, electrocardiogram and Doppler echocardiography. Although heart rates were similar between patients and controls, arterial blood pressures were significantly lower in patients (mean pressure 92.7 mm Hg, SD 7.9, v. mean 102.1 mm Hg, SD 3.5; p < 0.001). No patient was found to have congestive heart failure. Patients with chronic anemia had larger diameters of the left (end-systolic 35.28, SD 4.20, v. 33.73, SD 2.08 mm, p < 0.05; end-diastolic 53.33, SD 4.55, v. 50.37, SD 2.10 mm, p < 0.001) and right ventricles (30.76, SD 3.98, v. 29.04, SD 2.04 mm; p < 0.05), and greater left-ventricular mass (277.64, SD 62.85, v. 212.91, SD 24.87 g; p < 0.001). Fractional shortening did not differ significantly (0.33, SD 0.04, v. 0.33, SD 0.03). The load-independent end-systolic index was lower in patients (2.67, SD 0.56, v. 3.87, SD 0.49 kdyn x m2/cm5; p < 0.001) along with end-systolic stress and total systemic resistance (p < 0.001) than controls, whereas the cardiac index was higher (4.31, SD 1.29, v. 2.73, SD 0.51 L/min/m2; p < 0.001). Differences between the 2 groups in diastolic function indices and pulmonary arterial pressures were not statistically significant. Chronic severe anemia is well tolerated by the aging heart. Neither congestive heart failure nor clearly evident left-ventricular dysfunction were encountered. The heart exhibited an adaptive potential through remodelling by means of the Frank-Starling mechanism and afterload reduction. However, the lower end-systolic index in patients suggests that ventricular performance was marginally compromised. This state of high output was achieved mainly by increased stroke volume, with little contribution from heart rate.


Specificity and generalization in perceptual adaptation to accented speech.
The present study investigated the degree to which perceptual adaptation to foreign-accented speech is specific to the regularities in pronunciation associated with a particular accent. Across experiments, the conditions under which generalization of learning did or did not occur were evaluated. In Experiment 1, listeners trained on word-length utterances in Korean-accented English and tested with words produced by the same or different set of Korean-accented speakers. Listeners performed better than untrained controls when tested with novel words from the same or different speakers. In Experiment 2, listeners were trained with Spanish-, Korean-, or mixed-accented speech and transcribed novel words produced by unfamiliar Korean- or Spanish-accented speakers at test. The findings revealed relative specificity of learning. Listeners trained and tested on the same variety of accented speech showed better transcription at test than those trained with a different accent or untrained controls. Performance after mixed-accent training was intermediate. Patterns of errors and analysis of acoustic properties for accented vowels suggested perceptual improvement for regularities arising from each accent, with learning dependent on the relative similarity of linguistic form within and across accents.


Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies.
Tau proteins belong to the microtubule associated protein family and are mainly expressed in neurons. Tau accumulates in patients' brain in several neurodegenerative diseases, including Fronto-temporal dementia and Alzheimer's disease. Recently, we described a 17q21.31 duplication in patients presenting different cognitive or motor symptoms and characterized by the accumulation of different Tau isoforms. This duplication involves four genes, including the MAPT gene that encodes the Tau protein. The main pathophysiological consequence associated with this duplication was a 1.6-1.9-fold increase in the MAPT messenger RNA as measured in blood samples of duplication carriers. However, the pathophysiological consequences of this duplication in a cell type relevant for neurodegenerative diseases have never been explored so far. In this study, we developed the first model of primary tauopathy linked to a 17q21.31 duplication in iPSC-induced neurons from 2 unrelated carriers. As in patients' blood, we demonstrated that this duplication was associated with an increase in MAPT mRNA resulting in elevated Tau protein levels in iPSC-derived cortical neurons. We believe that these iPSC lines will be a pertinent tool to elucidate how a same genetic cause could lead to distinct types of tauopathies and the pathophysiological mechanisms associated with Tau-mediated neurodegeneration in the 17q21.31 duplication context.


Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene.
Benign metastasizing leiomyoma (BML) is an orphan neoplasm commonly characterized by pulmonary metastases consisting of smooth muscle cells. Patients with BML have usually a current or previous uterine leiomyoma, which is therefore suggested to be the most probable source of this tumour. The purpose of this case report was to determine the possible genetic grounds for pulmonary BML. We present a case report in an asymptomatic 44-year-old female patient, who has developed uterine leiomyoma with subsequent pulmonary BML. Whole exome sequencing (WES) was used to detect somatic mutations in BML lesion. Somatic single nucleotide mutations were identified by comparing the WES data between the pulmonary metastasis and blood sample of the same BML patient. One heterozygous somatic mutation was selected for validation by Sanger sequencing. Clonality of the pulmonary metastasis and uterine leiomyoma was assessed by X-chromosome inactivation assay. We describe a potentially deleterious somatic heterozygous mutation in bone morphogenetic protein 8B (BMP8B) gene (c.1139A > G, Tyr380Cys) that was identified in the pulmonary metastasis and was absent from blood and uterine leiomyoma, and may play a facilitating role in the metastasizing of BML. The clonality assay confirmed a skewed pattern of X-chromosome inactivation, suggesting monoclonal origin of the pulmonary metastases.


A quantum chemical calculation on Fe(CO)5 revealing the operation of the Dewar-Chatt-Duncanson model.
A nonstandard computational scheme has been applied to calculate Fe(CO)(5) with the aim to illustrate the operation of the Dewar-Chatt-Duncanson model by computation. A full configuration interaction (CI) calculation in an active space has been performed. The active space is built from naturally localized molecular orbitals (NLMOs) localized in bond regions or forming lone pairs. For selecting this active space, Weinhold's perturbation theory formulated in the natural bond orbital (NBO) space has been applied. Bonding, lone pair, and antibond NBOs exhibiting large interaction energies serve to define the active space. The actually applied active space, however, comprises NLMOs that are close in shape to the NBOs indicated by perturbation theory. Thus, a CI calculation with localized orbitals has been performed meeting the classical reasoning of chemists that is often based on local bonding concepts. The computational scheme yields the Lewis structure for Fe(CO)(5) whose energy is identical to the Hartree-Fock energy. The Lewis energy comprises CO → Fe σ-electron transfer (ET) and CO ← Fe electron back donation (BD). This Lewis energy gets lowered by localized correlation energy contributions caused by ET processes where electrons are back donated from the Fe d-lone pairs into the CO ligands. Thus, electron correlation within the selected active space is dominated by electron BD. Energies and electron populations of the NBOs support the notion that electrons are preferentially back donated into the equatorial CO ligands. Weights of local Slater determinants, determining the correlation energy, also point to a predominant BD into the equatorial CO ligands. Correlation energy increments resulting from electron BD into single antibond orbitals of the CO ligands have been calculated. These energy quantities also demonstrate that BD into the equatorial CO ligands is more energy lowering than BD into the axial CO ligands.


Thrombotic microangiopathy and human immunodeficiency virus in the era of eculizumab.
Thrombotic microangiopathies (TMAs) include thrombotic thromobocytopenic purpura and hemolytic uremic syndrome (HUS). Among these conditions, atypical HUS is now recognized to be a disease of alternative complement pathway dysregulation. Eculizumab is a recombinant humanized monoclonal antibody that binds to the complement protein C5 and prevents the cleavage of C5 to C5a and C5b. Eculizumab has been used as a novel treatment for complement-mediated TMA. We present a case of a patient with human immunodeficiency virus infection who developed TMA and was successfully treated with eculizumab. The effect of long-term treatment with this new medication is unknown, and further studies are needed to establish guidelines in the management of this condition.


The Analysis of Characteristics in Dry and Wet Environments of Silicon Nanowire-Biosensor.
Our study investigates differences in sensitivity of dry and wet environment in the field of biosensing experiment in detail and depth. The sensitivity of biosensing varies by means of surrounding conditions of silicon nanowire field effect transistor (SiNW FET). By examining charged polymer reaction in the silicon nanowire transistor (SiNW), we have discovered that the threshold voltage (V(T)) shift and change of subthreshold slope (SS) in wet environment are smaller than that of the air. Furthermore, we analyzed the sensitivity through modifying electrolyte concentration in the wet condition, and confirmed that V(T) shift increases in low concentration condition of phosphate buffered saline (PBS) due to the Debye length. We believe that the results we have found in this study would be the cornerstone in contributing to advanced biosensing experiment in the future.


[Location of the binding position for HBV X protein functional interaction with cytochrome C oxidase III].
To identify the binding site position of the hepatitis B virus (HBV) X protein (HBx) functional interaction with the cytochrome C oxidase subunit III (COX III, a key regulator of mitochondrial function) by using a yeast two-hybrid system. Two fragments of HBx mutants (X1 1-72aa and X2 1-117aa) were amplified by PCR and inserted into the bait plasmid pAS2-1.The resultant mutant plasmids were transfected into yeast cells using the lithium acetate-method.PCR and gene sequencing were used to confirm that the mutant fragments were expressed properly in yeast cells.Western blotting was used to verify that the mutant proteins were translated accurately in the yeast cells.Filter assay was used to exclude autoactivated mutants.Hybridization in solid medium and beta-gal activity detection were used to determine the precise position of the binding site for HBx and COX III interaction. The two mutant plasmids containing HBx 1-72aa and 1-117aa respectively were successfully constructed and the mutants were both properly expressed and translated in yeast cells; no autoactivated mutants were detected throughout the experimental process.The binding site of HBx and COX III was found to be encompass the amino acids 72 through 117 of HBx. Amino acids 72 through 117 of HBx are the key domain of the HBx functional interaction With COX III; this domain may represent a useful target for molecular-based therapies to treat HBV-related diseases.


Hypervirulent Klebsiella pneumoniae (hypermucoviscous and aerobactin positive) infection over 6 years in the elderly in China: antimicrobial resistance patterns, molecular epidemiology and risk factor.
The definition of hypervirulent Klebsiella pneumoniae (hvKp), traditionally regarded as hypermucoviscosity, is controversial. However, data based on both phenotype (hypermucoviscous) and genetic (aerobactin) criteria are limited. A retrospective study was conducted in 175 geriatric patients between January 2008 and January 2014. The clinical and molecular data, including antimicrobial susceptibility testing, extended-spectrum-β-lactamase (ESBL) production, virulence gene, and multilocus sequence typing of the hvKp-group (hypermucoviscosity and aerobactin positive) were compared with those of classic K. pneumoniae (cKp) isolates. Of 175 Kp isolates, 45.7% were hvKp. In pathogenicity, K1, K2, magA, rmpA, and rmpA2 genes were strongly associated with hvKp (P < 0.01). In the hvKp group, invasive infections (P < 0.000), liver abscess (P = 0.008), abdominal infection (P = 0.002) and septic shock (P = 0.035) are significantly higher than cKp group. Patients with better nutritional status were frequently infected with hvKp. However, host inflammatory reaction is most severe in hvKp group. Patients with diabetes (odds ratio [OR] = 2.548) and digestive diseases (OR = 2.196) are more likely to be infected with hvKp. Importantly, the detection of hvKp isolates increased from January 2008 to January 2010, January 2010 to January 2012, and January 2010 to January 2014 (12, 30, and 48 isolates, respectively). Overall, 16.3% of hvKp isolates produced ESBLs and 20.0% were MDR-hvKp. Multivariate analysis implied that infection occurred in the ICU (OR = 5.826) and patients with indwelling stomach tubes (OR = 6.461) are independent risk factors for ESBL-hvKp infection. HvKp, especially ESBL-hvKp and MDR-hvKp, is emerging in the elderly. It is essential to enhance clinical awareness and management of hvKp infections.


Relationship between DNA strand breaks and inhibition of poly (ADP-ribosylation): enhancement of carcinogen-induced transformation.
Inhibition of poly(ADP-Rib) by benzamide (BA) or 3-amino-benzamide (3AB) for a limited period (i.e., when ADP-ribosylation is elevated) during and shortly following X-ray or MNNG-induced DNA damage of BALB/3T3 cells significantly (3- to 30-fold) enhanced transformation frequency by these agents. Individual Type III foci isolated from benzamide, X-ray, or X-ray plus benzamide treated cultures were established and characterized for growth in soft agar and for tumor induction in nude mice. DNA isolated from representative transformed lines established as a result of BA, X-ray or X-ray and BA treatments was transfected onto NIH/3T3 cells. Transformation efficiencies ranging from 0.17 to 0.28 foci/micrograms of DNA were observed suggesting the possibility that dominant transforming gene(s) were responsible for the oncogenic phenotype of radiation and benzamide transformed DNA.


Hepatitis E virus as a newly identified cause of acute viral hepatitis during human immunodeficiency virus infection.
The recent description of chronic hepatitis E in organ transplant recipients deserves increased awareness in the context of hepatitis E virus (HEV) infection in immunocompromised individuals. Reported here is what is apparently the first PCR-documented case of acute hepatitis E in a human immunodeficiency virus (HIV)-1-infected patient. The CD4(+) T-lymphocyte count was 246/mm(3). The IgM anti-HEV antibody and HEV RNA tests results from serum were positive. Hepatitis was benign, and chronic HEV infection was ruled out. The HEV genotype was 3f. The patient did not report recent travel abroad. HEV should be tested in HIV-infected individuals presenting with acute hepatitis. HEV RNA detection is useful in diagnosing HEV infection and in monitoring recovery.


Effect of space allowance and antibiotic feeding on performance of nursery pigs. NCR-89 committee on confinement management of swine.
The relationship between space allowance and feeding antibiotics to pigs weaned at 3 to 6 wk of age was investigated in a cooperative study that involved nine experiment stations in the North Central Region of the United States. Treatments, arranged factorially, were control vs antibiotics (110 mg chlortetracycline, 110 mg sulfamethazine and 55 mg penicillin/kg of diet) and .14 vs .23 m2 of floor space/pig. Treatments were replicated 45 times, utilizing 1,724 pigs. Pigs allowed .23 m2, compared with .14 m2, had 10.6% greater (P less than .01) rate of gain and 3.6% improved (P less than .05) feed/gain. Pigs fed antibiotics had 13.2% faster (P less than .01) rate of gain and 4.7% improved (P less than .01) feed/gain in the 4-wk experimental period. There were no interactions between antibiotic and space allowance for performance measurements, except for average daily gain (P less than .05) in the 0 to 3 wk period. In this period the antibiotic response was greater among pigs allowed .23 m2, as compared with those allowed .14 m2.


A new approach for structure analysis of two-dimensional membrane protein crystals using X-ray powder diffraction data.
The application of powder diffraction methods to problems in structural biology is generally regarded as intractable because of the large number of unresolved, overlapping X-ray reflections. Here, we use information about unit cell lattice parameters, space group transformations, and chemical composition as a priori information in a bootstrap process that resolves the ambiguities associated with overlapping reflections. The measured ratios of reflections that can be resolved experimentally are used to refine the position, the shape, and the orientation of low-resolution molecular structures within the unit cell, in leading to the resolution of the overlapping reflections. The molecular model is then made progressively more sophisticated as additional diffraction information is included in the analysis. We apply our method to the recovery of the structure of the bacteriorhodopsin molecule (bR) to a resolution of 7 Å using experimental data obtained from two-dimensional purple membrane crystals. The approach can be used to determine the structure factors directly or to provide reliable low-resolution phase information that can be refined further by the conventional methods of protein crystallography.


Systematic review of communication partner training in aphasia: methodological quality.
Twenty-three studies identified from a previous systematic review examining the effects of communication partner training on persons with aphasia and their communication partners were evaluated for methodological quality. Two reviewers rated the studies on defined methodological quality criteria relevant to each study design. There were 11 group studies, seven single-subject participant design studies, and five qualitative studies. Quality scores were derived for each study. The mean inter-rater reliability of scores for each study design ranged from 85-93%, with Cohen's Kappa indicating substantial agreement between raters. Methodological quality of research on communication partner training in aphasia was highly varied. Overall, group studies employed the least rigorous methodology as compared to single subject and qualitative research. Only two of 11 group studies complied with more than half of the quality criteria. No group studies reported therapist blinding and only one group study reported participant blinding. Across all types of studies, the criterion of treatment fidelity was most commonly omitted. Failure to explicitly report certain methodological quality criteria may account for low ratings. Using methodological rating scales specific to the type of study design may help improve the methodological quality of aphasia treatment studies, including those on communication partner training.


[Hypokalemic paralysis after prolonged absorption of a non-alcoholic pastis in a diabetic].
A typical case of glycyrrhizin-induced hypokalemic paralysis in a diabetic patient is presented. Hypokalemia was responsible for a generalized muscle weakness with a rise in serum muscular enzymes and cardiovascular disorders, which improved under potassium supplementation and spironolactone therapy. The pseudoaldosteronism syndrome with low plasma renin activity and aldosteron suggested aldosteron -like liquorice intoxication. Patient's interrogation revealed regular consumption of a common aperitive drink: a non-alcoholic pastis containing small amounts of glycyrrhizin. The discrepancy between the severity of clinical manifestations and the ingested amounts of glycyrrhizin is explained by the diabetic state.


Human complement C3b/C4b receptor (CR1) mRNA polymorphism that correlates with the CR1 allelic molecular weight polymorphism.
The human C3b/C4b receptor (CR1) is a Mr approximately equal to 200,000 single-chain integral membrane glycoprotein of human erythrocytes and leukocytes. It functions both as a receptor for C3b- and C4b-coated ligands and as a regulator of complement activation. Prior structural studies have defined an unusual molecular weight allelic polymorphism in which the allelic products differ in molecular weight by as much as 90,000. On peripheral blood cells there is codominant expression of CR1 gene products of Mr 190,000 (A), 220,000 (B), 160,000 (C), and 250,000 (D). Results of prior biosynthetic and tryptic peptide mapping experiments have suggested that the most likely basis for the allelic molecular weight differences is at the polypeptide level. In order to define further the molecular basis for these molecular weight differences, human CR1 was purified to homogeneity, tryptic peptide fragments were isolated by HPLC and sequenced, oligonucleotide probes were prepared, and a CR1 cDNA was identified. A subclone of this CR1 cDNA was used as a probe of RNA blots of Epstein-Barr virus-transformed cell lines expressing the allelic variants. Each allelic variant encodes two distinct transcripts. A mRNA size polymorphism was identified that correlated with the gene product molecular weight polymorphism. This finding, in addition to a prior report of several homologous repeats in CR1, is consistent with the hypothesis that the molecular weight polymorphism is determined at the genomic level and may have been generated by unequal crossing-over.


High-deductible Health Plans and Nonfatal Opioid Overdose.
Opioid-related overdose is a public health emergency in the United States. Meanwhile, high-deductible health plans (HDHPs) have become more prevalent in the United States over the last 2 decades, raising concern about their potential for discouraging high-need populations, like those with opioid use disorder (OUD), from engaging in care that may mitigate the probability of overdose. This study assesses the impact of an employer offering an HDHP on nonfatal opioid overdose among commercially insured individuals with OUD in the United States. We used deidentified insurance claims data from 2007 to 2017 with 97,788 person-years. We used an intent-to-treat, difference-in-differences regression framework to estimate the change in the probability of a nonfatal opioid overdose among enrollees with OUD whose employers began offering an HDHP insurance option during the study period compared with the change among those whose employer never offered an HDHP. We also used an event-study model to account for dynamic time-varying treatment effects. Across both comparison and treatment groups, 2% of the sample experienced a nonfatal opioid overdose during the study period. Our primary model and robustness checks revealed no impact of HDHP offer on the probability of a nonfatal overdose. Our study suggests that HDHP offer was not associated with an observed increase in the probability of nonfatal opioid overdose among commercially insured person-years with OUD. However, given the strong evidence that medications for OUD (MOUD) can reduce the risk of overdose, research should explore which facets of insurance design may impact MOUD use.


Red blood cell deformability is reduced in homozygous sickle cell disease patients with leg ulcers.
Previous reports differ as to whether a decreased elongation index (EI), a proxy for red blood cell (RBC) deformability, is associated with leg ulcers (LU) in people with homozygous sickle cell disease (SCD). We sought to determine whether erythrocyte deformability (ED) and haematological indices were associated with the presence of LU in patients with SCD. The study design was cross-sectional. Twenty-seven patients with LU and 23 with no history of ulceration were recruited into the study. A laser assisted rotational red cell analyzer was used in the determination of the EI. Haematological indices were determined using a CELL-DYN Ruby haematology analyzer. Data were normally distributed and presented as means±SD. Two-sample t-test was used to test for associations between haemorheological variables in SCD patients with and without LU. Statistical significance was taken as p < 0.05. The EI was significantly lower in the group with ulcers (0.30±0.07 vs. 0.35±0.07, p = 0.02). Haematological indices were comparable in patients with and without LU. Erythrocyte deformability, but not haematological indices, was associated with LU in patients with SCD.


[The effect of the calcium channel blockers cinnarizine and flunarizine on the duration of hexobarbital-induced sleep i rats].
The effect of the calcium channel blockers cinnarizine (20 mg/kg) and flunarizine (10 mg/kg) on hexobarbital sleeping time in rats has been studied. We have found that cinnarizine when applied intraperitoneally once 1 h or 4 h before hexobarbital and repeatedly for 5 days once daily prolongs sleeping time significantly. When cinnarizine has been introduced simultaneously with phenobarbital (60 mg/kg) for 5 days once daily the sleeping time that was expected to be shortened by phenobarbital only has been obtained to return to control values. Flunarizine has not been found to affect sleeping time significantly either alone or in the presence of phenobarbital. Latencies have not been altered by any of both agents.


Reexamination of the sequence of the sea urchin egg receptor for sperm: implications with respect to its properties.
A reexamination of the cDNA clones of the Strongylocentrotus purpuratus sea urchin egg receptor for sperm resulted in several important changes to the sequence. By using both rapid amplification of cDNA ends (RACE) and Northern blot analysis for confirmation, the corrected deduced amino acid sequence was shown to lack a classical signal peptide. In addition, a frame shift resulted in a stop codon terminating the deduced sequence prior to a putative transmembrane domain, thereby truncating the protein to 889 amino acids. The deduced amino acid sequence of the receptor has high sequence similarity to the hsp 110 subfamily of proteins. These findings on the primary structure of the egg receptor for sperm raise important questions concerning the mechanism by which the heavily glycosylated receptor is localized to the extracellular surface of the egg and to the cortical granules.


Improving computer aided disease detection using knowledge of disease appearance.
The accurate quantification of disease patterns in medical images allows radiologists to track the progress of a disease. Various computer vision techniques are able to automatically detect different patterns that appear on images. However, classical pattern detection approaches do not perform satisfactorily on medical images. The problem is that texture descriptors, alone, do not capture information that is pertinent to medical images, i.e. the disease appearance and distribution. We present a method that uses knowledge of anatomy and specialised knowledge about disease appearance to improve computer-aided detection. The system has been tested on detecting honeycombing - a diffuse lung disease pattern in HRCT images of the lung. The results show that the proposed knowledge guided approach improves the accuracy of honeycombing detection. A paired t-test, shows the improvement in accuracy to be statistically significant (p<0.0001).


Characterization of Enzymes Involved in Nintedanib Metabolism in Humans.
Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non-small cell lung cancer, is metabolized to a pharmacologically inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can be hydrolytically cleaved to BIBF1202. In this study, we sought to characterize these metabolic reactions in the human liver and intestine. Nintedanib hydrolysis was detected in human liver microsomes (HLMs) (Clearance [CL int]: 102.8 ± 18.9 µL/min per mg protein) but not in small intestinal preparations. CES1 was suggested to be responsible for nintedanib hydrolysis according to experiments using recombinant hydrolases and hydrolase inhibitors as well as proteomic correlation analysis using 25 individual HLM. BIBF1202 glucuronidation in HLM (3.6 ± 0.3 µL/min per mg protein) was higher than that in human intestinal microsomes (1.5 ± 0.06 µL/min per mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202 glucuronidation. An inhibition study and proteomic correlation analysis suggested that β-glucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic reactions of nintedanib in the human liver and intestine were quantitatively and thoroughly elucidated. This information could be helpful to understand the inter- and intraindividual variability in the efficacy of nintedanib. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to characterize the enzymes responsible for each step of nintedanib metabolism in the human body. This study found that β-glucuronidase may contribute to BIBF1202-G deglucuronidation.


Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle.
RPE65 is essential for isomerization of vitamin A to the visual chromophore. Mutations in RPE65 cause early-onset blindness, and Rpe65-deficient mice lack 11-cis-retinal but overaccumulate alltrans-retinyl esters in the retinal pigment epithelium (RPE). RPE65 is proposed to be a substrate chaperone but may have an enzymatic role because it is closely related to carotenoid oxygenases. We hypothesize that, by analogy with other carotenoid oxygenases, the predicted iron-coordinating residues of RPE65 are essential for retinoid isomerization. To clarify RPE65's role in isomerization, we reconstituted a robust minimal visual cycle in 293-F cells. Only cells transfected with RPE65 constructs produced 11-cis-retinoids, but coexpression with lecithin:retinol acyltransferase was needed for high-level production. Accumulation was significant, amounting to >2 nmol of 11-cis-retinol per culture. Transfection with constructs harboring mutations in residues of RPE65 homologous to those required for interlinked enzymatic activity and iron coordination in related enzymes abolish this isomerization. Iron chelation also abolished isomerization activity. Mutating cysteines implicated in palmitoylation of RPE65 had generally little effect on isomerization activity. Mutations associated with Leber congenital amaurosis/early-onset blindness cause partial to total loss of isomerization activity in direct relation to their clinical effects. These findings establish a catalytic role, in conjunction with lecithin:retinol acyltransferase, for RPE65 in synthesis of 11-cis-retinol, and its identity as the isomerohydrolase.


The HIQA's Health Technology Assessment of Breast Screening: Highlighting Some of the Challenges Posed by Evaluations of Screening Programs.
A review of the Health Information and Quality Authority's (HIQA) assessment of breast cancer surveillance cancer criticized how the results were presented and interpreted. The health technology assessment (HTA) investigated surveillance options for women aged less than 50 years who were at elevated risk of breast cancer. Surveillance strategies using digital mammography, magnetic resonance imaging, or a combination of the two modalities were modeled on the basis of diagnostic test accuracy. The HTA faced a number of issues, including the use of diagnostic test accuracy as a surrogate for long-term outcomes; modeling interventions that were not considered acceptable to clinicians; and extrapolating for screening intervals and age ranges not directly supported by available evidence. The evaluation of screening programs gives rise to challenges in terms of balancing an adequate exploration of the possible options while also being cognizant of what is appropriately supported by evidence. In this article, the authors of the HIQA report discuss the challenges posed by this particular HTA.


Metastatic choriocarcinoma presenting in a gravid woman.
Choriocarcinoma coexistent with an intrauterine pregnancy is rare and requires decisions affecting mother and child to treat this aggressive tumor. An instance of this situation is presented to highlight clinical circumstances that warrant departure from accepted dogma. Pathologic aspects of choriocarcinoma are also discussed. Diagnosis of choriocarcinoma during an otherwise normal pregnancy requires a high index of suspicion and consideration of unconventional diagnostic maneuvers.


Evolving patterns of resistance to respiratory pathogens in Canada.
Active surveillance of changing resistance patterns is difficult but important for rational therapeutic choices. In Canada, penicillin resistance in Streptococcus pneumoniae has evolved more slowly than in other countries (in Europe and Israel rates exceed 50%). Currently, penicillin resistance is found in roughly 21% of Canadian isolates, and cross-resistance is becoming common. Beta-lactamase production is now found in approximately 28% of Haemophilus influenzae isolates, although more recently, rates over 30% have been found in some areas of Canada. In Moraxella catarrhalis, beta-lactamases are produced by 80% to 90% of bacteria, with resistance to trimethoprim/sulphamethoxazole also found. To date, there have been only a few reports of resistance to the fluoroquinolones. The apparent increase in the rate of development of resistance and cross-resistance will lead to new therapeutic challenges.


Rhodobacter capsulatus porphobilinogen synthase, a high activity metal ion independent hexamer.
The enzyme porphobilinogen synthase (PBGS), which is central to the biosynthesis of heme, chlorophyll and cobalamins, has long been known to use a variety of metal ions and has recently been shown able to exist in two very different quaternary forms that are related to metal ion usage. This paper reports new information on the metal ion independence and quaternary structure of PBGS from the photosynthetic bacterium Rhodobacter capsulatus. The gene for R. capsulatus PBGS was amplified from genomic DNA and sequencing revealed errors in the sequence database. R. capsulatus PBGS was heterologously expressed in E. coli and purified to homogeneity. Analysis of an unusual phylogenetic variation in metal ion usage by PBGS enzymes predicts that R. capsulatus PBGS does not utilize metal ions such as Zn2+, or Mg2+, which have been shown to act in other PBGS at either catalytic or allosteric sites. Studies with these ions and chelators confirm the predictions. A broad pH optimum was determined to be independent of monovalent cations, approximately 8.5, and the Km value shows an acidic pKa of approximately 6. Because the metal ions of other PBGS affect the quaternary structure, gel permeation chromatography and analytical ultracentrifugation experiments were performed to examine the quaternary structure of metal ion independent R. capsulatus PBGS. The enzyme was found to be predominantly hexameric, in contrast with most other PBGS, which are octameric. A protein concentration dependence to the specific activity suggests that the hexameric R. capsulatus PBGS is very active and can dissociate to smaller, less active, species. A homology model of hexameric R. capsulatus PBGS is presented and discussed. The evidence presented in this paper supports the unusual position of the R. capsulatus PBGS as not requiring any metal ions for function. Unlike other wild-type PBGS, the R. capsulatus protein is a hexamer with an unusually high specific activity when compared to other octameric PBGS proteins.


Chiral hydroperoxides as oxygen source in the catalytic stereoselective epoxidation of allylic alcohols by sandwich-type polyoxometalates: control of enantioselectivity through a metal-coordinated template.
The epoxidation of allylic alcohols is shown to be efficiently and selectively catalyzed by the oxidatively resistant sandwich-type polyoxometalates, POMs, namely [WZnM(2)(ZnW(9)O(34))(2)](q)(-) [M = OV(IV), Mn(II), Ru(III), Fe(III), Pd(II), Pt(II), Zn(II); q = 10-12], with organic hydroperoxides as oxygen source. Conspicuous is the fact that the nature of the transition metal M in the central ring of polyoxometalate affects significantly the reactivity, chemoselectivity, regioselectivity, and stereoselectivity of the allylic alcohol epoxidation. For the first time, it is demonstrated that the oxovanadium(IV)-substituted POM, namely [ZnW(VO)(2)(ZnW(9)O(34))(2)](12-), is a highly chemoselective, regioselective, and also stereoselective catalyst for the clean epoxidation of allylic alcohols. A high enantioselectivity (er values up to 95:5) has been achieved with [ZnW(VO)(2)(ZnW(9)O(34))(2)](12)(-) and the sterically demanding TADOOL-derived hydroperoxide TADOOH as regenerative chiral oxygen source. Thus, a POM-catalyzed asymmetric epoxidation of excellent catalytic efficiency (up to 42 000 TON) has been made available for the development of sustainable oxidation processes. The high reactivity and selectivity of this unprecedented oxygen-transfer process are mechanistically rationalized in terms of a peroxy-type vanadium(V) template.


"Senseless" antiviral polyribonucleotides: poly (1-propargylinosinic acid).
Previous work has shown that novel amphipathic oligo and polyribonucleotides exhibiting secondary structure in solution are potent inhibitors of HIV and HCMV replication and cytopathicity in tissue culture. It was hypothesized that the mechanism(s) of action for these compounds might be inhibition of retroviral reverse transcriptase (RT) and/or viral uptake by cells. Pursuit of the essential pharmacophore has led to the discovery of poly (1-propargylinosinic acid) (10), an HIV and HCMV-active polyribonucleotide lacking the secondary structure previously thought to be essential for the observed antiviral activity.


Barriers to preventive health practices in women with spinal cord impairments.
Women with spinal cord impairment (SCI) encounter many barriers to receiving satisfactory health care. Problems associated with access to health care decrease the likelihood of health promotion and disease prevention activities for women with disabilities such as SCI. A convenience sample of 28 women was recruited from community settings to participate in this qualitative investigation. This study examined three factors that impact preventative health practices of women with SCI. These are: inadequate knowledge of women with SCI regarding health care risks and health care needs, reliance on caregivers to facilitate preventative health practices, and perceived access to competent health care providers (HCP). Audiotaped interviews were conducted using qualitative data analysis through analytical induction and constant comparison. Saturation of information revealed three common domains: self-management, interactions with caregivers, and interactions with the health care system. Several recommendations are made to facilitate provisions of health promotion and disease prevention activities for women with SCI.


Protective effects of taurine against closed head injury in rats.
Taurine, an abundant amino acid in the nervous system, is reported to reduce ischemic brain injury in a dose-dependent manner. This study was designed to investigate whether taurine protected the brain against closed head injury (CHI) in rats. Taurine was administered intravenously 30 min after CHI. It was found that taurine lessened body-weight loss and improved neurological functions at 7 days after CHI. Moreover, it lowered brain edema and blood-brain barrier permeability, enhanced activity of superoxide dismutase and the level of glutathione, and reduced levels of malondialdehyde and lactic acid in traumatic tissue 24 h after CHI. In addition, it attenuated neuronal cell death in hippocampal CA1 and CA3 subfields 7 days after CHI. All of these effects were dose dependent. These data demonstrated the dose-dependent protection of taurine against experimental CHI and suggest that taurine treatment might be beneficial in reducing trauma-induced oxidative damage to the brain, thus showing the potential for clinical implications.


Efficacy and safety of concomitant 177Lu-DOTATATE and low-dose capecitabine in advanced medullary thyroid carcinoma: a single-centre experience.
Peptide receptor radionuclide therapy (PRRT) has been shown to be useful in inoperable/metastatic medullary thyroid carcinoma (MTC). However, the role of concomitant PRRT and low-dose capecitabine therapy has not yet been studied in these patients. This study was conducted to evaluate the efficacy and safety of this combination approach in advanced MTC. This was a retrospective, single-centre study. Data of consecutive patients of advanced inoperable/metastatic MTC treated with concomitant Lu-DOTATATE+capecitabine, from January 2014 to August 2018, were collected and analysed for radiological, molecular and biochemical responses and treatment-related toxicity. Eight patients with advanced MTC received a median cumulative dose of 20.9 GBq (interquartile range 8.9-27.7 GBq) Lu-DOTATATE over 1-4 cycles and 1250 mg/m capecitabine from days 0 to 14 of each PRRT cycle. Radiological response according to Response Evaluation Criteria in Solid Tumours 1.1 criteria could be assessed in seven patients. Six out of seven patients (86%) had stable disease, while disease progression was observed in 1/7 (14%) patients. However, molecular response, as per the European Organization for Research and Treatment of Cancer criteria, was observed in all the seven patients. Biochemical response with reduction in serum calcitonin levels was observed in 3/5 (60%) patients. With the exception of grade 2 anaemia in one patient, no other significant toxicity was observed in this cohort. Our results indicate the efficacy and safety of concomitant Lu-DOTATATE and capecitabine in advanced MTC. Larger randomized controlled trials are, however, required to establish the role of capecitabine as a radiosensitizer along with PRRT in these patients.


The dynamic changes of X chromosome inactivation during early culture of human embryonic stem cells.
X chromosome inactivation (XCI) is required for dosage compensation of X-linked genes in human female cells. Several previous reports have described the promiscuous XCI status in long-term cultured female human embryonic stem cells (hESCs), and the majority of them exhibit non-random XCI. However, when and how such female hESCs acquire the aberrant XCI states during culture is unknown. Herein, through comparing the XCI states in 18 paired hES cell lines throughout early culture, we revealed a uniform dynamic change during this culture period under a widely used culture condition. The female initial hESCs (ihESCs, P4-P9) expressed XIST RNA, H3K27me3 punctate enrichment and displayed random XCI pattern. By further culturing, the female early hESCs (ehESCs, P20-P30) lost the expression of XIST RNA, H3K27me3 punctate enrichment and exhibited a completely skewed XCI pattern. Importantly, a subset of X-linked genes was up-regulated in ehESCs, including some cancer-related genes. At last, we found 5% physiological oxygen was beneficial for the expression of XIST and H3K27me3 punctate enrichment, but not for the XCI pattern. We conclude that the XCI dynamic change is a frequent epigenetic instability event during early culture, which is accompanied by the up-regulation of some X-linked genes. Furthermore, we emphasize that physiological oxygen is beneficial for XCI fidelity.


Nadir CD4+ T cell count predicts response to subcutaneous recombinant interleukin-2.
Community Program for Clinical Research on AIDS 059 was a multicenter study conducted among human immunodeficiency virus (HIV)-infected individuals with CD4+ cell counts > or =300 cells/mm3 who were randomly assigned to receive antiretroviral therapy with or without intermittent subcutaneously administered recombinant interleukin-2 (rIL-2). To identify factors associated with a response to IL-2, a secondary analysis was performed that included the subset of rIL-2 recipients who were able to complete all 3 initial treatment cycles. Predictors of a change in CD4+ cell count between baseline and 1 month after the start of treatment cycle 3 were examined in a multivariate model that included sex, race, body surface area, rIL-2 dose, HIV load, and both baseline and nadir CD4+ cell count. The combination of race and sex (P=.027) and the nadir CD4+ cell count (P=.005) were significant predictors of mean CD4+ cell count response. Baseline CD4+ cell count had no significant effect. The strong association between nadir CD4+ cell count and CD4+ cell count response suggests that immunologic losses resulting from HIV-mediated CD4+ cell depletion may be irreversible.


Role of carbon monoxide in cardiovascular function.
Carbon monoxide (CO) is an endogenously derived gas formed from the breakdown of heme by the enzyme heme oxygenase. Although long considered an insignificant and potentially toxic waste product of heme catabolism, CO is now recognized as a key signaling molecule that regulates numerous cardiovascular functions. Interestingly, alterations in CO synthesis are associated with many cardiovascular disorders, including atherosclerosis, septic shock, hypertension, metabolic syndrome, and ischemia-reperfusion injury. Significantly, restoration of physiologic CO levels exerts a beneficial effect in many of these settings, suggesting a crucial role for CO in maintaining cardiovascular homeostasis. In this review, we outline the actions of CO in the cardiovascular system and highlight this gas as a potential therapeutic target in treating a multitude of cardiovascular disorders.


[Prevalence study of nosocomial infections in university hospitals in the Czech Republic].
In 2005-2010, a nosocomial infection prevalence study was conducted in 12 university hospitals, namely at the departments of surgery, urology, neurology, cardiology, neurosurgery, otorhinolaryngology, and traumatology. The primary objective was to evaluate the overall epidemiological situation of nosocomial infections (NI) at the highest risk departments of selected healthcare facilities in the Czech Republic and to characterize the NI detected. To collect data, a questionnaire survey method was used, as it suited the routine operation conditions in healthcare facilities and was inexpensive, easy to understand, reproducible, and repeatable if needed. The questionnaire was designed according to the protocol recommended by the working group HELICS (Hospital in Europe Link for Infection Control through Surveillance). In each of the participating hospitals, the medical records of all patients hospitalized at the respective departments were analyzed. The patient data, hospitalization data, potential risk factors, and occurrence of hospital infection, if any, were derived from the medical records and entered in the questionnaire. Overall, data on 1889 hospitalized patients were analyzed. Eighty-one confirmed NI cases were found, i.e. the prevalence rate in this study was 4.3% (the percentage of HI per the number of hospitalized patients), which is in agreement with the recent data reported in the European Union. The most common causative agents were Pseudomonas spp. (16%), Staphylococcus aureus (15%), Escherichia coli (12%), Proteus spp. (10%), and Klebsiella spp. (4%), with the urinary tract (41%) and respiratory tract (23%) being affected most often.


Photoluminescence of ZnO Nanowires: A Review.
One-dimensional ZnO nanostructures (nanowires/nanorods) are attractive materials for applications such as gas sensors, biosensors, solar cells, and photocatalysts. This is due to the relatively easy production process of these kinds of nanostructures with excellent charge carrier transport properties and high crystalline quality. In this work, we review the photoluminescence (PL) properties of single and collective ZnO nanowires and nanorods. As different growth techniques were obtained for the presented samples, a brief review of two popular growth methods, vapor-liquid-solid (VLS) and hydrothermal, is shown. Then, a discussion of the emission process and characteristics of the near-band edge excitonic emission (NBE) and deep-level emission (DLE) bands is presented. Their respective contribution to the total emission of the nanostructure is discussed using the spatial information distribution obtained by scanning transmission electron microscopy-cathodoluminescence (STEM-CL) measurements. Also, the influence of surface effects on the photoluminescence of ZnO nanowires, as well as the temperature dependence, is briefly discussed for both ultraviolet and visible emissions. Finally, we present a discussion of the size reduction effects of the two main photoluminescent bands of ZnO. For a wide emission (near ultra-violet and visible), which has sometimes been attributed to different origins, we present a summary of the different native point defects or trap centers in ZnO as a cause for the different deep-level emission bands.


Time- and population-dependent genetic patterns underlie bovine milk somatic cell count.
The objective of this study was to determine whether genetic regulation of bovine milk somatic cell count (SCC) varied throughout the course of an individual lactation and to identify quantitative trait loci (QTL) that may differentiate populations of chronically mastitic and robustly healthy cows. Milk SCC has long been a proxy for clinical mastitis diagnosis in management and genetic improvement strategies to control the disease. Cows (n = 471) were genotyped on the Illumina BovineHD 777K BeadChip (Illumina Inc., San Diego, CA), and composite milk samples were collected for SCC at 0-1 d in milk (DIM), 3-5 DIM, 10-14 DIM, 90-110 DIM, and 210-230 DIM, with each time span representing key physiological transitions for the cow. Median lactation somatic cell score (SCS) and area under the SCS curve were calculated from farm test data. A total of 8 genome-wide associations were performed and 167 SNP spanning the genome were significantly associated (false discovery rate <0.05). Of these associated regions, 27 of 48 associated QTL were novel for clinical mastitis or SCC. The linkage disequilibrium block surrounding the associated QTL or a 1-Mb window in the absence of linkage disequilibrium was interrogated for candidate genes, and many of those identified were related to multiple arms of the immune system, including toll-like receptor signaling, macrophage activation, B-cell maturation, T-cell recruitment, and the complement pathway. These genes included EXOC4, BAMBI, ITSN2, IL34, FCN3, CD8A, and CD8B. In addition, we identified populations of robustly healthy (SCS ≤4 from 10-14 DIM until study end), chronically mastitic (SCS >4 from 10-14 DIM until study end), and average cows with fluctuating SCS, and calculated fixation indices to identify regions of the genome differentiating these 3 populations. A total of 12 SNP were identified that showed moderate allelic differentiation (Wright's F statistic, FST ≥ 0.4) between the "chronic," "healthy," and "average" populations of cows. Candidate genes in the region surrounding differentiated QTL were related to cell signaling and immune response, such as JAKMIP1 and MADCAM1. The wide range of significantly associated QTL spanning the genome and the diversity of gene functions reinforces that mastitis is a complex trait and suggests that selection based on lactation stage-specific SCS rather than a generalized score may lead to greater success in breeding mastitis-resistant cows.


Pi-complex structure of gaseous benzene-NO cations assayed by IR multiple photon dissociation spectroscopy.
[C(6)H(6)NO](+) ions, in two isomeric forms involved as key intermediates in the aromatic nitrosation reaction, have been produced in the gas phase and analyzed by IR multiple photon dissociation (IRMPD) spectroscopy in the 800-2200 cm(-)(1) fingerprint wavenumber range, exploiting the high fluence and wide tunability of a free electron laser (FEL) source. The IRMPD spectra were compared with the IR absorption spectra calculated for the optimized structures of potential isomers, thus allowing structural information on the absorbing species. [C(6)H(6)NO](+) ions were obtained by two routes, taking advantage of the FEL coupling to two different ion traps. In the first one, an FT-ICR mass spectrometer, a sequence of ion-molecule reactions was allowed to occur, ultimately leading to an NO(+) transfer process to benzene. The so-formed ions displayed IRMPD features characteristic of a [benzene,NO](+) pi-complex structure, including a prominent band at 1963 cm(-)(1), within the range for the N-O bond stretching vibration of NO (1876 cm(-)(1)) and NO(+) (2344 cm(-)(1)). A quite distinct species is formed by electrospray ionization (ESI) of a methanol solution of nitrosobenzene. The ions transferred and stored in a Paul ion trap showed the IRMPD features of substituent protonated nitrosobenzene, the most stable among conceivable [C(6)H(6)NO](+) isomers according to computations. It is noteworthy that IRMPD is successful in allowing a discrimination between isomeric [C(6)H(6)NO](+) species, whereas high-energy collision-induced dissociation fails in this task. The [benzene,NO](+) pi-complex is characterized by IRMPD spectroscopy as an exemplary noncovalent ionic adduct between two important biomolecular moieties.


Nature of Si-H interactions in a series of ruthenium silazane complexes using multinuclear solid-state NMR and neutron diffraction.
Three new N-heterocyclic-silazane compounds, 1a-c, were prepared and employed as bidentate ligands to ruthenium, resulting in a series of [Ru(H){(κ-Si,N-(SiMe2-N-heterocycle)}3] complexes (3a-c) featuring the same RuSi3H motif. Detailed structural characterization of the RuSi3H complexes with X-ray diffraction, and in the case of triazabicyclo complex [Ru(H){κ-Si,N-(SiMe2)(C7H12N3)}3] (3a), neutron diffraction, enabled a reliable description of the molecular geometry. The hydride ligand of (3a) is located closer to two of the silicon atoms than it is to the third. Such a geometry differs from that of the previously reported complex [Ru(H){(κ-Si,N-(SiMe2)N(SiMe2H)(C5H4N)}3] (3d), also characterized by neutron diffraction, where the hydride was found to be equidistant from all three silicon atoms. A DFT study revealed that the symmetric and less regular isomers are essentially degenerate. Information on the dynamics and on the Ru···H···Si interactions was gained from multinuclear solid-state ((1)H wPMLG, (29)Si CP MAS, and 2D (1)H-(29)Si dipolar HETCOR experiments) and solution NMR studies. The corresponding intermediate complexes, [Ru{κ-Si,N-(SiMe2-N-heterocycle)}(η(4)-C8H12)(η(3)-C8H11)] (2a-c), involving a single silazane ligand were isolated and characterized by multinuclear NMR and X-ray diffraction. Protonation of the RuSi3H complexes was also studied. Reaction of 3a with NH4PF6 gave rise to [Ru(H)(η(2)-H -SiMe2)κ-N-(C7H12N3){κ-Si,N-(SiMe2)(C7H12N3)}2](+)[PF6](-)(4aPF6) which was isolated and characterized by NMR spectroscopy, X-ray crystallography, and DFT studies. The nature of the Si-H interactions in this silazane series was analyzed in detail.


Dark citizen science.
Citizen science is often celebrated. We interrogate this position through exploration of socio-technoscientific phenomena that mirror citizen science yet are disaligned with its ideals. We term this 'Dark Citizen Science'. We identify five conceptual dimensions of citizen science - purpose, process, perceptibility, power and public effect. Dark citizen science mirrors traditional citizen science in purpose and process but diverges in perceptibility, power and public effect. We compare two Internet-based categorisation processes, Citizen Science project Galaxy Zoo and Dark Citizen Science project Google's reCAPTCHA. We highlight that the reader has, likely unknowingly, provided unpaid technoscientific labour to Google. We apply insights from our analysis of dark citizen science to traditional citizen science. Linking citizen science as practice and normative democratic ideal ignores how some science-citizen configurations actively pit practice against ideal. Further, failure to fully consider the implications of citizen science for science and society allows exploitative elements of citizen science to evade the sociological gaze.


Epidemiology of childhood diabetes mellitus in Japan.
The incidence of type 1 diabetes mellitus (T1DM) in Japan among those below 15 years of age is reportedly 1.5-2.5 per 100,000; however, population-based data have not been available in recent years. Although the incidence of T1DM in Japan is extremely low compared with that in Caucasians, the vast majority of Japanese children who are diagnosed with diabetes before the age of 10 years have T1DM. The incidence of type 2 diabetes mellitus (T2DM) in childhood is approximately 3.0 per 100,000, with the figure among junior high school children being 3-6 times higher than that among primary school children. The most common type of diabetes in children appears to shift from T1DM to T2DM with advancing age, especially after puberty. The mortality risk of patients with childhood-onset T1DM diagnosed between 1965 and 1979 is 12.9-fold higher than that of the general population. However, due to efforts aimed at improving medical care and ameliorating the effects of diabetes among children and adolescents, the standardized mortality ratio (SMR) has declined markedly over the past 30 years. The progression of complications in T2DM appears to be more rapid than that in T1DM, primarily due to the number of drop-out cases. Therefore, appropriate education and treatment programs are necessary to protect against diabetic complications in the younger generation. The establishment of an ongoing population-based national T1DM and T2DM registry system is critical for identifying risk factors associated with diabetes and its complications.


Metabonomics analysis of flavonoids in seeds and sprouts of two Chinese soybean cultivars.
A popular food in China, soybean seeds and sprouts contained many biologically active substances which are beneficial to the human body, such as flavonoids. Northeast of China is the main producing area of soybean. The experimental materials came from the main soybean producing areas in Northeast China, this study compared flavonoids of two China cultivars of soybeans, Heinong52(HN52) and Heinong71(HN71). Here, we also considered the effects of germination on the chemical profile of flavonoids. Using a LC-ESI-MS/MS system, 114 differential flavonoid metabolites were identified. A total of 18 metabolites were significantly different between the two soybean varieties before germination, of which 14 were up-regulated and 4 were down-regulated. After germination, 33 significantly different metabolites were found in the two soybean sprouts, of which 19 were up-regulated and 14 were down-regulated. These experimental results revealed significant up-regulation of metabolites in soybean sprouts compared with soybean seeds, thus suggesting that soybean germination may increase content of flavonoid metabolites. There are six main pathways for the synthesis of flavonoids: isoflavonoid biosynthesis, flavonoid biosynthesis, flavone and flavonol biosynthesis, biosynthesis of secondary metabolites, and biosynthesis of phenylpropanoids. Soybean seeds lack flavone and flavanol biosynthesis and develop the capacity for this biosynthetic pathway after germination as sprouts. Isoflavonoid biosynthesis is the most abundantly utilized pathway.


Resonance properties of thick plasmonic split ring resonators for sensing applications.
We investigate in detail the optical response of dense split ring resonator (SRR) arrays as a function of their thickness, for normally impinging light in the VIS-NIR spectral range. We find that, for sufficiently tall SRRs, several vertical Fabry-Perot resonances can be excited, which may interact with the well-known horizontal SRR resonant paths. Furthermore, we analyze the possibility to exploit these nanostructures to detect bio-chemical quantities. In particular, we find that the coexistence of vertical and horizontal resonances yields an increased sensitivity. Well ordered, large arrays of thick SRRs are obtained by exploiting a fabrication process based on X-Ray Lithography. A very good agreement is found between numerical and measured transmittances. A preliminary detection test evidences the potential of this geometry as a sensing platform.


Sustainable Brownfields Redevelopment in the European Union: An Overview of Policy and Funding Frameworks.
This first article in a series of three on land reuse highlights sustainable brownfields redevelopment in Europe. Sustainability is a key European concept. Europe's densely populated urban areas are facing specific challenges that include urban sprawl and environmental pollution. Redeveloping brownfields, or reusing the abandoned built landscape, can positively impact the economic, social, and environmental health security of cities. Many European Union (EU) cities benefit from policy and financial assistance in renovating their urban areas. This article reviews the EU's policy and funding frameworks that support sustainable brownfields redevelopment. Brownfield site problems are common to many countries in Europe and around the world, and this article aims to share knowledge and resources that support the transformation of these abandoned or underused areas into public or private uses.


Mechanism underlying superantigen-induced clonal deletion of mature T lymphocytes.
We observed that peripheral T cells activated in vivo or in vitro by superantigens are susceptible to cell death when their antigen receptor is cross-linked with the appropriate anti-alpha beta TCR mAb. TCR ligation by mAbs specifically drove the T cell clonal deletion in both CD4+ and CD8+ cell subsets. An IL-2/IL-2R interaction seems to be a critical step in predisposing superantigen activated cells to death; in fact, in vivo IL-2R blockade reversed T cell deletion in superantigen plus anti-alpha beta TCR mAb treated mice. TCR ligation by mAbs also produced cell death of the relevant targets in in vitro IL-2 activated T cells. Surprisingly, no T cell deletion was demonstrable in IL-2 activated cells following staphylococcal enterotoxin B--TCR interaction, ruling out the possibility that superantigen in itself can induce cell death. Thus, while superantigen activation opens the cell death program, a subsequent TCR--antigen (self) interaction appears necessary to produce clonal deletion in mature T lymphocytes.


Complicated forms of tachycardia-mediated cardiomyopathy associated with idiopathic left ventricular tachycardia.
Idiopathic left ventricular tachycardia is an infrequent form of ventricular tachycardia associated with a structurally normal heart. The prognosis is usually benign; however, sustained cases have been reported. In this report, we describe two cases of persistent idiopathic left ventricular tachycardia complicated by tachycardia-mediated cardiomyopathy. In the first case, the patient developed a right ventricular thrombus with subsequent pulmonary embolism. In the second case, the patient developed acute pulmonary edema. Both cases were cured by catheter ablation.


Association between NF-κB expression and drug resistance of liver cancer.
Association between the expression of nuclear factor κB (NF-κB) and the drug resistance of hepatoma cells was investigated. HepG-2 cells and HepG2/ADM cells were cultured, respectively. The morphology and status of the two groups of cells were observed by cell white light. The immunofluorescence by NF-κB and MDR1 staining on HepG-2 cells and HepG2/ADM cells, respectively, was applied and the fluorescence expression in the two groups of cells was observed. RT-qPCR was used to detect the expression of NF-κB and MDR1 mRNA, the NF-κB and MDR1 protein expression was detected by western blot analysis. The results of cell white illumination showed that the structure of HepG-2 and HepG2/ADM cells was complete and the cell morphology was normal, and there was no significant difference, and could be used for comparative study. Immunofluorescence staining showed that the expression of NF-κB and MDR1 in HepG-2 cells was very low, while the expression of NF-κB and MDR1 in HepG2/ADM cells was increased significantly. The RT-qPCR results showed that NF-κB and MDR1 mRNA expression in HepG-2 cells was very low, while NF-κB and MDR1 mRNA expression in HepG-2/ADM cells was significantly increased, and western blot results showed that NF-κB and MDR1 protein expression in HepG-2 cells was very low, while NF-κB and MDR1 protein expression in HepG-2/ADM cells was increased significantly. The results of variance analysis showed that there was significant difference in the expression of the control group and paeonol group (P<0.01). In conclusion, the expression of NF-κB in the drug-resistant cells of liver cancer is closely related to the resistance-related gene MDR1. This result may provide a new solution for the drug resistance of liver cancer.


Reversal of pressure-induced tremors in rats by step decompression and by inert gases.
A method for continuously recording the motor activity of pressurized rats was used to monitor their condition after 1) holding pressure constant after compression, 2) decompression, and 3) adding nitrogen prior to holding pressure constant. After procedures 1 and 2 the logarithm of activity plotted linearly against time in two distinct phases. A short initial decline was followed by a slower, longer decline that was incomplete after 5 h. The rate of the second, slower decline was inversely related to the holding pressure and unaffected by prior convulsions. The addition of 4.8 atm N2 was very effective at decreasing the activity at constant pressure compared to a large (43%) decompression step. The slopes obtained from plots of activity against pressure, which provide a measure of the sensitivity of the animal to compression, were unaltered by the early inclusion of 4.8 atm N2 or 0.19 atm N2O but were displaced to higher pressures. Activity appears to be the net result of activity-generating and accommodation processes, and there was no evidence that it was in equilibrium with pressure.