The epsilon glutathione S-transferases contribute to the malathion resistance in the oriental fruit fly, Bactrocera dorsalis (Hendel).
Epsilon glutathione S-transferases (eGSTs) play important roles in xenobiotics detoxification and insecticides resistance in insects. However, the molecular mechanisms of eGSTs-mediated insecticide resistance remain largely unknown in the Bactrocera dorsalis (Hendel), one of the most notorious pests in the world. Here, we investigated the roles of eight GST genes which belonged to epsilon class (BdGSTe1, BdGSTe2, BdGSTe3, BdGSTe4, BdGSTe5, BdGSTe6, BdGSTe7 and BdGSTe9) in conferring malathion resistance in B. dorsalis. Adult developmental stage-, sex- and tissue-specific expression patterns of the eight eGST genes were analyzed via quantitative reverse transcription PCR. The results showed that BdGSTe2, BdGSTe3, BdGSTe4 and BdGSTe9 were abundant in the midgut, fat body and Malpighian tubules. Notably, BdGSTe2, BdGSTe4 and BdGSTe9 were significantly overexpressed in a malathion-resistant (MR) strain of B. dorsalis compared to the malathion-susceptible (MS) strain. Functional expression and cytotoxicity assays showed significantly higher malathion detoxification capabilities in BdGSTe2-, BdGSTe3-, BdGSTe4- and BdGSTe9-expressing Sf9 cells compared to the parental and green fluorescent protein (GFP)-expressing Sf9 cells. Moreover, malathion susceptibility in MS adults was increased 30%, 14%, and 33% when BdGSTe2, BdGSTe3 and BdGSTe4 mRNA levels were repressed by RNA interference (RNAi)-mediated knockdown, respectively. Taken together, overexpression of the isoforms of eGSTs, including BdGSTe2, BdGSTe4, and particularly, BdGSTe9 plays an important role in the malathion resistant development in B. dorsalis.


Multiple displacement amplification prior to single nucleotide polymorphism genotyping in epidemiologic studies.
We assessed the whole genome amplification strategy, known as multiple displacement amplification (MDA), for use with the TaqMan genotyping platform for DNA samples derived from two case-control studies nested in the Nurses' Health Study and the Physicians' Health Study. Our objectives were to (1) quantify DNA yield from samples of varying starting concentrations and (2) assess whether MDA products give an accurate representation of the original genomic sequence. Multiple displacement amplification yielded a mean 23000-fold increase in DNA quantity and genotyping results demonstrate 99.95% accuracy across six SNPs from four genes for 352 samples included in this study. These results suggest that MDA will provide a sufficiently robust amplification of limiting samples of genomic DNA that can be used for SNP genotyping in large case-control studies of complex diseases.


Clinical judgment versus geriatric assessment for frailty in older patients with cancer.
Geriatric assessment (GA) is an appropriate method for identifying frailty in older patients with cancer, but a shorter instrument may be easier to use in clinical practice. Clinical judgment is always available and requires no investments in time or resources. The purpose of this study was to assess correlations between clinical judgment for frailty of the cancer specialist, the general practitioner and patient's self-assessment, and the correlation between clinical judgment and GA. This was a dual-center inception cohort study of patients with cancer aged ≥70 years starting curative or first-line palliative chemotherapy. GA included the following domains: (instrumental) activities of daily living, nutrition, mobility, cognition, mood, and polypharmacy. Clinical judgment for frailty was rated on a scale from 0 to 10 (0 = not frail, 10 = frail). Correlation was tested using Kendall's tau-b correlation coefficient. Of all 55 patients, 76% had ≥2 geriatric impairments. Median clinical judgment frailty score was 3 (range 1-10 for cancer specialist and patient and range 0-10 for general practitioner) and did not vary much according to the number of impaired geriatric domains (ranging from 2 for 0-1 impaired domains to 4 for ≥3 impaired domains). Correlations between mutual clinical judgment scores and between clinical judgment and GA were negligible or low. Correlations between clinical judgment scores and between clinical judgment and GA were poor. Most patients with multiple geriatric impairments had low 'subjective' frailty scores. Other frailty assessments, such as frailty screening tools or GA, should be considered in addition to clinical judgment when selecting older patients for potential treatment with chemotherapy.


Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
This study sought to determine whether tight glycemic control with a modified glucose-insulin-potassium (GIK) solution in diabetic coronary artery bypass graft (CABG) patients would improve perioperative outcomes. One hundred forty-one diabetic patients undergoing CABG were prospectively randomized to tight glycemic control (serum glucose, 125 to 200 mg/dL) with GIK or standard therapy (serum glucose <250 mg/dL) using intermittent subcutaneous insulin beginning before anesthesia and continuing for 12 hours after surgery. GIK patients had lower serum glucose levels (138+/-4 versus 260+/-6 mg/dL; P<0.0001), a lower incidence of atrial fibrillation (16.6% versus 42%; P=0.0017), and a shorter postoperative length of stay (6.5+/-0.1 versus 9.2+/-0.3 days; P=0.003). GIK patients also showed a survival advantage over the initial 2 years after surgery (P=0.04) and decreased episodes of recurrent ischemia (5% versus 19%; P=0.01) and developed fewer recurrent wound infections (1% versus 10%, P=0.03). Tight glycemic control with GIK in diabetic CABG patients improves perioperative outcomes, enhances survival, and decreases the incidence of ischemic events and wound complications.


Clinical developments of chemotherapeutic nanomedicines: polymers and liposomes for delivery of camptothecins and platinum (II) drugs.
For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small molecule chemotherapeutics, increasing tumor bearing animal survival times, and improving drug targeting. Although a number of macromolecular-drug conjugates have progressed to clinical trials, tuning drug release to maintain efficacy in conjunction with controlling drug toxicity has prevented the clinical adoption of many vehicles. In this article, we review the motivations for and approaches to polymer and liposomal delivery with regard to camptothecin and cisplatin delivery.


Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8.
The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of drugs and exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver. Nearly all previous works about polymorphic variants of CYP2C8 were focused on unpurified proteins, either cells or human liver microsomes; therefore their structure-function relationships were unclear. In this study, two polymorphic enzymes of CYP2C8 (CYP2C8.4 (I264M) and CYP2C8 P404A) were expressed in E. coli and purified. Metabolic activities of paclitaxel by the two purified polymorphic enzymes were observed. The activity of CYP2C8.4 was 25% and CYP2C8 P404A was 30% of that of WT CYP2C8, respectively. Their structure-function relationships were systematically investigated for the first time. Paclitaxel binding ability of CYP2C8.4 increased about two times while CYP2C8 P404A decreased about two times than that of WT CYP2C8. The two polymorphic mutant sites of I264 and P404, located far from active site and substrate binding sites, significantly affect heme and/or substrate binding. This study indicated that two important nonsubstrate recognition site (SRS) residues of CYP2C8 are closely related to heme binding and/or substrate binding. This discovery could be valuable for explaining clinically individual differences in the metabolism of drugs and provides instructed information for individualized medication.


Shifts in chain-melting transition temperature of liposomal membranes by polymer-grafted lipids.
The chain-melting transition temperature of dipalmitoyl phosphatidylcholine (DPPC) bilayer membranes containing poly(ethylene glycol)-grafted dipalmitoyl phosphatidylethanolamine (PEG-DPPE) was determined by optical turbidity measurements. The dependence on content, Xp, of PEG-DPPE lipid was studied for different polar headgroup sizes, np, of the polymer lipid, throughout the lamellar phase of the mixtures with DPPC. Mean-field theory for the polymer brush regime predicts that the downward shift in transition temperature should vary with polymer size and content as npXp(5/3) (approximately npXp(11/6) for scaling theory). Any shift induced by the charge on PEG-lipids is independent of polymer size. These predictions are reasonably borne out for the longer polymer lipids (PEG molecular masses 750, 2000 and 5000 Da). Transition temperature shifts in the lamellar phase, before the onset of micellisation, are in the region of -1 to -2 degrees C (+/-0.1-0.2 degrees C) in reasonable accord with theoretical estimates of the lateral pressure exerted by the polymer brush. Shifts of this size are significant to the design of liposomes for controlled release of contents by mild hyperthermia.


Ultrasound attenuation estimation using the LMSE filters and the median filter.
The ultrasound attenuation coefficient in known to increase with frequency in soft biological tissue within the diagnostic frequency range. The frequency dependent attenuation coefficient is an important parameter in clinical tissue characterization, especially in liver, and in ultrasonic quantitative B-scan imaging. But, because of the random spatial variation in the backscattered signal amplitude, the estimator variance becomes very large, making it difficult to estimate the attenuation slope from the backscattered ultrasound signal. In this paper we suggest a new ultrasound attenuation estimator based on the calibrated log spectral difference. The proposed estimation process consists of Wiener filtering, Kalman filtering, and median filtering in this order. The simulation results and experimental results with tissue equivalent (TE) phantoms show that combination of the above filterings yields a considerably reduced estimator variance compared with the conventional estimators.


Isolation and characterization of pollen-specific maize genes with sequence homology to ragweed allergens and pectate lyases.
A cDNA clone (Zm58.1) was isolated by differential screening from a cDNA library made to mature Zea mays pollen, and shown to be pollen-specific by RNA blot analysis. When this partial-length clone was used to probe a genomic library, a similar but distinct pollen-specific genomic clone (68% sequence identity) was isolated (Zm58.2). The putative proteins coded for by these two clones show sequence homology to several flower-expressed gene products from various plant species, including known pollen allergens from short ragweed (Ambrosia artemisiifolia), and to pectate lyases from the plant pathogenic bacteria Erwinia spp. The two genes map to different chromosomes.


The renin-angiotensin-aldosterone system in the newborn lamb: response to furosemide.
Nine newborn lambs between 24 and 48 hr of age were studied before and after infusion of furosemide (2 mg/kg) over 1-2 min. Plasma renin activity (PRA) increased within 8 min after furosemide from a baseline value of 12.6 +/- 3.5 ng/ml/hr (mean and SEM) to a level of 24.1 +/- 8.6 ng/ml/hr (P less than 0.05), and peaked 20 mins after the furosemide infusion at a level of 33.1 +/- 8.0 ng/ml/hr. Plasma aldosterone concentration increased from a baseline of 12.2 +/- 3.1 to 22.8 +/- 9.1 ng/dl 35 min after the furosemide infusion, P less than 0.05. There were no changes in plasma sodium or blood hemoatocrit and minimal changes in blood pressure and plasma protein concentrations during the first 35 min after the furosemide infusion. The results indicate that the renin-angiotensin-aldosterone system responds promptly to furosemide stimulation despite initially high PRA and aldosterone levels.


Radiotherapy and temozolomide for anaplastic astrocytic gliomas.
We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m(2)), and six adjuvant 28-day cycles of either dose-dense (150 mg/m(2), days 1-7, 15-21) or metronomic (50 mg/m(2), days 1-28) temozolomide. Subsequently, maintenance RA (100 mg/m(2), days 1-21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan-Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28-74), median KPS 90 (range 60-100). Extent of resection was gross-total in 35%, subtotal 23%, and biopsy 42%. Histology was AA in 90%, and AOA in 10%. MGMT promoter methylation was methylated in 20%, unmethylated in 50%, and uninformative in 30% of 30 tested. Median progression-free survival was 2.1 years (95% CI 0.95-Not Reached), and overall survival 2.9 years (95 % CI 2.0-Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials.


Nine things to keep in mind about mathematical modelling in ecology and evolution.
Modelling in ecology and evolution, especially in India, is often done by researchers trained in physics or engineering without much experience of studying living systems. This is partly driven by a fallacious conviction that modelling is largely about mathematical skills and that, consequently, modellers can equally effectively apply their skills to problems in fields as diverse as physics/engineering and ecology/evolution. I discuss why this fallacy arises, and the many ways in which modelling in ecology or evolution is actually a very different endeavour from that in much of physics, even though the form of the equations deployed across disciplines is typically quite similar. Since modelling is not primarily about the mathematics but about the system being studied, I believe that a reasonable degree of comfort with models and modelling is important for those researchers in ecology and evolution who primarily undertake empirical studies, whether in the laboratory or the field. Equally, I suggest that researchers doing modelling in ecology and evolution, who were trained in the mathematical or physical sciences, need to understand the systems they attempt to model and also appreciate how modelling ecological and evolutionary processes differs from much of the modelling done in classical physics and allied fields. I also discuss what models are, whether modelling is subjective or objective, and what modelling entails if it is to meaningfully add to scientific understanding. This article is aimed primarily at young researchers interested in ecological and evolutionary questions, whether coming from a background in the biological or physical/mathematical sciences.


Internet-based Treatment for Vulvodynia (EMBLA) - A Randomized Controlled Study.
Internet-based ACT (Acceptance and commitment therapy) treatment may improve accessibility and reduce stigma related to seeking health care, but there are a lack of studies investigating internet-based treatment using ACT principles for women with vulvodynia. The aim of this study was to investigate the effects of an internet-based treatment of pain during intercourse for women with provoked vulvodynia compared with no intervention during the waiting period before clinical treatment. A multicenter randomized controlled trial was conducted during 2016 to 2020, in which 99 participants were included. Participants were randomized to either a 6 week guided internet-based treatment using ACT principles or usual care. Data were collected at baseline, 6 weeks after baseline, and approximately 10 months after baseline. Pain-related (pain during intercourse, tampon test, impact of pain on sexual function) and pain behavior-related outcomes (attempts at intercourse, sexual activities besides intercourse, willingness to perform the tampon test, chronic pain acceptance questionnaire) were used as outcomes. Treatment was efficacious in what concerns pain during intercourse and pain acceptance. Less pain during intercourse among women in the intervention group was observed at both post-treatment (primary endpoint, P = .01, Cohen's d = 1.4, 95% CI = 0.33, 2.4), and follow-up (P = .04). Absolut mean difference between groups for pain during intercourse at post-treatment was -2.84, (95 % CI = -4.91, -0.78), and -1.58 at follow-up, (95 % CI = -3.17, 0.02), where the intervention group rated less pain than controls. No differences between groups over time were found for tampon test measures or impact of pain on sexual function. There was a significant difference between groups at all timepoints indicating fewer attempts at intercourse among participants in the intervention group. At post-treatment, women who underwent internet-based treatment reported higher pain acceptance and a rise in activity engagement compared with the control group. There is an indication that internet-based treatment could be incorporated into clinical practice as a complement to clinical treatment. Study strengths included using several forms of recruitment and an intervention built by different professions with long experience of treating patients with vulvodynia. High dropout rate was a limitation of this study. Internet-based treatment may have an impact on pain during intercourse and positive effects on pain acceptance. However, conclusions must be drawn with caution due to the small sample size. Engström AH, Bohm-Starke N, Kullinger M, et al. Internet-based Treatment for Vulvodynia (EMBLA) - A Randomized Controlled Study. J Sex Med 2022;19:319-330.


Chordal geometry determines the shape and extent of systolic anterior mitral motion: in vitro studies.
In patients with hypertrophic cardiomyopathy, the mitral valve moves anteriorly and assumes a unique shape, with mitral-septal contact centrally and preserved valve orifice area laterally. This shape is not clearly predicted by the Venturi mechanism, which stresses flow above the valve as opposed to changes intrinsic to the valve. On the other hand, it has been suggested that displacement of the papillary muscles anteriorly and toward one another, as observed in this disease, can promote anterior mitral valve motion and produce this unusual shape. The purpose of this in vitro study was to test the hypotheses that anterior motion of a membrane in a flow field can be generated by altering the distribution or effectiveness of chordal tension tethering the membrane, and that the shape achieved by this membrane depends on the geometry of chordal tension. Accordingly, a horizontal leaflet mounted in a flow chamber was attached by chords at its distal end to a series of upstream screws. Chordal tension could be varied by turning the screws or redirected by shifting the screws anteriorly. Anterior leaflet motion having the same unusual configuration seen in patients was reproduced by decreasing central chordal restraint while tension on the leaflet edges was maintained. Directing chordal tension anteriorly caused greater degrees of anterior motion at earlier stages in the release of chordal restraint; increased flow rate had a similar but less marked effect. These studies suggest that primary geometric alterations in the papillary-mitral apparatus can play an important role in determining the presence and geometry of systolic anterior mitral motion. The nature of these alterations suggests a role for anterior and inward papillary muscle displacement in promoting such motion. The geometric factors embodied in this model can explain many observed features of this motion not adequately explained by the Venturi effect, such as early systolic onset and the importance of a distal residual leaflet. Finally, flow visualization studies emphasize the importance in this process of drag forces caused by interposing the leaflet into the flow stream, and of geometric factors that enhance such forces.


Trends in peritoneal surface malignancies: evidence from a Czech nationwide population-based study.
The aim of this study is to identify the incidence trends of primary and secondary peritoneal surface malignancies in a representative Czech population. Data were obtained from patients registered in the Czech National Cancer Registry between 1979 and 2016. The incidence rates were analyzed between 2012 and 2016. To observe the incidence trends, we analyzed the data from two time periods, 1979-2005 and 2006-2016. The analyzed data included age, sex, and the histological types and primary origins of the malignancies. The Cochrane-Armitage test for linear trends was used for verification of the null hypothesis. The significance level established for hypothesis testing was p = 0.05. Between 2012 and 2016, 230 patients with primary peritoneal tumors were identified and divided into the following groups according to their "International Statistical Classification of Diseases and Related Health Problems, 10th revision" codes: malignant neoplasm of specified parts of the peritoneum (C48.1); malignant neoplasm of the peritoneum, unspecified (C48.2); and malignant neoplasm of overlapping sites of the retroperitoneum and peritoneum (C48.8). Moreover, 549 primary tumors of the appendix (C18.1, encompassing all appendiceal malignancies) and 3137 secondary synchronous peritoneal carcinomatoses of other primary origins were documented. The age-adjusted incidence of primary peritoneal tumors in 2012-2016 was 4.36/year/1,000,000 inhabitants. The age-adjusted incidence of synchronous secondary peritoneal malignancies in 2014-2016 was 99.0/year/1,000,000 inhabitants. The diagnoses of primary peritoneal malignancies followed a stable trend between 1979 and 2016. However, the incidences of primary tumors of the appendix increased by 76.7%. The data produced in our study ought to clarify the status of peritoneal surface malignancies in the Czech Republic, which can lead to improved planning and development of therapeutic interventions as well as physician training.


Proteomic analysis of the hepatic response to a pollutant mixture in mice. The protective action of selenium.
Metals and pharmaceuticals contaminate water and food worldwide, forming mixtures where they can interact to enhance their individual toxicity. Here we use a shotgun proteomic approach to evaluate the toxicity of a pollutant mixture (PM) of metals (As, Cd, Hg) and pharmaceuticals (diclofenac, flumequine) on mice liver proteostasis. These pollutants are abundant in the environment, accumulate in the food chain, and are toxic to humans primarily through oxidative damage. Thus, we also evaluated the putative antagonistic effect of low-dose dietary supplementation with the antioxidant trace element selenium. A total of 275 proteins were affected by PM treatment. Functional analyses revealed an increased abundance of proteins involved in the integrated stress response that promotes translation, the inflammatory response, carbohydrate and lipid metabolism, and the sustained expression of the antioxidative response mediated by NRF2. As a consequence, a reductive stress situation arises in the cell that inhibits the RICTOR pathway, thus activating the early stage of autophagy, impairing xenobiotic metabolism, and potentiating lipid biosynthesis and steatosis. PM exposure-induced hepato-proteostatic alterations were significantly reduced in Se supplemented mice, suggesting that the use of this trace element as a dietary supplement may at least partially ameliorate liver damage caused by exposure to environmental mixtures.


Fatty acid composition of erythrocytes in hereditary spherocytosis.
The fatty acid distribution of the four major phospholipids has been determined in the erythrocytes of five patients with hereditary spherocytosis and in five control subjects. In contrast to a report by other workers, we are unable to confirm their findings of a defect in fatty acid chain lengthening activity leading to disappearance of long chain fatty acid conjugates of more than 20 carbon atoms in some of the phospholipid fractions.


Role of NO on pressure-natriuresis in Wistar-Kyoto and spontaneously hypertensive rats.
We investigated the role of the endothelium-derived relaxing factor nitric oxide (NO) on pressure-natriuresis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using in vivo perfusion studies. Differences in the neural and hormonal background to the kidney were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. In WKY, elevation of renal perfusion pressure (RPP) from 115 to 157 mm Hg increased urinary sodium excretion 4.5 to 14.8 microEq/min/g kidney wt, and the slope of its linear regression was 0.21 microEq/min/g kidney wt/mm Hg. Infusion of an inhibitor of NO synthase, L-NMMA (1 mg/min/kg), lowered this slope (P < 0.05) but L-arginine (3 mg/min/kg) did not change it. By contrast, the impaired pressure-natriuresis response of SHR was ameliorated by L-arginine (slope: 0.08 to 0.16; P < 0.05), while L-NMMA did not blunt it further. GFR and renal plasma flow (RPF) were well autoregulated in both strains, but L-NMMA lowered RPF significantly (SHR: from 4.2 to 2.6 ml/min/g kidney wt; WKY: 4.5 to 2.5 ml/min/g kidney wt). Moreover, when infused simultaneously, all these individual effects of L-NMMA and L-arginine were nullified. These results suggest that NO plays an important role in the pressure-natriuresis mechanism.


TLR Stimulation during T-cell Activation Lowers PD-1 Expression on CD8+ T Cells.
Expression of T-cell checkpoint receptors can compromise antitumor immunity. Blockade of these receptors, notably PD-1 and LAG-3, which become expressed during T-cell activation with vaccination, can improve antitumor immunity. We evaluated whether T-cell checkpoint expression could be separated from T-cell activation in the context of innate immune stimulation with TLR agonists. We found that ligands for TLR1/2, TLR7, and TLR9 led to a decrease in expression of PD-1 on antigen-activated CD8+ T cells. These effects were mediated by IL12 released by professional antigen-presenting cells. In two separate tumor models, treatment with antitumor vaccines combined with TLR1/2 or TLR7 ligands induced antigen-specific CD8+ T cells with lower PD-1 expression and improved antitumor immunity. These findings highlight the role of innate immune activation during effector T-cell development and suggest that at least one mechanism by which specific TLR agonists can be strategically used as vaccine adjuvants is by modulating the expression of PD-1 during CD8+ T-cell activation. Cancer Immunol Res; 6(11); 1364-74. ©2018 AACR.


LDH-C can be differentially expressed during fermentation of CHO cells.
Expression of CHO mRNA was measured with special microarrays from the Consortium for Chinese Hamster Ovary (CHO) Cell Genomics led by Prof. Wei-Shou Hu of the University of Minnesota and Prof. Miranda Yap of the Bioprocess Technology Institute of A*STAR, Singapore (http://hugroup.cems.umn.edu/CHO/cho_index.html). Cultivation experiments were performed in small scale 2L stirred tank bioreactors. During fermentation a temperature shift of -3°C was performed. This was accompanied by a reduction of the cell specific lactate production rate. The analysis of transcriptome samples before and after the temperature shift with microarrays showed several changes in the expression of available gene markers. LDH-C expression raised about 2 fold after temperature shift. LDH-A did not change. As LDH-C is known to be a specialized isoenzyme in sperm cells for consuming lactate in a lactate containing milieu, LDH-C could be proposed as a target for genetic engineering, facilitating lactate consumption in the late phase of high cell density cultures and prolonging longevity of CHO production cultures by reducing lactate and base accumulation.


Simian virus 40 production after viral uncoating in the CV-1 cell nucleus.
A normal yield of infectious simian virus 40 was produced by a CV-1 cell culture after inoculation of a few cells with an average of one particle per nucleus by microinjection.


Clipping Over the Scope for Recurrent Peptic Ulcer Bleeding is Cost-Effective as Compared to Standard Therapy: An Initial Assessment.
Clipping over the scope (C-OTS) is a novel closure technique used for the treatment of nonvariceal gastrointestinal bleeding, especially for high-risk lesions. C-OTS devices cost more than clipping through the scope and thermal devices. The high upfront cost of C-OTS may pose a barrier to its use and the cost-effectiveness of C-OTS for peptic ulcer disease bleeding is unknown. Cost-effectiveness studies of C-OTS for peptic ulcer bleeding as both first-line and second-line therapy can provide the current estimate of the conditions in which the use of C-OTS is cost-effective and give insights of the determinants to the cost-effectiveness of C-OTS.


Afforestation influences soil organic carbon and its fractions associated with aggregates in a karst region of Southwest China.
Variations in soil organic carbon (SOC) and its fractions within soil aggregates in response to land-use change are important to understand the carbon cycles in terrestrial ecosystem. However, responses of total SOC, SOC fractions, and SOC stability in different soil aggregates to land-use change are less addressed, especially in karst regions with serious land degradation. Therefore, bulk soil samples were collected under four land uses with similar geographical characteristics and previous framing practices including farmland (FL), Bamboo forest (BA), landscape tree planting (LAT), and orange orchards (ORO) in a karst region of Southwest China. Contents of total SOC and three carbon fractions based on their degree of oxidizability (F1, very labile; F2, inert; F3, oxidizable resistant) in bulk soil and different soil aggregates (macro-aggregate, micro-aggregate, and silt+clay fraction) were measured. Afforestation significantly increased contents of total SOC and three carbon fractions in bulk soil and soil aggregates, and the influence was more obvious in macro-aggregate than the other aggregates. Contents of total SOC, F1, F2, and F3 under afforestation land increased by 41.73%, 58.19%, 33.91%, and 40.55%, respectively, in bulk soil, by 55.60%, 79.24%, 121.77%, and 43.30%, respectively, in macro-aggregate, by 52.80%, 33.57%, 20.14%, and 75.02%, respectively, in micro-aggregate, and by 26.21%, 35.60%, 29.26%, and 23.75%, respectively, in silt+clay fraction than those under FL. In bulk soil and soil aggregates, proportions of F1, F2, and F3 in total SOC ranged from 0.11 to 0.18, from 0.13 to 0.22, and from 0.60 to 0.73, respectively, suggesting that the stable carbon was the predominant carbon fraction in the study area. Afforestation decreased the values of stability of SOC in macro-aggregate and silt+clay fraction, while it increased the value in micro-aggregate. Although both BA and ORO had higher SOC content in bulk soil than the LAT, but the SOC stability in bulk soil under BA was significantly lower than that under ORO. In conclude, afforestation form FL improved SOC content and altered SOC stability in bulk soil and soil aggregates, and conversion of FL to ORO might be the best choice to increase SOC sequestration in the four land-use types compared in karst regions of Southwest China.


Sensitivity to CCK-4 in women with and without premenstrual dysphoric disorder (PMDD) during their follicular and luteal phases.
The authors determined whether women with premenstrual dysphoric disorder (PMDD) exhibit a heightened sensitivity to the panicogenic effects of CCK-4 administration and whether this enhanced sensitivity to CCK-4 would vary with the phase of the menstrual cycle at the time of CCK-4 injection. Twenty-one normal controls and 18 PMDD women were randomly assigned to receive the first and second CCK-4 injection during the follicular phase and the luteal phase or vice versa. PMDD women showed a greater anxiety and panic response to CCK-4. These preliminary results suggest that the CCK-B system may play a role in the pathophysiology of PMDD.


The diagnostic significance of the 3D-reconstructed MRI in vestibular schwannoma surgery: prediction of tumor origin.
In hearing preservation surgery for the treatment of vestibular schwannoma (VS), one of the important factors is the determination of the origin of VS. In this study, we investigated the diagnostic significance of using an MRI obtained by the three-dimensional Fourier transform fast spin-echo technique (3D-reconstructed MRI) in order to determine the origin of VS. The subjects consisted of 20 patients with mainly intra-canalicular sized VS who underwent tumor removal at our hospital. The origin of VS was determined from the 3D-reconstructed MRI findings and the results of the caloric test. These findings were then compared with the surgical findings. In 15 out of 20 patients, the MRI findings closely corresponded to the surgical ones, while the origin of VS hardly could be detected when a tumor filled up to the fundus acoustics on the MRI findings of the axial sections. On the other hand, 6 out of 15 patients (40%) whose tumor originated from the inferior vestibular nerve showed canal paresis. In conclusion, 3D-reconstructed MRI is considered to be helpful in obtaining more precise information regarding the origin of VS compared to the caloric test.


Atypical hemolytic uremic syndrome: Consensus of diagnosis and treatment in Taiwan.
Atypical hemolytic uremic syndrome (aHUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is a rare but life-threatening systemic disorder caused by the dysregulation of the complement pathway. Current advances in molecular analysis and pathogenesis have facilitated the establishment of diagnosis and development of effective complement blockade. Based on this recent consensus, we provide suggestions regarding the diagnosis and management of aHUS in Taiwan. The diagnosis of aHUS is made by the presence of TMA with normal ADAMTS13 activity without known secondary causes. Although only 60% of patients with aHUS have mutations in genes involving the compliment and coagulation systems, molecular analysis is suggestive for helping establish diagnosis, clarifying the underlying pathophysiology, guiding the treatment decision-making, predicting the prognosis, and deciding renal transplantation. Complement blockade, anti-C5 monoclonal antibody, is the first-line therapy for patients with aHUS. Plasma therapy should be considered for removing autoantibody in patients with atypical HUS caused by anti-CFH or complement inhibitor is unavailable.


Jumpstarting post-conflict strategic water resources protection from a changing global perspective: gaps and prospects in Afghanistan.
Notwithstanding ambiguities, long-term economic resurgence in Afghanistan amidst water insecurity exacerbated by climate change decisively requires a water protection strategy that will complement a multitude of agroindustrial and socioeconomic activities in an environmentally sustainable and climate resilient manner. In this paper, we begin with a perspective on institutions, legislation, and key issues in the water sector of Afghanistan. We then embark on linking the integrated water resources management (IWRM) and strategic environmental assessment (SEA) approaches as a novel framework for strategic water management and subsequently propose a strategy for post-conflict water protection based on the coalesced IWRM and SEA. Context relevant good practices worldwide are presented to provide empirical evidence for this approach whereas perceived opportunities and vulnerabilities in the Afghan context are discussed. Examination of post-conflict water sector initiatives in Afghanistan reveals the critical role of foreign assistance in both water infrastructure rehabilitation and modernization of the institutional aspect of water management. The introduction of IWRM as the basis for a progressive water sector strategy has been seen as a major milestone which is detrimentally matched by substantial deficiency in national capacity for implementation. Concurrently, the role of extra-national actors in relevant policy interventions has been considered catalytic despite criticisms of proposed regulations as being anachronistic to field realities. Therefore the view is maintained to practicable policies by accelerating policy learning in the country's water and environment sectors to encourage homegrown water strategy innovations. Demonstratively, mainstreaming IWRM-SEA coalescence will bridge institutional gaps for better feedback between local and national water stakeholders, providing a venue for improved delivery of water services to sustain post-conflict socioeconomic recovery and promote environmental stewardship.


Role of clearance and treatment zones in contrast sensitivity: significance in refractive surgery.
To evaluate the relationship between contrast sensitivity, surgical treatment zone, and clearance (ablation or clear zone-pupil diameter) in photorefractive keratectomy (PRK) and radial keratotomy (RK). Saint Louis University Eye Institute, St. Louis, Missouri, and Hunkeler Eye Center, Kansas City, Missouri, USA. Thirteen patients had PRK and 20, RK. Contrast sensitivity was measured with the Stereo Optical F.A.C.T. (F.A.C.T.) and VectorVision CSV-1000 (VV) charts. Pupils were measured with the Rosenbaum card. In the PRK group, VV contrast sensitivity at 6 and 12 cycles per degree (cpd) correlated with the ablation zone (r2 = 0.18 and 0.22, respectively), while visual acuity and F.A.C.T. contrast sensitivity did not correlate. In the RK group, both VV and F.A.C.T. contrast sensitivity at 6 cpd correlated with clearance (r2 = 0.29 and 0.12, respectively). Pupils were larger with the VV test than with the F.A.C.T. chart because ambient chart luminance was less in the former. Contrast sensitivity is likely a more sensitive indicator of visual function than acuity in refractive surgery. The VV system unmasks aberrations from the transition zone of ablated and unablated cornea in PRK. Larger samples are needed to determine the critical ablation clearance of the pupil to avoid loss of visual function.


Application of Internet+-based Tsinghua PINS Remote Tech to improve sacral neuromodulation programming procedure.
To explore the feasibility and safety of the Tsinghua PINS Remote Tech to facilitate sacral neuromodulation programming procedure. For 22 patients who had previously participated in the phase III clinical trial for treating overactive bladder with the Tsinghua PINS sacral neuromodulation system during several Hospital, PINS Remote Tech was applied to perform postoperative parameter adjustment in order to evaluate the safety and reliability of this new technique. Telephone surveys on Remote Tech-related questionnaires were also conducted. 17/22 patients underwent 26 parameter adjustments, average adjustment frequency was 1.53 times per person; the average adjustment time was 23.4 ± 5.1 min (15-32 min). The total effective rate of the Remote control was 14/17 (82.3%). 7/17 (41.1%) patients' symptoms recurrence due to not knowing how to handle patient controller, these patients were instructed on how to use it correctly through Remote Tech even without reprogramming it. Other 10 patients received reprogramming. There was no discomfort during and after parameter adjustment. The questionnaire survey showed that the remote technology saved patients' time and lowered financial costs, significantly improved patient satisfaction. All patients expressed their willingness to recommend it to other patients. The PINS Remote Tech can significantly reduce the financial cost and provide a remote reprogram control service that is as safe and reliable as outpatient program control.


Short course albendazole treatment for neurocysticercosis in Columbia.
The efficacy of albendazole was evaluated in 20 Colombian patients with neurocysticercosis showing neurological symptoms. All had parenchymal non-enhancing cystic images by computerized tomography and a positive enzyme-linked immunosorbent assay for cysticercus antibodies in serum or cerebrospinal fluid. They stayed in hospital for 8 d during treatment with albendazole, 15 mg/kg/d in 2 divided doses, and were then followed for at least 6 months after treatment. The number of cysts was reduced by 50% after 6 months. In 7 (35%) all cysts disappeared, in 7 (35%) the number was reduced, and in the remaining 6 (30%) the number was unchanged. In the 13 patients who still had cysts at 6 months, 11 showed a moderate decrease in average cyst size and in 2 the size was unchanged. Side effects during treatment were observed in 60% of the cases, but only 3 required corticosteroids.


Current understanding and perspectives on the potential mechanisms of immune priming in beetles.
Beetles are the most diverse group of insects in Insecta which can be found in almost every habitat and environment on Earth. The possessing of the rapid and effective immune defenses is one of the important factors for their success. It is generally recognized that beetles only rely on the non-specific innate immune defense, without immunological memory, to fight against pathogens. However, there was cumulative evidence for the innate immune memory in invertebrates, including beetles, over the last decades, implying that insect innate immunity is more complex and has more features than previously thought. In beetles, it has been well documented that the specific or nonspecific enhanced immunocompetence can persist throughout development within generations and can even be transferred to the descendents in the next generation. Although insect immune priming might be shaped by epigenetic modifications and transferring effectors, mRNA and microbial signals, the solid experimental evidence to support the causal relationship between any of them and immune priming is still scarce. The combined usage of 'omics' approaches and CRISPR/Cas9 in the appropriate insect models with well-known genetic background, Tribolium castaneum and Tenebrio molitor, will help us to decipher the molecular mechanisms by which immune priming occurs in beetles in depth.


Self-teaching to improve patient confidence in resuscitation skills: A quality improvement project.
Sudden cardiac death occurs predominantly at home where cardiopulmonary resuscitation (CPR) is often not provided. We tested the hypothesis that a self-teaching kit distributed to patients would effectively increase self-confidence in CPR. Patients seen by an advanced registered nurse practitioner in a general cardiology clinic were offered a self-teaching kit to learn CPR. Four-point scale survey questions were assessed at distribution and via phone call at 30 days. Kits were distributed to 21 patients; of whom, 17 (81%) patients used the kit. Patients reported greater self-confidence of performing CPR (2.6 before versus 3.2 after, p < .05) and greater comfort if someone needed CPR (2.4 before versus 3.1 after, p < .05). Self-teaching CPR kits were used by the substantial majority of patients and were effective at increasing both self-confidence and willingness to perform CPR. Similar nurse-run programs could increase awareness and impact of CPR in communities.


Human immunodeficiency virus testing practices among buprenorphine-prescribing physicians.
Despite the Centers for Disease Control and Prevention recommendations for annual HIV testing of at-risk populations, including those with substance use disorders, there are no data on the human immunodeficiency virus (HIV) testing practices of buprenorphine-prescribing physicians. To describe HIV testing practices among buprenorphine-prescribing physicians. We conducted a cross-sectional survey of physicians enrolled in a national system to support buprenorphine prescribing between July and August 2008. The electronic survey included questions on demographics; clinical training and experience; clinical practice; patient characteristics; and physician screening practices, including HIV testing. Only 46% of 382 respondent physicians conducted HIV testing. On univariate analysis, physicians who conducted HIV testing were more likely to report addiction specialty training (33% vs 19%, P = 0.001), practicing in addiction settings (28% vs 16%, P = 0.006), and having treated more than 50 patients with buprenorphine (50% vs 31%, P < 0.0001) than those who did not. Compared with physicians who did not conduct HIV testing, physicians who conducted HIV testing had a lower proportion of buprenorphine patients who were white (75% vs 82%, P = 0.01) or dependent upon prescription opioids (57% vs 70%, P < 0.0001). In multivariate analysis, physicians who conducted HIV testing were more likely to have treated more than 50 patients with buprenorphine (odds ratio = 1.777, 95% CI 1.011-3.124) and had fewer patients dependent upon prescription opioids (odds ratio = 0.986 95% CI 0.975-0.998) than physicians who did not. Interventions to increase HIV testing among physicians prescribing buprenorphine are needed.


[Morphobiophysical features of the duodenal mucosa in patients with duodenal ulcers].
Chronic duodenitis in patients with duodenal ulcer is characterized by substantial morphofunctional changes in the mucosa, decreased transmural potential difference and definite patterns of carbohydrate-containing biopolymer production, the initial changes being manifested as neutral glycoprotein hypersecretion with their subsequent diminished synthesis rates, followed by a more pronounced drop of sialo- and sulfoglycoprotein levels. A correlation was found between the severity of duodenitis, morphometric and histochemical parameters, and gastric pepsin secretion rates (hypersecretion). It is suggested that these changes are etiopathogenetically common.


Morphometric studies of the ligamentum flavum: a correlative microanatomical and MRI study of the lumbar spine.
Foraminal degenerative lumbar stenosis is traditionally considered a result of bony narrowing due to osteophytic appositions on the superior articular process. Clinical experience reveals that significant additional compression of the neural structures is due to degenerative hypertrophy of the adjacent ligamentum flavum. Therefore, microanatomical and neuroradiological investigations were performed to determine the microtopography of this ligament, especially with respect to its lateral extension. Lumbar spine specimens of eight mid-aged human cadavers (mean age 34.5 years) were collected, and MRI studies with T1-weighted images were performed. The specially embedded specimens were sectioned horizontally at the level of the spinal ganglion (slice thickness: 2 mm). Anatomical morphometric data were correlated with identical measurements based on neuroradiological imaging and were analyzed statistically. The distance between midline and extraforaminal extension of the ligamentum flavum showed a mean value of 17 mm. The distance increased to 19 mm when the lateral insertion was correlated to the origin of the ligamentum flavum at the anterior margin of the lamina. The farthest lateral segment of the ligamentum flavum was determined in each case; it covered the synovial cavity of the lumbar facet joint in the direction of the extraforaminal segment of the intervertebral canal. Measurements from mid-aged cadavers show the extent of the ligamentum flavum including its intra- and extraforaminal parts. Due to this anatomical situation a hypertrophic ligamentum flavum may contribute significantly to nerve root compression at the level of the lateral spinal recess. This has to be kept in mind during surgical decompression, which might be incomplete unless these hypertrophied parts are completely removed.


The role of succulent halophytes in the water balance of salt marsh rodents.
The role of succulent halophytes in the water balance and ecology of salt marsh rodents is dependent upon an evaluation of the composition of the available sources and the physiological properties of their potential consumers. Studies of the osmotic properties of succulent halophytes from southern California coastal salt marshes are presented, together with experiments regarding the utilization of Common Pickleweed (Salicornia virginica L.) by indigenous populations of cricetid rodents (harvest mouse Reithrodontomys megalotis limicola Von Bloecker, and meadow-mouse Microtus californicus stephensi Von Bloecker). These data are discussed in relation to other available information concerning the ecology of coastal salt marshes, particularly in western North America.Extruded sap of Common Pickleweed was found to have a mean total osmotic pressure (TOP) of 1,450 mOsm/liter, with an average chloride ion content of 876 mEq/liter (about 70% of the TOP). A related species, Salicornia subterminale, had a slightly lower TOP (1,300 mOsm/liter), of which about 29% was accounted for by chloride ion concentration. Sea Blight (Suaeda fruticosa) was the only species in which the TOP correlated with the distance from the tide level; sap TOP increased away from the lagoon's edge. In both Sea Blight and Common Pickle weed, TOP was not directly related to chloride content, indicating the importance of other osmotically active solutes.Harvest mice were placed on three experimental regimes: 1) millet seeds only, 2) pickleweed only, and 3) pickleweed and millet seed. Meadow mice were tested on the last regime only. Harvest mice survived best on a strict millet seed diet; when Salicornia was consumed to a detectable extent, the mice did not survive. Meadow mice, however, could survive using Salicornia as a dietary source in conjunction with seeds. Kidney electrolyte concentrating abilities indicated that harvest mice should be able to utilize pickleweed; this was not confirmed in my experiments. It is suggested that cathartic ions (possibly magnesium, sulphate, or oxalate) prohibit the utilization of certain halophytes. The mechanisms that enable meadow mice to utilize Salicornia are not clearly understood.Measurements of harvest mouse evaporative water loss are among the highest reported for small mammals (1.35 mg H2O/cc O2 consumed). On the basis of these data and other information in the literature, a water budget was constructed. The results suggest that harvest mice may enter daily torpor in response to osmotic stress or water deprivation.The role of dew and fog precipitation in the ecology of small rodents inhabiting coastal marshes is discussed. Apparently a sufficient amount of free water is available to meet the requirements of the salt marsh populations, although the quality of the available water may be influenced by salt-excretion activity of certain halophytes. Less halophytic succulents are available in the coastal marshes; these species may be more readily utilized than Salicornia by small vertebrates.


Spontaneous rupture of the pulmonary artery.
A 45-year-old man presented with the sudden onset of diaphoresis, generalized weakness, and bilaterally achy arms. Physical examination revealed cyanosis of the head, neck, and upper chest with dyspnea and hypotension. He had distant heart sounds. An upright portable chest radiograph suggested widening of the mediastinum. A right arm venogram was consistent with extrinsic obstruction of the superior vena cava. A computed axial tomography scan demonstrated blood in the pericardium and indistinct widening of the pulmonary outflow tract. Autopsy revealed three tears of the pulmonary artery above the level of valve cusps, and thinning of the artery walls suggested cystic medial necrosis. These findings are suggestive of an acute spontaneous rupture of the pulmonary artery, possibly secondary to cystic medial necrosis.


Magnetic resonance fistulogram demonstration of urethrovesicovaginal fistula in a case of müllerian agenesis due to traumatic urethral coitus.
Vesicovaginal fistula is not uncommon in women of childbearing age, and can occur due to a multitude of causes, the chief ones being infection and neoplasia. An extensive PUBMED search yielded only a few reports describing causation of such a lesion due to traumatic urethral coitus. The classic method to demonstrate such fistulas is by direct contrast-enhanced fistulography. Herein we report a case of urethrovesicovaginal fistula with müllerian agenesis caused by traumatic urethral coitus, as demonstrated using indirect magnetic resonance fistulography.


Growth and decline of shoreline industry in Sydney estuary (Australia) and influence on adjacent estuarine sediments.
Sydney estuary (Australia), like many urbanised waterways, is degraded due to an extended history of anthropogenic activity. Two major sources of contamination to this estuary are discharge by former shoreline industries and historic and contemporary catchment stormwater. The objectives of the present study were to document changes in shoreline land use from European settlement to the present day and determine the influence of this trend on the metal content of adjacent estuarine sediments. Temporal analysis of land use for seven time horizons between 1788 and 2010 showed rapid expansion of industry along much of the Sydney estuary foreshore soon after European settlement due to the benefits of easy and inexpensive access and readily available water for cooling and power. Shoreline industry attained maximum development in 1978 (32-km length) and declined rapidly to the present-day (9-km length) through redevelopment of industrial sites into medium- to high-density, high-value residential housing. Cores taken adjacent to 11 long-term industrial sites showed that past industrial practices contributed significantly to contamination of estuarine sediment. Subsurface metal concentrations were up to 35 times that of present-day surface sediment and over 100 times greater than natural background concentrations. Sedimentation rates for areas adjacent to shoreline industry were between 0.6 and 2.5 cm/year, and relaxation times were estimated at 50 to 100 years. Natural relaxation and non-disturbance of sediments may be the best management practice in most locations.


Long-term outcomes in older patients with hyperglycemia on admission for ischemic stroke.
Evaluate the association between admission blood glucose (ABG) and mortality in older patients with or without diabetes mellitus (DM) hospitalized for acute ischemic stroke (AIS). Observational data of patients ≥65years, admitted for AIS between January 2011 and December 2013. ABG levels were classified to categories: ≤70 (low), 70-110 (normal), 111-140 (mildly elevated), 141-180mg/dl (moderately elevated) and >180mg/dl (markedly elevated). Main outcome was all-cause mortality at the end-of-follow-up. Cohort included 854 patients, 347 with (mean±SD age 80±8, 44% male), and 507 without DM (mean±SD age 78±8, 53% male). There was a significant interaction between DM, ABG and mortality at end-of-follow-up (p≤0.05). In patients without DM there was a dose-dependent association between ABG category and mortality: adjusted hazard ratios (95% CI) compared to normal ABG were 1.8 (1.2-2.8), 2.9 (1.6-5.2) and 4.5 (2.1-9.7), respectively, for mildly, moderately and markedly elevated ABG. In patients with DM there was no association between ABG and mortality. There was no interaction between DM, ABG and in-hospital mortality or length of stay (LOS). Irrespective of DM status, compared to normal ABG levels, increased ABG category was associated with increased in-hospital mortality: adjusted odds ratios were 3.9 (1.1-13.4), 7.0 (1.8-28.1), and 20.3 (4.6-89.6) with mildly, moderately and markedly elevated ABG, respectively. Mean LOS was 6±5, 7±8, 8±7, and 8±8days, respectively. In older patients without DM hospitalized for AIS, elevated ABG is associated with increased long-term mortality. Irrespective of DM status, elevated ABG was associated with increased in-hospital mortality and LOS.


High-Performance Non-Fullerene Polymer Solar Cells Based on a Pair of Donor-Acceptor Materials with Complementary Absorption Properties.
A 7.3% efficiency non-fullerene polymer solar cell is realized by combining a large-bandgap polymer PffT2-FTAZ-2DT with a small-bandgap acceptor IEIC. The complementary absorption of donor polymer and small-molecule acceptor is responsible for the high-performance of the solar-cell device. This work provides important guidance to improve the performance of non-fullerene polymer solar cells.


Calcium channel blockers that prolong the QT interval.
The development of a group of calcium channel blockers that prolong the QT interval has raised interest in their possible proarrhythmic potential. In animal experiments lidoflazine has no observed arrhythmogenic potential and no antiarrhythmic potential in a model sensitive to the antiarrhythmic properties of both conventional and investigational agents. This lack of antiarrhythmic potential reduces the possible proarrhythmic potential even further, since it has been my observation that many of the more potent antiarrhythmic agents may facilitate arrhythmias in a considerable percentage of the most severely ill patients. Bepridil has both slow channel blocking properties and fast channel blocking effects and thus possesses an antiarrhythmic effect beyond the prolongation of repolarization. Even though early studies with humans showed the drug to be no more effective than the conventional reference agent procainamide, its potential cannot be fully assessed by these preliminary studies. The assessment of arrhythmogenicity is determined by use of the technique of PES. This technique has been shown effective in identifying patients with electrical instability and in identifying the effectiveness of antiarrhythmic agents in preventing VT and sudden death. Thus it seems probable that PES studies may be effective in predicting which drug or agent would facilitate arrhythmias. Alcohol, caffeine, cigarette smoke, and catecholamines facilitate PES induction of VT, lending support to the hypothesis that PES studies can be used to identify proarrhythmic drugs. In fact, patients who experience cardiac arrest on a class I agent can have VT provoked on that agent but not on antiarrhythmic drug therapy. PES thus identifies the proarrhythmic effect of the drug in that particular patient.(ABSTRACT TRUNCATED AT 250 WORDS)


Enhancement of Ca2+-induced Ca2+ release in calpain treated rabbit skinned muscle fibers.
Calpain treatment of rabbit skinned muscle fibers resulted in proteolysis of junctional foot protein or Ca2+ release channel of the sarcoplasmic reticulum. Electrophoretic and immunoblot analyses indicate that calpain cleaves off approximately 130 kDa peptide from the N-terminus. After such treatment, Ca2+ capacity of the sarcoplasmic reticulum remained normal and both Ca2+ and adenine nucleotide dependence of Ca2+-induced Ca2+ release mechanism were retained. However, the Ca2+-activated Ca2+ release rate was increased by two fold after the proteolysis. The results suggest the presence of functional domains in the junctional foot protein, and the N-terminus domain controls the activity of the Ca2+ channel without changing Ca2+ and nucleotide sensitivities.


Total peripheral resistance changes in dogs during aversive classical conditioning.
The arterial pressure, heart rate, stroke volume, cardiac output and total peripheral resistance of laboratory dogs were monitored continuously before and during a 30 min period in which aversive classical conditioning procedures were applied. The experimental stimulation generated inhibition of behavioral activity ("freezing") together with sustained increases in arterial pressure averaging 30%, and increases in heart rate anc cardiac output of 60-70%. The calculated total peripheral resistance decreased by an average of 20%. The behavioral and cardiovascular responses were sustained during the aversive conditioning period. The results suggest that significant peripheral vasodilation occurred under these conditions which was probably not due to metabolic byproducts of behavioral activity, but probably reflected sympathetic cholinergic effects upon blood vessels in the skeletal muscles. These data document the significance of the skeletal muscle circulation in the total peripheral resistance to blood flow in unanesthetized animals.


Muscle proteins and the changes in shape of avian oxynticopeptic cells in relation to secretion.
A combined ultrastructural and biochemical study of the avian oxynticopeptic cell was performed. Scanning electron microscopy demonstrates that this cell undergoes great changes in the shape of its apical pole in relation to secretory activity. These changes are confirmed by transmission electron microscopy and by freeze-fracture images. The biochemical finding of actin- and myosin-like proteins in high-speed supernatants of homogenates of these cells as well as the ultrastructural and cytochemical localization of actin-like filaments in their apical poles suggest a possible participation of these proteins in the above-mentioned changes. Thus, the study of cytoplasmic matrix elements and of their organization may be highly relevant in the search for a correlation between structure and function in these cells.


Effect of second-order magnetic anisotropy on nonlinearity of conductance in CoFeB/MgO/CoFeB magnetic tunnel junction for magnetic sensor devices.
We studied the effect of second-order magnetic anisotropy on the linear conductance output of magnetic tunnel junctions (MTJs) for magnetic-field-sensor applications. Experimentally, CoFeB/MgO/CoFeB-based MTJs were fabricated, and the nonlinearity, NL was evaluated for different thicknesses, t of the CoFeB free layer from the conductance. As increasing t from 1.5 to 2.0 nm, maximum NL, NLmax was found to decrease from 1.86 to 0.17% within the dynamic range, Hd = 1.0 kOe. For understanding the origin of such NL behavior, a theoretical model based on the Slonczewski model was constructed, wherein the NL was demonstrated to be dependent on both the normalized second-order magnetic anisotropy field of Hk2/|Hkeff| and the normalized dynamic range of Hd/|Hkeff|. Here, Hkeff, Hk2, are the effective and second-order magnetic anisotropy field of the free layer in MTJ. Remarkably, experimental NLmax plotted as a function of Hk2/|Hkeff| and Hd/|Hkeff|, which were measured from FMR technique coincided with the predictions of our model. Based on these experiment and calculation, we conclude that Hk2 is the origin of NL and strongly influences its magnitude. This finding gives us a guideline for understanding NL and pioneers a new prospective for linear-output MTJ sensors to control sensing properties by Hk2.


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A preliminary investigation of the efficacy of oral motor exercises for children with mild articulation disorders.
Although oral motor therapy is sometimes used to treat articulation disorders in school-age children, several reports question its efficacy. In this case study, four first-grade students, two boys and two girls, received 15 half-hour sessions of oral motor treatment based on Easy Does it for Articulation: An Oral Motor Approach (Strode and Chamberlain,1997). Pre- and post-test measures of the children's articulation indicated no real differences in speech production. These results question the efficacy of general and discrete oral motor exercises because they did not enhance the children's speech production.


[The radiologic diagnosis of inguinal hernias. Experience with the use of intraperitoneal iodinated contrast media (author's transl)].
By injecting an iodine contrast medium into the abdominal cavity and by placing the patient in a position with the table somewhat elevated, it is easy to visualize the inguinal region. The examination is performed with the X-ray tube angulated caudally, and exposures are made while the patient is straining. The method is well adapted for patients with obscure pains in the groins, for patients operated for hernias but not cured of pain and for patients in whom symptoms recur postoperatively without clinical evidence of hernial relapse. The value of the methode appears from four short case reports.


Influence of the stress hormone cortisol on fear conditioning in humans: evidence for sex differences in the response of the prefrontal cortex.
The stress hormone cortisol is known to influence declarative memory and associative learning. In animals, stress has often been reported to have opposing effects on memory and learning in males and females. In humans, the effects of cortisol have mainly been studied at the behavioral level. The aim of the present experiment was to characterize the effects of a single cortisol dose (30 mg) on the hemodynamic correlates of fear conditioning. In a double-blind group comparison study subjects (17 females and 17 males) received 30 mg cortisol or placebo orally before participating in a discriminative fear conditioning paradigm. Results revealed that cortisol impaired electrodermal signs of learning (the first interval response) in males, while no conditioned SCRs emerged for the females independent of treatment. fMRI results showed that cortisol reduced activity for the CS+ > CS- comparison in the anterior cingulate, the lateral orbitofrontal cortex and the medial prefrontal cortex in males. Opposite findings (increase in these regions under cortisol) were detected in females. In addition, cortisol reduced the habituation in the CS+ > CS- contrast in the dorsolateral prefrontal cortex independent of sex. Finally, cortisol also modified the response to the electric shock (the UCS) by enhancing the activity of the anterior as well as the posterior cingulate. In sum, these findings demonstrate that in humans cortisol mostly influences prefrontal brain activation during fear conditioning and that these effects appear to be modulated by sex.


Culturable heterotrophic bacteria associated with healthy and bleached scleractinian Madracis decactis and the fireworm Hermodice carunculata from the remote St. Peter and St. Paul Archipelago, Brazil.
We report on the first characterization of the culturable heterotrophic bacteria of the scleractinian Madracis decactis. In addition, we characterized the culturable bacteria associated with the fireworm Hermodice carunculata, observed predating partially bleached coral colonies. Our study was carried out in the remote St. Peter and St. Paul Archipelago (SPSPA), Mid-Atlantic Ridge, Brazil. We constituted a 403 isolates collection and subsequently characterized it by means of pyrH and 16S rRNA partial sequences. We identified Photobacterium, Bacillus, and Vibrio species as members of the culturable microbiota of healthy M. decactis. V. campbellii, V. harveyi, V. communis, and V. maritimus were the most commonly found Vibrio species in healthy corals, representing more than 60 % of all vibrio isolates. Most of the vibrios isolated from the fireworm's tissues (n = 143; >90 %) were identified as V. shiloi. However, we did not recover V. shiloi from bleached M. decactis. Instead, we isolated V. communis, a novel Photobacterium species, Bacillus, Kocuria, and Pseudovibrio, suggesting a possible role of other facultative anaerobic bacteria and/or environmental features (such as water quality) in the onset of bleaching in SPSPA's M. decactis.


Striatal ups and downs: their roles in vulnerability to addictions in humans.
Susceptibility to addictive behaviors has been related to both increases and decreases in striatal function. Both profiles have been reported in humans as well as in animal models. Yet, the mechanisms underlying these opposing effects and the manner in which they relate to the behavioral development and expression of addiction remain unclear. In the present review of human studies, we describe a number of factors that could influence whether striatal hyper- or hypo-function is observed and propose a model that integrates the influence of these opposite responses on the expression of addiction related behaviors. Central to this model is the role played by the presence versus absence of addiction related cues and their ability to regulate responding to abused drugs and other rewards. Striatal function and incentive motivational states are increased in the presence of these cues and decreased in their absence. Alternations between these states might account for the progressive narrowing of interests as addictions develop and point to relevant processes to target in treatment.


Comparison of testing methods for the detection of BRAF V600E mutations in malignant melanoma: pre-approval validation study of the companion diagnostic test for vemurafenib.
The cobas 4800 BRAF V600 Mutation Test is a CE-marked and FDA-approved in vitro diagnostic assay used to select patients with metastatic melanoma for treatment with the selective BRAF inhibitor vemurafenib. We describe the pre-approval validation of this test in two external laboratories. Melanoma specimens were tested for BRAF V600 mutations at two laboratories with the: cobas BRAF Mutation Test; ABI BRAF test; and bidirectional direct sequencing. Positive (PPA) and negative (NPA) percent agreements were determined between the cobas test and the other assays. Specimens with discordant results were tested with massively parallel pyrosequencing (454). DNA blends with 5% mutant alleles were tested to assess detection rates. Invalid results were observed in 8/116 specimens (6·9%) with Sanger, 10/116 (8·6%) with ABI BRAF, and 0/232 (0%) with the cobas BRAF test. PPA was 97·7% for V600E mutation for the cobas BRAF test and Sanger, and NPA was 95·3%. For the cobas BRAF test and ABI BRAF, PPA was 71·9% and NPA 83·7%. For 16 cobas BRAF test-negative/ABI BRAF-positive specimens, 454 sequencing detected no codon 600 mutations in 12 and variant codon 600 mutations in four. For eight cobas BRAF test-positive/ABI BRAF-negative specimens, four were V600E and four V600K by 454 sequencing. Detection rates for 5% mutation blends were 100% for the cobas BRAF test, 33% for Sanger, and 21% for the ABI BRAF. Reproducibility of the cobas BRAF test was 111/116 (96%) between the two sites. It is feasible to evaluate potential companion diagnostic tests in external laboratories simultaneously to the pivotal clinical trial validation. The health authority approved assay had substantially better performance characteristics than the two other methods. The overall success of the cobas BRAF test is a proof of concept for future biomarker development.


Identification of an HLA-A*0201-restricted T-cell epitope derived from the prostate cancer-associated protein prostein.
The development of T-cell-based immunotherapies of cancer largely depends on the availability of tumour-associated antigens capable of eliciting tumour-directed cytotoxic T-cell responses. In prostate cancer, the number of antigens defined as suitable targets of cytotoxic T lymphocytes (CTLs) is still limited. Recently, prostein was identified as a transmembrane protein that is highly restricted to prostate tissues. In our study, prostein transcripts were found to be abundant in both malignant and nonmalignant prostate tissue samples. To identify immunogenic CD8+ T-cell epitopes, human leucocyte antigen-A(*)0201-binding peptides were selected from the amino-acid sequence of prostein and were used for the in vitro stimulation of CD8+ T lymphocytes. Specific CTLs were raised against the prostein-derived peptide CLAAGITYV that were capable of lysing prostate cancer cells, indicating that this peptide is naturally generated by tumour cells. Our data suggest that prostein is a suitable candidate to be included in a T-cell-based immunotherapy of prostate cancer.


Draft Genome Sequence of Lactobacillus delbrueckii subsp. bulgaricus CFL1, a Lactic Acid Bacterium Isolated from French Handcrafted Fermented Milk.
Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus) is a lactic acid bacterium widely used for the production of yogurt and cheeses. Here, we report the genome sequence of L. bulgaricus CFL1 to improve our knowledge on its stress-induced damages following production and end-use processes.


Relative contributions of optical and neural limitations to human contrast sensitivity at different luminance levels.
The relative contributions of optical and neural constraints on human contrast sensitivity as a function of spatial frequency were assessed for a range of luminances. First, the overall two-dimensional contrast sensitivity function (CSF) was obtained for three eyes at three luminances (0.05, 0.5 and 20 cd/m2) using a standard two-alternative forced-choice procedure. Second, the two-dimensional modulation transfer function (MTF) of the optics was measured for the same eyes and pupil sizes using a hybrid optical-digital method. The two-dimensional neural transfer function (NTF) was obtained as the ratio between the CSF and the MTF. Minor factors, such as the effect of cone aperture, were also considered in the computations. Our results show that at all luminances, the fall off in contrast sensitivity at high spatial frequencies is mainly due to optical factors. The losses in contrast sensitivity with decreasing luminance are, however, primarily due to noise limitations.


Alteration of microvascular permeability in acute kidney injury.
Functional and structural abnormalities in the renal microvasculature are important processes contributing to the pathophysiology of ischemic acute kidney injury (AKI). Renewed interest in the complex interplay between tubular injury, inflammation and microvascular alterations has emerged in order to gain a better understanding of acute kidney injury syndromes. This review examines alterations of the renal microvasculature as they relate to ischemic and septic AKI with an emphasis on the mechanisms involved in altered microvascular permeability.


Advanced in vitro models for renal cell carcinoma therapy design.
Renal cell carcinoma (RCC) and its principal subtype, clear cell RCC, are the most diagnosed kidney cancer. Despite substantial improvement over the last decades, current pharmacological intervention still fails to achieve long-term therapeutic success. RCC is characterized by a high intra- and inter-tumoral heterogeneity and is heavily influenced by the crosstalk of the cells composing the tumor microenvironment, such as cancer-associated fibroblasts, endothelial cells and immune cells. Moreover, multiple physicochemical properties such as pH, interstitial pressure or oxygenation may also play an important role. These elements are often poorly recapitulated in in vitro models used for drug development. This inadequate recapitulation of the tumor is partially responsible for the current lack of an effective and curative treatment. Therefore, there are needs for more complex in vitro or ex vivo drug screening models. In this review, we discuss the current state-of-the-art of RCC models and suggest strategies for their further development.


PTEN protein phosphatase activity regulates hepatitis C virus secretion through modulation of cholesterol metabolism.
Hepatitis C virus (HCV) infection is dependent on lipid metabolism. Hepatocyte steatosis occurs frequently in HCV infection, but the relationship between steatosis and HCV life cycle is unclear. We showed that HCV induces steatosis via the downregulation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). We here investigated how PTEN may affect HCV production. The effect of overexpression or silencing of PTEN on HCV secretion was assessed in genomic-length Jc1 infected HuH7 cells. The role of PTEN protein and lipid phosphatase activities on lipid metabolism and infectious viral particle secretion was investigated using dominant-negative PTEN mutants. The importance of cholesterol metabolism for PTEN-dependent lipid droplet biogenesis and viral particle secretion was examined using statins. PTEN silencing in Jc1 infected HuH7 cells stimulated HCV particle secretion, while PTEN overexpression decreased virus egress. Viral secretion was also increased by overexpression of protein phosphatase-deleted (PTENY138L), but not lipid phosphatase-deleted (PTENG129E), PTEN mutant, thus indicating that the protein phosphatase activity of PTEN controls viral secretion. Similarly, PTENY138L, but not PTENG129E mutant induced the formation of large lipid droplets. PTENY138L mutant did not affect biosynthesis of triglycerides, but promoted the biosynthesis of cholesterol esters. Consistently, statins prevented the increased cholesterol ester production, large lipid droplet formation, and viral secretion in cells expressing the PTENY138L mutant. Downregulation of PTEN protein phosphatase activity by HCV affects cholesterol metabolism, thereby inducing the appearance of large lipid droplets and increasing virion egress.


Hypertension in master endurance athletes.
To determine whether long-term very vigorous endurance training prevents hypertension. Cohort study of master orienteering runners and controls. Finland. In 1995, a health questionnaire was completed by 264 male orienteering runners (response rate 90.4%) who had been top-ranked in competitions among men aged 35-59 years in 1984, and by 388 similarly aged male controls (response rate 87.1%) who were healthy at the age of 20 years and free of overt ischemic heart disease in 1985. Self-report of medication for hypertension. In the endurance athlete group, the crude prevalence (8.7%) of subjects who had used medication for hypertension was less than a third of that in the control group (27.8%). Even after adjusting for age and body mass index, the difference between the groups was still significant (odds ratio for athletes 0.43, 95% confidence interval 0.25-0.76). Long-term vigorous endurance training is associated with a low prevalence of hypertension. Some of the effect can be explained by a lower body mass, but exercise seems to induce a lower rate of hypertension by other mechanisms than by decreasing body weight


Incidence and Risk Factors for Cerebrovascular-Specific Mortality in Patients with Colorectal Cancer: A Registry-Based Cohort Study Involving 563,298 Patients.
Colorectal cancer (CRC) is one of the most prevalent diseases and the second leading cause of death worldwide. However, the relationship between CRC and cerebrovascular-specific mortality (CVSM) remains elusive, and less is known about the influencing factors associated with CVSM in CRC. Here, we aimed to analyze the incidence as well as the risk factors of CVSM in CRC. Patients with a primary CRC diagnosed between 1973 and 2015 were identified from the Surveillance Epidemiology and End Results database, with follow-up data available until 31 December 2016. Conditional standardized mortality ratios were calculated to compare the incidence of CVSM between CRC patients and the general U.S. Univariate and multivariate survival analyses with a competing risk model were used to interrogate the risk factors for CVSM. A total of 563,298 CRC individuals were included. The CVSM in CRC patients was significantly higher than the general population in all age subgroups. Among the competing causes of death in patients, the cumulative mortality caused by cerebrovascular-specific diseases steadily increased during the study period. While age, surgery, other/unknown race and tumors located at the transverse colon positively influenced CVSM on both univariate and multivariate analyses, male patients and those who had radiotherapy, chemotherapy, a more recent year (2001-2015) of diagnosis, a grade II or III CRC, rectal cancer, or multiple primary or distant tumors experienced a lower risk of CVSM. Our data suggest a potential role for CRC in the incidence of CVSM and also identify several significant predictors of CVSM that may be helpful for risk stratification and the therapeutic optimization of cerebrovascular-specific diseases in CRC patients.


Effect of TFC-612, a 7-thia prostaglandin E1 derivative, on intimal thickening after endothelial injury with balloon catheter in rats.
The effect of TFC-612, methyl-6-[(1R,2S,3R)-hydroxy-2-](1E,3S,5R)-3- hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl)thio] hexanoate, on intimal thickening of carotid artery 14 days after endothelium denudation with a balloon catheter was examined in rats. This compound significantly suppressed the neointimal area and the ratio of intimal and medial layer by 41.1% and 31.4%, respectively, at 3.2 micrograms/rat/h s.c. infusion. At this dose, this compound did not inhibit platelet aggregation induced by either collagen or ADP. It did not inhibit bromodeoxyuridine incorporation into medial smooth muscle cells at 3 days after injury. In in vitro experiments, TFC-612 did not inhibit the [3H]thymidine uptake into cultured smooth muscle cells, but it showed significant inhibition of smooth muscle cell migration induced by platelet-derived growth factor (PDGF) at more than 10(-9) M. This compound increased cyclic AMP levels dose dependently in cultured smooth muscle cells at more than 10(-8) M. These results suggest that TFC-612 inhibits intimal thickening by inhibition of smooth muscle cell migration from media to intima through cyclic AMP elevation.


Serpentine-like right atrial mass and fulminant bilateral pulmonary embolism during treatment with rivaroxaban.
Imaging work-up of a 80-year-old woman with sudden onset of dyspnea during current rivaroxaban therapy: computer tomography angiography revealed fulminant bilateral pulmonary embolism. Furthermore, a serpentine-like huge mass in the right atrium was detected, highly suggestive of thrombus or a giant chiari network, respectively. This case highlights the importance of adequate dose regimen of factor Xa inhibitors, as well as the need of thorough differential diagnostic considerations of net like structures in the right atrium.


Bactericidal activity of a granule extract from human polymorphonuclear leukocytes against Bacteroides species.
The microbicidal activity of an acetate extract of human polymorphonuclear leukocyte granules was tested against Bacteroides fragilis, Bacteroides vulgatus, Bacteroides distasonis and Bacteroides thetaiotaomicron. All strains tested were killed by the extract, and there were no significant differences between the different Bacteroides species.


Large unilamellar liposomes with low uptake into the reticuloendothelial system.
Particulate drug carriers, including liposomes, are rapidly removed from blood by cells of the reticuloendothelial system (RES) with resulting adverse effects on this important host defense system. In order to overcome this and other major disadvantages of liposomes, we have altered liposome composition in an effort to achieve prolonged circulation half-lives. Gangliosides and sphingomyelin act synergistically to dramatically diminish the rate and extent of uptake of liposomes by macrophages in vivo. The significantly extended circulation times achieved by these modified large unilamellar liposomes overcome an important barrier to the targeting of particulate drug carriers to specific tissues in vivo.


Peer tutoring and mathematics in secondary education: literature review, effect sizes, moderators, and implications for practice.
A literature review was undertaken to compile all data on peer tutoring in secondary education (7th to 12th grade) mathematics from existing articles. Data from 42 independent studies were included in this research. All data regarding participants' roles (fixed vs. reciprocal), participants' ages (same-age vs. cross-age), the methodological approach taken (quantitative or qualitative), the type of design for those studies that involved a quantitative approach, the variables analyzed, and the organizational matters (number of participants, duration of the program, sessions per week, and duration of the sessions) are included in the article. The effect sizes of the 42 studies were calculated and examined. The main goal of the study was to determine those variables that were moderators of effect size, that is, the variables that significantly influenced students' academic achievement outcomes. Inferential statistical analyses (Student's t-test and ANOVAs) were carried out for the variables. Of the 42 studies examined, 88% showed positive effect sizes with the means being close to medium (Cohen's d = 0.38). Conclusions suggest the implementation of same-age over cross-age tutoring, during programs of fewer than 8 weeks, in sessions of less than 30 minutes is optimal for improving students' academic outcomes. Inclusion of control groups in similar future studies is recommended so effect sizes are not overestimated.


The mechanism of propagation of variation potentials in wheat leaves.
Here we examined the mechanism of propagation of variation potential (VP) induced by burning in wheat leaves. Participation of hydraulic and chemical mechanisms in VP transmission was analyzed by optical coherent tomography and a radioactive tracer method, respectively. The speed of the hydraulic signal considerably exceeded the VP velocity. Investigation of a chemical substance spreading from the zone of local wounding was based on experimental data for radioactive marker transmission derived with a one-dimensional diffusion equation. The speed of the marker transmission was in accordance with VP velocity. The elimination of the potential transmission of a chemical signal by a timed severing of the leaf between the burn site and the recorded site blocked VP propagation. We suggest that a VP is formed by the transmission of a wound substance, the velocity of which is likely increased by hydraulic wave propagation.


Gallus NME/NM23 nucleoside diphosphate kinase 2 interacts with viral σA and affects the replication of avian reovirus.
Our present study aimed to identify host cell proteins that may interact with avian reovirus (ARV) σA protein and their potential effect on ARV replication. The ARV structural protein σA has been demonstrated to suppress interferon production and confirmed to activate the PI3K/Akt pathway. However, host cell factors interacting with σA to affect ARV replication remain unknown. In current study, a cDNA library of chicken embryo fibroblasts (CEFs) was constructed, and host cell proteins interacting with σA were screened by a yeast two-hybrid system. We identified four candidate cellular proteins that interact with ARV σA protein. Among them, Gallus NME/NM23 nucleoside diphosphate kinase 2 (NME2) was further validated as a σA-binding protein through co-immunoprecipitation. The key interaction domain was identified at amino acids (aa) 121-416 in NME2 and at aa 71-139 in σA, respectively. We demonstrated that overexpression of NME2 substantially inhibited ARV replication. In addition silencing NME2 by small interfering RNAs (siRNAs) resulted in marked enhancement of ARV replication. Our work has demonstrated that NME2 is a σA-binding protein that may affect ARV replication in CEF cells.


First synthesis of alternating SATE-phosphotriester/phosphodiester prooligonucleotides on solid support.
Prooligonucleotides with alternating S-Acyl-ThioEthyl (SATE) phosphotriester and phosphodiester linkages or a gap were synthesized by elimination of cyanoethyl group with non-nucleophilic base DBU. Their half-lives in the presence of Pig Liver Esterases (PLE) and in total cell extract were determined.


Empirically Derived Age-Based Vital Signs for Children in the Out-of-Hospital Setting.
To compare Pediatric Advanced Life Support (PALS) vital signs criteria to empirically derived vital signs cut-points for predicting out-of-hospital interventions in children. We performed a cross-sectional study of pediatric encounters (<18 years) using the 2019 to 2020 datasets of the National Emergency Medical Services Information System, which we randomly divided into equal size derivation and validation samples. We developed age-based centile curves for initial heart rate, respiratory rate, and systolic blood pressure using generalized additive models for location, scale, and shape, which we evaluated in the validation sample. In addition, we compared the proportion of encounters with at least 1 abnormal vital sign when using empirically derived and PALS criteria and calculated their associations with the delivery of out-of-hospital medical interventions (eg, vascular access, medication delivery, or airway maneuvers). We included 3,704,398 encounters. Among encounters with all 3 vital signs recorded (n=2,595,217), 45.9% had at least 1 abnormal vital sign using empirically derived criteria and 75.6% with PALS derived criteria. A higher proportion of encounters with a heart rate, respiratory rate, or systolic blood pressure less than 10th or more than 90th age-based empirically derived percentile had medical interventions than those with abnormal vital signs using PALS criteria. PALS criteria classified a high proportion of children as having abnormal vital signs. Empirically derived vital signs developed from out-of-hospital encounters more accurately predict the delivery of the out-of-hospital medical interventions. If externally validated and correlated to inhospital outcomes, these cut-points may provide a useful assessment tool for children in the out-of-hospital setting.


Procedural Teaching: Focusing on the Conscious Patient.
In this perspective, the authors discuss how to teach procedures at the bedside with an awake patient. The teaching process is divided into 3 stages: preprocedural, intraprocedural, and postprocedural. Each stage focuses on a specific set of educational goals and aims for the learner, with specific tips for how the faculty member should be teaching the learner. We discuss how to deal with challenging situations, such as when the faculty member needs to take over the procedure, and how to allow the learner to troubleshoot if they come across the unexpected. With the guidance provided in this perspective, we aim to make procedural teaching at the bedside less daunting for faculty members.


Higher-energy C-trap dissociation for peptide modification analysis.
Peptide sequencing is the basis of mass spectrometry-driven proteomics. Here we show that in the linear ion trap-orbitrap mass spectrometer (LTQ Orbitrap) peptide ions can be efficiently fragmented by high-accuracy and full-mass-range tandem mass spectrometry (MS/MS) via higher-energy C-trap dissociation (HCD). Immonium ions generated via HCD pinpoint modifications such as phosphotyrosine with very high confidence. Additionally we show that an added octopole collision cell facilitates de novo sequencing.


The HIPARCO-2 study: long-term effect of continuous positive airway pressure on blood pressure in patients with resistant hypertension: a multicenter prospective study.
Short-term treatment with continuous positive airway pressure (CPAP) produces a clinically significant reduction in blood pressure (BP) in patients with obstructive sleep apnea (OSA) and resistant hypertension. However, it is unknown whether this effect continues over the long-term. Our objective was to assess the effect of long-term CPAP on BP in patients with OSA and resistant hypertension. The study included 161 patients diagnosed with both OSA [apnea--hypopnea index (AHI) ≥15] and resistant hypertension diagnosed via 24-hour ambulatory BP measurement (24-h ABPM), in whom a second analysis via 24-h ABPM was performed at the end of the follow-up. Patients were followed up within 59 months [interquartile range (IQR): 44-70]. CPAP treatment was prescribed to 82% of the patients (70% with good adherence to CPAP defined as use of CPAP at least 4 h/night). A comparison between the adherent group and nonadherent group (including those with CPAP not prescribed) showed that CPAP adherents had a significant drop in the 24-h BP, both systolic [-3.9 mmHg; 95% confidence interval (CI): -8.1 to 0.3] and diastolic pressure (-3.5 mmHg [95% [CI]: -6.4-0.5]), with a higher magnitude during the night (-5.5 and -4.9 mmHg, respectively). The CPAP adherent group needed a mean of 1.1 less antihypertensive drugs (particularly spironolactone). Finally, there was a positive correlation between the drop in 24-h SBP and the hours of CPAP use (r = 0.24; P = 0.01). Good adherence to long-term CPAP treatment largely succeeded in significantly reducing BP in those patients with OSA and resistant hypertension, despite the use of a lower number of antihypertensive drugs.


Patient perception and approval of faecal microbiota transplantation (FMT) as an alternative treatment option for obesity.
Fecal microbiota transplantation (FMT) represents a treatment option for some diseases, e.g. recurring Clostridium difficile-associated colitis. However, there is also evidence that FMT can be effective in treating obesity. This pilot study established the approval and willingness of obese patients to undergo FMT. We conducted a survey of adults with obesity using a questionnaire containing 21 both multiple choice and open questions was dispatched to a cohort of 101 persons with obesity. It included questions aiming at the process of FMT itself, donors as well as possible concerns. Additionally aspects of social background and disease activity were dealt with. The response rate amounted to 30.1% (n = 31). In our population, mean BMI was 40.5 kg/m2 while the vast majority already tried out treatment modalities to lose weight before. 25.8% of persons with obesity were aware of FMT. 62.1% were willing to undergo FMT if the donor was healthy and anonymous while only 6.9% clearly refused this option. Sixty preferred an anonymous donor or a person proposed by their doctor while colonoscopy was the preferred application by 76.7%. The absence of risks of the procedure (47.8%) formed the principal motivation while reduction of medication was considered as least important reason (in 26.1). Insufficient testing of the faeces concerning infections raised the most concerns (in 61.6%). For the majority of the persons with obesity surveyed FMT represents a treatment option. Approximately two thirds of the questionees would consider FMT as an alternative treatment option, even in spite of a satisfactory disease response to current standard therapies. Unsurprisingly there are concerns in regard to the transmission of possible infectious agents as well as to the hygieneic implementation of FMT itself.


Histamine in the regulation of wakefulness.
The histaminergic system is exclusively localized within the posterior hypothalamus with projection to almost all the major regions of the central nervous system. Strong and consistent evidence exist to suggest that histamine, acting via H₁ and/or H₃ receptor has a pivotal role in the regulation of sleep-wakefulness. Administration of histamine or H₁ receptor agonists induces wakefulness, whereas administration of H₁ receptor antagonists promotes sleep. The H₃ receptor functions as an auto-receptor and regulates the synthesis and release of histamine. Activation of H₃ receptor reduces histamine release and promotes sleep. Conversely, blockade of H₃ receptor promotes wakefulness. Histamine release in the hypothalamus and other target regions is highest during wakefulness. The histaminergic neurons display maximal activity during the state of high vigilance, and cease their activity during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The cerebrospinal levels of histamine are reduced in diseased states where hypersomnolence is a major symptom. The histamine deficient L-histidine decarboxylase knockout (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, and in novel environment. Similar results have been obtained when histamine neurons are lesioned. These studies strongly implicate the histaminergic neurons of the TMN to play a critical role in the maintenance of high vigilance state during wakefulness.


[Objective measurement of skin colour with the help of spectral photometry (author's transl)].
The colour of the human skin can be measured exactly by a new equipment which is described here. The method is based on the analysis of the reflexionproperties of the skin in the region of the visible light. On the basis of the measured reflexionproperties the colour of a probe can be computed as a function of physical parameters.


Molecular medicine for the brain: silencing of disease genes with RNA interference.
The recent discovery of RNA interference (RNAi) has revolutionised biological research and now holds promise as a potential therapy for human diseases. Currently untreatable neurological diseases are especially attractive targets. Scientists have already succeeded in using RNAi to suppress dominant disease genes in vitro; in some cases, this suppression has been allele-specific, silencing the disease-causing allele while maintaining expression of the normal allele. The challenge now is to bring this powerful technology in vivo to animal models to suppress disease genes and correct disease phenotypes. In the confrontation of this challenge, research should benefit from recent advances in viral and non-viral delivery of therapy to the brain.


Unpredictable seed-set: a defence mechanism against seed-eating insects inProtea species (Proteaceae).
Extent of pre-dispersal seed destruction by insects and seed survival were measured for variousProtea species (Proteaceae) and related to seed-set, variation in seed-set, the percentage of barren infructescences and infructescence age. The hypothesis that low and variable seed-set would act as a defence mechanism against insect seed predators was tested. Results indicated that seed survival and variation in seed-set were highly positively correlated, while seed survival and seed-set were negatively correlated. Variation in seed-set was identified as the most important determinant of seed survival for the range ofProtea species studied.