Heart bypass surgery

MedlinePlus

Off-pump coronary artery bypass; OPCAB; Beating heart surgery; Bypass surgery - heart; CABG; Coronary artery bypass graft; Coronary artery bypass surgery; Coronary bypass surgery; Coronary artery disease - CABG; CAD - CABG; Angina - ...

A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening

PubMed Central

McCollister, Faye P.; Sabo, Diane L.; Shoup, Angela G.; Owen, Kris E.; Woodruff, Julie L.; Cox, Edith; Mohamed, Lisa S.; Choo, Daniel I.; Boppana, Suresh B.

2017-01-01

BACKGROUND AND OBJECTIVE: Congenital cytomegalovirus (cCMV) infection remains a leading cause of childhood hearing loss. Currently universal CMV screening at birth does not exist in the United States. An alternative approach could be testing infants who do not pass their newborn hearing screening (NHS) for cCMV. This study was undertaken to evaluate whether a targeted approach will identify infants with CMV-related sensorineural hearing loss (SNHL). METHODS: Infants born at 7 US medical centers received NHS and were also screened for cCMV while in the newborn nursery. Infants who tested positive for CMV received further diagnostic audiologic evaluations to identify or confirm hearing loss. RESULTS: Between 2007 and 2012, 99 945 newborns were screened for both hearing impairment and cCMV. Overall, 7.0% of CMV-positive infants did not pass NHS compared with 0.9% of CMV-negative infants (P < .0001). Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL. In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy. NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period. CONCLUSIONS: A targeted CMV approach that tests newborns who fail their NHS identified the majority of infants with CMV-related SNHL at birth. However, 43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS. PMID:28049114

Added value of second biopsy target in screen-detected widespread suspicious breast calcifications.

PubMed

Falkner, Nathalie M; Hince, Dana; Porter, Gareth; Dessauvagie, Ben; Jeganathan, Sanjay; Bulsara, Max; Lo, Glen

2018-06-01

There is controversy on the optimal work-up of screen-detected widespread breast calcifications: whether to biopsy a single target or multiple targets. This study evaluates agreement between multiple biopsy targets within the same screen-detected widespread (≥25 mm) breast calcification to determine if the second biopsy adds value. Retrospective observational study of women screened in a statewide general population risk breast cancer mammographic screening program from 2009 to 2016. Screening episodes recalled for widespread calcifications where further views indicated biopsy, and two or more separate target areas were sampled within the same lesion were included. Percentage agreement and Cohen's Kappa were calculated. A total of 293317 women were screened during 761124 separate episodes with recalls for widespread calcifications in 2355 episodes. In 171 women, a second target was biopsied within the same lesion. In 149 (86%) cases, the second target biopsy result agreed with the first biopsy (κ = 0.6768). Agreement increased with increasing mammography score (85%, 86% and 92% for score 3, 4 and 5 lesions). Same day multiple biopsied lesions were three times more likely to yield concordant results compared to post-hoc second target biopsy cases. While a single target biopsy is sufficient to discriminate a benign vs. malignant diagnosis in most cases, in 14% there is added value in performing a second target biopsy. Biopsies performed prospectively are more likely to yield concordant results compared to post-hoc second target biopsy cases, suggesting a single prospective biopsy may be sufficient when results are radiological-pathological concordant; discordance still requires repeat sampling. © 2018 The Royal Australian and New Zealand College of Radiologists.

TINS, target immobilized NMR screening: an efficient and sensitive method for ligand discovery.

PubMed

Vanwetswinkel, Sophie; Heetebrij, Robert J; van Duynhoven, John; Hollander, Johan G; Filippov, Dmitri V; Hajduk, Philip J; Siegal, Gregg

2005-02-01

We propose a ligand screening method, called TINS (target immobilized NMR screening), which reduces the amount of target required for the fragment-based approach to drug discovery. Binding is detected by comparing 1D NMR spectra of compound mixtures in the presence of a target immobilized on a solid support to a control sample. The method has been validated by the detection of a variety of ligands for protein and nucleic acid targets (K(D) from 60 to 5000 muM). The ligand binding capacity of a protein was undiminished after 2000 different compounds had been applied, indicating the potential to apply the assay for screening typical fragment libraries. TINS can be used in competition mode, allowing rapid characterization of the ligand binding site. TINS may allow screening of targets that are difficult to produce or that are insoluble, such as membrane proteins.

Large scale RNAi screen in Tribolium reveals novel target genes for pest control and the proteasome as prime target.

PubMed

Ulrich, Julia; Dao, Van Anh; Majumdar, Upalparna; Schmitt-Engel, Christian; Schwirz, Jonas; Schultheis, Dorothea; Ströhlein, Nadi; Troelenberg, Nicole; Grossmann, Daniela; Richter, Tobias; Dönitz, Jürgen; Gerischer, Lizzy; Leboulle, Gérard; Vilcinskas, Andreas; Stanke, Mario; Bucher, Gregor

2015-09-03

Insect pest control is challenged by insecticide resistance and negative impact on ecology and health. One promising pest specific alternative is the generation of transgenic plants, which express double stranded RNAs targeting essential genes of a pest species. Upon feeding, the dsRNA induces gene silencing in the pest resulting in its death. However, the identification of efficient RNAi target genes remains a major challenge as genomic tools and breeding capacity is limited in most pest insects impeding whole-animal-high-throughput-screening. We use the red flour beetle Tribolium castaneum as a screening platform in order to identify the most efficient RNAi target genes. From about 5,000 randomly screened genes of the iBeetle RNAi screen we identify 11 novel and highly efficient RNAi targets. Our data allowed us to determine GO term combinations that are predictive for efficient RNAi target genes with proteasomal genes being most predictive. Finally, we show that RNAi target genes do not appear to act synergistically and that protein sequence conservation does not correlate with the number of potential off target sites. Our results will aid the identification of RNAi target genes in many pest species by providing a manageable number of excellent candidate genes to be tested and the proteasome as prime target. Further, the identified GO term combinations will help to identify efficient target genes from organ specific transcriptomes. Our off target analysis is relevant for the sequence selection used in transgenic plants.

Aspirin resistance in patients with hemodynamic cerebral ischemia undergoing extracranial-intracranial bypass surgery.

PubMed

Jussen, Daniel; Horn, Peter; Vajkoczy, Peter

2013-01-01

Aspirin (acetylsalicylic acid, ASA) is the treatment of choice for prevention of vascular events in symptomatic steno-occlusive cerebrovascular disease (CVD). Cerebral revascularization using standard extracranial-intracranial (EC-IC) bypass surgery may be used to revert hemodynamic compromise. Aspirin is prescribed as standard medication in order to avoid bypass failure. Accumulating evidence of an increased risk of major adverse clinical events led to this study, in which we aimed to assess the prevalence of aspirin resistance and prothrombotic disorders among patients scheduled for EC-IC bypass surgery, and the effectiveness of aspirin dose escalation. We prospectively screened patients with circumscribed high-grade stenosis or occlusion of brain-supplying vessels fulfilling the hemodynamic criteria for EC-IC bypass surgery for aspirin resistance using a platelet function analyzer (PFA-100®) test. We also determined their smoking habits and screened for prothrombotic disorders and comorbidities. The patients were divided into 2 major groups: group A had atherosclerotic steno-occlusive CVD and group B consisted of patients with nonatherosclerotic steno-occlusive CVD (moyamoya disease) and a subgroup of pediatric moyamoya patients (pediatric subgroup). Bypass patency was documented via digital subtraction angiography. Standard initial ASA dose applied was 100 mg/day. In cases of aspirin resistance, doses were increased and the PFA-100 test was repeated. A total of 56 patients were included over a time period of 6 months. In group A (n = 25), we found a ratio of 40% of patients with primary resistance to aspirin 100 mg/day. In contrast, in group B (n = 25), only 20% of the patients were resistant to aspirin 100 mg/day; in the pediatric population (n = 6), there was no primary aspirin resistance. After a dose escalation to 300 mg/day, the ratio of aspirin resistance was reduced to 20% in group A and to 0% in group B. Altogether 5 patients with atherosclerotic steno

Universal Versus Targeted Screening for Lynch Syndrome: Comparing Ascertainment and Costs Based on Clinical Experience.

PubMed

Erten, Mujde Z; Fernandez, Luca P; Ng, Hank K; McKinnon, Wendy C; Heald, Brandie; Koliba, Christopher J; Greenblatt, Marc S

2016-10-01

Strategies to screen colorectal cancers (CRCs) for Lynch syndrome are evolving rapidly; the optimal strategy remains uncertain. We compared targeted versus universal screening of CRCs for Lynch syndrome. In 2010-2011, we employed targeted screening (age < 60 and/or Bethesda criteria). From 2012 to 2014, we screened all CRCs. Immunohistochemistry for the four mismatch repair proteins was done in all cases, followed by other diagnostic studies as indicated. We modeled the diagnostic costs of detecting Lynch syndrome and estimated the 5-year costs of preventing CRC by colonoscopy screening, using a system dynamics model. Using targeted screening, 51/175 (29 %) cancers fit criteria and were tested by immunohistochemistry; 15/51 (29 %, or 8.6 % of all CRCs) showed suspicious loss of ≥1 mismatch repair protein. Germline mismatch repair gene mutations were found in 4/4 cases sequenced (11 suspected cases did not have germline testing). Using universal screening, 17/292 (5.8 %) screened cancers had abnormal immunohistochemistry suspicious for Lynch syndrome. Germline mismatch repair mutations were found in only 3/10 cases sequenced (7 suspected cases did not have germline testing). The mean cost to identify Lynch syndrome probands was ~$23,333/case for targeted screening and ~$175,916/case for universal screening at our institution. Estimated costs to identify and screen probands and relatives were: targeted, $9798/case and universal, $38,452/case. In real-world Lynch syndrome management, incomplete clinical follow-up was the major barrier to do genetic testing. Targeted screening costs 2- to 7.5-fold less than universal and rarely misses Lynch syndrome cases. Future changes in testing costs will likely change the optimal algorithm.

A gain-of-function screen for genes that influence axon guidance identifies the NF-kappaB protein dorsal and reveals a requirement for the kinase Pelle in Drosophila photoreceptor axon targeting.

PubMed

Mindorff, Elizabeth N; O'Keefe, David D; Labbé, Alain; Yang, Jennie Ping; Ou, Yimiao; Yoshikawa, Shingo; van Meyel, Donald J

2007-08-01

To identify novel regulators of nervous system development, we used the GAL4-UAS misexpression system in Drosophila to screen for genes that influence axon guidance in developing embryos. We mobilized the Gene Search (GS) P element and identified 42 lines with insertions in unique loci, including leak/roundabout2, which encodes an axon guidance receptor and confirms the utility of our screen. The genes we identified encode proteins of diverse classes, some acting near the cell surface and others in the cytoplasm or nucleus. We found that one GS line drove misexpression of the NF-kappaB transcription factor Dorsal, causing motor axons to bypass their correct termination sites. In the developing visual system, Dorsal misexpression also caused photoreceptor axons to reach incorrect positions within the optic lobe. This mistargeting occurred without observable changes of cell fate and correlated with localization of ectopic Dorsal in distal axons. We found that Dorsal and its inhibitor Cactus are expressed in photoreceptors, though neither was required for axon targeting. However, mutation analyses of genes known to act upstream of Dorsal revealed a requirement for the interleukin receptor-associated kinase family kinase Pelle for layer-specific targeting of photoreceptor axons, validating our screen as a means to identify new molecular determinants of nervous system development in vivo.

Coronary–Coronary Bypass

PubMed Central

Erdil, Nevzat; Ates, Sanser; Demirkilic, Ufuk; Tatar, Harun; Sag, Cemal

2002-01-01

There is increased risk of systemic embolism during cardiopulmonary bypass in patients with a severely atherosclerotic ascending aorta. We report a coronary–coronary bypass in a 74-year-old man with a porcelain aorta. He underwent a proximal right coronary–distal right coronary artery bypass with a saphenous vein graft, combined with a pedicled arterial graft (left internal mammary artery) to the left anterior descending artery, in the presence of a beating heart without cardiopulmonary bypass. The patient survived without evidence of perioperative myocardial infarction or cerebrovascular accident. One year later, follow-up angiography showed graft patency with good distal runoff. Coronary–coronary bypass on a beating heart without cardiopulmonary bypass can be performed safely in a patient with porcelain aorta. (Tex Heart Inst J 2002;29:54–5) PMID:11995853

Gastric bypass surgery - discharge

MedlinePlus

... bypass - discharge; Gastric bypass - Roux-en-Y - discharge; Obesity gastric bypass discharge; Weight loss - gastric bypass discharge ... al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised ...

California bypass study : the economic impacts of bypasses.

DOT National Transportation Integrated Search

2006-05-01

The California Department of Transportation (Caltrans) sponsored the California : Bypass Study to improve basic knowledge about the impacts of bypasses on small-town : economies. The study included an investigation into the economic impacts of recent...

Cervical cancer screening in Malaysia: Are targeted interventions necessary?

PubMed

Dunn, Richard A; Tan, Andrew K G

2010-09-01

This study examines the determinants of Papanicolaou Smear Test (PST) screening for cervical cancer among women in Malaysia. Attention is focused on the reasons different population subgroups give for non-screening. We find that Indian women are the least likely to have had a PST and also the least likely to know the reasons why one is screened. Malay women are less likely than Chinese women to have received a PST and are more likely to report embarrassment as the reason for not being tested. Urban women are less likely than rural women to have been tested and more likely to state lack of time as the reason. These results suggest targeted interventions may be necessary to increase screening rates in Malaysia. Copyright 2010 Elsevier Ltd. All rights reserved.

Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification.

PubMed

Deans, Richard M; Morgens, David W; Ökesli, Ayşe; Pillay, Sirika; Horlbeck, Max A; Kampmann, Martin; Gilbert, Luke A; Li, Amy; Mateo, Roberto; Smith, Mark; Glenn, Jeffrey S; Carette, Jan E; Khosla, Chaitan; Bassik, Michael C

2016-05-01

Broad-spectrum antiviral drugs targeting host processes could potentially treat a wide range of viruses while reducing the likelihood of emergent resistance. Despite great promise as therapeutics, such drugs remain largely elusive. Here we used parallel genome-wide high-coverage short hairpin RNA (shRNA) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens to identify the cellular target and mechanism of action of GSK983, a potent broad-spectrum antiviral with unexplained cytotoxicity. We found that GSK983 blocked cell proliferation and dengue virus replication by inhibiting the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). Guided by mechanistic insights from both genomic screens, we found that exogenous deoxycytidine markedly reduced GSK983 cytotoxicity but not antiviral activity, providing an attractive new approach to improve the therapeutic window of DHODH inhibitors against RNA viruses. Our results highlight the distinct advantages and limitations of each screening method for identifying drug targets, and demonstrate the utility of parallel knockdown and knockout screens for comprehensive probing of drug activity.

Small Molecule Screen for Candidate Antimalarials Targeting Plasmodium Kinesin-5*

PubMed Central

Liu, Liqiong; Richard, Jessica; Kim, Sunyoung; Wojcik, Edward J.

2014-01-01

Plasmodium falciparum and vivax are responsible for the majority of malaria infections worldwide, resulting in over a million deaths annually. Malaria parasites now show measured resistance to all currently utilized drugs. Novel antimalarial drugs are urgently needed. The Plasmodium Kinesin-5 mechanoenzyme is a suitable “next generation” target. Discovered via small molecule screen experiments, the human Kinesin-5 has multiple allosteric sites that are “druggable.” One site in particular, unique in its sequence divergence across all homologs in the superfamily and even within the same family, exhibits exquisite drug specificity. We propose that Plasmodium Kinesin-5 shares this allosteric site and likewise can be targeted to uncover inhibitors with high specificity. To test this idea, we performed a screen for inhibitors selective for Plasmodium Kinesin-5 ATPase activity in parallel with human Kinesin-5. Our screen of nearly 2000 compounds successfully identified compounds that selectively inhibit both P. vivax and falciparum Kinesin-5 motor domains but, as anticipated, do not impact human Kinesin-5 activity. Of note is a candidate drug that did not biochemically compete with the ATP substrate for the conserved active site or disrupt the microtubule-binding site. Together, our experiments identified MMV666693 as a selective allosteric inhibitor of Plasmodium Kinesin-5; this is the first identified protein target for the Medicines of Malaria Venture validated collection of parasite proliferation inhibitors. This work demonstrates that chemical screens against human kinesins are adaptable to homologs in disease organisms and, as such, extendable to strategies to combat infectious disease. PMID:24737313

[How to facilitate protein consumption after gastric bypass?].

PubMed

Clarisse, Muriel; Di Vetta, Véronique; Siegrist, Carine; Giusti, Vittorio

2013-03-27

After a gastric bypass, covering protein needs is impossible. This deficit is co-responsible for several postoperative complications so it is essential to inform, prepare and train every patient candidate for such an intervention. To increase protein intake, it is important to work on two different aspects: on the one hand on food sources, targeting the richest food and, on the other hand, on food tolerance so that these foods can be consumed. In fact, gastric bypass induces not only a reduction in gastric volume, but also reduces the passage from the stomach to the intestine. Changes in feeding behavior are much needed to improve food tolerance.

The effect of interventions targeting screen time reduction: A systematic review and meta-analysis.

PubMed

Wu, Lei; Sun, Samio; He, Yao; Jiang, Bin

2016-07-01

Previous studies have evaluated the effectiveness of interventions aimed at screen time reduction, but the results have been inconsistent. We therefore conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to summarize the accumulating evidence of the impact of interventions targeting screen time reduction on body mass index (BMI) reduction and screen time reduction. The PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for RCTs on the effect of interventions targeting screen time reduction. The primary and secondary outcomes were the mean difference between the treatment and control groups in the changes in BMI and changes in screen viewing time. A random effects model was used to calculate the pooled mean differences. Fourteen trials including 2238 participants were assessed. The pooled analysis suggested that interventions targeting screen time reduction had a significant effect on BMI reduction (-0.15 kg/m, P < 0.001, I = 0) and on screen time reduction (-4.63 h/w, P = 0.003, I = 94.6%). Subgroup analysis showed that a significant effect of screen time reduction was observed in studies in which the duration of intervention was <7 months and that the types of interventions in those studies were health promotion curricula or counseling. Interventions for screen time reduction might be effective in reducing screen time and preventing excess weight. Further rigorous investigations with larger samples and longer follow-up periods are still needed to evaluate the efficacy of screen time reduction both in children and in adults.

Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening

PubMed Central

Abrahams, Garth L.; Kumar, Anuradha; Savvi, Suzana; Hung, Alvin W.; Wen, Shijun; Abell, Chris; Barry, Clifton E.; Sherman, David R.; Boshoff, Helena I.M.; Mizrahi, Valerie

2012-01-01

SUMMARY Whole-cell screening of Mycobacterium tuberculosis (Mtb) remains a mainstay of drug discovery but subsequent target elucidation often proves difficult. Conditional mutants that under-express essential genes have been used to identify compounds with known mechanism of action by target-based whole-cell screening (TB-WCS). Here, the feasibility of TB-WCS in Mtb was assessed by generating mutants that conditionally express pantothenate synthetase (panC), diaminopimelate decarboxylase (lysA) and isocitrate lyase (icl1). The essentiality of panC and lysA, and conditional essentiality of icl1 for growth on fatty acids, was confirmed. Depletion of PanC and Icl1 rendered the mutants hypersensitive to target-specific inhibitors. Stable reporter strains were generated for use in high-throughput screening, and their utility demonstrated by identifying compounds that display greater potency against a PanC-depleted strain. These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. PMID:22840772

Impact of mean arterial pressure on sublingual microcirculation during cardiopulmonary bypass - secondary outcome from a randomised clinical trial.

PubMed

Holmgaard, Frederik; Vedel, Anne G; Ravn, Hanne Berg; Nilsson, Jens C; Rasmussen, Lars S

2018-05-13

In this substudy of a randomised, clinical trial, we explored the sublingual microcirculation during cardiac surgery at two different levels of blood pressure. We hypothesised that a higher mean arterial pressure during cardiopulmonary bypass would cause higher Microvascular Flow Index. Thirty-six cardiac surgery patients undergoing coronary artery bypass grafting were included and randomised to either low (40-50 mmHg) or high (70-80 mmHg) mean arterial pressure during cardiopulmonary bypass. Sidestream Dark Field video images were recorded from the sublingual mucosa. Recordings were analysed in a blinded fashion to quantify microcirculatory variables. Mean arterial pressure during cardiopulmonary bypass in the low target group was 45.0 mmHg (SD 5.3) vs. 67.2 mmHg (SD 8.9) in the high target group. We found no significant difference between the two groups in Microvascular Flow Index during cardiopulmonary bypass evaluated for all vessels: 2.91 vs. 2.90 (p = 0.82). For small vessels (< 20 micrometers), the corresponding values were 2.87 and 2.85 in the low and high target groups, respectively (p = 0.82). We found no significant difference in sublingual microcirculatory flow expressed as Microvascular Flow Index according to two different levels of mean arterial pressure during cardiopulmonary bypass. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Distal small bowel bypass for weight regain after gastric bypass: safety and efficacy threshold occurs at <70% bypass.

PubMed

Caruana, Joseph A; Monte, Scott V; Jacobs, David M; Voytovich, Catherine; Ghanim, Husam; Dandona, Paresh

2015-01-01

For patients with poor weight loss (WL) after Roux-en-Y gastric bypass (RYGB) there are few well-tolerated and effective surgical options. Revision to distal bypass by shortening of the common channel (CC) induces significant WL but often produces protein calorie malnutrition (PCM) and severe diarrhea. The aim of this study was to identify a safe and effective threshold for distal small bowel bypass when done for revision of gastric bypass. Academic Institution, United States. We performed revision of RYGB for WL in 20 patients by shortening the CC to a new length of 120-300 cm. The Roux limb length was unchanged. WL and PCM were monitored. A threshold for percent of small bowel bypassed at which PCM was avoided was retrospectively determined. WL was then compared in patients above and below this threshold. Five patients completed a 250-kcal mixed meal challenge before and 3 months after revision to determine selected gut hormone responses. Bypassing ≥70% small bowel resulted in PCM in 4 of 10 patients but in none of 10 patients below that threshold. PCM was observed as late as 2 years after revision and necessitated rerevision by lengthening of the CC in 3 patients. Additionally, nocturnal diarrhea was more common and more intractable when ≥70% bypass was done. Both groups had significant excess body WL over 2 years, but it was greater in patients with ≥70% bypass (47±19 versus 26±17; P<.05). A favorable gut hormone response was observed with 3-hour decrease in glucose-dependent insulinotropic peptide (GIP) by 25% and increase in glucagon-like peptide-1 (GLP-1) by 25%, whereas fasting peptide-YY (PYY) increased by 71% (P<.05 for all). Revision of RYGB to distal bypass when it is <70% of a patient's small bowel length results in an acceptable balance of WL and a positive safety profile. WL may be mediated through an enhanced gut hormone effect, an aversion to ingested fat, and possibly other mechanisms. Copyright © 2015 American Society for Bariatric

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

NASA Astrophysics Data System (ADS)

Machutta, Carl A.; Kollmann, Christopher S.; Lind, Kenneth E.; Bai, Xiaopeng; Chan, Pan F.; Huang, Jianzhong; Ballell, Lluis; Belyanskaya, Svetlana; Besra, Gurdyal S.; Barros-Aguirre, David; Bates, Robert H.; Centrella, Paolo A.; Chang, Sandy S.; Chai, Jing; Choudhry, Anthony E.; Coffin, Aaron; Davie, Christopher P.; Deng, Hongfeng; Deng, Jianghe; Ding, Yun; Dodson, Jason W.; Fosbenner, David T.; Gao, Enoch N.; Graham, Taylor L.; Graybill, Todd L.; Ingraham, Karen; Johnson, Walter P.; King, Bryan W.; Kwiatkowski, Christopher R.; Lelièvre, Joël; Li, Yue; Liu, Xiaorong; Lu, Quinn; Lehr, Ruth; Mendoza-Losana, Alfonso; Martin, John; McCloskey, Lynn; McCormick, Patti; O'Keefe, Heather P.; O'Keeffe, Thomas; Pao, Christina; Phelps, Christopher B.; Qi, Hongwei; Rafferty, Keith; Scavello, Genaro S.; Steiginga, Matt S.; Sundersingh, Flora S.; Sweitzer, Sharon M.; Szewczuk, Lawrence M.; Taylor, Amy; Toh, May Fern; Wang, Juan; Wang, Minghui; Wilkins, Devan J.; Xia, Bing; Yao, Gang; Zhang, Jean; Zhou, Jingye; Donahue, Christine P.; Messer, Jeffrey A.; Holmes, David; Arico-Muendel, Christopher C.; Pope, Andrew J.; Gross, Jeffrey W.; Evindar, Ghotas

2017-07-01

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

Depression screening with patient-targeted feedback in cardiology: DEPSCREEN-INFO randomised clinical trial.

PubMed

Löwe, Bernd; Blankenberg, Stefan; Wegscheider, Karl; König, Hans-Helmut; Walter, Dirk; Murray, Alexandra M; Gierk, Benjamin; Kohlmann, Sebastian

2017-02-01

International guidelines advocate depression screening in patients with coronary heart disease (CHD) and other chronic illnesses, but evidence is lacking. To test the differential efficacy of written patient-targeted feedback v. no written patient feedback after depression screening. Patients with CHD or hypertension from three cardiology settings were randomised and screened for depression (ClinicalTrials.gov Identifier: NCT01879111). Compared with the control group, where only cardiologists received written feedback, in the intervention group both cardiologists and patients received written feedback regarding depression status. Depression severity was measured 1 month (primary outcome) and 6 months after screening. The control group (n = 220) and the patient-feedback group (n = 155) did not differ in depression severity 1 month after screening. Six months after screening, the patient-feedback group showed significantly greater improvements in depression severity and was twice as likely to seek information about depression compared with the control group. Patient-targeted feedback in addition to screening has a significant but small effect on depression severity after 6 months and may encourage patients to take an active role in the self-management of depression. © The Royal College of Psychiatrists 2017.

Discovery of novel drug targets and their functions using phenotypic screening of natural products.

PubMed

Chang, Junghwa; Kwon, Ho Jeong

2016-03-01

Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

Temporary bypass for superior vena cava reconstruction with Anthron bypass tubeTM

PubMed Central

Yamasaki, Naoya; Tsuchiya, Tomoshi; Miyazaki, Takuro; Kamohara, Ryotaro; Hatachi, Go; Nagayasu, Takeshi

2017-01-01

Total superior vena cava (SVC) clamping for SVC replacement or repair can be used in thoracic surgery. A bypass technique is an option to avoid hemodynamic instability and cerebral venous hypertension and hypoperfusion. The present report describes a venous bypass technique using Anthron bypass tubeTM for total SVC clamping. Indications for this procedure include the need for a temporary bypass between the brachiocephalic vein and atrium for complete tumor resection. This procedure allows the surgeons sufficient time to complete replacement of SVC or partial resection of SVC without adverse effects. Further, it is a relatively simple procedure requiring minimal time. PMID:28840027

Functional Dissection of the Blocking and Bypass Activities of the Fab-8 Boundary in the Drosophila Bithorax Complex.

PubMed

Kyrchanova, Olga; Mogila, Vladic; Wolle, Daniel; Deshpande, Girish; Parshikov, Alexander; Cléard, Fabienne; Karch, Francois; Schedl, Paul; Georgiev, Pavel

2016-07-01

Functionally autonomous regulatory domains direct the parasegment-specific expression of the Drosophila Bithorax complex (BX-C) homeotic genes. Autonomy is conferred by boundary/insulator elements that separate each regulatory domain from its neighbors. For six of the nine parasegment (PS) regulatory domains in the complex, at least one boundary is located between the domain and its target homeotic gene. Consequently, BX-C boundaries must not only block adventitious interactions between neighboring regulatory domains, but also be permissive (bypass) for regulatory interactions between the domains and their gene targets. To elucidate how the BX-C boundaries combine these two contradictory activities, we have used a boundary replacement strategy. We show that a 337 bp fragment spanning the Fab-8 boundary nuclease hypersensitive site and lacking all but 83 bp of the 625 bp Fab-8 PTS (promoter targeting sequence) fully rescues a Fab-7 deletion. It blocks crosstalk between the iab-6 and iab-7 regulatory domains, and has bypass activity that enables the two downstream domains, iab-5 and iab-6, to regulate Abdominal-B (Abd-B) transcription in spite of two intervening boundary elements. Fab-8 has two dCTCF sites and we show that they are necessary both for blocking and bypass activity. However, CTCF sites on their own are not sufficient for bypass. While multimerized dCTCF (or Su(Hw)) sites have blocking activity, they fail to support bypass. Moreover, this bypass defect is not rescued by the full length PTS. Finally, we show that orientation is critical for the proper functioning the Fab-8 replacement. Though the inverted Fab-8 boundary still blocks crosstalk, it disrupts the topology of the Abd-B regulatory domains and does not support bypass. Importantly, altering the orientation of the Fab-8 dCTCF sites is not sufficient to disrupt bypass, indicating that orientation dependence is conferred by other factors.

Functional Dissection of the Blocking and Bypass Activities of the Fab-8 Boundary in the Drosophila Bithorax Complex

PubMed Central

Wolle, Daniel; Deshpande, Girish; Parshikov, Alexander; Cléard, Fabienne; Karch, Francois; Schedl, Paul; Georgiev, Pavel

2016-01-01

Functionally autonomous regulatory domains direct the parasegment-specific expression of the Drosophila Bithorax complex (BX-C) homeotic genes. Autonomy is conferred by boundary/insulator elements that separate each regulatory domain from its neighbors. For six of the nine parasegment (PS) regulatory domains in the complex, at least one boundary is located between the domain and its target homeotic gene. Consequently, BX-C boundaries must not only block adventitious interactions between neighboring regulatory domains, but also be permissive (bypass) for regulatory interactions between the domains and their gene targets. To elucidate how the BX-C boundaries combine these two contradictory activities, we have used a boundary replacement strategy. We show that a 337 bp fragment spanning the Fab-8 boundary nuclease hypersensitive site and lacking all but 83 bp of the 625 bp Fab-8 PTS (promoter targeting sequence) fully rescues a Fab-7 deletion. It blocks crosstalk between the iab-6 and iab-7 regulatory domains, and has bypass activity that enables the two downstream domains, iab-5 and iab-6, to regulate Abdominal-B (Abd-B) transcription in spite of two intervening boundary elements. Fab-8 has two dCTCF sites and we show that they are necessary both for blocking and bypass activity. However, CTCF sites on their own are not sufficient for bypass. While multimerized dCTCF (or Su(Hw)) sites have blocking activity, they fail to support bypass. Moreover, this bypass defect is not rescued by the full length PTS. Finally, we show that orientation is critical for the proper functioning the Fab-8 replacement. Though the inverted Fab-8 boundary still blocks crosstalk, it disrupts the topology of the Abd-B regulatory domains and does not support bypass. Importantly, altering the orientation of the Fab-8 dCTCF sites is not sufficient to disrupt bypass, indicating that orientation dependence is conferred by other factors. PMID:27428541

Results of a Targeted Screening Program for Congenital Cytomegalovirus Infection in Infants Who Fail Newborn Hearing Screening.

PubMed

Vancor, Emily; Shapiro, Eugene D; Loyal, Jaspreet

2018-01-24

Congenital cytomegalovirus (CMV) infection is a major cause of sensorineural hearing loss. By law, newborns in Connecticut who fail newborn hearing screening are tested for infection with CMV. This targeted screening is controversial, because most children with congenital CMV infection are asymptomatic, and CMV-related hearing loss can have a delayed onset. Our hospital uses a saliva polymerase chain reaction (PCR) assay (confirmed by a urine PCR assay) to detect CMV. Here, we report the results of the first year of our screening program. We reviewed the medical records of newborns in the Yale New Haven Health System who failed the newborn hearing screening test between January 1 and December 31, 2016. Of 10964 newborns, 171 failed newborn hearing screening, and 3 of these newborns had positive saliva CMV PCR test results. Of these 3 newborns, 2 had positive results on the confirmatory test (for 1 of them the confirmatory test was not performed until the infant was 10 weeks old), and 1 had a negative result on the confirmatory test. Three additional newborns with congenital CMV infection were tested because of clinical indications (1 for ventriculomegaly on prenatal ultrasound and 2 for CMV infection of the mother). Results of audiology follow-up were available for 149 (87.1%) of the 171 newborns who failed newborn hearing screening; 127 (85.2%) had normal results. Our targeted screening program for congenital CMV infection had a low yield. Consideration should be given to other strategies for identifying children at risk of hearing loss as a result of congenital CMV infection. © The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Turbine and superheater bypass evaluation. Final report. [Faster startup in cycling operation and less erosion with steam bypass systems, including bypass design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosard, D.D.; Steltz, W.G.

1986-10-01

Properly sized turbine and boiler bypass systems permit two-shift cycling operation of units, shorten start-up time, and reduce life expenditures of plant components. With bypasses installed, faster startups can reduce fuel costs by $100,000 per year for a typical 500-MW fossil-fired unit. This report discusses the technical characteristics of existing bypass systems and provides guidelines for sizing bypass systems to achieve economical and reliable two-shift operation. The collection and analysis of startup data from several generating units were used in conjunction with computer simulations to illustrate the effects of adding various arrangements and sizes of steam bypass systems. The report,more » which indicates that shutdown procedures have significant impact on subsequent startup and loading time, describes operating practices to optimize the effectiveness of bypass systems. To determine the effectiveness of large turbine bypass systems of less than 100% capacity in preventing boiler trips following load rejection, transient field data were compared to a load rejection simulation using the modular modeling system (MMS). The MMS was then used to predict system response to other levels of load rejection. 7 refs., 87 figs., 8 tabs.« less

A personalized medicine approach to the design of dry powder inhalers: Selecting the optimal amount of bypass.

PubMed

Kopsch, Thomas; Murnane, Darragh; Symons, Digby

2017-08-30

In dry powder inhalers (DPIs) the patient's inhalation manoeuvre strongly influences the release of drug. Drug release from a DPI may also be influenced by the size of any air bypass incorporated in the device. If the amount of bypass is high less air flows through the entrainment geometry and the release rate is lower. In this study we propose to reduce the intra- and inter-patient variations of drug release by controlling the amount of air bypass in a DPI. A fast computational method is proposed that can predict how much bypass is needed for a specified drug delivery rate for a particular patient. This method uses a meta-model which was constructed using multiphase computational fluid dynamic (CFD) simulations. The meta-model is applied in an optimization framework to predict the required amount of bypass needed for drug delivery that is similar to a desired target release behaviour. The meta-model was successfully validated by comparing its predictions to results from additional CFD simulations. The optimization framework has been applied to identify the optimal amount of bypass needed for fictitious sample inhalation manoeuvres in order to deliver a target powder release profile for two patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Depression and Anxiety following Coronary Artery Bypass Graft: Current Indian Scenario

PubMed Central

Saini, Rajiv; Bakhla, Ajay Kumar; Singh, Jaswinder

2016-01-01

Epidemiological studies have shown a high prevalence of coronary artery disease among the Indian Population. Due to increasing availability and affordability of tertiary care in many parts of India, carefully selected patients undergo coronary artery bypass surgery to improve cardiac function. However, the procedure is commonly associated with depression and anxiety which can adversely affect overall prognosis. The objective of this review is to highlight early identifiable symptoms of depression and anxiety following coronary artery bypass graft (CABG) in Indian context so as to facilitate prompt intervention for better outcome. The current review was able to establish firm evidence in support of screening for depression and anxiety following CABG. Management of depression and anxiety following CABG is briefly reviewed. PMID:27034884

Single-Cell Droplet Microfluidic Screening for Antibodies Specifically Binding to Target Cells.

PubMed

Shembekar, Nachiket; Hu, Hongxing; Eustace, David; Merten, Christoph A

2018-02-20

Monoclonal antibodies are a main player in modern drug discovery. Many antibody screening formats exist, each with specific advantages and limitations. Nonetheless, it remains challenging to screen antibodies for the binding of cell-surface receptors (the most important class of all drug targets) or for the binding to target cells rather than purified proteins. Here, we present a high-throughput droplet microfluidics approach employing dual-color normalized fluorescence readout to detect antibody binding. This enables us to obtain quantitative data on target cell recognition, using as little as 33 fg of IgG per assay. Starting with an excess of hybridoma cells releasing unspecific antibodies, individual clones secreting specific binders (of target cells co-encapsulated into droplets) could be enriched 220-fold after sorting 80,000 clones in a single experiment. This opens the way for therapeutic antibody discovery, especially since the single-cell approach is in principle also applicable to primary human plasma cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Low-Voltage Bypass Device

NASA Technical Reports Server (NTRS)

Wilson, J. P.

1994-01-01

Improved bypass device provides low-resistance current shunt around low-voltage power cell when cell fails in open-circuit condition during operation. In comparison with older bypass devices for same application, this one weighs less, generates less heat, and has lower voltage drop (less resistance). Bypass device connected in parallel with power cell. Draws very little current during normal operation of cell.

[Target and non-target screening of volatile organic compounds in industrial exhaust gas using thermal desorption-gas chromatography-mass spectrometry].

PubMed

Ma, Huilian; Jin, Jing; Li, Yun; Chen, Jiping

2017-10-08

A method of comprehensive screening of the target and non-target volatile organic compounds (VOCs) in industrial exhaust gas using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) has been developed. In this paper, two types of solid phase adsorption column were compared, and the Tenex SS TD Tube was selected. The analytes were enriched into the adsorption tube by constant flow sampling, and detected by TD-GC-MS in full scan mode. Target compounds were quantified by internal standard method, and the quantities of non-target compounds were calculated by response coefficient of toluene. The method detection limits (MDLs) for the 24 VOCs were 1.06 to 5.44 ng, and MDLs could also be expressed as 0.004 to 0.018 mg/m 3 assuming that the sampling volume was 300 mL. The average recoveries were in the range of 78.4% to 89.4% with the relative standard deviations (RSDs) of 3.9% to 14.4% ( n =7). The established analytical method was applied for the comprehensive screening of VOCs in a waste incineration power plant in Dalian city. Twenty-nine VOCs were identified. In these compounds, only five VOCs were the target compounds set in advance, which accounted for 26.7% of the total VOCs identified. Therefore, this study further proved the importance of screening non-target compounds in the analysis of VOCs in industrial exhaust gas, and has certain reference significance for the complete determination of VOCs distribution.

Combined direct and indirect bypass for moyamoya: quantitative assessment of direct bypass flow over time.

PubMed

Amin-Hanjani, Sepideh; Singh, Amritha; Rifai, Hashem; Thulborn, Keith R; Alaraj, Ali; Aletich, Victor; Charbel, Fady T

2013-12-01

The optimal revascularization strategy for symptomatic adult moyamoya remains controversial. Whereas direct bypass offers immediate revascularization, indirect bypass can effectively induce collaterals over time. Using angiography and quantitative magnetic resonance angiography, we examined the relative contributions of direct and indirect bypass in moyamoya patients after combined direct superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass and indirect encephaloduroarteriosynangiosis (EDAS). A retrospective review of moyamoya patients undergoing combined STA-MCA bypass and EDAS was conducted, excluding pediatric patients and hemorrhagic presentation. Patients with quantitative magnetic resonance angiography measurements of the direct bypass immediately and > 6 months postoperatively were included. Angiographic follow-up, when available, was used to assess EDAS collaterals at similar time intervals. Of 16 hemispheres in 13 patients, 11 (69%) demonstrated a significant (> 50%) decline in direct bypass flow at > 6 months compared with baseline, averaging a drop from 99 ± 35 to 12 ± 7 mL/min. Conversely, angiography in these hemispheres demonstrated prominent indirect collaterals, in concert with shrinkage of the STA graft. Decline in flow was apparent at a median of 9 months but was evident as early as 2 to 3 months. In this small cohort, a reciprocal relationship between direct STA bypass flow and indirect EDAS collaterals frequently occurred. This substantiates the notion that combined direct/indirect bypass can provide temporally complementary revascularization.

Heart bypass surgery

MedlinePlus Videos and Cool Tools

Heart bypass surgery begins with an incision made in the chest, with the breastbone cut exposing the heart. Next, a portion of the saphenous vein is ... used to bypass the blocked arteries in the heart. The venous graft is sewn to the aorta ...

Metabolic Profiles Predict Adverse Events Following Coronary Artery Bypass Grafting

PubMed Central

Shah, Asad A.; Craig, Damian M.; Sebek, Jacqueline K.; Haynes, Carol; Stevens, Robert C.; Muehlbauer, Michael J.; Granger, Christopher B.; Hauser, Elizabeth R.; Newby, L. Kristin; Newgard, Christopher B.; Kraus, William E.; Hughes, G. Chad; Shah, Svati H.

2012-01-01

Objectives Clinical models incompletely predict outcomes following coronary artery bypass grafting. Novel molecular technologies may identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in patients undergoing coronary artery bypass grafting. Methods The study population comprised 478 subjects from the CATHGEN biorepository of patients referred for cardiac catheterization who underwent coronary artery bypass grafting after enrollment. Targeted mass spectrometry-based profiling of 69 metabolites was performed in frozen, fasting plasma samples collected prior to surgery. Principal-components analysis and Cox proportional hazards regression modeling were used to assess the relation between metabolite factor levels and a composite outcome of post-coronary artery bypass grafting myocardial infarction, need for percutaneous coronary intervention, repeat coronary artery bypass grafting, or death. Results Over a mean follow-up of 4.3 ± 2.4 years, 126 subjects (26.4%) suffered an adverse event. Three principal-components analysis-derived factors were significantly associated with adverse outcome in univariable analysis: short-chain dicarboxylacylcarnitines (factor 2, P=0.001); ketone-related metabolites (factor 5, P=0.02); and short-chain acylcarnitines (factor 6, P=0.004). These three factors remained independently predictive of adverse outcome after multivariable adjustment: factor 2 (adjusted hazard ratio 1.23; 95% confidence interval [1.10-1.38]; P<0.001), factor 5 (1.17 [1.01-1.37], P=0.04), and factor 6 (1.14 [1.02-1.27], P=0.03). Conclusions Metabolic profiles are independently associated with adverse outcomes following coronary artery bypass grafting. These profiles may represent novel biomarkers of risk that augment existing tools for risk stratification of coronary artery bypass grafting patients and may elucidate novel biochemical pathways that mediate risk. PMID:22306227

Estimating the Effect of Targeted Screening Strategies: An Application to Colonoscopy and Colorectal Cancer.

PubMed

Thomas, Duncan C

2017-07-01

Screening behavior depends on previous screening history and family members' behaviors, which can act as both confounders and intermediate variables on a causal pathway from screening to disease risk. Conventional analyses that adjust for these variables can lead to incorrect inferences about the causal effect of screening if high-risk individuals are more likely to be screened. Analyzing the data in a manner that treats screening as randomized conditional on covariates allows causal parameters to be estimated; inverse probability weighting based on propensity of exposure scores is one such method considered here. I simulated family data under plausible models for the underlying disease process and for screening behavior to assess the performance of alternative methods of analysis and whether a targeted screening approach based on individuals' risk factors would lead to a greater reduction in cancer incidence in the population than a uniform screening policy. Simulation results indicate that there can be a substantial underestimation of the effect of screening on subsequent cancer risk when using conventional analysis approaches, which is avoided by using inverse probability weighting. A large case-control study of colonoscopy and colorectal cancer from Germany shows a strong protective effect of screening, but inverse probability weighting makes this effect even stronger. Targeted screening approaches based on either fixed risk factors or family history yield somewhat greater reductions in cancer incidence with fewer screens needed to prevent one cancer than population-wide approaches, but the differences may not be large enough to justify the additional effort required. See video abstract at, http://links.lww.com/EDE/B207.

Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains.

PubMed

Shi, Junwei; Wang, Eric; Milazzo, Joseph P; Wang, Zihua; Kinney, Justin B; Vakoc, Christopher R

2015-06-01

CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9-induced mutations to the 5' exons of candidate genes, but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia cells identifies six known drug targets and 19 additional dependencies. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting.

Development of Peritoneal Tumor-Targeting Vector by In Vivo Screening with a Random Peptide-Displaying Adenovirus Library

PubMed Central

Yoshida, Kimiko; Goto, Naoko; Ohnami, Shumpei; Aoki, Kazunori

2012-01-01

The targeting of gene transfer at the cell-entry level is one of the most attractive challenges in vector development. However, attempts to redirect adenovirus vectors to alternative receptors by engineering the capsid-coding region have shown limited success, because the proper targeting ligands on the cells of interest are generally unknown. To overcome this limitation, we have constructed a random peptide library displayed on the adenoviral fiber knob, and have successfully selected targeted vectors by screening the library on cancer cell lines in vitro. The infection of targeted vectors was considered to be mediated by specific receptors on target cells. However, the expression levels and kinds of cell surface receptors may be substantially different between in vitro culture and in vivo tumor tissue. Here, we screened the peptide display-adenovirus library in the peritoneal dissemination model of AsPC-1 pancreatic cancer cells. The vector displaying a selected peptide (PFWSGAV) showed higher infectivity in the AsPC-1 peritoneal tumors but not in organs and other peritoneal tumors as compared with a non-targeted vector. Furthermore, the infectivity of the PFWSGAV-displaying vector for AsPC-1 peritoneal tumors was significantly higher than that of a vector displaying a peptide selected by in vitro screening, indicating the usefulness of in vivo screening in exploring the targeting vectors. This vector-screening system can facilitate the development of targeted adenovirus vectors for a variety of applications in medicine. PMID:23029088

Circling motion and screen edges as an alternative input method for on-screen target manipulation.

PubMed

Ka, Hyun W; Simpson, Richard C

2017-04-01

To investigate a new alternative interaction method, called circling interface, for manipulating on-screen objects. To specify a target, the user makes a circling motion around the target. To specify a desired pointing command with the circling interface, each edge of the screen is used. The user selects a command before circling the target. To evaluate the circling interface, we conducted an experiment with 16 participants, comparing the performance on pointing tasks with different combinations of selection method (circling interface, physical mouse and dwelling interface) and input device (normal computer mouse, head pointer and joystick mouse emulator). A circling interface is compatible with many types of pointing devices, not requiring physical activation of mouse buttons, and is more efficient than dwell-clicking. Across all common pointing operations, the circling interface had a tendency to produce faster performance with a head-mounted mouse emulator than with a joystick mouse. The performance accuracy of the circling interface outperformed the dwelling interface. It was demonstrated that the circling interface has the potential as another alternative pointing method for selecting and manipulating objects in a graphical user interface. Implications for Rehabilitation A circling interface will improve clinical practice by providing an alternative pointing method that does not require physically activating mouse buttons and is more efficient than dwell-clicking. The Circling interface can also work with AAC devices.

Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.

PubMed

Bancroft, Elizabeth K; Page, Elizabeth C; Castro, Elena; Lilja, Hans; Vickers, Andrew; Sjoberg, Daniel; Assel, Melissa; Foster, Christopher S; Mitchell, Gillian; Drew, Kate; Mæhle, Lovise; Axcrona, Karol; Evans, D Gareth; Bulman, Barbara; Eccles, Diana; McBride, Donna; van Asperen, Christi; Vasen, Hans; Kiemeney, Lambertus A; Ringelberg, Janneke; Cybulski, Cezary; Wokolorczyk, Dominika; Selkirk, Christina; Hulick, Peter J; Bojesen, Anders; Skytte, Anne-Bine; Lam, Jimmy; Taylor, Louise; Oldenburg, Rogier; Cremers, Ruben; Verhaegh, Gerald; van Zelst-Stams, Wendy A; Oosterwijk, Jan C; Blanco, Ignacio; Salinas, Monica; Cook, Jackie; Rosario, Derek J; Buys, Saundra; Conner, Tom; Ausems, Margreet G; Ong, Kai-ren; Hoffman, Jonathan; Domchek, Susan; Powers, Jacquelyn; Teixeira, Manuel R; Maia, Sofia; Foulkes, William D; Taherian, Nassim; Ruijs, Marielle; Helderman-van den Enden, Apollonia T; Izatt, Louise; Davidson, Rosemarie; Adank, Muriel A; Walker, Lisa; Schmutzler, Rita; Tucker, Kathy; Kirk, Judy; Hodgson, Shirley; Harris, Marion; Douglas, Fiona; Lindeman, Geoffrey J; Zgajnar, Janez; Tischkowitz, Marc; Clowes, Virginia E; Susman, Rachel; Ramón y Cajal, Teresa; Patcher, Nicholas; Gadea, Neus; Spigelman, Allan; van Os, Theo; Liljegren, Annelie; Side, Lucy; Brewer, Carole; Brady, Angela F; Donaldson, Alan; Stefansdottir, Vigdis; Friedman, Eitan; Chen-Shtoyerman, Rakefet; Amor, David J; Copakova, Lucia; Barwell, Julian; Giri, Veda N; Murthy, Vedang; Nicolai, Nicola; Teo, Soo-Hwang; Greenhalgh, Lynn; Strom, Sara; Henderson, Alex; McGrath, John; Gallagher, David; Aaronson, Neil; Ardern-Jones, Audrey; Bangma, Chris; Dearnaley, David; Costello, Philandra; Eyfjord, Jorunn; Rothwell, Jeanette; Falconer, Alison; Gronberg, Henrik; Hamdy, Freddie C; Johannsson, Oskar; Khoo, Vincent; Kote-Jarai, Zsofia; Lubinski, Jan; Axcrona, Ulrika; Melia, Jane; McKinley, Joanne; Mitra, Anita V; Moynihan, Clare; Rennert, Gad; Suri, Mohnish; Wilson, Penny; Killick, Emma; Moss, Sue; Eeles, Rosalind A

2014-09-01

Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. To report the first year's screening results for all men at enrollment in the study. We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy. PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the

Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study

PubMed Central

Bancroft, Elizabeth K.; Page, Elizabeth C.; Castro, Elena; Lilja, Hans; Vickers, Andrew; Sjoberg, Daniel; Assel, Melissa; Foster, Christopher S.; Mitchell, Gillian; Drew, Kate; Mæhle, Lovise; Axcrona, Karol; Evans, D. Gareth; Bulman, Barbara; Eccles, Diana; McBride, Donna; van Asperen, Christi; Vasen, Hans; Kiemeney, Lambertus A.; Ringelberg, Janneke; Cybulski, Cezary; Wokolorczyk, Dominika; Selkirk, Christina; Hulick, Peter J.; Bojesen, Anders; Skytte, Anne-Bine; Lam, Jimmy; Taylor, Louise; Oldenburg, Rogier; Cremers, Ruben; Verhaegh, Gerald; van Zelst-Stams, Wendy A.; Oosterwijk, Jan C.; Blanco, Ignacio; Salinas, Monica; Cook, Jackie; Rosario, Derek J.; Buys, Saundra; Conner, Tom; Ausems, Margreet G.; Ong, Kai-ren; Hoffman, Jonathan; Domchek, Susan; Powers, Jacquelyn; Teixeira, Manuel R.; Maia, Sofia; Foulkes, William D.; Taherian, Nassim; Ruijs, Marielle; den Enden, Apollonia T. Helderman-van; Izatt, Louise; Davidson, Rosemarie; Adank, Muriel A.; Walker, Lisa; Schmutzler, Rita; Tucker, Kathy; Kirk, Judy; Hodgson, Shirley; Harris, Marion; Douglas, Fiona; Lindeman, Geoffrey J.; Zgajnar, Janez; Tischkowitz, Marc; Clowes, Virginia E.; Susman, Rachel; Ramón y Cajal, Teresa; Patcher, Nicholas; Gadea, Neus; Spigelman, Allan; van Os, Theo; Liljegren, Annelie; Side, Lucy; Brewer, Carole; Brady, Angela F.; Donaldson, Alan; Stefansdottir, Vigdis; Friedman, Eitan; Chen-Shtoyerman, Rakefet; Amor, David J.; Copakova, Lucia; Barwell, Julian; Giri, Veda N.; Murthy, Vedang; Nicolai, Nicola; Teo, Soo-Hwang; Greenhalgh, Lynn; Strom, Sara; Henderson, Alex; McGrath, John; Gallagher, David; Aaronson, Neil; Ardern-Jones, Audrey; Bangma, Chris; Dearnaley, David; Costello, Philandra; Eyfjord, Jorunn; Rothwell, Jeanette; Falconer, Alison; Gronberg, Henrik; Hamdy, Freddie C.; Johannsson, Oskar; Khoo, Vincent; Kote-Jarai, Zsofia; Lubinski, Jan; Axcrona, Ulrika; Melia, Jane; McKinley, Joanne; Mitra, Anita V.; Moynihan, Clare; Rennert, Gad; Suri, Mohnish; Wilson, Penny; Killick, Emma; Moss, Sue; Eeles, Rosalind A.

2014-01-01

Background Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year's screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40–69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%—double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions The IMPACT screening network will be useful

A screen to identify drug resistant variants to target-directed anti-cancer agents

PubMed Central

Azam, Mohammad; Raz, Tal; Nardi, Valentina; Opitz, Sarah L.

2003-01-01

The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia (CML)-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair. PMID:14615817

Ranking targets in structure-based virtual screening of three-dimensional protein libraries: methods and problems.

PubMed

Kellenberger, Esther; Foata, Nicolas; Rognan, Didier

2008-05-01

Structure-based virtual screening is a promising tool to identify putative targets for a specific ligand. Instead of docking multiple ligands into a single protein cavity, a single ligand is docked in a collection of binding sites. In inverse screening, hits are in fact targets which have been prioritized within the pool of best ranked proteins. The target rate depends on specificity and promiscuity in protein-ligand interactions and, to a considerable extent, on the effectiveness of the scoring function, which still is the Achilles' heel of molecular docking. In the present retrospective study, virtual screening of the sc-PDB target library by GOLD docking was carried out for four compounds (biotin, 4-hydroxy-tamoxifen, 6-hydroxy-1,6-dihydropurine ribonucleoside, and methotrexate) of known sc-PDB targets and, several ranking protocols based on GOLD fitness score and topological molecular interaction fingerprint (IFP) comparison were evaluated. For the four investigated ligands, the fusion of GOLD fitness and two IFP scores allowed the recovery of most targets, including the rare proteins which are not readily suitable for statistical analysis, while significantly filtering out most false positive entries. The current survey suggests that selecting a small number of targets (<20) for experimental evaluation is achievable with a pure structure-based approach.

Tuberculosis Screening and Targeted Testing of College and University Students

ERIC Educational Resources Information Center

Journal of American College Health, 2011

2011-01-01

Screening and targeted testing for tuberculosis (TB) is a key strategy for controlling and preventing infection on college and university campuses. Early detection provides an opportunity to promote the health of affected individuals through prompt diagnosis and treatment while preventing potential spread to others. Implementation of a screening…

Age-standardisation when target setting and auditing performance of Down syndrome screening programmes.

PubMed

Cuckle, Howard; Aitken, David; Goodburn, Sandra; Senior, Brian; Spencer, Kevin; Standing, Sue

2004-11-01

To describe and illustrate a method of setting Down syndrome screening targets and auditing performance that allows for differences in the maternal age distribution. A reference population was determined from a Gaussian model of maternal age. Target detection and false-positive rates were determined by standard statistical modelling techniques, except that the reference population rather than an observed population was used. Second-trimester marker parameters were obtained for Down syndrome from a large meta-analysis, and for unaffected pregnancies from the combined results of more than 600,000 screens in five centres. Audited detection and false-positive rates were the weighted average of the rates in five broad age groups corrected for viability bias. Weights were based on the age distributions in the reference population. Maternal age was found to approximate reasonably well to a Gaussian distribution with mean 27 years and standard deviation 5.5 years. Depending on marker combination, the target detection rates were 59 to 64% and false-positive rate 4.2 to 5.4% for a 1 in 250 term cut-off; 65 to 68% and 6.1 to 7.3% for 1 in 270 at mid-trimester. Among the five centres, the audited detection rate ranged from 7% below target to 10% above target, with audited false-positive rates better than the target by 0.3 to 1.5%. Age-standardisation should help to improve screening quality by allowing for intrinsic differences between programmes, so that valid comparisons can be made. Copyright 2004 John Wiley & Sons, Ltd.

Biological Functionalization of Drug Delivery Carriers to Bypass Size Restrictions of Receptor-Mediated Endocytosis Independently from Receptor Targeting

PubMed Central

Ansar, Maria; Serrano, Daniel; Papademetriou, Iason; Bhowmick, Tridib Kumar; Muro, Silvia

2014-01-01

Targeting of drug carriers to cell-surface receptors involved in endocytosis is commonly used for intracellular drug delivery. However, most endocytic receptors mediate uptake via clathrin or caveolar pathways associated with ≤200-nm vesicles, restricting carrier design. We recently showed that endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1), which differs from clathrin- and caveolar-mediated pathways, allows uptake of nano- and micro-carriers in cell culture and in vivo due to recruitment of cellular sphingomyelinases to the plasmalemma. This leads to ceramide generation at carrier binding sites and formation of actin stress-fibers, enabling engulfment and uptake of a wide size-range of carriers. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors associated with size-restricted pathways. We coated sphingomyelinase onto model (polystyrene) submicro- and micro-carriers targeted to clathrin-associated mannose-6-phosphate receptor. In endothelial cells, this provided ceramide enrichment at the cell surface and actin stress-fiber formation, modifying the uptake pathway and enhancing carrier endocytosis without affecting targeting, endosomal transport, cell-associated degradation, or cell viability. This improvement depended on the carrier size and enzyme dose, and similar results were observed for other receptors (transferrin receptor) and cell types (epithelial cells). This phenomenon also enhanced tissue accumulation of carriers after intravenous injection in mice. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size-restrictions of its associated endocytic route by functionalization of drug carriers with biological elements mimicking the ICAM-1 pathway. This strategy holds considerable promise to enhance flexibility of design of targeted drug delivery systems. PMID:24237309

Biological functionalization of drug delivery carriers to bypass size restrictions of receptor-mediated endocytosis independently from receptor targeting.

PubMed

Ansar, Maria; Serrano, Daniel; Papademetriou, Iason; Bhowmick, Tridib Kumar; Muro, Silvia

2013-12-23

Targeting of drug carriers to cell-surface receptors involved in endocytosis is commonly used for intracellular drug delivery. However, most endocytic receptors mediate uptake via clathrin or caveolar pathways associated with ≤200-nm vesicles, restricting carrier design. We recently showed that endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1), which differs from clathrin- and caveolae-mediated pathways, allows uptake of nano- and microcarriers in cell culture and in vivo due to recruitment of cellular sphingomyelinases to the plasmalemma. This leads to ceramide generation at carrier binding sites and formation of actin stress-fibers, enabling engulfment and uptake of a wide size-range of carriers. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors associated with size-restricted pathways. We coated sphingomyelinase onto model (polystyrene) submicro- and microcarriers targeted to clathrin-associated mannose-6-phosphate receptor. In endothelial cells, this provided ceramide enrichment at the cell surface and actin stress-fiber formation, modifying the uptake pathway and enhancing carrier endocytosis without affecting targeting, endosomal transport, cell-associated degradation, or cell viability. This improvement depended on the carrier size and enzyme dose, and similar results were observed for other receptors (transferrin receptor) and cell types (epithelial cells). This phenomenon also enhanced tissue accumulation of carriers after intravenous injection in mice. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size restrictions of its associated endocytic route by functionalization of drug carriers with biological elements mimicking the ICAM-1 pathway. This strategy holds considerable promise to enhance flexibility of design of targeted drug delivery systems.

Depression screening with patient-targeted feedback in cardiology: The cost-effectiveness of DEPSCREEN-INFO

PubMed Central

Kohlmann, Sebastian; Gierk, Benjamin

2017-01-01

Background Although depression is common in patients with heart disease, screening for depression is much debated. DEPSCREEN-INFO showed that a patient-targeted feedback in addition to screening results in lower depression level six months after screening. The purpose of this analysis was to perform a cost-effectiveness analysis of DEPSCREEN-INFO. Methods Patients with coronary heart disease or arterial hypertension were included. Participants in both groups were screened for depression. Participants in the intervention group additionally received a patient-targeted feedback of their result and recommended treatment options. A cost-utility analysis using quality-adjusted life years (QALY) based on the EQ-5D was performed. The time horizon was 6 months. Resource utilization was assessed by a telephone interview. Multiple imputation using chained equations was used. Net-benefit regressions controlled for prognostic variables at baseline were performed to construct cost-effectiveness acceptability curves. Different sensitivity analyses were performed. Results 375 participants (intervention group: 155; control group: 220) were included at baseline. After 6 months, in the intervention group adjusted total costs were lower (-€2,098; SE: €1,717) and more QALY were gained (0.0067; SD: 0.0133); yet differences were not statistically significant. The probability of cost-effectiveness was around 80% independent of the willingness-to-pay (range: €0/QALY–€130,000/QALY). The results were robust. Conclusions A patient-targeted feedback in addition to depression screening in cardiology is cost-effective with a high probability. This underpins the use of the patient-targeted feedbacks and the PHQ-9 that are both freely available and easy to implement in routine care. PMID:28806775

Depression screening with patient-targeted feedback in cardiology: The cost-effectiveness of DEPSCREEN-INFO.

PubMed

Brettschneider, Christian; Kohlmann, Sebastian; Gierk, Benjamin; Löwe, Bernd; König, Hans-Helmut

2017-01-01

Although depression is common in patients with heart disease, screening for depression is much debated. DEPSCREEN-INFO showed that a patient-targeted feedback in addition to screening results in lower depression level six months after screening. The purpose of this analysis was to perform a cost-effectiveness analysis of DEPSCREEN-INFO. Patients with coronary heart disease or arterial hypertension were included. Participants in both groups were screened for depression. Participants in the intervention group additionally received a patient-targeted feedback of their result and recommended treatment options. A cost-utility analysis using quality-adjusted life years (QALY) based on the EQ-5D was performed. The time horizon was 6 months. Resource utilization was assessed by a telephone interview. Multiple imputation using chained equations was used. Net-benefit regressions controlled for prognostic variables at baseline were performed to construct cost-effectiveness acceptability curves. Different sensitivity analyses were performed. 375 participants (intervention group: 155; control group: 220) were included at baseline. After 6 months, in the intervention group adjusted total costs were lower (-€2,098; SE: €1,717) and more QALY were gained (0.0067; SD: 0.0133); yet differences were not statistically significant. The probability of cost-effectiveness was around 80% independent of the willingness-to-pay (range: €0/QALY-€130,000/QALY). The results were robust. A patient-targeted feedback in addition to depression screening in cardiology is cost-effective with a high probability. This underpins the use of the patient-targeted feedbacks and the PHQ-9 that are both freely available and easy to implement in routine care.

Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery.

PubMed

Macrae, Calum A

2010-07-01

IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. AREAS COVERED IN THIS REVIEW: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. WHAT THE READER WILL GAIN: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. TAKE HOME MESSAGE: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease

High-Throughput Screening of HECT E3 Ubiquitin Ligases Using UbFluor.

PubMed

Foote, Peter K; Krist, David T; Statsyuk, Alexander V

2017-09-14

HECT E3 ubiquitin ligases are responsible for many human disease phenotypes and are promising drug targets; however, screening assays for HECT E3 inhibitors are inherently complex, requiring upstream E1 and E2 enzymes as well as ubiquitin, ATP, and detection reagents. Intermediate ubiquitin thioesters and a complex mixture of polyubiquitin products provide further opportunities for off-target inhibition and increase the complexity of the assay. UbFluor is a novel ubiquitin thioester that bypasses the E1 and E2 enzymes and undergoes direct transthiolation with HECT E3 ligases. The release of fluorophore upon transthiolation allows fluorescence polarization detection of HECT E3 activity. In the presence of inhibitors, HECT E3 activity is ablated, and thus no reaction and no change in FP are observed. This assay has been adapted for high-throughput screening of small molecules against HECT E3 ligases, and its utility has been proven in the discovery of HECT E3 ligase inhibitors. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Low Morbidity after Extracranial-Intracranial Bypass Operation. The Danish Extracranial-Intracranial Bypass Study: A Nationwide Survey.

PubMed

von Weitzel-Mudersbach, Paul; Andersen, Grethe; Rosenbaum, Sverre

2018-06-07

Patients with symptomatic atherosclerotic carotid artery occlusion (SACAO) have a high risk of a recurrent stroke. Extracranial-intracranial bypass (EC-IC bypass) has been shown not to improve outcome compared with medical treatment alone because long-term prevention of recurrent stroke in operated patients was offset by high perioperative stroke rates. We report our experience with EC-IC bypass operated at an experienced high-volume centre. We conducted a nationwide observational study of EC-IC bypass patients operated in the years 2007-2016 due to SACAO with ongoing clinical symptoms or progression on MRI and severe haemodynamic failure (SHF). Perioperative stroke and death within 30 days after the operation, ipsilateral stroke, bypass patency, transient ischaemic attack, and all-stroke events and deaths during long-term follow-up were registered prospectively. EC-IC bypass was performed in 48 patients with SHF and SACAO. The mean age was 64 (45-83) years. The mean follow-up was 3.6 years. The stroke rate after 30 days was 4.2%. No further ipsilateral strokes occurred during follow-up. Clinical symptoms arrested in all patients. Bypass patency rate was 94%. The perioperative stroke rate in EC-IC bypass operation, performed at a highly experienced centre, was low. During long-term follow-up, no ipsilateral stroke occurred. Consequently, EC-IC-bypass should still be considered for selected patients with SACAO, if operation can be carried out in experienced centres with low perioperative morbidity. © 2018 S. Karger AG, Basel.

Your diet after gastric bypass surgery

MedlinePlus

Gastric bypass surgery - your diet; Obesity - diet after bypass; Weight loss - diet after bypass ... et al. American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery ...

Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes

NASA Astrophysics Data System (ADS)

Kamstra, Rhiannon L.; Dadgar, Saedeh; Wigg, John; Chowdhury, Morshed A.; Phenix, Christopher P.; Floriano, Wely B.

2014-11-01

Our group has recently demonstrated that virtual screening is a useful technique for the identification of target-specific molecular probes. In this paper, we discuss some of our proof-of-concept results involving two biologically relevant target proteins, and report the development of a computational script to generate large databases of fluorescence-labelled compounds for computer-assisted molecular design. The virtual screening of a small library of 1,153 fluorescently-labelled compounds against two targets, and the experimental testing of selected hits reveal that this approach is efficient at identifying molecular probes, and that the screening of a labelled library is preferred over the screening of base compounds followed by conjugation of confirmed hits. The automated script for library generation explores the known reactivity of commercially available dyes, such as NHS-esters, to create large virtual databases of fluorescence-tagged small molecules that can be easily synthesized in a laboratory. A database of 14,862 compounds, each tagged with the ATTO680 fluorophore was generated with the automated script reported here. This library is available for downloading and it is suitable for virtual ligand screening aiming at the identification of target-specific fluorescent molecular probes.

High-stringency screening of target-binding partners using a microfluidic device

DOEpatents

Soh, Hyongsok; Lou, Xinhui; Lagally, Eric

2015-12-01

The invention provides a method of screening a library of candidate agents by contacting the library with a target in a reaction mixture under a condition of high stringency, wherein the target includes a tag that responds to a controllable force applied to the tag, and passing the members of the library through a microfluidic device in a manner that exposes the library members to the controllable force, thereby displacing members of the library that are bound to the target relative to their unbound counterparts. Kits and systems for use with the methods of the invention are also provided.

Linitis plastica of the bypassed stomach 7 years after Roux-en-Y gastric bypass: a case report.

PubMed

Haenen, Filip Wn; Gys, Ben; Moreels, Tom; Michielsen, Maartje; Gys, Tobie; Lafullarde, Thierry

2017-12-01

Laparoscopic Roux-en-Y gastric bypass (RYGB) is currently the preferred surgical procedure to treat morbid obesity. It has proven its effects on excess weight loss and its positive effect on comorbidities. One of the main issues, however, is the post-operative evaluation of the bypassed gastric remnant. In literature, cancer of the excluded stomach after RYGB is rare. We describe the case of a 52-year-old woman with gastric linitis plastica in the bypassed stomach after Roux-en-Y gastric bypass, diagnosed by means of laparoscopy and Single-Balloon enteroscopy, and it is clinical importance. Linitis plastica of the excluded stomach after RYGB is a very rare entity. This case report shows the importance of long-term post-operative follow-up, and the importance of single-balloon enteroscopy for visualization of the bypassed stomach remnant, when other investigations remain without results. This case report is only the second report of a linitis plastica in the bypassed stomach after Roux-en-Y gastric bypass.

Genome-scale measurement of off-target activity using Cas9 toxicity in high-throughput screens.

PubMed

Morgens, David W; Wainberg, Michael; Boyle, Evan A; Ursu, Oana; Araya, Carlos L; Tsui, C Kimberly; Haney, Michael S; Hess, Gaelen T; Han, Kyuho; Jeng, Edwin E; Li, Amy; Snyder, Michael P; Greenleaf, William J; Kundaje, Anshul; Bassik, Michael C

2017-05-05

CRISPR-Cas9 screens are powerful tools for high-throughput interrogation of genome function, but can be confounded by nuclease-induced toxicity at both on- and off-target sites, likely due to DNA damage. Here, to test potential solutions to this issue, we design and analyse a CRISPR-Cas9 library with 10 variable-length guides per gene and thousands of negative controls targeting non-functional, non-genic regions (termed safe-targeting guides), in addition to non-targeting controls. We find this library has excellent performance in identifying genes affecting growth and sensitivity to the ricin toxin. The safe-targeting guides allow for proper control of toxicity from on-target DNA damage. Using this toxicity as a proxy to measure off-target cutting, we demonstrate with tens of thousands of guides both the nucleotide position-dependent sensitivity to single mismatches and the reduction of off-target cutting using truncated guides. Our results demonstrate a simple strategy for high-throughput evaluation of target specificity and nuclease toxicity in Cas9 screens.

Genome-scale measurement of off-target activity using Cas9 toxicity in high-throughput screens

PubMed Central

Morgens, David W.; Wainberg, Michael; Boyle, Evan A.; Ursu, Oana; Araya, Carlos L.; Tsui, C. Kimberly; Haney, Michael S.; Hess, Gaelen T.; Han, Kyuho; Jeng, Edwin E.; Li, Amy; Snyder, Michael P.; Greenleaf, William J.; Kundaje, Anshul; Bassik, Michael C.

2017-01-01

CRISPR-Cas9 screens are powerful tools for high-throughput interrogation of genome function, but can be confounded by nuclease-induced toxicity at both on- and off-target sites, likely due to DNA damage. Here, to test potential solutions to this issue, we design and analyse a CRISPR-Cas9 library with 10 variable-length guides per gene and thousands of negative controls targeting non-functional, non-genic regions (termed safe-targeting guides), in addition to non-targeting controls. We find this library has excellent performance in identifying genes affecting growth and sensitivity to the ricin toxin. The safe-targeting guides allow for proper control of toxicity from on-target DNA damage. Using this toxicity as a proxy to measure off-target cutting, we demonstrate with tens of thousands of guides both the nucleotide position-dependent sensitivity to single mismatches and the reduction of off-target cutting using truncated guides. Our results demonstrate a simple strategy for high-throughput evaluation of target specificity and nuclease toxicity in Cas9 screens. PMID:28474669

Research on target information optics communications transmission characteristic and performance in multi-screens testing system

NASA Astrophysics Data System (ADS)

Li, Hanshan

2016-04-01

To enhance the stability and reliability of multi-screens testing system, this paper studies multi-screens target optical information transmission link properties and performance in long-distance, sets up the discrete multi-tone modulation transmission model based on geometric model of laser multi-screens testing system and visible light information communication principle; analyzes the electro-optic and photoelectric conversion function of sender and receiver in target optical information communication system; researches target information transmission performance and transfer function of the generalized visible-light communication channel; found optical information communication transmission link light intensity space distribution model and distribution function; derives the SNR model of information transmission communication system. Through the calculation and experiment analysis, the results show that the transmission error rate increases with the increment of transmission rate in a certain channel modulation depth; when selecting the appropriate transmission rate, the bit error rate reach 0.01.

Targeted Screening With Combined Age- and Morphology-Based Criteria Enriches Detection of Lynch Syndrome in Endometrial Cancer.

PubMed

Lin, Douglas I; Hecht, Jonathan L

2016-06-01

Endometrial cancer is associated with Lynch syndrome in 2% to 6% of cases. Adequate screening may prevent of a second cancer and incident cancers in family members via risk-reducing strategies. The goal of the study was to evaluate the detection rate of Lynch syndrome via a targeted screening approach. In 2009, we incorporated targeted Lynch syndrome screening via immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, followed by MLH1 promoter hypermethylation, in select cases of endometrial carcinoma. Criteria for patient selection included (1) all patients <50 years; (2) patients of any age with tumors showing features of microsatellite instability (lower uterine segment-centered tumors, hard to classify carcinomas, increased peritumoral or tumor infiltrating lymphocytes and cases with synchronous ovarian carcinomas); (3) clinician's request based on family or personal history; and (4) ad hoc retrospective testing based on the established criteria on patients discovered on follow-up visits. By using a targeted screening approach in a 4.5-year period, approximately 2.1% of endometrial cancers (7 of 328) were potentially associated with Lynch syndrome. Therefore, targeted screening with combined age and morphology based criteria enriches detection of Lynch syndrome in endometrial cancer. However, the detection rate is lower than the rates from published series that offer universal screening. © The Author(s) 2016.

Cost-effectiveness of targeted screening for abdominal aortic aneurysm. Monte Carlo-based estimates.

PubMed

Pentikäinen, T J; Sipilä, T; Rissanen, P; Soisalon-Soininen, S; Salo, J

2000-01-01

This article reports a cost-effectiveness analysis of targeted screening for abdominal aortic aneurysm (AAA). A major emphasis was on the estimation of distributions of costs and effectiveness. We performed a Monte Carlo simulation using C programming language in a PC environment. Data on survival and costs, and a majority of screening probabilities, were from our own empirical studies. Natural history data were based on the literature. Each screened male gained 0.07 life-years at an incremental cost of FIM 3,300. The expected values differed from zero very significantly. For females, expected gains were 0.02 life-years at an incremental cost of FIM 1,100, which was not statistically significant. Cost-effectiveness ratios and their 95% confidence intervals were FIM 48,000 (27,000-121,000) and 54,000 (22,000-infinity) for males and females, respectively. Sensitivity analysis revealed that the results for males were stable. Individual variation in life-year gains was high. Males seemed to benefit from targeted AAA screening, and the results were stable. As far as the cost-effectiveness ratio is considered acceptable, screening for males seemed to be justified. However, our assumptions about growth and rupture behavior of AAAs might be improved with further clinical and epidemiological studies. As a point estimate, females benefited in a similar manner, but the results were not statistically significant. The evidence of this study did not justify screening of females.

21 CFR 870.4350 - Cardiopulmonary bypass oxygenator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass oxygenator. 870.4350... bypass oxygenator. (a) Identification. A cardiopulmonary bypass oxygenator is a device used to exchange... the FDA guidance document entitled “Guidance for Cardiopulmonary Bypass Oxygenators 510(k) Submissions...

21 CFR 870.4350 - Cardiopulmonary bypass oxygenator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass oxygenator. 870.4350... bypass oxygenator. (a) Identification. A cardiopulmonary bypass oxygenator is a device used to exchange... the FDA guidance document entitled “Guidance for Cardiopulmonary Bypass Oxygenators 510(k) Submissions...

Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer

PubMed Central

Azorsa, David O; Gonzales, Irma M; Basu, Gargi D; Choudhary, Ashish; Arora, Shilpi; Bisanz, Kristen M; Kiefer, Jeffrey A; Henderson, Meredith C; Trent, Jeffrey M; Von Hoff, Daniel D; Mousses, Spyro

2009-01-01

Background Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement. Methods In order to improve gemcitabine response in pancreatic cancer cells, we utilized a synthetic lethal RNAi screen targeting 572 known kinases to identify genes that when silenced would sensitize pancreatic cancer cells to gemcitabine. Results Results from the RNAi screens identified several genes that, when silenced, potentiated the growth inhibitory effects of gemcitabine in pancreatic cancer cells. The greatest potentiation was shown by siRNA targeting checkpoint kinase 1 (CHK1). Validation of the screening results was performed in MIA PaCa-2 and BxPC3 pancreatic cancer cells by examining the dose response of gemcitabine treatment in the presence of either CHK1 or CHK2 siRNA. These results showed a three to ten-fold decrease in the EC50 for CHK1 siRNA-treated cells versus control siRNA-treated cells while treatment with CHK2 siRNA resulted in no change compared to controls. CHK1 was further targeted with specific small molecule inhibitors SB 218078 and PD 407824 in combination with gemcitabine. Results showed that treatment of MIA PaCa-2 cells with either of the CHK1 inhibitors SB 218078 or PD 407824 led to sensitization of the pancreatic cancer cells to gemcitabine. Conclusion These findings demonstrate the effectiveness of synthetic lethal RNAi screening as a tool for identifying sensitizing targets to chemotherapeutic agents. These results also indicate that CHK1 could serve as a putative therapeutic target for sensitizing pancreatic cancer cells to gemcitabine. PMID

21 CFR 870.4230 - Cardiopulmonary bypass defoamer.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass defoamer. 870.4230 Section... bypass defoamer. (a) Identification. A cardiopulmonary bypass defoamer is a device used in conjunction with an oxygenator during cardiopulmonary bypass surgery to remove gas bubbles from the blood. (b...

21 CFR 870.4230 - Cardiopulmonary bypass defoamer.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass defoamer. 870.4230 Section... bypass defoamer. (a) Identification. A cardiopulmonary bypass defoamer is a device used in conjunction with an oxygenator during cardiopulmonary bypass surgery to remove gas bubbles from the blood. (b...

Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

PubMed Central

Guillemet, Mélanie; Soler, Charles; Morvan, Claire; Halpern, David; Pourcel, Christine; Vu Thien, Hoang; Lamberet, Gilles

2017-01-01

ABSTRACT The need for new antimicrobials to treat bacterial infections has led to the use of type II fatty acid synthesis (FASII) enzymes as front-line targets. However, recent studies suggest that FASII inhibitors may not work against the opportunist pathogen Staphylococcus aureus, as environmental fatty acids favor emergence of multi-anti-FASII resistance. As fatty acids are abundant in the host and one FASII inhibitor, triclosan, is widespread, we investigated whether fatty acid pools impact resistance in clinical and veterinary S. aureus isolates. Simple addition of fatty acids to the screening medium led to a 50% increase in triclosan resistance, as tested in 700 isolates. Moreover, nonculturable triclosan-resistant fatty acid auxotrophs, which escape detection under routine conditions, were uncovered in primary patient samples. FASII bypass in selected isolates correlated with polymorphisms in the acc and fabD loci. We conclude that fatty-acid-dependent strategies to escape FASII inhibition are common among S. aureus isolates and correlate with anti-FASII resistance and emergence of nonculturable variants. PMID:28193654

A Phenotypic Cell-Binding Screen Identifies a Novel Compound Targeting Triple-Negative Breast Cancer.

PubMed

Chen, Luxi; Long, Chao; Youn, Jonghae; Lee, Jiyong

2018-06-11

We describe a "phenotypic cell-binding screen" by which therapeutic candidate targeting cancer cells of a particular phenotype can be isolated without knowledge of drug targets. Chemical library beads are incubated with cancer cells of the phenotype of interest in the presence of cancer cells lacking the phenotype of interest, and then the beads bound to only cancer cells of the phenotype of interest are selected as hits. We have applied this screening strategy in discovering a novel compound (LC129-8) targeting triple-negative breast cancer (TNBC). LC129-8 displayed highly specific binding to TNBC in cancer cell lines and patient-derived tumor tissues. LC129-8 exerted anti-TNBC activity by inducing apoptosis, inhibiting proliferation, reversing epithelial-mesenchymal transition, downregulating cancer stem cell activity and blocking in vivo tumor growth.

Synergistic Interactions Between Direct and Indirect Bypasses in Combined Procedures: The Significance of Indirect Bypasses in Moyamoya Disease.

PubMed

Uchino, Haruto; Kim, Jae-Hoon; Fujima, Noriyuki; Kazumata, Ken; Ito, Masaki; Nakayama, Naoki; Kuroda, Satoshi; Houkin, Kiyohiro

2017-02-01

Whether additional indirect bypasses effectively contribute to revascularization in combined procedures remains unclear in patients with moyamoya disease. To evaluate the longitudinal changes associated with combined procedures while following up pediatric and adult patients long term and to assess whether any other clinical factors or hemodynamic parameters affected these changes to determine an optimal surgical strategy. We studied 58 hemispheres in 43 adults and 39 hemispheres in 26 children who underwent combined revascularization for moyamoya disease. To evaluate bypass development, we assessed the sizes of the superficial temporal artery and middle meningeal artery using magnetic resonance angiography. Multivariate analysis determined the effects of multiple variables on bypass development. Indirect bypass (middle meningeal artery) development occurred in 95% and 78% of the pediatric and adult hemispheres, respectively. Of these, dual development of direct and indirect bypasses occurred in 54% of the pediatric hemispheres and in 47% of the adult hemispheres. Reciprocal superficial temporal artery regression occurred in 28% of the hemispheres during the transition from the postoperative acute phase to the chronic phase during indirect bypass development. Good indirect bypass development was associated with adult hemispheres at Suzuki stage 4 or greater (odds ratio, 7.4; 95% confidence interval, 1.4-39.4; P = .02). Disease onset type and preoperative hemodynamic parameters were not considered predictors for the development of surgical revascularization. Simultaneous direct and indirect bypass development was most frequently observed, regardless of patient age and hemodynamic status. Applying indirect bypass as an adjunct to direct bypass could maximize revascularization in adults and children.

Culturally targeted patient navigation for increasing african americans' adherence to screening colonoscopy: a randomized clinical trial.

PubMed

Jandorf, Lina; Braschi, Caitlyn; Ernstoff, Elizabeth; Wong, Carrie R; Thelemaque, Linda; Winkel, Gary; Thompson, Hayley S; Redd, William H; Itzkowitz, Steven H

2013-09-01

Patient navigation has been an effective intervention to increase cancer screening rates. This study focuses on predicting outcomes of screening colonoscopy for colorectal cancer among African Americans using different patient navigation formats. In a randomized clinical trial, patients more than 50 years of age without significant comorbidities were randomized into three navigation groups: peer-patient navigation (n = 181), pro-patient navigation (n = 123), and standard (n = 46). Pro-patient navigations were health care professionals who conducted culturally targeted navigation, whereas peer-patient navigations were community members trained in patient navigation who also discussed their personal experiences with screening colonoscopy. Two assessments gathered sociodemographic, medical, and intrapersonal information. Screening colonoscopy completion rate was 75.7% across all groups with no significant differences in completion between the three study arms. Annual income more than $10,000 was an independent predictor of screening colonoscopy adherence. Unexpectedly, low social influence also predicted screening colonoscopy completion. In an urban African American population, patient navigation was effective in increasing screening colonoscopy rates to 15% above the national average, regardless of patient navigation type or content. Because patient navigation successfully increases colonoscopy adherence, cultural targeting may not be necessary in some populations.

A Cell-Based Screen Reveals that the Albendazole Metabolite, Albendazole Sulfone, Targets Wolbachia

PubMed Central

Bray, Walter M.; White, Pamela M.; Ruybal, Jordan; Lokey, R. Scott; Debec, Alain; Sullivan, William

2012-01-01

Wolbachia endosymbionts carried by filarial nematodes give rise to the neglected diseases African river blindness and lymphatic filariasis afflicting millions worldwide. Here we identify new Wolbachia-disrupting compounds by conducting high-throughput cell-based chemical screens using a Wolbachia-infected, fluorescently labeled Drosophila cell line. This screen yielded several Wolbachia-disrupting compounds including three that resembled Albendazole, a widely used anthelmintic drug that targets nematode microtubules. Follow-up studies demonstrate that a common Albendazole metabolite, Albendazole sulfone, reduces intracellular Wolbachia titer both in Drosophila melanogaster and Brugia malayi, the nematode responsible for lymphatic filariasis. Significantly, Albendazole sulfone does not disrupt Drosophila microtubule organization, suggesting that this compound reduces titer through direct targeting of Wolbachia. Accordingly, both DNA staining and FtsZ immunofluorescence demonstrates that Albendazole sulfone treatment induces Wolbachia elongation, a phenotype indicative of binary fission defects. This suggests that the efficacy of Albendazole in treating filarial nematode-based diseases is attributable to dual targeting of nematode microtubules and their Wolbachia endosymbionts. PMID:23028321

The interdependence between screening methods and screening libraries.

PubMed

Shelat, Anang A; Guy, R Kiplin

2007-06-01

The most common methods for discovery of chemical compounds capable of manipulating biological function involves some form of screening. The success of such screens is highly dependent on the chemical materials - commonly referred to as libraries - that are assayed. Classic methods for the design of screening libraries have depended on knowledge of target structure and relevant pharmacophores for target focus, and on simple count-based measures to assess other properties. The recent proliferation of two novel screening paradigms, structure-based screening and high-content screening, prompts a profound rethink about the ideal composition of small-molecule screening libraries. We suggest that currently utilized libraries are not optimal for addressing new targets by high-throughput screening, or complex phenotypes by high-content screening.

[Pedal bypass using venous allograft].

PubMed

Pluháčková, H; Staffa, R; Konečný, Z; Kříž, Z; Vlachovský, R

Pedal or distal crural bypass surgery for limb salvage is a method with very good long-term results. For patients in whom a suitable autologous venous graft is not available, the use of a venous allograft is an alternative procedure. A 68 years old man with ischaemic disease of lower extremities and gangrene of the left foot was admitted to our Centre in August 2014. He underwent percutaneous transluminal angioplasty of crural arteries of his left lower extremity. This, however, failed to improve peripheral circulation. The patient was then indicated for pedal or distal crural vascular reconstruction. Since no suitable autologous vein was available, distal bypass surgery using a donor graft remained the only option for limb salvage. Amputation of the toes on the left foot due to gangrene was necessary. Subsequently, femoro-pedal bypass to the left common plantar artery was performed using a great saphenous vein allograft. The post-operative course was without complications, the pedal bypass was patent and toe amputation was with good healing. The patient remained in follow-up care. A good outcome of vascular reconstruction with an allograft depends on the availability of a suitable allograft and good patient compliance with post-operative care. In the case presented here, the pedal bypass grafting by means of an allograft helped to save the patients limb. pedal bypass venous allograft limb salvage.

[Simplified laparoscopic gastric bypass. Initial experience].

PubMed

Hernández-Miguelena, Luis; Maldonado-Vázquez, Angélica; Cortes-Romano, Pablo; Ríos-Cruz, Daniel; Marín-Domínguez, Raúl; Castillo-González, Armando

2014-01-01

Obesity surgery includes various gastrointestinal procedures. Roux-en-Y gastric bypass is the prototype of mixed procedures being the most practiced worldwide. A similar and novel technique has been adopted by Dr. Almino Cardoso Ramos and Dr. Manoel Galvao called "simplified bypass," which has been accepted due to the greater ease and very similar results to the conventional technique. The aim of this study is to describe the results of the simplified gastric bypass for treatment of morbid obesity in our institution. We performed a descriptive, retrospective study of all patients undergoing simplified gastric bypass from January 2008 to July 2012 in the obesity clinic of a private hospital in Mexico City. A total of 90 patients diagnosed with morbid obesity underwent simplified gastric bypass. Complications occurred in 10% of patients; these were more frequent bleeding and internal hernia. Mortality in the study period was 0%. The average weight loss at 12 months was 72.7%. Simplified gastric bypass surgery is safe with good mid-term results and a loss of adequate weight in 71% of cases.

shRNA target prediction informed by comprehensive enquiry (SPICE): a supporting system for high-throughput screening of shRNA library.

PubMed

Kamatuka, Kenta; Hattori, Masahiro; Sugiyama, Tomoyasu

2016-12-01

RNA interference (RNAi) screening is extensively used in the field of reverse genetics. RNAi libraries constructed using random oligonucleotides have made this technology affordable. However, the new methodology requires exploration of the RNAi target gene information after screening because the RNAi library includes non-natural sequences that are not found in genes. Here, we developed a web-based tool to support RNAi screening. The system performs short hairpin RNA (shRNA) target prediction that is informed by comprehensive enquiry (SPICE). SPICE automates several tasks that are laborious but indispensable to evaluate the shRNAs obtained by RNAi screening. SPICE has four main functions: (i) sequence identification of shRNA in the input sequence (the sequence might be obtained by sequencing clones in the RNAi library), (ii) searching the target genes in the database, (iii) demonstrating biological information obtained from the database, and (iv) preparation of search result files that can be utilized in a local personal computer (PC). Using this system, we demonstrated that genes targeted by random oligonucleotide-derived shRNAs were not different from those targeted by organism-specific shRNA. The system facilitates RNAi screening, which requires sequence analysis after screening. The SPICE web application is available at http://www.spice.sugysun.org/.

Targeting the brain--surmounting or bypassing the blood-brain barrier.

PubMed

Potschka, Heidrun

2010-01-01

The constituents of the blood-brain barrier, including its efflux transporter system, can efficiently limit brain penetration of potential CNS therapeutics. Effective extrusion from the brain by transporters is a frequent reason for the pharmaceutical industry to exclude novel compounds from further development for CNS therapeutics. Moreover, high transporter expression levels that are present in individual patients or may be generally associated with the pathophysiology seem to be a major cause of therapeutic failure in a variety of CNS diseases including brain tumors, epilepsy, brain HIV infection, and psychiatric disorders. Increasing knowledge of the structure and function of the blood-brain barrier creates a basis for the development of strategies which aim to enhance brain uptake of beneficial pharmaceutical compounds. The different strategies discussed in this review aim to modulate blood-brain barrier function or to bypass constituents of the blood-brain barrier.

21 CFR 870.4390 - Cardiopulmonary bypass pump tubing.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass pump tubing. 870.4390... bypass pump tubing. (a) Identification. A cardiopulmonary bypass pump tubing is polymeric tubing which is... through the cardiopulmonary bypass circuit. (b) Classification. Class II (performance standards). ...

21 CFR 870.4390 - Cardiopulmonary bypass pump tubing.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass pump tubing. 870.4390... bypass pump tubing. (a) Identification. A cardiopulmonary bypass pump tubing is polymeric tubing which is... through the cardiopulmonary bypass circuit. (b) Classification. Class II (performance standards). ...

A graph-based approach to construct target-focused libraries for virtual screening.

PubMed

Naderi, Misagh; Alvin, Chris; Ding, Yun; Mukhopadhyay, Supratik; Brylinski, Michal

2016-01-01

Due to exorbitant costs of high-throughput screening, many drug discovery projects commonly employ inexpensive virtual screening to support experimental efforts. However, the vast majority of compounds in widely used screening libraries, such as the ZINC database, will have a very low probability to exhibit the desired bioactivity for a given protein. Although combinatorial chemistry methods can be used to augment existing compound libraries with novel drug-like compounds, the broad chemical space is often too large to be explored. Consequently, the trend in library design has shifted to produce screening collections specifically tailored to modulate the function of a particular target or a protein family. Assuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. On this account, we developed eSynth, an exhaustive graph-based search algorithm to computationally synthesize new compounds by reconnecting these building blocks following their connectivity patterns. We conducted a series of benchmarking calculations against the Directory of Useful Decoys, Enhanced database. First, in a self-benchmarking test, the correctness of the algorithm is validated with the objective to recover a molecule from its building blocks. Encouragingly, eSynth can efficiently rebuild more than 80 % of active molecules from their fragment components. Next, the capability to discover novel scaffolds is assessed in a cross-benchmarking test, where eSynth successfully reconstructed 40 % of the target molecules using fragments extracted from chemically distinct compounds. Despite an enormous chemical space to be explored, eSynth is computationally efficient; half of the molecules are rebuilt in less than a second, whereas 90 % take only about a minute to be generated. eSynth can successfully reconstruct chemically feasible molecules from molecular fragments

Bypass Surgery after Endovascular Therapy for Infrapopliteal Lesion Is Not a Poor Outcome Compared with Initial Bypass Surgery by Vascular Surgeons.

PubMed

Morisaki, Koichi; Yamaoka, Terutoshi; Iwasa, Kazuomi; Ohmine, Takahiro

2017-11-01

It is unclear whether prior endovascular therapy (EVT) adversely affects bypass surgery. The aim of this study is to investigate treatment outcomes between initial bypass (bypass-first) and bypass surgery after EVT (EVT-first). We conducted a retrospective analysis of critical limb ischemia patients undergoing infrapopliteal bypass between November 2006 and December 2015. Graft patency, limb salvage (LS), amputation-free survival (AFS), and overall survival (OS) were examined between bypass-first and EVT-first groups. The subjects in this study were 75 patients and 82 limbs in the bypass-first group and 24 patients and 24 limbs in the EVT-first group. The average age was higher in EVT-first group (P = 0.03). The percentage of inframalleolar bypass was higher in the EVT-first group (P = 0.002). Primary patency at 1 and 2 years was 72.0% and 67.5% for the bypass-first group and 53.1% and 47.2% for the EVT-first group, respectively (P = 0.04). Inframalleolar bypass was a risk factor for lower primary patency (hazard ratio 3.07, 95% confidence interval 1.18-8.51, P = 0.02) in multivariate analysis, while there were no differences in secondary patency, LS, AFS, and OS. Bypass surgery after EVT has lower primary patency rates in comparison with primary bypass in patients submitted to infrapopliteal revascularization. Although very heterogeneous study population with a lot of bias in the indication of the revascularization, LS, OS and AFS are not affected by previous EVT. Copyright © 2017 Elsevier Inc. All rights reserved.

siRNA screen identifies QPCT as a druggable target for Huntington's disease.

PubMed

Jimenez-Sanchez, Maria; Lam, Wun; Hannus, Michael; Sönnichsen, Birte; Imarisio, Sara; Fleming, Angeleen; Tarditi, Alessia; Menzies, Fiona; Dami, Teresa Ed; Xu, Catherine; Gonzalez-Couto, Eduardo; Lazzeroni, Giulia; Heitz, Freddy; Diamanti, Daniela; Massai, Luisa; Satagopam, Venkata P; Marconi, Guido; Caramelli, Chiara; Nencini, Arianna; Andreini, Matteo; Sardone, Gian Luca; Caradonna, Nicola P; Porcari, Valentina; Scali, Carla; Schneider, Reinhard; Pollio, Giuseppe; O'Kane, Cahir J; Caricasole, Andrea; Rubinsztein, David C

2015-05-01

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development.

The cost-effectiveness of targeted or universal screening for vasa praevia at 18-20 weeks of gestation in Ontario.

PubMed

Cipriano, L E; Barth, W H; Zaric, G S

2010-08-01

To estimate the cost-effectiveness of targeted and universal screening for vasa praevia at 18-20 weeks of gestation in singleton and twin pregnancies. Cost-utility analysis based on a decision-analytic model comparing relevant strategies and life-long outcomes for mother and infant(s). Ontario, Canada. A cohort of pregnant women in 1 year. We constructed a decision-analytic model to estimate the lifetime incremental costs and benefits of screening for vasa praevia. Inputs were estimated from the literature. Costs were collected from the London Health Sciences Centre, the Ontario Health Insurance Program, and other sources. We used one-way, scenario and probabilistic sensitivity analysis to determine the robustness of the results. Incremental costs, life expectancy, quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER). Universal transvaginal ultrasound screening of twin pregnancies has an ICER of $5488 per QALY-gained. Screening all singleton pregnancies with the risk factors low-lying placentas, in vitro fertilisation (IVF) conception, accessory placental lobes, or velamentous cord insertion has an ICER of $15,764 per QALY-gained even though identifying some of these risk factors requires routine use of colour Doppler during transabdominal examinations. Screening women with a marginal cord insertion costs an additional $27,603 per QALY-gained. Universal transvaginal screening for vasa praevia in singleton pregnancies costs $579,164 per QALY compared with targeted screening. Compared with current practice, screening all twin pregnancies for vasa praevia with transvaginal ultrasound is cost-effective. Among the alternatives considered, the use of colour Doppler at all transabdominal ultrasound examinations of singleton pregnancies and targeted use of transvaginal ultrasound for IVF pregnancies or when the placenta has been found to be associated with one or more risk factors is cost-effective. Universal screening of singleton pregnancies

Target-Based Screen Against a Periplasmic Serine Protease That Regulates Intrabacterial pH Homeostasis in Mycobacterium tuberculosis

PubMed Central

2015-01-01

Mycobacterium tuberculosis (Mtb) maintains its intrabacterial pH (pHIB) near neutrality in the acidic environment of phagosomes within activated macrophages. A previously reported genetic screen revealed that Mtb loses this ability when the mycobacterial acid resistance protease (marP) gene is disrupted. In the present study, a high throughput screen (HTS) of compounds against the protease domain of MarP identified benzoxazinones as inhibitors of MarP. A potent benzoxazinone, BO43 (6-chloro-2-(2′-methylphenyl)-4H-1,3-benzoxazin-4-one), acylated MarP and lowered Mtb’s pHIB and survival during incubation at pH 4.5. BO43 had similar effects on MarP-deficient Mtb, suggesting the existence of additional target(s). Reaction of an alkynyl-benzoxazinone, BO43T, with Mycobacterium bovis variant bacille Calmette-Guérin (BCG) followed by click chemistry with azido-biotin identified both the MarP homologue and the high temperature requirement A1 (HtrA1) homologue, an essential protein. Thus, the chemical probe identified through a target-based screen not only reacted with its intended target in the intact cells but also implicated an additional enzyme that had eluded a genetic screen biased against essential genes. PMID:25457457

21 CFR 870.4400 - Cardiopulmonary bypass blood reservoir.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass blood reservoir. 870.4400... bypass blood reservoir. (a) Identification. A cardiopulmonary bypass blood reservoir is a device used in conjunction with short-term extracorporeal circulation devices to hold a reserve supply of blood in the bypass...

21 CFR 870.4400 - Cardiopulmonary bypass blood reservoir.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass blood reservoir. 870.4400... bypass blood reservoir. (a) Identification. A cardiopulmonary bypass blood reservoir is a device used in conjunction with short-term extracorporeal circulation devices to hold a reserve supply of blood in the bypass...

21 CFR 870.4400 - Cardiopulmonary bypass blood reservoir.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass blood reservoir. 870.4400... bypass blood reservoir. (a) Identification. A cardiopulmonary bypass blood reservoir is a device used in conjunction with short-term extracorporeal circulation devices to hold a reserve supply of blood in the bypass...

21 CFR 870.4400 - Cardiopulmonary bypass blood reservoir.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass blood reservoir. 870.4400... bypass blood reservoir. (a) Identification. A cardiopulmonary bypass blood reservoir is a device used in conjunction with short-term extracorporeal circulation devices to hold a reserve supply of blood in the bypass...

21 CFR 870.4400 - Cardiopulmonary bypass blood reservoir.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass blood reservoir. 870.4400... bypass blood reservoir. (a) Identification. A cardiopulmonary bypass blood reservoir is a device used in conjunction with short-term extracorporeal circulation devices to hold a reserve supply of blood in the bypass...

Gastric bypass reduces fat intake and preference

PubMed Central

Bueter, Marco; Theis, Nadine; Werling, Malin; Ashrafian, Hutan; Löwenstein, Christian; Athanasiou, Thanos; Bloom, Stephen R.; Spector, Alan C.; Olbers, Torsten; Lutz, Thomas A.

2011-01-01

Roux-en-Y gastric bypass is the most effective therapy for morbid obesity. This study investigated how gastric bypass affects intake of and preference for high-fat food in an experimental (rat) study and within a trial setting (human). Proportion of dietary fat in gastric bypass patients was significantly lower 6 yr after surgery compared with patients after vertical-banded gastroplasty (P = 0.046). Gastric bypass reduced total fat and caloric intake (P < 0.001) and increased standard low-fat chow consumption compared with sham controls (P < 0.001) in rats. Compared with sham-operated rats, gastric bypass rats displayed much lower preferences for Intralipid concentrations > 0.5% in an ascending concentration series (0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%) of two-bottle preference tests (P = 0.005). This effect was demonstrated 10 and 200 days after surgery. However, there was no difference in appetitive or consummatory behavior in the brief access test between the two groups (P = 0.71) using similar Intralipid concentrations (0.005% through 5%). Levels of glucagon-like peptide-1 (GLP-1) were increased after gastric bypass as expected. An oral gavage of 1 ml corn oil after saccharin ingestion in gastric bypass rats induced a conditioned taste aversion. These findings suggest that changes in fat preference may contribute to long-term maintained weight loss after gastric bypass. Postingestive effects of high-fat nutrients resulting in conditioned taste aversion may partially explain this observation; the role of GLP-1 in mediating postprandial responses after gastric bypass requires further investigation. PMID:21734019

Gastric bypass reduces fat intake and preference.

PubMed

le Roux, Carel W; Bueter, Marco; Theis, Nadine; Werling, Malin; Ashrafian, Hutan; Löwenstein, Christian; Athanasiou, Thanos; Bloom, Stephen R; Spector, Alan C; Olbers, Torsten; Lutz, Thomas A

2011-10-01

Roux-en-Y gastric bypass is the most effective therapy for morbid obesity. This study investigated how gastric bypass affects intake of and preference for high-fat food in an experimental (rat) study and within a trial setting (human). Proportion of dietary fat in gastric bypass patients was significantly lower 6 yr after surgery compared with patients after vertical-banded gastroplasty (P = 0.046). Gastric bypass reduced total fat and caloric intake (P < 0.001) and increased standard low-fat chow consumption compared with sham controls (P < 0.001) in rats. Compared with sham-operated rats, gastric bypass rats displayed much lower preferences for Intralipid concentrations > 0.5% in an ascending concentration series (0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%) of two-bottle preference tests (P = 0.005). This effect was demonstrated 10 and 200 days after surgery. However, there was no difference in appetitive or consummatory behavior in the brief access test between the two groups (P = 0.71) using similar Intralipid concentrations (0.005% through 5%). Levels of glucagon-like peptide-1 (GLP-1) were increased after gastric bypass as expected. An oral gavage of 1 ml corn oil after saccharin ingestion in gastric bypass rats induced a conditioned taste aversion. These findings suggest that changes in fat preference may contribute to long-term maintained weight loss after gastric bypass. Postingestive effects of high-fat nutrients resulting in conditioned taste aversion may partially explain this observation; the role of GLP-1 in mediating postprandial responses after gastric bypass requires further investigation.

Early Adoption of a Multi-target Stool DNA Test for Colorectal Cancer Screening

PubMed Central

Finney Rutten, Lila J.; Jacobson, Robert M.; Wilson, Patrick M.; Jacobson, Debra J.; Fan, Chun; Kisiel, John B.; Sweetser, Seth R.; Tulledge-Scheitel, Sidna M.; St. Sauver, Jennifer L.

2017-01-01

Objective To characterize early adoption of a novelmulti-target stool deoxyribonucleic acid (MTsDNA) screening test for colorectal cancer (CRC) and test the hypothesis that adoption differs by demographic characteristics, prior CRC screening behavior, and proceeds predictably over time. Patients and Methods We used the Rochester Epidemiology Project infrastructure to assess MTsDNA screening test use among adults aged 50–75 years, and identified 27,147 individuals eligible/due for screening colonoscopy from November 1, 2014 through November 30, 2015, and living in Olmsted County, Minnesota in2014. We used electronic Current Procedure Terminology and Health Care Common Procedure codes to evaluate early adoption of MTsDNA screening test in this population and to test whether early adoption varies by age, sex, race, and prior screening behavior. Results Overall, 2,193 (8.1%) and 974 (3.6%) of individuals were screened by colonoscopy and MT-sDNA, respectively. Age, sex, race, and prior screening were significantly and independently associated with MT-sDNA screening use compared to colonoscopy use after adjustment for all other variables. Rates of adoption of MTsDNA screening increased over time and were highest among those aged 50–54 years, females, whites, and had a prior history of screening. MT-sDNA screening use varied predictably by insurance coverage. Rates of colonoscopy decreased over time, while overall CRC screening rates remained steady. Conclusion Our results are generally consistent with predictions derived from prior research and Diffusion of Innovation framework, pointing to increasing use of the new screening test over time, and early adoption by younger patients, females, whites and those with prior CRC screening. PMID:28473037

Exhaust gas bypass valve control for thermoelectric generator

DOEpatents

Reynolds, Michael G; Yang, Jihui; Meisner, Greogry P.; Stabler, Francis R.; De Bock, Hendrik Pieter Jacobus; Anderson, Todd Alan

2012-09-04

A method of controlling engine exhaust flow through at least one of an exhaust bypass and a thermoelectric device via a bypass valve is provided. The method includes: determining a mass flow of exhaust exiting an engine; determining a desired exhaust pressure based on the mass flow of exhaust; comparing the desired exhaust pressure to a determined exhaust pressure; and determining a bypass valve control value based on the comparing, wherein the bypass valve control value is used to control the bypass valve.

Capacity analysis of a bypass of roundabouts

NASA Astrophysics Data System (ADS)

Sedlačik, Ivan; Slabý, Petr

2017-09-01

The capacity of the roads network mainly depends on the capacity of its nodal points - intersections. A connecting branch or a bypass is a lane or lanes inserted between two adjacent branches of a roundabout, providing redirection of vehicles, that would otherwise burden a circular lane. A bypass effect to the capacity of roundabouts, but also other types of level intersections, is undeniable. A connecting branch increases the total capacity of an intersection that takes a part of vehicles performing a manoeuver of the first right turn completely out of an intersection area. Redirecting vehicles reduces delay times at intersections and reduces queues at the entrance to an intersection. Bypasses improve the quality of transport. Limiting for the capacity of bypasses is the point of disconnection from the entrance into the roundabout and the connection point into the exit from the roundabout. Central parts of the bypasses have minimal effects on the capacity. The length of a bypass has to match with the maximum length of a queue of waiting vehicles at a given intensity level. The article deals with analysis of the bypass capacity at the roundabouts.

Cardiopulmonary bypass for pediatric cardiac surgery.

PubMed

Hirata, Yasutaka

2018-02-01

The management of cardiopulmonary bypass for pediatric cardiac surgery is more challenging than that in adults due to the smaller size, immaturity, and complexity of the anatomy in children. Despite major improvements in cardiopulmonary bypass, there remain many subjects of debate. This review article discusses the physiology of cardiopulmonary bypass for pediatric and congenital heart surgery, including topics related to hemodilution, hypothermia, acid-base strategies, inflammatory response, and myocardial protection.

Spiritual Bypass: A Preliminary Investigation

ERIC Educational Resources Information Center

Cashwell, Craig S.; Glosoff, Harriet L.; Hammond, Cheree

2010-01-01

The phenomenon of spiritual bypass has received limited attention in the transpersonal psychology and counseling literature and has not been subjected to empirical inquiry. This study examines the phenomenon of spiritual bypass by considering how spirituality, mindfulness, alexithymia (emotional restrictiveness), and narcissism work together to…

Targeting and tailoring message-framing: the moderating effect of racial identity on receptivity to colorectal cancer screening among African-Americans.

PubMed

Lucas, Todd; Manning, Mark; Hayman, Lenwood W; Blessman, James

2018-06-07

This study demonstrates the potential of racial identity to moderate how gain and loss-framed messaging, as well as culturally-targeted messaging, can affect receptivity to preventive health screening. African-Americans (N = 132) who were noncompliant with recommended colorectal cancer (CRC) screening completed a measure of racial identity centrality-encompassing the extent to which racial identity is a core component of self-concept-and then participated in an online education module about CRC screening, during which either gain or loss-framed messaging was introduced. Half of African-Americans were also exposed to a culturally-targeted self-help message about preventing CRC. Theory of Planned Behavior measures of attitudes, normative beliefs, perceived behavioral control, and intentions to obtain a CRC screen served as outcomes. Results confirmed that effects of messaging on receptivity to CRC screening depended on racial identity. Among low racial identity African Americans, gain-framed messaging most effectively increased normative beliefs about obtaining CRC screening, whereas among high racial identity African Americans loss-framed messaging was most compelling. However, these effects most strongly emerged when culturally-targeted self-help messaging was included. We discuss implications for health disparities theory and research, including a potential to simultaneously deploy culturally-targeted and tailored messaging based on racial identity.

Comprehensive predictions of target proteins based on protein-chemical interaction using virtual screening and experimental verifications.

PubMed

Kobayashi, Hiroki; Harada, Hiroko; Nakamura, Masaomi; Futamura, Yushi; Ito, Akihiro; Yoshida, Minoru; Iemura, Shun-Ichiro; Shin-Ya, Kazuo; Doi, Takayuki; Takahashi, Takashi; Natsume, Tohru; Imoto, Masaya; Sakakibara, Yasubumi

2012-04-05

Identification of the target proteins of bioactive compounds is critical for elucidating the mode of action; however, target identification has been difficult in general, mostly due to the low sensitivity of detection using affinity chromatography followed by CBB staining and MS/MS analysis. We applied our protocol of predicting target proteins combining in silico screening and experimental verification for incednine, which inhibits the anti-apoptotic function of Bcl-xL by an unknown mechanism. One hundred eighty-two target protein candidates were computationally predicted to bind to incednine by the statistical prediction method, and the predictions were verified by in vitro binding of incednine to seven proteins, whose expression can be confirmed in our cell system.As a result, 40% accuracy of the computational predictions was achieved successfully, and we newly found 3 incednine-binding proteins. This study revealed that our proposed protocol of predicting target protein combining in silico screening and experimental verification is useful, and provides new insight into a strategy for identifying target proteins of small molecules.

Photovoltaic module bypass diode encapsulation

NASA Technical Reports Server (NTRS)

Shepard, N. J., Jr.

1983-01-01

The design and processing techniques necessary to incorporate bypass diodes within the module encapsulant are presented. The Semicon PN junction diode cells were selected. Diode junction to heat spreader thermal resistance measurements, performed on a variety of mounted diode chip types and sizes, have yielded values which are consistently below 1 deg C per watt, but show some instability when thermally cycled over the temperature range from -40 to 150 deg C. Three representative experimental modules, each incorporating integral bypass diode/heat spreader assemblies of various sizes, were designed. Thermal testing of these modules enabled the formulation of a recommended heat spreader plate sizing relationship. The production cost of three encapsulated bypass diode/heat spreader assemblies were compared with similarly rated externally mounted packaged diodes. It is concluded that, when proper designed and installed, these bypass diode devices will improve the overall reliability of a terrestrial array over a 20 year design lifetime.

WISDOM-II: screening against multiple targets implicated in malaria using computational grid infrastructures.

PubMed

Kasam, Vinod; Salzemann, Jean; Botha, Marli; Dacosta, Ana; Degliesposti, Gianluca; Isea, Raul; Kim, Doman; Maass, Astrid; Kenyon, Colin; Rastelli, Giulio; Hofmann-Apitius, Martin; Breton, Vincent

2009-05-01

Despite continuous efforts of the international community to reduce the impact of malaria on developing countries, no significant progress has been made in the recent years and the discovery of new drugs is more than ever needed. Out of the many proteins involved in the metabolic activities of the Plasmodium parasite, some are promising targets to carry out rational drug discovery. Recent years have witnessed the emergence of grids, which are highly distributed computing infrastructures particularly well fitted for embarrassingly parallel computations like docking. In 2005, a first attempt at using grids for large-scale virtual screening focused on plasmepsins and ended up in the identification of previously unknown scaffolds, which were confirmed in vitro to be active plasmepsin inhibitors. Following this success, a second deployment took place in the fall of 2006 focussing on one well known target, dihydrofolate reductase (DHFR), and on a new promising one, glutathione-S-transferase. In silico drug design, especially vHTS is a widely and well-accepted technology in lead identification and lead optimization. This approach, therefore builds, upon the progress made in computational chemistry to achieve more accurate in silico docking and in information technology to design and operate large scale grid infrastructures. On the computational side, a sustained infrastructure has been developed: docking at large scale, using different strategies in result analysis, storing of the results on the fly into MySQL databases and application of molecular dynamics refinement are MM-PBSA and MM-GBSA rescoring. The modeling results obtained are very promising. Based on the modeling results, In vitro results are underway for all the targets against which screening is performed. The current paper describes the rational drug discovery activity at large scale, especially molecular docking using FlexX software on computational grids in finding hits against three different targets (Pf

Diagnostic tools for post-gastric bypass hypoglycaemia.

PubMed

Emous, M; Ubels, F L; van Beek, A P

2015-10-01

In spite of its evident success, several late complications can occur after gastric bypass surgery. One of these is post-gastric bypass hypoglycaemia. No evidence-based guidelines exist in the literature on how to confirm the presence of this syndrome. This study aims to describe and compare the tests aimed at making a diagnosis of post-gastric bypass hypoglycaemia and to provide a diagnostic approach based upon the available evidence. A search was conducted in PubMed, Cochrane and Embase. A few questionnaires have been developed to measure the severity of symptoms in post-gastric bypass hypoglycaemia but none has been validated. The gold standard for provocation of a hypoglycaemic event is the oral glucose tolerance test or the liquid mixed meal tolerance test. Both show a high prevalence of hypoglycaemia in post-gastric bypass patients with and without hypoglycaemic complaints as well as in healthy volunteers. No uniformly established cut-off values for glucose concentrations are defined in the literature for the diagnosis of post-gastric bypass hypoglycaemia. For establishing an accurate diagnosis of post-gastric bypass hypoglycaemia, a validated questionnaire, in connection with the diagnostic performance of provocation tests, is the most important thing missing. Given these shortcomings, we provide recommendations based upon the current literature. © 2015 World Obesity.

Variable volume combustor with an air bypass system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Thomas Edward; Ziminsky, Willy Steve; Ostebee, Heath Michael

The present application provides a combustor for use with flow of fuel and a flow of air in a gas turbine engine. The combustor may include a number of micro-mixer fuel nozzles positioned within a liner and an air bypass system position about the liner. The air bypass system variably allows a bypass portion of the flow of air to bypass the micro-mixer fuel nozzles.

Uptake of atrial fibrillation screening aiming at stroke prevention: geo-mapping of target population and non-participation.

PubMed

Engdahl, Johan; Holmén, Anders; Rosenqvist, Mårten; Strömberg, Ulf

2013-08-03

In a screening study for silent atrial fibrillation (AF), which is a frequent source of cardiac emboli with ischemic stroke, the proportion of non-participants was considerable and their clinical profile differed from the participants' profile. We intended to geo-map the target population and non-participation in an attempt to understand factors related to screening uptake and, thereby, obtain useful information needed to intervene for improved uptake. In the municipality of Halmstad, Sweden, all residents born in 1934-1935 were invited to the screening study during April 2010 to February 2012. The total study group included 848 participants and 367 non-participants from 12 parishes. Geo-maps displaying participation, along with target-population-based geo-maps displaying proportion of immigrants and ischemic stroke incidence, were used. Smoothed non-participation ratios (SmNPR) varied from 0.81 to 1.24 across different parishes (SmNRP=1 corresponds to the expected participation based on the total study group). Among high risk individuals, the geographical variation was more pronounced (SmNPR range 0.75-1.51). Two parishes with higher share of immigrants and elevated population-based ischemic stroke incidence showed markedly lower participation, particularly among high-risk individuals. AF screening uptake varied evidently between parishes, particularly among high-risk individuals. Geo-mapping of target population and non-participation yielded useful information needed to intervene for improved screening uptake.

Evaluation of nutritional screening tools for patients scheduled for cardiac surgery.

PubMed

Lomivorotov, Vladimir V; Efremov, Sergey M; Boboshko, Vladimir A; Nikolaev, Dmitry A; Vedernikov, Pavel E; Lomivorotov, Vladimir N; Karaskov, Alexander M

2013-02-01

The aim of this study was to assess the prognostic value of different nutritional screening tools in patients undergoing cardiopulmonary bypass with regard to an adverse clinical course. This prospective cohort study analyzed 894 adult patients who underwent cardiopulmonary bypass. Patients were screened using four nutritional screening tools: Nutritional Risk Screening 2002 (NRS-2002), the Malnutrition Universal Screening Tool (MUST), the Mini-Nutritional Assessment (MNA), and the Short Nutritional Assessment Questionnaire (SNAQ). Nutritional status was assessed using the Subjective Global Assessment. In-hospital mortality, postoperative complications, length of stay in the intensive care unit, and length of hospitalization were analyzed. The sensitivities of the SNAQ, MUST, and NRS-2002 to detect the malnutrition confirmed by the Subjective Global Assessment were 91.5%, 97.9%, and 38.3%, respectively, and the MNA showed a sensitivity of 81.8% for the elderly. Malnutrition detected by the SNAQ, MUST, and NRS-2002 was associated with postoperative complications (odds ratios [ORs] 1.75, 1.98, and 1.82, respectively) and a stay in the intensive care unit longer than 2 d (ORs 1.46, 1.56, and 2.8). Malnutrition as detected by the SNAQ and MUST was also associated with prolonged hospitalization (ORs 1.49 and 1.59). According to multivariate logistic regression analysis, postoperative complications were independently predicted by the European System for Cardiac Operative Risk Evaluation (OR 1.1, P < 0.0001), cardiopulmonary bypass time (OR 1.01, P < 0.0001), and malnutrition identified by the MUST (OR 1.2, P = 0.01). The MUST independently predicts postoperative complications. The SNAQ and MUST have comparable accuracy in detecting malnutrition. Whether preoperative nutritional therapy would improve the outcome in malnourished patients needs to be studied. Copyright © 2013 Elsevier Inc. All rights reserved.

Graft type for femoro-popliteal bypass surgery.

PubMed

Ambler, Graeme K; Twine, Christopher P

2018-02-11

Femoro-popliteal bypass is implemented to save limbs that might otherwise require amputation, in patients with ischaemic rest pain or tissue loss; and to improve walking distance in patients with severe life-limiting claudication. Contemporary practice involves grafts using autologous vein, polytetrafluoroethylene (PTFE) or Dacron as a bypass conduit. This is the second update of a Cochrane review first published in 1999 and last updated in 2010. To assess the effects of bypass graft type in the treatment of stenosis or occlusion of the femoro-popliteal arterial segment, for above- and below-knee femoro-popliteal bypass grafts. For this update, the Cochrane Vascular Information Specialist searched the Vascular Specialised Register (13 March 2017) and CENTRAL (2017, Issue 2). Trial registries were also searched. We included randomised trials comparing at least two different types of femoro-popliteal grafts for arterial reconstruction in patients with femoro-popliteal ischaemia. Randomised controlled trials comparing bypass grafting to angioplasty or to other interventions were not included. Both review authors (GKA and CPT) independently screened studies, extracted data, assessed trials for risk of bias and graded the quality of the evidence using GRADE criteria. We included nineteen randomised controlled trials, with a total of 3123 patients (2547 above-knee, 576 below-knee bypass surgery). In total, nine graft types were compared (autologous vein, polytetrafluoroethylene (PTFE) with and without vein cuff, human umbilical vein (HUV), polyurethane (PUR), Dacron and heparin bonded Dacron (HBD); FUSION BIOLINE and Dacron with external support). Studies differed in which graft types they compared and follow-up ranged from six months to 10 years.Above-knee bypassFor above-knee bypass, there was moderate-quality evidence that autologous vein grafts improve primary patency compared to prosthetic grafts by 60 months (Peto odds ratio (OR) 0.47, 95% confidence interval (CI

Heat exchanger bypass system for an absorption refrigeration system

DOEpatents

Reimann, Robert C.

1984-01-01

A heat exchanger bypass system for an absorption refrigeration system is disclosed. The bypass system operates to pass strong solution from the generator around the heat exchanger to the absorber of the absorption refrigeration system when strong solution builds up in the generator above a selected level indicative of solidification of strong solution in the heat exchanger or other such blockage. The bypass system includes a bypass line with a gooseneck located in the generator for controlling flow of strong solution into the bypass line and for preventing refrigerant vapor in the generator from entering the bypass line during normal operation of the refrigeration system. Also, the bypass line includes a trap section filled with liquid for providing a barrier to maintain the normal pressure difference between the generator and the absorber even when the gooseneck of the bypass line is exposed to refrigerant vapor in the generator. Strong solution, which may accumulate in the trap section of the bypass line, is diluted, to prevent solidification, by supplying weak solution to the trap section from a purge system for the absorption refrigeration system.

21 CFR 870.4320 - Cardiopulmonary bypass pulsatile flow generator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass pulsatile flow generator... Cardiopulmonary bypass pulsatile flow generator. (a) Identification. A cardiopulmonary bypass pulsatile flow... device is placed in a cardiopulmonary bypass circuit downstream from the oxygenator. (b) Classification...

21 CFR 870.4420 - Cardiopulmonary bypass cardiotomy return sucker.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass cardiotomy return sucker... Cardiopulmonary bypass cardiotomy return sucker. (a) Identification. A cardiopulmonary bypass cardiotomy return... from the chest or heart during cardiopulmonary bypass surgery. (b) Classification. Class II...

21 CFR 870.4420 - Cardiopulmonary bypass cardiotomy return sucker.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass cardiotomy return sucker... Cardiopulmonary bypass cardiotomy return sucker. (a) Identification. A cardiopulmonary bypass cardiotomy return... from the chest or heart during cardiopulmonary bypass surgery. (b) Classification. Class II...

21 CFR 870.4320 - Cardiopulmonary bypass pulsatile flow generator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass pulsatile flow generator... Cardiopulmonary bypass pulsatile flow generator. (a) Identification. A cardiopulmonary bypass pulsatile flow... device is placed in a cardiopulmonary bypass circuit downstream from the oxygenator. (b) Classification...

40 CFR 403.17 - Bypass.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) Definitions. (1) Bypass means the intentional diversion of wastestreams from any portion of an Industrial User... applicable Pretreatment Standards or Requirements. An Industrial User may allow any bypass to occur which... paragraphs (c) and (d) of this section. (c) Notice. (1) If an Industrial User knows in advance of the need...

40 CFR 403.17 - Bypass.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) Definitions. (1) Bypass means the intentional diversion of wastestreams from any portion of an Industrial User... applicable Pretreatment Standards or Requirements. An Industrial User may allow any bypass to occur which... paragraphs (c) and (d) of this section. (c) Notice. (1) If an Industrial User knows in advance of the need...

40 CFR 403.17 - Bypass.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) Definitions. (1) Bypass means the intentional diversion of wastestreams from any portion of an Industrial User... applicable Pretreatment Standards or Requirements. An Industrial User may allow any bypass to occur which... paragraphs (c) and (d) of this section. (c) Notice. (1) If an Industrial User knows in advance of the need...

40 CFR 403.17 - Bypass.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) Definitions. (1) Bypass means the intentional diversion of wastestreams from any portion of an Industrial User... applicable Pretreatment Standards or Requirements. An Industrial User may allow any bypass to occur which... paragraphs (c) and (d) of this section. (c) Notice. (1) If an Industrial User knows in advance of the need...

40 CFR 403.17 - Bypass.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) Definitions. (1) Bypass means the intentional diversion of wastestreams from any portion of an Industrial User... applicable Pretreatment Standards or Requirements. An Industrial User may allow any bypass to occur which... paragraphs (c) and (d) of this section. (c) Notice. (1) If an Industrial User knows in advance of the need...

Bypass apparatus and method for series connected energy storage devices

DOEpatents

Rouillard, Jean; Comte, Christophe; Daigle, Dominik

2000-01-01

A bypass apparatus and method for series connected energy storage devices. Each of the energy storage devices coupled to a common series connection has an associated bypass unit connected thereto in parallel. A current bypass unit includes a sensor which is coupled in parallel with an associated energy storage device or cell and senses an energy parameter indicative of an energy state of the cell, such as cell voltage. A bypass switch is coupled in parallel with the energy storage cell and operable between a non-activated state and an activated state. The bypass switch, when in the non-activated state, is substantially non-conductive with respect to current passing through the energy storage cell and, when in the activated state, provides a bypass current path for passing current to the series connection so as to bypass the associated cell. A controller controls activation of the bypass switch in response to the voltage of the cell deviating from a pre-established voltage setpoint. The controller may be included within the bypass unit or be disposed on a control platform external to the bypass unit. The bypass switch may, when activated, establish a permanent or a temporary bypass current path.

Brain microvascular function during cardiopulmonary bypass

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sorensen, H.R.; Husum, B.; Waaben, J.

1987-11-01

Emboli in the brain microvasculature may inhibit brain activity during cardiopulmonary bypass. Such hypothetical blockade, if confirmed, may be responsible for the reduction of cerebral metabolic rate for glucose observed in animals subjected to cardiopulmonary bypass. In previous studies of cerebral blood flow during bypass, brain microcirculation was not evaluated. In the present study in animals (pigs), reduction of the number of perfused capillaries was estimated by measurements of the capillary diffusion capacity for hydrophilic tracers of low permeability. Capillary diffusion capacity, cerebral blood flow, and cerebral metabolic rate for glucose were measured simultaneously by the integral method, different tracersmore » being used with different circulation times. In eight animals subjected to normothermic cardiopulmonary bypass, and seven subjected to hypothermic bypass, cerebral blood flow, cerebral metabolic rate for glucose, and capillary diffusion capacity decreased significantly: cerebral blood flow from 63 to 43 ml/100 gm/min in normothermia and to 34 ml/100 gm/min in hypothermia and cerebral metabolic rate for glucose from 43.0 to 23.0 mumol/100 gm/min in normothermia and to 14.1 mumol/100 gm/min in hypothermia. The capillary diffusion capacity declined markedly from 0.15 to 0.03 ml/100 gm/min in normothermia but only to 0.08 ml/100 gm/min in hypothermia. We conclude that the decrease of cerebral metabolic rate for glucose during normothermic cardiopulmonary bypass is caused by interruption of blood flow through a part of the capillary bed, possibly by microemboli, and that cerebral blood flow is an inadequate indicator of capillary blood flow. Further studies must clarify why normal microvascular function appears to be preserved during hypothermic cardiopulmonary bypass.« less

Targeting the FANCJ–BRCA1 interaction promotes a switch from recombination to polη-dependent bypass

PubMed Central

Xie, J; Litman, R; Wang, S; Peng, M; Guillemette, S; Rooney, T; Cantor, SB

2010-01-01

BRCA1 and the DNA helicase FANCJ (also known as BACH1 or BRIP1) have common functions in breast cancer suppression and DNA repair. However, the functional significance of the direct interaction between BRCA1 and FANCJ remains unclear. Here, we have discovered that BRCA1 binding to FANCJ regulates DNA damage repair choice. Thus, when FANCJ binding to BRCA1 is ablated, the molecular mechanism chosen for the repair of damaged DNA is dramatically altered. Specifically, a FANCJ protein that cannot be phosphorylated at serine 990 or bind BRCA1 inhibits DNA repair via homologous recombination and promotes polη-dependent bypass. Furthermore, the polη-dependent bypass promoted by FANCJ requires the direct binding to the mismatch repair (MMR) protein, MLH1. Together, our findings implicate that in human cells BRCA1 binding to FANCJ is critical to regulate DNA repair choice and promote genomic stability. Moreover, unregulated FANCJ function could be associated with cancer and/or chemoresistance. PMID:20173781

Femoropopliteal Bypass with Varicose Greater Saphenous Vein

PubMed Central

Mun, Yun Su; Cho, Byung Sun; Jang, Je-Ho; Lee, Moon-Soo; Kwon, Oh Sang

2015-01-01

Surgical bypass for peripheral arterial occlusive disease can be performed using different graft materials. Autogenous greater saphenous vein (GSV) is the treatment of choice because of its superior long-term patency. We report a case of femoropopliteal bypass with varicose GSV in a 77-year-old man who was presented with limb ischemia and both varicose veins. We successfully performed bypass with varicose vein. He has been doing well for 15 months after the operation, and a computed tomography angiography of the lower leg, performed on the 15th postoperative month, demonstrated widely patent femoropopliteal bypass graft and no structural change. PMID:28031670

In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.

PubMed

Manguso, Robert T; Pope, Hans W; Zimmer, Margaret D; Brown, Flavian D; Yates, Kathleen B; Miller, Brian C; Collins, Natalie B; Bi, Kevin; LaFleur, Martin W; Juneja, Vikram R; Weiss, Sarah A; Lo, Jennifer; Fisher, David E; Miao, Diana; Van Allen, Eliezer; Root, David E; Sharpe, Arlene H; Doench, John G; Haining, W Nicholas

2017-07-27

Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

Inclusion of populations at risk of advanced melanoma in an opportunistic targeted screening project involving general practitioners

PubMed Central

Rat, Cédric; Quereux, Gaelle; Grimault, Charlotte; Fernandez, Jérémy; Poiraud, Mickael; Gaultier, Aurélie; Chaslerie, Anicet; Pivette, Jacques; Khammari, Amir; Dreno, Brigitte; Nguyen, Jean-Michel

2016-01-01

Objective The study objective was to measure the rates of inclusion of populations at risk of advanced melanoma in a pilot targeted screening project involving general practitioners. Design This cross-sectional database study compared the inclusion rates of patients who signed inclusion in a targeted screening project with those of patients who did not, during a period in which both groups of patients consulted investigators. Setting Data were extracted from the national healthcare insurance records in western France from 11 April to 30 October 2011. Patients Patients, older than 18, considered for the data extraction had consulted one of the 78 participating GPs during the study period, and were affiliated with the national healthcare insurance. Main outcome measures Inclusion in the screening was the main outcome measure. Patients at risk of advanced melanoma were characterized by male gender, age over 50, low income, rural residence, farmer, and presence of chronic disease. Results A total of 57,279 patients consulted GPs during the inclusion period and 2711 (4.73%) were included in the targeted screening. Populations at risk of advanced melanoma were less included: men (OR = 0.67; 95%CI [0.61–0.73]; p < 0.001), older than 50 (OR = 0.67; 95%CI [0.60–0.74]; p < 0.001), low income (OR = 0.65; 95%CI [0.55–0.77]; p < 0.001), farmer (OR = 0.23; 95%CI [0.17–0.30]; p < 0.001) and presence of a chronic disease (OR = 0.87; 95%CI [0.77–0.98]; p < 0.028). Conclusion This study demonstrated inequalities in the inclusion of patients in a melanoma screening. Patients at risk of advanced cancer were screened less often. Further studies should focus on GPs ability to identify and screen these patients. Key Points Advanced melanoma is more frequently diagnosed in men, older patients and socioeconomically disadvantaged populations, which leads to survival inequalities.• Despite the involvement of general practitioners, the

21 CFR 870.4310 - Cardiopulmonary bypass coronary pressure gauge.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Cardiopulmonary bypass coronary pressure gauge. (a) Identification. A cardiopulmonary bypass coronary pressure gauge is a device used in cardiopulmonary bypass surgery to measure the pressure of the blood perfusing... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass coronary pressure gauge...

21 CFR 870.4310 - Cardiopulmonary bypass coronary pressure gauge.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Cardiopulmonary bypass coronary pressure gauge. (a) Identification. A cardiopulmonary bypass coronary pressure gauge is a device used in cardiopulmonary bypass surgery to measure the pressure of the blood perfusing... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass coronary pressure gauge...

21 CFR 870.4310 - Cardiopulmonary bypass coronary pressure gauge.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Cardiopulmonary bypass coronary pressure gauge. (a) Identification. A cardiopulmonary bypass coronary pressure gauge is a device used in cardiopulmonary bypass surgery to measure the pressure of the blood perfusing... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass coronary pressure gauge...

21 CFR 870.4310 - Cardiopulmonary bypass coronary pressure gauge.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Cardiopulmonary bypass coronary pressure gauge. (a) Identification. A cardiopulmonary bypass coronary pressure gauge is a device used in cardiopulmonary bypass surgery to measure the pressure of the blood perfusing... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass coronary pressure gauge...

21 CFR 870.4310 - Cardiopulmonary bypass coronary pressure gauge.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Cardiopulmonary bypass coronary pressure gauge. (a) Identification. A cardiopulmonary bypass coronary pressure gauge is a device used in cardiopulmonary bypass surgery to measure the pressure of the blood perfusing... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass coronary pressure gauge...

Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis.

PubMed

Stoletov, Konstantin; Willetts, Lian; Paproski, Robert J; Bond, David J; Raha, Srijan; Jovel, Juan; Adam, Benjamin; Robertson, Amy E; Wong, Francis; Woolner, Emma; Sosnowski, Deborah L; Bismar, Tarek A; Wong, Gane Ka-Shu; Zijlstra, Andries; Lewis, John D

2018-06-14

Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.

Large-Scale Chemical Similarity Networks for Target Profiling of Compounds Identified in Cell-Based Chemical Screens

PubMed Central

Lo, Yu-Chen; Senese, Silvia; Li, Chien-Ming; Hu, Qiyang; Huang, Yong; Damoiseaux, Robert; Torres, Jorge Z.

2015-01-01

Target identification is one of the most critical steps following cell-based phenotypic chemical screens aimed at identifying compounds with potential uses in cell biology and for developing novel disease therapies. Current in silico target identification methods, including chemical similarity database searches, are limited to single or sequential ligand analysis that have limited capabilities for accurate deconvolution of a large number of compounds with diverse chemical structures. Here, we present CSNAP (Chemical Similarity Network Analysis Pulldown), a new computational target identification method that utilizes chemical similarity networks for large-scale chemotype (consensus chemical pattern) recognition and drug target profiling. Our benchmark study showed that CSNAP can achieve an overall higher accuracy (>80%) of target prediction with respect to representative chemotypes in large (>200) compound sets, in comparison to the SEA approach (60–70%). Additionally, CSNAP is capable of integrating with biological knowledge-based databases (Uniprot, GO) and high-throughput biology platforms (proteomic, genetic, etc) for system-wise drug target validation. To demonstrate the utility of the CSNAP approach, we combined CSNAP's target prediction with experimental ligand evaluation to identify the major mitotic targets of hit compounds from a cell-based chemical screen and we highlight novel compounds targeting microtubules, an important cancer therapeutic target. The CSNAP method is freely available and can be accessed from the CSNAP web server (http://services.mbi.ucla.edu/CSNAP/). PMID:25826798

21 CFR 870.4380 - Cardiopulmonary bypass pump speed control.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass pump speed control. 870... Cardiopulmonary bypass pump speed control. (a) Identification. A cardiopulmonary bypass pump speed control is a... control the speed of blood pumps used in cardiopulmonary bypass surgery. (b) Classification. Class II...

21 CFR 870.4380 - Cardiopulmonary bypass pump speed control.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass pump speed control. 870... Cardiopulmonary bypass pump speed control. (a) Identification. A cardiopulmonary bypass pump speed control is a... control the speed of blood pumps used in cardiopulmonary bypass surgery. (b) Classification. Class II...

Prolonged partial cardiopulmonary bypass in rats.

PubMed

Alexander, B; Al Ani, H R

1983-07-01

Membrane oxygenators have been shown to be atraumatic during cardiopulmonary bypass. A novel design for a membrane tubing oxygenator originated in this laboratory was used for prolonged partial supportive cardiopulmonary bypass in lambs and displayed excellent biocompatability characteristics. This was miniaturized, to result in a prime volume of 12 ml, in order to investigate the feasibility of prolonged partial supportive cardiopulmonary bypass in rats. The performance of this miniaturized circuit over perfusion periods up to 6 hr is described, with particular reference to hematological changes.

Volatile anaesthesia during cardiopulmonary bypass.

PubMed

McMullan, V; Alston, R P; Tyrrell, J

2015-01-01

Since its inception, administering and ensuring anaesthesia during cardiopulmonary bypass has been challenging. Partly because of the difficulty of administering volatile agents during cardiopulmonary bypass, total intravenous anaesthesia has been a popular technique used by cardiac anaesthetists in the last two decades. However, the possibility that volatile agents reduce mortality and the incidence of myocardial infarction by preconditioning the myocardium has stimulated a resurgence of interest in their use for cardiac anaesthesia. The aim of this review is to provide an overview of the administration of volatile anaesthetic agents during cardiopulmonary bypass for the maintenance of anaesthesia and to address some of the practical issues that are involved in doing so. © The Author(s) 2014.

Direct Bypass Versus Indirect Bypass in Adult Moyamoya Angiopathy with Symptoms or Hemodynamic Instability: A Meta-analysis of Comparative Studies.

PubMed

Kim, Hoon; Jang, Dong-Kyu; Han, Young-Min; Sung, Jae Hoon; Park, Ik Seong; Lee, Kwan-Sung; Yang, Ji-Ho; Huh, Pil Woo; Park, Young Sup; Kim, Dal-Soo; Han, Kyung-Do

2016-10-01

It remains controversial which bypass methods are optimal for treating adult moyamoya angiopathy patients. This study aimed to analyze the literature about whether different bypass methods affect differently outcome results of adult moyamoya patients with symptoms or hemodynamic instability. A systematic search of the PubMed, Embase, and Cochrane Central databases was performed for articles published between 1990 and 2015. Comparative studies about the effect of direct or combined bypass (direct bypass group) and indirect bypass (indirect bypass group) in patients with moyamoya angiopathy at 18 years of age or older were selected. For stroke incidence at the end of the follow-up period, the degree of angiographic revascularization, hemodynamic improvement, and perioperative complication rates within 30 days, pooled relative risks were calculated between the 2 groups with a 95% confidence interval. A total of 8 articles (including 536 patients and 732 treated hemispheres) were included in the meta-analysis. There were no significant differences between the 2 groups when we compared the overall stroke rate, the hemodynamic improvement rate, or the perioperative complication rate at the end of the follow-up period. The direct bypass group, however, had a lower risk than the indirect bypass group for obtaining a poor angiographic revascularization rate (risk ratio, 0.35; 95% confidence interval, 0.15-0.84; P = 0.02). The current meta-analysis suggests that the direct or combined bypass surgical method is better for angiographic revascularization in adult moyamoya patients with symptoms or hemodynamic instability. Future studies may be necessary to confirm these findings. Copyright © 2016 Elsevier Inc. All rights reserved.

21 CFR 870.4250 - Cardiopulmonary bypass temperature controller.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass temperature controller. 870.4250 Section 870.4250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Cardiopulmonary bypass temperature controller. (a) Identification. A cardiopulmonary bypass temperature controller...

21 CFR 870.4250 - Cardiopulmonary bypass temperature controller.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass temperature controller. 870.4250 Section 870.4250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Cardiopulmonary bypass temperature controller. (a) Identification. A cardiopulmonary bypass temperature controller...

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

PubMed Central

Gerby, Bastien; Veiga, Diogo F.T.; Krosl, Jana; Nourreddine, Sami; Ouellette, Julianne; Haman, André; Lavoie, Geneviève; Fares, Iman; Tremblay, Mathieu; Litalien, Véronique; Ottoni, Elizabeth; Geoffrion, Dominique; Maddox, Paul S.; Chagraoui, Jalila; Hébert, Josée; Sauvageau, Guy; Kwok, Benjamin H.; Roux, Philippe P.

2016-01-01

Current chemotherapies for T cell acute lymphoblastic leukemia (T-ALL) efficiently reduce tumor mass. Nonetheless, disease relapse attributed to survival of preleukemic stem cells (pre-LSCs) is associated with poor prognosis. Herein, we provide direct evidence that pre-LSCs are much less chemosensitive to existing chemotherapy drugs than leukemic blasts because of a distinctive lower proliferative state. Improving therapies for T-ALL requires the development of strategies to target pre-LSCs that are absolutely dependent on their microenvironment. Therefore, we designed a robust protocol for high-throughput screening of compounds that target primary pre-LSCs maintained in a niche-like environment, on stromal cells that were engineered for optimal NOTCH1 activation. The multiparametric readout takes into account the intrinsic complexity of primary cells in order to specifically monitor pre-LSCs, which were induced here by the SCL/TAL1 and LMO1 oncogenes. We screened a targeted library of compounds and determined that the estrogen derivative 2-methoxyestradiol (2-ME2) disrupted both cell-autonomous and non–cell-autonomous pathways. Specifically, 2-ME2 abrogated pre-LSC viability and self-renewal activity in vivo by inhibiting translation of MYC, a downstream effector of NOTCH1, and preventing SCL/TAL1 activity. In contrast, normal hematopoietic stem/progenitor cells remained functional. These results illustrate how recapitulating tissue-like properties of primary cells in high-throughput screening is a promising avenue for innovation in cancer chemotherapy. PMID:27797342

Cost-effectiveness of targeted versus tailored interventions to promote mammography screening among women military veterans in the United States.

PubMed

Lairson, David R; Chan, Wen; Chang, Yu-Chia; del Junco, Deborah J; Vernon, Sally W

2011-05-01

We conducted an economic evaluation of mammography promotion interventions in a population-based, nationally representative sample of 5500 women veterans. Women 52 years and older were randomly selected from the National Registry of Women Veterans and randomly assigned to a survey-only control group and two intervention groups that varied in the extent of personalization (tailored vs. targeted). Effectiveness measures were the prevalence of at least one self-reported post-intervention mammogram and two post-intervention mammograms 6-15 months apart. Incremental cost-effectiveness ratios (ICERs) were the incremental cost per additional person screened. Uncertainty was examined with sensitivity analysis and bootstrap simulation. The targeted intervention cost $25 per person compared to $52 per person for the tailored intervention. About 27% of the cost was incurred in identifying and recruiting the eligible population. The percent of women reporting at least one mammogram were .447 in the control group, .469 in the targeted group, and .460 in the tailored group. The ICER was $1116 comparing the targeted group to the control group (95% confidence interval (CI)=$493 to dominated). The tailored intervention was dominated (more costly and less effective) by the targeted intervention. Decision-makers should consider effectiveness evidence and the full recruitment and patient time costs associated with the implementation of screening interventions when making investments in mammography screening promotion programs. Identification and recruitment of eligible participants add substantial costs to outreach screening promotion interventions. Tailoring adds substantial cost to the targeted mammography promotion strategy without a commensurate increase in effectiveness. Although cost-effectiveness has been reported to be higher for some in-reach screening promotion interventions, a recent meta-analysis revealed significant heterogeneity in the effect sizes of published health

RNAi screen for rapid therapeutic target identification in leukemia patients

PubMed Central

Tyner, Jeffrey W.; Deininger, Michael W.; Loriaux, Marc M.; Chang, Bill H.; Gotlib, Jason R.; Willis, Stephanie G.; Erickson, Heidi; Kovacsovics, Tibor; O'Hare, Thomas; Heinrich, Michael C.; Druker, Brian J.

2009-01-01

Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses. Here, we report an RNAi-assisted protein target identification (RAPID) technology that individually assesses targeting of each member of the tyrosine kinase gene family. We demonstrate that RAPID screening of primary leukemia cells from 30 patients identifies targets that are critical to survival of the malignant cells from 10 of these individuals. We identify known, activating mutations in JAK2 and K-RAS, as well as patient-specific sensitivity to down-regulation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS. We also describe a previously undescribed, somatic, activating mutation in the thrombopoietin receptor that is sensitive to down-stream pharmacologic inhibition. Hence, the RAPID technique can quickly identify molecular vulnerabilities in malignant cells. Combination of this technique with whole-genome sequencing will represent an ideal tool for oncogenic target identification such that specific therapies can be matched with individual patients. PMID:19433805

Long-term patency of superficial temporal artery to middle cerebral artery bypass for cerebral atherosclerotic disease: factors determining the bypass patent.

PubMed

Matano, Fumihiro; Murai, Yasuo; Tateyama, Kojiro; Tamaki, Tomonori; Mizunari, Takayuki; Matsukawa, Hideoshi; Teramoto, Akira; Morita, Akio

2016-10-01

Long-term patency of superficial temporal artery to middle cerebral artery (STA-MCA) bypass surgery for atherosclerotic disease and associated risk factors for loss of patency have rarely been discussed. We retrospectively analyzed long-term patency following STA-MCA bypass and evaluated various demographic and clinical factors to identify the ones predictive of postsurgical loss of patency using records of 84 revascularization procedures (58 patients, 45 males; mean age at surgery 63.6 years, range 31-78 years). Bypass patency was diagnosed based on magnetic resonance angiography or three-dimensional computed tomography. The mean follow-up period was 24.7 months (range 6-63 months). Decreased bypass patency was observed in 4 of 58 patients (6.9 %) who collectively underwent 6 bypasses (7.1 %) of 84. All cases of decreased bypass patency were first detected within 6 months of surgery. Bypass patency was not correlated with age, sex, number of anastomoses, postoperative cerebral infarction, or control of postoperative diabetes mellitus. We found a significant association of bypass patency with hyperperfusion (p = 0.01) and postoperative smoking (p = 0.0036). Furthermore, we found a significant association of hyperperfusion with STA diameter (p < 0.0001), location of anastomosis (p = 0.075), and preoperative cerebral blood flow (p = 0.0399). In our retrospective study, hyperperfusion and smoking after surgery may be risk factors for decreased bypass patency in cerebral atherosclerotic disease patients. Careful monitoring of patency to prevent hyperperfusion and cessation of smoking are recommended, particularly within 6 months of the surgery.

Occipital-posterior cerebral artery bypass via the occipital interhemispheric approach

PubMed Central

Kazumata, Ken; Yokoyama, Yuka; Sugiyama, Taku; Asaoka, Katsuyuki

2013-01-01

Background: The unavailability of the superficial temporal artery (STA) and the location of lesions pose a more technically demanding challenge when compared with conventional STA-superior cerebellar or posterior cerebral artery (PCA) bypass in vascular reconstruction procedures. To describe a case series of patients with cerebrovascular lesions who were treated using an occipital artery (OA) to PCA bypass via the occipital interhemispheric approach. Methods: We retrospectively reviewed three consecutive cases of patients with cerebrovascular lesions who were treated using OA-PCA bypass. Results: OA-PCA bypass was performed via the occipital interhemispheric approach. This procedure included: (1) OA-PCA bypass (n = 1), and combined OA-posterior inferior cerebellar artery and OA-PCA saphenous vein interposition graft bypass (n = 1) in patients with vertebrobasilar ischemia; (2) OA-PCA radial artery interposition graft bypass in one patient with residual PCA aneurysm. Conclusions: OA-PCA bypass represents a useful alternative to conventional STA-SCA or PCA bypass. PMID:23956933

21 CFR 870.4250 - Cardiopulmonary bypass temperature controller.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass temperature controller. 870... Cardiopulmonary bypass temperature controller. (a) Identification. A cardiopulmonary bypass temperature controller is a device used to control the temperature of the fluid entering and leaving a heat exchanger. (b...

21 CFR 870.4250 - Cardiopulmonary bypass temperature controller.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass temperature controller. 870... Cardiopulmonary bypass temperature controller. (a) Identification. A cardiopulmonary bypass temperature controller is a device used to control the temperature of the fluid entering and leaving a heat exchanger. (b...

21 CFR 870.4250 - Cardiopulmonary bypass temperature controller.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass temperature controller. 870... Cardiopulmonary bypass temperature controller. (a) Identification. A cardiopulmonary bypass temperature controller is a device used to control the temperature of the fluid entering and leaving a heat exchanger. (b...

21 CFR 870.4240 - Cardiopulmonary bypass heat exchanger.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass heat exchanger. 870.4240... bypass heat exchanger. (a) Identification. A cardiopulmonary bypass heat exchanger is a device, consisting of a heat exchange system used in extracorporeal circulation to warm or cool the blood or...

21 CFR 870.4240 - Cardiopulmonary bypass heat exchanger.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass heat exchanger. 870.4240... bypass heat exchanger. (a) Identification. A cardiopulmonary bypass heat exchanger is a device, consisting of a heat exchange system used in extracorporeal circulation to warm or cool the blood or...

21 CFR 870.4205 - Cardiopulmonary bypass bubble detector.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass bubble detector. 870.4205 Section 870.4205 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... bypass bubble detector. (a) Identification. A cardiopulmonary bypass bubble detector is a device used to...

21 CFR 870.4205 - Cardiopulmonary bypass bubble detector.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass bubble detector. 870.4205 Section 870.4205 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... bypass bubble detector. (a) Identification. A cardiopulmonary bypass bubble detector is a device used to...

21 CFR 870.4205 - Cardiopulmonary bypass bubble detector.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass bubble detector. 870.4205 Section 870.4205 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... bypass bubble detector. (a) Identification. A cardiopulmonary bypass bubble detector is a device used to...

21 CFR 870.4205 - Cardiopulmonary bypass bubble detector.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass bubble detector. 870.4205 Section 870.4205 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... bypass bubble detector. (a) Identification. A cardiopulmonary bypass bubble detector is a device used to...

21 CFR 870.4205 - Cardiopulmonary bypass bubble detector.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass bubble detector. 870.4205 Section 870.4205 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... bypass bubble detector. (a) Identification. A cardiopulmonary bypass bubble detector is a device used to...

21 CFR 870.4240 - Cardiopulmonary bypass heat exchanger.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass heat exchanger. 870.4240... bypass heat exchanger. (a) Identification. A cardiopulmonary bypass heat exchanger is a device, consisting of a heat exchange system used in extracorporeal circulation to warm or cool the blood or...

21 CFR 870.4240 - Cardiopulmonary bypass heat exchanger.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass heat exchanger. 870.4240... bypass heat exchanger. (a) Identification. A cardiopulmonary bypass heat exchanger is a device, consisting of a heat exchange system used in extracorporeal circulation to warm or cool the blood or...

21 CFR 870.4240 - Cardiopulmonary bypass heat exchanger.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass heat exchanger. 870.4240... bypass heat exchanger. (a) Identification. A cardiopulmonary bypass heat exchanger is a device, consisting of a heat exchange system used in extracorporeal circulation to warm or cool the blood or...

Multiresidue pesticide analysis in ginseng and spinach by nontargeted and targeted screening procedures.

PubMed

Hayward, Douglas G; Wong, Jon W; Zhang, Kai; Chang, James; Shi, Feng; Banerjee, Kaushik; Yang, Paul

2011-01-01

Five different mass spectrometers interfaced to GC or LC were evaluated for their application to targeted and nontargeted screening of pesticides in two foods, spinach and ginseng. The five MS systems were capillary GC/MS/MS, GC-high resolution time-of-flight (GC/HR-TOF)-MS, TOF-MS interfaced with a comprehensive multidimensional GC (GCxGC/TOF-MS), an MS/MS ion trap hybrid mass (qTrap) system interfaced with an ultra-performance liquid chromatograph (UPLC-qTrap), and UPLC interfaced to an orbital trap high resolution mass spectrometer (UPLC/Orbitrap HR-MS). Each MS system was tested with spinach and ginseng extracts prepared through a modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) procedure. Each matrix was fortified at 10 and 50 ng/g for spinach or 25 and 100 ng/g for ginseng with subsets of 486 pesticides, isomers, and metabolites representing most pesticide classes. HR-TOF-MS was effective in a targeted search for characteristic accurate mass ions and identified 97% of 170 pesticides in ginseng at 25 ng/g. A targeted screen of either ginseng or spinach found 94-95% of pesticides fortified for analysis at 10 ng/g with GC/MS/MS or LC/MS/MS using multiple reaction monitoring (MRM) procedures. Orbitrap-MS successfully found 89% of 177 fortified pesticides in spinach at 25 ng/g using a targeted search of accurate mass pseudomolecular ions in the positive electrospray ionization mode. A comprehensive GCxGC/TOF-MS system provided separation and identification of 342 pesticides and metabolites in a single 32 min acquisition with standards. Only 67 or 81% of the pesticides were identified in ginseng and spinach matrixes at 25 ng/g or 10 ng/g, respectively. MS/MS or qTrap-MS operated in the MRM mode produced the lowest false-negative rates, at 10 ng/g. Improvements to instrumentation, methods, and software are needed for efficient use of nontargeted screens in parallel with triple quadrupole MS.

Bypass transition to turbulence and research Desiderata

NASA Technical Reports Server (NTRS)

Morkovin, M. V.

1985-01-01

Bypass transitions are seldom mentioned in texts or meetings on instability and transition to wall turbulence. The nature of a number of bypass transitions is illustrated by example. Until this characteristics is truly understood predicting transition on the basis of theory or statistically inadequate correlations (as they all are) entails risks that should be considered in justifying any design involving transition. A historical overview of bypass transition identified on blunt bodies is given.

Virtual screening of phytochemicals to novel targets in Haemophilus ducreyi towards the treatment of Chancroid.

PubMed

Tripathi, Pranav; Chaudhary, Ritu; Singh, Ajeet

2014-01-01

Conventionally, drugs are discovered by testing chemically synthesized compounds against a battery of in vivo biological screens. Information technology and Omic science enabled us for high throughput screening of compound libraries against biological targets and hits are then tested for efficacy in cells or animals. Chancroid, caused by Haemophilus ducreyi is a public health problem and has been recognized as a cofactor for Human Immunodeficiency Virus (HIV) transmission. It facilitates HIV transmission by providing an accessible portal entry, promoting viral shedding, and recruiting macrophages as well as CD4 cells to the skin. So, there is a requirement to develop an efficient drug to combat Chancroid that can also diminish HIV infection. In-silico screening of potential inhibitors against the target may facilitate in detection of the novel lead compounds for developing an effective chemo preventive strategy against Haemophilus ducreyi. The present study has investigated the effects of approximately 1100 natural compounds that inhibit three vital enzymes viz. Phosphoenolpyruvate phosphotransferase, Acetyl-coenzyme A carboxylase and Fructose 1, 6-bisphosphatase of Haemophilus ducreyi in reference to a commercial drug Rifabutin. Results reveal that the lead compound uses less energy to bind to target. The lead compound parillin has also been predicted as less immunogenic in comparison to Rifabutin. Further, better molecular dynamics, pharmacokinetics, pharmacodynamics and ADME-T properties establish it as an efficient chancroid preventer.

Battery Cell By-Pass Circuit

NASA Technical Reports Server (NTRS)

Mumaw, Susan J. (Inventor); Evers, Jeffrey (Inventor); Craig, Calvin L., Jr. (Inventor); Walker, Stuart D. (Inventor)

2001-01-01

The invention is a circuit and method of limiting the charging current voltage from a power supply net work applied to an individual cell of a plurality of cells making up a battery being charged in series. It is particularly designed for use with batteries that can be damaged by overcharging, such as Lithium-ion type batteries. In detail. the method includes the following steps: 1) sensing the actual voltage level of the individual cell; 2) comparing the actual voltage level of the individual cell with a reference value and providing an error signal representative thereof; and 3) by-passing the charging current around individual cell necessary to keep the individual cell voltage level generally equal a specific voltage level while continuing to charge the remaining cells. Preferably this is accomplished by by-passing the charging current around the individual cell if said actual voltage level is above the specific voltage level and allowing the charging current to the individual cell if the actual voltage level is equal or less than the specific voltage level. In the step of bypassing the charging current, the by-passed current is transferred at a proper voltage level to the power supply. The by-pass circuit a voltage comparison circuit is used to compare the actual voltage level of the individual cell with a reference value and to provide an error signal representative thereof. A third circuit, designed to be responsive to the error signal, is provided for maintaining the individual cell voltage level generally equal to the specific voltage level. Circuitry is provided in the third circuit for bypassing charging current around the individual cell if the actual voltage level is above the specific voltage level and transfers the excess charging current to the power supply net work. The circuitry also allows charging of the individual cell if the actual voltage level is equal or less than the specific voltage level.

Ethical issues in cancer screening and prevention.

PubMed

Plutynski, Anya

2012-06-01

November 2009's announcement of the USPSTF's recommendations for screening for breast cancer raised a firestorm of objections. Chief among them were that the panel had insufficiently valued patients' lives or allowed cost considerations to influence recommendations. The publicity about the recommendations, however, often either simplified the actual content of the recommendations or bypassed significant methodological issues, which a philosophical examination of both the science behind screening recommendations and their import reveals. In this article, I discuss two of the leading ethical considerations at issue in screening recommendations: respect for patient autonomy and beneficence and then turn to the most significant methodological issues raised by cancer screening: the potential biases that may infect a trial of screening effectiveness, the problem of base rates in communicating risk, and the trade-offs involved in a judgment of screening effectiveness. These issues reach more broadly, into the use of "evidence-based" medicine generally, and have important implications for informed consent.

Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

PubMed

Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

2012-02-01

Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority <15.4%) of the individual target inhibitors of the same target pair and 0.58-7.1% of the other 6 targets outside the target pair. COMBI-SVMs showed low dual inhibitor false hit rates (0.006-0.056%, 0.042-0.21%, 0.2-4%) in screening 17 million PubChem compounds, 168,000 MDDR compounds, and 7-8181 MDDR compounds similar to the dual inhibitors. Compared with similarity searching, k-NN and PNN methods, COMBI-SVM produced comparable dual inhibitor yields, similar target selectivity, and lower false hit rate in screening 168,000 MDDR compounds. The annotated classes of many COMBI-SVMs identified MDDR virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. Copyright © 2011 Elsevier Inc. All rights reserved.

Surgical outcomes for moyamoya angiopathy at barrow neurological institute with comparison of adult indirect encephaloduroarteriosynangiosis bypass, adult direct superficial temporal artery-to-middle cerebral artery bypass, and pediatric bypass: 154 revascularization surgeries in 140 affected hemispheres.

PubMed

Abla, Adib A; Gandhoke, Gurpreet; Clark, Justin C; Oppenlander, Mark E; Velat, Gregory J; Zabramski, Joseph M; Albuquerque, Felipe C; Nakaji, Peter; Spetzler, Robert F; Wanebo, John E

2013-09-01

Untreated, moyamoya angiopathy is a progressive vaso-occlusive process that can lead to ischemic or hemorrhagic stroke. To review 1 institution's surgical experience with both direct and indirect bypass (encephaloduroarteriosynangiosis) in adult and pediatric groups. A retrospective review was conducted of a consecutive series of patients treated for moyamoya angiopathy between 1995 and 2009. Thirty-nine adult patients underwent indirect bypass as their initial therapy; 29 adult patients underwent direct bypass. Twenty-four pediatric patients included 20 indirect bypasses and 4 direct bypasses. Overall, 140 hemispheres were treated; 48 patients received revascularization of both hemispheres. There were 14 additional revascularization procedures (10% per hemisphere) performed over a site of continued hypoperfusion postoperatively. Fourteen postoperative ischemic strokes occurred during the entire follow-up (10% per hemisphere), and the Kaplan-Meier analysis was not significantly different between groups (P = .59). Four grafts (9.09%) had failed at radiographic follow-up of the 44 direct bypasses performed. Before the initial surgery, the modified Rankin Scale score was 1.58 ± 0.93, 1.48 ± 0.74, and 1.8 ± 1.1 in the pediatric, adult direct, and adult indirect groups (P = .39). At last follow-up, it was 1.29 ± 1.31, 1.09 ± 0.90, and 1.94 ± 1.51 (P = .04) in the pediatric, adult direct, and adult indirect groups. This series demonstrates that both direct and indirect bypasses can be equally effective in preventing stroke. However, in adult patients, direct bypass patients had significantly greater improvement in symptoms, as seen in modified Rankin Scale scores. Pediatric patients, despite undergoing predominantly indirect bypasses, fared roughly the same as the adults in the direct bypass group.

30 CFR 57.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Overtravel by-pass switches. 57.19018 Section... Hoisting Hoists § 57.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 56.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Overtravel by-pass switches. 56.19018 Section... Hoisting Hoists § 56.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 57.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Overtravel by-pass switches. 57.19018 Section... Hoisting Hoists § 57.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 56.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Overtravel by-pass switches. 56.19018 Section... Hoisting Hoists § 56.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 57.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Overtravel by-pass switches. 57.19018 Section... Hoisting Hoists § 57.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 56.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Overtravel by-pass switches. 56.19018 Section... Hoisting Hoists § 56.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 57.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Overtravel by-pass switches. 57.19018 Section... Hoisting Hoists § 57.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 57.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Overtravel by-pass switches. 57.19018 Section... Hoisting Hoists § 57.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 56.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Overtravel by-pass switches. 56.19018 Section... Hoisting Hoists § 56.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

30 CFR 56.19018 - Overtravel by-pass switches.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Overtravel by-pass switches. 56.19018 Section... Hoisting Hoists § 56.19018 Overtravel by-pass switches. When an overtravel by-pass switch is installed, the switch shall function so as to allow the conveyance to be moved through the overtravel position when the...

Long-term Effects of Off-Pump Coronary Bypass Versus Conventional Coronary Bypass Grafting on Renal Function.

PubMed

Hynes, Conor F; Colo, Sanchez; Amdur, Richard L; Chawla, Lakhmir S; Greenberg, Michael D; Trachiotis, Gregory D

2016-01-01

This study aimed to evaluate the short- and long-term effects of conventional on-pump coronary bypass grafting (cCABG) compared with off-pump coronary artery bypass (OPCAB) on renal function. A retrospective review of patients undergoing coronary bypass grafting from 2004 through 2013 at a single center was conducted. Preoperative renal function, perioperative acute kidney injury, and long-term glomerular filtration were evaluated. Multivariable analyses were used to determine factors contributing to short- and long-term renal impairment. A total of 234 patients underwent cCABG, and 582 underwent OPCAB. Patients undergoing OPCAB were significantly older, had greater preoperative renal dysfunction, had greater functional dependence, and took more hypertension medications. Multivariable analyses found that 30-day acute kidney injury was an independent risk factor for a 10% decline in glomerular filtration rate at 1 and 5 years (P < 0.0001 and 0.002, respectively). However, the use of cardiopulmonary bypass was not found to influence long-term renal function (P = 0.78 at 1 year, P = 0.76 at 5 years). The percentage of patients experiencing a 10% drop in renal function from baseline at 1 year (33% OPCAB, 35% cCABG; P = 0.73) and 5 years (16% OPCAB, 16% cCABG; P = 0.93) were not significantly different. Independent predictors of acute kidney injury included baseline kidney function (P = 0.04) and age (P < 0.0001), whereas cardiopulmonary bypass did not affect the incidence (P = 0.17). A propensity-matched analysis confirmed these findings. Acute kidney injury is a risk factor for long-term renal dysfunction after either bypass method and was not greater after cCABG compared with OPCAB. Patients undergoing OPCAB did not experience greater decrease in long-term kidney function despite having worse baseline kidney function.

Composite versus conventional coronary artery bypass grafting strategy for the anterolateral territory: study protocol for a randomized controlled trial

PubMed Central

2013-01-01

Background In severe coronary artery disease, coronary artery bypass grafting (CABG) surgery is indicated to re-establish an adequate blood supply to the ischemic myocardium. Effectiveness of CABG surgery for symptom relief and mortality decrease should therefore depend on bypass graft patency. As bypass using a left internal mammary artery (LIMA)-to-left anterior descending coronary artery (LAD) anastomosis allows the best results in terms of graft patency, we designed a new surgical technique using a saphenous vein graft as a venous bridge to distribute the LIMA flow to the cardiac anterolateral territory. This novel strategy could extend the patency benefits associated to the LIMA. Other potential benefits of this technique include easier surgical technique, possibility to use saphenous vein grafts as vein patch angioplasty, shorter saphenous vein grafts requirement and reduced or eliminated manipulations of the ascendant aorta (and associated stroke risk). Methods/Design Between July 2012 and 2016, 200 patients undergoing a primary isolated CABG surgery using cardiopulmonary bypass with a LAD bypass graft and at least another target on the anterolateral territory will be randomized (1:1) according to 1) the new composite strategy and 2) the conventional strategy with a LIMA-to-LAD anastomosis and revascularization of the other anterolateral target(s) with a separated aorto-coronary saphenous vein graft. The primary objective of the trial is to assess whether the composite strategy allows non-inferior anterolateral graft patency index (proportion of non-occluded CABGs out of the total number of CABGs) compared to the conventional technique. The primary outcome is the anterolateral graft patency index, evaluated at one year by 256-slice computed tomography angiography. Ten years of clinical follow-up is planned to assess clinical outcomes including death, myocardial infarction and need for revascularization. Discussion This non-inferiority trial has the potential

Bypass of the maxillary artery to proximal middle cerebral artery.

PubMed

Ma, Lin; Ren, He-cheng; Huang, Ying

2015-03-01

The objective of this work was to explore the feasibility of bypass between the maxillary artery (MA) and proximity of middle cerebral artery (MCA). Ten fixed and perfused adult cadaver heads were dissected bilaterally, 20 sides in total. The superficial temporal artery and its 2 branches were dissected, and outer diameters were measured. The MA and its branch were exposed as well as deep temporal artery; outer diameter of MA was measured. The lengths between the external carotid artery, internal carotid artery, maxillary artery, and proximal middle cerebral artery were measured. Ten healthy adults as targets (20 sides), inner diameter and blood flow dynamic parameters of the common carotid artery, external carotid artery, internal carotid artery, maxillary artery, superficial temporal artery, and its 2 branches were done with ultrasound examination. The mean outer diameter of MA (2.60 ± 0.20 mm) was larger than that of the temporal artery trunk (1.70 ± 0.30 mm). The mean lengths of graft vessels between the internal carotid artery, external carotid artery, and the bifurcation section of MCA (171.00 ± 2.70 and 162.40 ± 2.60 mm) were longer than the mean lengths of graft vessels between MA and MCA bifurcation section (61.70 ± 1.50 mm). In adults, the mean blood flow of the second part of MA (62.70 ± 13.30 mL/min) was more than that of the 2 branches of the superficial temporal artery (15.90 ± 3.70 mL/min and 17.70 ± 4.10 ml/min). Bypass between the maxillary artery and proximity of middle cerebral artery is feasible. It is a kind of effective high flow bypass with which the graft vessel is shorter and straighter than the bypass between internal carotid artery or external carotid artery and proximity of middle cerebral artery.

Integrative screening approach identifies regulators of polyploidization and targets for acute megakaryocytic leukemia

PubMed Central

Wen, Qiang; Goldenson, Benjamin; Silver, Serena J.; Schenone, Monica; Dancik, Vladimir; Huang, Zan; Wang, Ling-Zhi; Lewis, Timothy; An, W. Frank; Li, Xiaoyu; Bray, Mark-Anthony; Thiollier, Clarisse; Diebold, Lauren; Gilles, Laure; Vokes, Martha S.; Moore, Christopher B.; Bliss-Moreau, Meghan; VerPlank, Lynn; Tolliday, Nicola J.; Mishra, Rama; Vemula, Sasidhar; Shi, Jianjian; Wei, Lei; Kapur, Reuben; Lopez, Cécile K.; Gerby, Bastien; Ballerini, Paola; Pflumio, Francoise; Gilliland, D. Gary; Goldberg, Liat; Birger, Yehudit; Izraeli, Shai; Gamis, Alan S.; Smith, Franklin O.; Woods, William G.; Taub, Jeffrey; Scherer, Christina A.; Bradner, James; Goh, Boon-Cher; Mercher, Thomas; Carpenter, Anne E.; Gould, Robert J.; Clemons, Paul A.; Carr, Steven A.; Root, David E.; Schreiber, Stuart L.; Stern, Andrew M.; Crispino, John D.

2012-01-01

Summary The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. We found that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. A broadly applicable, highly integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora A kinase (AURKA), which has not been studied extensively in megakaryocytes. Moreover, we discovered that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in AMKL blasts and displayed potent anti-AMKL activity in vivo. This research provides the rationale to support clinical trials of MLN8237 and other inducers of polyploidization in AMKL. Finally, we have identified five networks of kinases that regulate the switch to polyploidy. PMID:22863010

High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction.

PubMed

Yang, Junyu; Brown, Milton E; Zhang, Hanshuo; Martinez, Mario; Zhao, Zhihua; Bhutani, Srishti; Yin, Shenyi; Trac, David; Xi, Jianzhong Jeff; Davis, Michael E

2017-05-01

Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases. NEW & NOTEWORTHY NADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecules is of great interest. In this study, we used high-throughput screening

Discovery of binding proteins for a protein target using protein-protein docking-based virtual screening.

PubMed

Zhang, Changsheng; Tang, Bo; Wang, Qian; Lai, Luhua

2014-10-01

Target structure-based virtual screening, which employs protein-small molecule docking to identify potential ligands, has been widely used in small-molecule drug discovery. In the present study, we used a protein-protein docking program to identify proteins that bind to a specific target protein. In the testing phase, an all-to-all protein-protein docking run on a large dataset was performed. The three-dimensional rigid docking program SDOCK was used to examine protein-protein docking on all protein pairs in the dataset. Both the binding affinity and features of the binding energy landscape were considered in the scoring function in order to distinguish positive binding pairs from negative binding pairs. Thus, the lowest docking score, the average Z-score, and convergency of the low-score solutions were incorporated in the analysis. The hybrid scoring function was optimized in the all-to-all docking test. The docking method and the hybrid scoring function were then used to screen for proteins that bind to tumor necrosis factor-α (TNFα), which is a well-known therapeutic target for rheumatoid arthritis and other autoimmune diseases. A protein library containing 677 proteins was used for the screen. Proteins with scores among the top 20% were further examined. Sixteen proteins from the top-ranking 67 proteins were selected for experimental study. Two of these proteins showed significant binding to TNFα in an in vitro binding study. The results of the present study demonstrate the power and potential application of protein-protein docking for the discovery of novel binding proteins for specific protein targets. © 2014 Wiley Periodicals, Inc.

Roux-en-Y gastric bypass operation in rats.

PubMed

Bueter, Marco; Abegg, Kathrin; Seyfried, Florian; Lutz, Thomas A; le Roux, Carel W

2012-06-11

Currently, the most effective therapy for the treatment of morbid obesity to induce significant and maintained body weight loss with a proven mortality benefit is bariatric surgery. Consequently, there has been a steady rise in the number of bariatric operations done worldwide in recent years with the Roux-en-Y gastric bypass (gastric bypass) being the most commonly performed operation. Against this background, it is important to understand the physiological mechanisms by which gastric bypass induces and maintains body weight loss. These mechanisms are yet not fully understood, but may include reduced hunger and increased satiation, increased energy expenditure, altered preference for food high in fat and sugar, altered salt and water handling of the kidney as well as alterations in gut microbiota. Such changes seen after gastric bypass may at least partly stem from how the surgery alters the hormonal milieu because gastric bypass increases the postprandial release of peptide-YY (PYY) and glucagon-like-peptide-1 (GLP-1), hormones that are released by the gut in the presence of nutrients and that reduce eating. During the last two decades numerous studies using rats have been carried out to further investigate physiological changes after gastric bypass. The gastric bypass rat model has proven to be a valuable experimental tool not least as it closely mimics the time profile and magnitude of human weight loss, but also allows researchers to control and manipulate critical anatomic and physiologic factors including the use of appropriate controls. Consequently, there is a wide array of rat gastric bypass models available in the literature reviewed elsewhere in more detail. The description of the exact surgical technique of these models varies widely and differs e.g. in terms of pouch size, limb lengths, and the preservation of the vagal nerve. If reported, mortality rates seem to range from 0 to 35%. Furthermore, surgery has been carried out almost exclusively in male

21 CFR 870.4430 - Cardiopulmonary bypass intracardiac suction control.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass intracardiac suction control. 870.4430 Section 870.4430 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND....4430 Cardiopulmonary bypass intracardiac suction control. (a) Identification. A cardiopulmonary bypass...

21 CFR 870.4430 - Cardiopulmonary bypass intracardiac suction control.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass intracardiac suction control. 870.4430 Section 870.4430 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND....4430 Cardiopulmonary bypass intracardiac suction control. (a) Identification. A cardiopulmonary bypass...

Modeling Sediment Bypassing around Rocky Headlands

NASA Astrophysics Data System (ADS)

George, D. A.; Largier, J. L.; Pasternack, G. B.; Erikson, L. H.; Storlazzi, C. D.; Barnard, P.

2016-12-01

Sediment bypassing rocky headlands remains understudied despite the importance of characterizing littoral processes and sediment budgets for erosion abatement, climate change adaptation, and beach management. This study was developed to identify controlling factors on and the mechanisms supporting sediment bypassing. Sediment flux around four idealized rocky headlands was investigated using the hydrodynamic model Delft3D and spectral wave model SWAN. The experimental design involved 120 simulations to explore the influence of headland morphology, substrate composition, sediment grain size, and oceanographic forcing. Headlands represented sizes and shapes found in natural settings, grain sizes ranged from fine to medium sand, and substrates from sandy beds to offshore bedrock reefs. The oceanography included a constructed representative tide, an alongshore background current, and four wave conditions derived from observational records in the eastern Pacific Ocean. A bypassing ratio was developed for alongshore flux between upstream and downstream cross-shore transects to determine the degree of blockage by a headland. Results showed that northwesterly oblique large waves (Hs = 7 m, Tp = 16 s) generated the most flux around headlands, whereas directly incident waves blocked flux across a headland apex. The headland shape heavily influenced the sediment fate by changing the relative angle between the shoreline and the incident waves. The bypassing ratio characterized each headland's capacity to allow alongshore flux under different wave conditions. All headlands may allow flux, although larger ones block sediment more effectively, promoting their ability to be littoral cell boundaries compared to smaller headlands. The controlling factors on sediment bypassing were determined to be wave angle, shape and size of the headland, and sediment grain size. This novel numerical modeling study advances headland modeling from the generic realm to broadly applicable classes of

Simple training tricks for mastering and taming bypass procedures in neurosurgery

PubMed Central

Hafez, Ahmad; Raj, Rahul; Lawton, Michael T.; Niemelä, Mika

2017-01-01

Background: Neurosurgeons devoted to bypass neurosurgery or revascularization neurosurgery are becoming scarcer. From a practical point of view, “bypass neurosurgeons” are anastomosis makers, vessels technicians, and time-racing repairers of vessel walls. This requires understanding the key features and hidden tricks of bypass surgery. The goal of this paper is to provide simple and inexpensive tricks for taming the art of bypass neurosurgery. Most of these tricks and materials described can be borrowed, donated, or purchased inexpensively. Methods: We performed a review of relevant training materials and recorded videos for training bypass procedures for 3 years between June 2014 and July 2017. In total, 1,300 training bypass procedures were performed, of which 200 procedures were chosen for this paper. Results: A training laboratory bypass procedures is required to enable a neurosurgeon to develop the necessary skills. The important skills for training bypass procedures gained through meticulous practice to be as reflexes are coordination, speed, agility, flexibility, and reaction time. Bypassing requires synchronization between the surgeon's gross movements, fine motoric skills, and mental strength. The suturing rhythm must be timed in a brain–body–hand fashion. Conclusion: Bypass-training is a critical part of neurosurgical training and not for a selected few. Diligent and meticulous training can enable every neurosurgeon to tame the art of bypass neurosurgery. This requires understanding the key features and hidden tricks of bypass surgery, as well as uncountable hours of training. In bypass neurosurgery, quality and time goes hand in hand. PMID:29285411

Non-target screening to trace ozonation transformation products in a wastewater treatment train including different post-treatments.

PubMed

Schollée, Jennifer E; Bourgin, Marc; von Gunten, Urs; McArdell, Christa S; Hollender, Juliane

2018-05-25

Ozonation and subsequent post-treatments are increasingly implemented in wastewater treatment plants (WWTPs) for enhanced micropollutant abatement. While this technology is effective, micropollutant oxidation leads to the formation of ozonation transformation products (OTPs). Target and suspect screening provide information about known parent compounds and known OTPs, but for a more comprehensive picture, non-target screening is needed. Here, sampling was conducted at a full-scale WWTP to investigate OTP formation at four ozone doses (2, 3, 4, and 5 mg/L, ranging from 0.3 to 1.0 gO 3 /gDOC) and subsequent changes during five post-treatment steps (i.e., sand filter, fixed bed bioreactor, moving bed bioreactor, and two granular activated carbon (GAC) filters, relatively fresh and pre-loaded). Samples were measured with online solid-phase extraction coupled to liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) using electrospray ionization (ESI) in positive and negative modes. Existing non-target screening workflows were adapted to (1) examine the formation of potential OTPs at four ozone doses and (2) compare the removal of OTPs among five post-treatments. In (1), data processing included principal component analysis (PCA) and chemical knowledge on possible oxidation reactions to prioritize non-target features likely to be OTPs. Between 394 and 1328 unique potential OTPs were detected in positive ESI for the four ozone doses tested; between 12 and 324 unique potential OTPs were detected in negative ESI. At a specific ozone dose of 0.5 gO 3 /gDOC, 27 parent compounds were identified and were related to 69 non-target features selected as potential OTPs. Two OTPs were confirmed with reference standards (venlafaxine N-oxide and chlorothiazide); 34 other potential OTPs were in agreement with literature data and/or reaction mechanisms. In (2), hierarchical cluster analysis (HCA) was applied on profiles detected in positive ESI mode across the

Chemogenomics profiling of drug targets of peptidoglycan biosynthesis pathway in Leptospira interrogans by virtual screening approaches.

PubMed

Bhattacharjee, Biplab; Simon, Rose Mary; Gangadharaiah, Chaithra; Karunakar, Prashantha

2013-06-28

Leptospirosis is a worldwide zoonosis of global concern caused by Leptospira interrogans. The availability of ligand libraries has facilitated the search for novel drug targets using chemogenomics approaches, compared with the traditional method of drug discovery, which is time consuming and yields few leads with little intracellular information for guiding target selection. Recent subtractive genomics studies have revealed the putative drug targets in peptidoglycan biosynthesis pathways in Leptospira interrogans. Aligand library for the murD ligase enzyme in the peptidoglycan pathway has also been identified. Our approach in this research involves screening of the pre-existing ligand library of murD with related protein family members in the putative drug target assembly in the peptidoglycan biosynthesis pathway. A chemogenomics approach has been implemented here, which involves screening of known ligands of a protein family having analogous domain architecture for identification of leads for existing druggable protein family members. By means of this approach, one murC and one murF inhibitor were identified, providing a platform for developing an antileptospirosis drug targeting the peptidoglycan biosynthesis pathway. Given that the peptidoglycan biosynthesis pathway is exclusive to bacteria, the in silico identified mur ligase inhibitors are expected to be broad-spectrum Gram-negative inhibitors if synthesized and tested in in vitro and in vivo assays.

21 CFR 870.4300 - Cardiopulmonary bypass gas control unit.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass gas control unit. 870.4300... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Surgical Devices § 870.4300 Cardiopulmonary bypass gas control unit. (a) Identification. A cardiopulmonary bypass gas control unit is a device used...

21 CFR 870.4300 - Cardiopulmonary bypass gas control unit.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass gas control unit. 870.4300... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Surgical Devices § 870.4300 Cardiopulmonary bypass gas control unit. (a) Identification. A cardiopulmonary bypass gas control unit is a device used...

Bypassing An Open-Circuit Power Cell

NASA Technical Reports Server (NTRS)

Wannemacher, Harry E.

1994-01-01

Collection of bypass circuits enables battery consisting series string of cells to continue to function when one of its cells fails in open-circuit (high-resistance) condition. Basic idea simply to shunt current around defective cell to prevent open circuit from turning off battery altogether. Bypass circuits dissipate little power and are nearly immune to false activation.

Identification of anti-cancer targets of eco-friendly waste Punica granatum peel by dual reverse virtual screening and binding analysis.

PubMed

Usha, Talambedu; Goyal, Arvind Kumar; Lubna, Syed; Prashanth, Hp; Mohan, T Madhan; Pande, Veena; Middha, Sushil Kumar

2014-01-01

Punica granatum (family: Lythraceae) is mainly found in Iran, which is considered to be its primary centre of origin. Studies on pomegranate peel have revealed antioxidant, anti-inflammatory, anti- angiogenesis activities, with prevention of premature aging and reducing inflammation. In addition to this it is also useful in treating various diseases like diabetes, maintaining blood pressure and treatment of neoplasms such as prostate and breast cancer. In this study we identified anti-cancer targets of active compounds like corilagin (tannins), quercetin (flavonoids) and pseudopelletierine (alkaloids) present in pomegranate peel by employing dual reverse screening and binding analysis. The potent targets of the pomegranate peel were annotated by the PharmMapper and ReverseScreen 3D, then compared with targets identified from different Bioassay databases (NPACT and HIT's). Docking was then further employed using AutoDock pyrx and validated through discovery studio for studying molecular interactions. A number of potent anti-cancerous targets were attained from the PharmMapper server according to their fit score and from ReverseScreen 3D server according to decreasing 3D scores. The identified targets now need to be further validated through in vitro and in vivo studies.

Roux-en-Y Gastric Bypass Operation in Rats

PubMed Central

Bueter, Marco; Abegg, Kathrin; Seyfried, Florian; Lutz, Thomas A.; le Roux, Carel W.

2012-01-01

Currently, the most effective therapy for the treatment of morbid obesity to induce significant and maintained body weight loss with a proven mortality benefit is bariatric surgery1,2. Consequently, there has been a steady rise in the number of bariatric operations done worldwide in recent years with the Roux-en-Y gastric bypass (gastric bypass) being the most commonly performed operation3. Against this background, it is important to understand the physiological mechanisms by which gastric bypass induces and maintains body weight loss. These mechanisms are yet not fully understood, but may include reduced hunger and increased satiation4,5, increased energy expenditure6,7, altered preference for food high in fat and sugar8,9, altered salt and water handling of the kidney10 as well as alterations in gut microbiota11. Such changes seen after gastric bypass may at least partly stem from how the surgery alters the hormonal milieu because gastric bypass increases the postprandial release of peptide-YY (PYY) and glucagon-like-peptide-1 (GLP-1), hormones that are released by the gut in the presence of nutrients and that reduce eating12. During the last two decades numerous studies using rats have been carried out to further investigate physiological changes after gastric bypass. The gastric bypass rat model has proven to be a valuable experimental tool not least as it closely mimics the time profile and magnitude of human weight loss, but also allows researchers to control and manipulate critical anatomic and physiologic factors including the use of appropriate controls. Consequently, there is a wide array of rat gastric bypass models available in the literature reviewed elsewhere in more detail 13-15. The description of the exact surgical technique of these models varies widely and differs e.g. in terms of pouch size, limb lengths, and the preservation of the vagal nerve. If reported, mortality rates seem to range from 0 to 35%15. Furthermore, surgery has been carried out

Aortic Arch Aneurysms: Treatment with Extra anatomical Bypass and Endovascular Stent-Grafting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kato, Noriyuki; Shimono, Takatsugu; Hirano, Tadanori

2002-10-15

Endovascular repair of thoracic aortic aneurysms is emerging as an attractive alternative to surgical graft replacement. However,patients with aortic arch aneurysms are often excluded from the target of endovascular repair because of lack of suitable landing zones, especially at the proximal ones. In this paper we describe our method for treating patients with aortic arch aneurysms using a combination of extra anatomical bypass surgery and endovascular stent-grafting.

TS-Chemscore, a Target-Specific Scoring Function, Significantly Improves the Performance of Scoring in Virtual Screening.

PubMed

Wang, Wen-Jing; Huang, Qi; Zou, Jun; Li, Lin-Li; Yang, Sheng-Yong

2015-07-01

Most of the scoring functions currently used in structure-based drug design belong to 'universal' scoring functions, which often give a poor correlation between the calculated scores and experimental binding affinities. In this investigation, we proposed a simple strategy to construct target-specific scoring functions based on known 'universal' scoring functions. This strategy was applied to Chemscore, a widely used empirical scoring function, which led to a new scoring function, termed TS-Chemscore. TS-Chemscore was validated on 14 protein targets, which cover a wide range of biological target categories. The results showed that TS-Chemscore significantly improved the correlation between the calculated scores and experimental binding affinities compared with the original Chemscore. TS-Chemscore was then applied in virtual screening to retrieve novel JAK3 and YopH inhibitors. Top 30 compounds for each target were selected for experimental validation. Six active compounds for JAK3 and four for YopH were obtained. These compounds were out of the lists of top 30 compounds sorted by Chemscore. Collectively, TS-Chemscore established in this study showed a better performance in virtual screening than its counterpart Chemscore. © 2014 John Wiley & Sons A/S.

Phenotypic high-throughput screening elucidates target pathway in breast cancer stem cell-like cells.

PubMed

Carmody, Leigh C; Germain, Andrew R; VerPlank, Lynn; Nag, Partha P; Muñoz, Benito; Perez, Jose R; Palmer, Michelle A J

2012-10-01

Cancer stem cells (CSCs) are resistant to standard cancer treatments and are likely responsible for cancer recurrence, but few therapies target this subpopulation. Due to the difficulty in propagating CSCs outside of the tumor environment, previous work identified CSC-like cells by inducing human breast epithelial cells into an epithelial-to-mesenchymal transdifferentiated state (HMLE_sh_ECad). A phenotypic screen was conducted against HMLE_sh_ECad with 300 718 compounds from the Molecular Libraries Small Molecule Repository to identify selective inhibitors of CSC growth. The screen yielded 2244 hits that were evaluated for toxicity and selectivity toward an isogenic control cell line. An acyl hydrazone scaffold emerged as a potent and selective scaffold targeting HMLE_sh_ECad. Fifty-three analogues were acquired and tested; compounds ranged in potency from 790 nM to inactive against HMLE_sh_ECad. Of the analogues, ML239 was best-in-class with an IC(50)= 1.18 µM against HMLE_sh_ECad, demonstrated a >23-fold selectivity over the control line, and was toxic to another CSC-like line, HMLE_shTwist, and a breast carcinoma cell line, MDA-MB-231. Gene expression studies conducted with ML239-treated cells showed altered gene expression in the NF-κB pathway in the HMLE_sh_ECad line but not in the isogenic control line. Future studies will be directed toward the identification of ML239 target(s).

Pilot validation of an individualised pharmacokinetic algorithm for protamine dosing after systemic heparinisation for cardiopulmonary bypass.

PubMed

Miles, Lachlan F; Marchiori, Paolo; Falter, Florian

2017-09-01

This manuscript represents a pilot study assessing the feasibility of a single-compartment, individualised, pharmacokinetic algorithm for protamine dosing after cardiopulmonary bypass. A pilot cohort study in a specialist NHS cardiothoracic hospital targeting patients undergoing elective cardiac surgery using cardiopulmonary bypass. Patients received protamine doses according to a pharmacokinetic algorithm (n = 30) or using an empirical, fixed-dose model (n = 30). Categorical differences between the groups were evaluated using the Chi-squared test or Fisher's exact test. Continuous data was analysed using a paired Student's t-test for parametric data and the paired samples Wilcoxon test for non-parametric data. Patients who had protamine dosing according to the algorithm demonstrated a lower protamine requirement post-bypass relative to empirical management as measured by absolute dose (243 ± 49mg vs. 305 ± 34.7mg; p<0.001) and the heparin to protamine ratio (0.79 ± 0.12 vs. 1.1 ± 0.15; p<0.001). There was no difference in the pre- to post-bypass activated clotting time (ACT) ratio (1.05 ± 0.12 vs. 1.02 ± 0.15; p=0.9). Patients who received protamine according to the algorithm had no significant difference in transfusion requirement (13.3% vs. 30.0%; p=0.21). This study showed that an individualized pharmacokinetic algorithm for the reversal of heparin after cardiopulmonary bypass is feasible in comparison with a fixed dosing strategy and may reduce the protamine requirement following on-pump cardiac surgery.

Combinatorially Screened Peptide as Targeted Covalent Binder: Alteration of Bait-Conjugated Peptide to Reactive Modifier.

PubMed

Uematsu, Shuta; Tabuchi, Yudai; Ito, Yuji; Taki, Masumi

2018-06-01

A peptide-type covalent binder for a target protein was obtained by combinatorial screening of fluoroprobe-conjugated peptide libraries on bacteriophage T7. The solvatochromic fluoroprobe works as a bait during the affinity selection process of phage display. To obtain the targeted covalent binder, the bait in the selected consensus peptide was altered into a reactive warhead possessing a sulfonyl fluoride. The reaction efficiency and site/position specificity of the covalent conjugation between the binder and the target protein were evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and rationalized by a protein-ligand docking simulation.

Host gene targets for novel influenza therapies elucidated by high-throughput RNA interference screens

PubMed Central

Meliopoulos, Victoria A.; Andersen, Lauren E.; Birrer, Katherine F.; Simpson, Kaylene J.; Lowenthal, John W.; Bean, Andrew G. D.; Stambas, John; Stewart, Cameron R.; Tompkins, S. Mark; van Beusechem, Victor W.; Fraser, Iain; Mhlanga, Musa; Barichievy, Samantha; Smith, Queta; Leake, Devin; Karpilow, Jon; Buck, Amy; Jona, Ghil; Tripp, Ralph A.

2012-01-01

Influenza virus encodes only 11 viral proteins but replicates in a broad range of avian and mammalian species by exploiting host cell functions. Genome-wide RNA interference (RNAi) has proven to be a powerful tool for identifying the host molecules that participate in each step of virus replication. Meta-analysis of findings from genome-wide RNAi screens has shown influenza virus to be dependent on functional nodes in host cell pathways, requiring a wide variety of molecules and cellular proteins for replication. Because rapid evolution of the influenza A viruses persistently complicates the effectiveness of vaccines and therapeutics, a further understanding of the complex host cell pathways coopted by influenza virus for replication may provide new targets and strategies for antiviral therapy. RNAi genome screening technologies together with bioinformatics can provide the ability to rapidly identify specific host factors involved in resistance and susceptibility to influenza virus, allowing for novel disease intervention strategies.—Meliopoulos, V. A., Andersen, L. E., Birrer, K. F., Simpson, K. J., Lowenthal, J. W., Bean, A. G. D., Stambas, J., Stewart, C. R., Tompkins, S. M., van Beusechem, V. W., Fraser, I., Mhlanga, M., Barichievy, S., Smith, Q., Leake, D., Karpilow, J., Buck, A., Jona, G., Tripp, R. A. Host gene targets for novel influenza therapies elucidated by high-throughput RNA interference screens. PMID:22247330

Ultra High Bypass Integrated System Test

NASA Image and Video Library

2015-09-14

NASA’s Environmentally Responsible Aviation Project, in collaboration with the Federal Aviation Administration (FAA) and Pratt & Whitney, completed testing of an Ultra High Bypass Ratio Turbofan Model in the 9’ x 15’ Low Speed Wind Tunnel at NASA Glenn Research Center. The fan model is representative of the next generation of efficient and quiet Ultra High Bypass Ratio Turbofan Engine designs.

Distal anastomotic vein adjunct usage in infrainguinal prosthetic bypasses.

PubMed

McPhee, James T; Goodney, Philip P; Schanzer, Andres; Shaykevich, Shimon; Belkin, Michael; Menard, Matthew T

2013-04-01

). The DVA group had a higher rate of completion angiogram performed (55.7% vs 37.5%; P =.002) and were more likely to be discharged on coumadin (53.4% vs 37.1%; P =.01). By multivariable analysis, use of a distal DVA was protective against MALEs (hazard ratio, 0.36; 95% confidence interval, 0.14-0.90; P = .03). This contemporary multi-institutional propensity-matched study demonstrates that patients that receive distal anastomotic vein adjuncts as part of infrainguinal prosthetic bypass operations in general have more extreme comorbidities and more technically challenging operations based on level of target vessel and prior bypass attempts. After propensity-matched analysis, the use of a DVA may protect against MALEs in prosthetic bypass surgery and should be considered when feasible. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Coronary Artery Bypass

MedlinePlus

... 000 procedures performed each year in the United States. Arteries can become clogged over time by the buildup of fatty plaque. Bypass surgery improves the blood flow to the heart with a new route or “ ...

Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem

PubMed Central

Lim, Hansaim; Gray, Paul; Xie, Lei; Poleksic, Aleksandar

2016-01-01

Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design. PMID:27958331

Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem.

PubMed

Lim, Hansaim; Gray, Paul; Xie, Lei; Poleksic, Aleksandar

2016-12-13

Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design.

Predicting target vessel location on robot-assisted coronary artery bypass graft using CT to ultrasound registration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, Daniel S.; Linte, Cristian; Chen, Elvis C. S.

Purpose: Although robot-assisted coronary artery bypass grafting (RA-CABG) has gained more acceptance worldwide, its success still depends on the surgeon's experience and expertise, and the conversion rate to full sternotomy is in the order of 15%-25%. One of the reasons for conversion is poor pre-operative planning, which is based solely on pre-operative computed tomography (CT) images. In this paper, the authors propose a technique to estimate the global peri-operative displacement of the heart and to predict the intra-operative target vessel location, validated via both an in vitro and a clinical study. Methods: As the peri-operative heart migration during RA-CABG hasmore » never been reported in the literatures, a simple in vitro validation study was conducted using a heart phantom. To mimic the clinical workflow, a pre-operative CT as well as peri-operative ultrasound images at three different stages in the procedure (Stage{sub 0}--following intubation; Stage{sub 1}--following lung deflation; and Stage{sub 2}--following thoracic insufflation) were acquired during the experiment. Following image acquisition, a rigid-body registration using iterative closest point algorithm with the robust estimator was employed to map the pre-operative stage to each of the peri-operative ones, to estimate the heart migration and predict the peri-operative target vessel location. Moreover, a clinical validation of this technique was conducted using offline patient data, where a Monte Carlo simulation was used to overcome the limitations arising due to the invisibility of the target vessel in the peri-operative ultrasound images. Results: For the in vitro study, the computed target registration error (TRE) at Stage{sub 0}, Stage{sub 1}, and Stage{sub 2} was 2.1, 3.3, and 2.6 mm, respectively. According to the offline clinical validation study, the maximum TRE at the left anterior descending (LAD) coronary artery was 4.1 mm at Stage{sub 0}, 5.1 mm at Stage{sub 1}, and 3.4 mm at

Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei

DOE Office of Scientific and Technical Information (OSTI.GOV)

Begley, Darren W.; Hartley, Robert C.; Davies, Douglas R.

As part of the Seattle Structural Genomics Center for Infectious Disease, we seek to enhance structural genomics with ligand-bound structure data which can serve as a blueprint for structure-based drug design. We have adapted fragment-based screening methods to our structural genomics pipeline to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms. In this study, we report fragment screening methods and structure determination results for 2C-methyl-D-erythritol-2,4-cyclo-diphosphate (MECP) synthase from Burkholderia pseudomallei, the gram-negative bacterium which causes melioidosis. Screening by nuclear magnetic resonance spectroscopy as well as crystal soaking followed by X-ray diffraction led to the identification ofmore » several small molecules which bind this enzyme in a critical metabolic pathway. A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site. These ligand-bound structures now serve to guide medicinal chemists and structural biologists in rational design of novel inhibitors for this enzyme.« less

Bypass diode for a solar cell

DOEpatents

Rim, Seung Bum [Palo Alto, CA; Kim, Taeseok [San Jose, CA; Smith, David D [Campbell, CA; Cousins, Peter J [Menlo Park, CA

2012-03-13

Bypass diodes for solar cells are described. In one embodiment, a bypass diode for a solar cell includes a substrate of the solar cell. A first conductive region is disposed above the substrate, the first conductive region of a first conductivity type. A second conductive region is disposed on the first conductive region, the second conductive region of a second conductivity type opposite the first conductivity type.

The impact of nurse-driven targeted HIV screening in 8 emergency departments: study protocol for the DICI-VIH cluster-randomized two-period crossover trial.

PubMed

Leblanc, Judith; Rousseau, Alexandra; Hejblum, Gilles; Durand-Zaleski, Isabelle; de Truchis, Pierre; Lert, France; Costagliola, Dominique; Simon, Tabassome; Crémieux, Anne-Claude

2016-02-01

In 2010, to reduce late HIV diagnosis, the French national health agency endorsed non-targeted HIV screening in health care settings. Despite these recommendations, non-targeted screening has not been implemented and only physician-directed diagnostic testing is currently performed. A survey conducted in 2010 in 29 French Emergency Departments (EDs) showed that non-targeted nurse-driven screening was feasible though only a few new HIV diagnoses were identified, predominantly among high-risk groups. A strategy targeting high-risk groups combined with current practice could be shown to be feasible, more efficient and cost-effective than current practice alone. DICI-VIH (acronym for nurse-driven targeted HIV screening) is a multicentre, cluster-randomized, two-period crossover trial. The primary objective is to compare the effectiveness of 2 strategies for diagnosing HIV among adult patients visiting EDs: nurse-driven targeted HIV screening combined with current practice (physician-directed diagnostic testing) versus current practice alone. Main secondary objectives are to compare access to specialist consultation and how early HIV diagnosis occurs in the course of the disease between the 2 groups, and to evaluate the implementation, acceptability and cost-effectiveness of nurse-driven targeted screening. The 2 strategies take place during 2 randomly assigned periods in 8 EDs of metropolitan Paris, where 42 % of France's new HIV patients are diagnosed every year. All patients aged 18 to 64, not presenting secondary to HIV exposure are included. During the intervention period, patients are invited to fill a 7-item questionnaire (country of birth, sexual partners and injection drug use) in order to select individuals who are offered a rapid test. If the rapid test is reactive, a follow-up visit with an infectious disease specialist is scheduled within 72 h. Assuming an 80 % statistical power and a 5 % type 1 error, with 1.04 and 3.38 new diagnoses per 10,000 patients in

Smart Plasmonic Glucose Nanosensors as Generic Theranostic Agents for Targeting-Free Cancer Cell Screening and Killing.

PubMed

Chen, Limei; Li, Haijuan; He, Haili; Wu, Haoxi; Jin, Yongdong

2015-07-07

Fast and accurate identification of cancer cells from healthy normal cells in a simple, generic way is very crucial for early cancer detection and treatment. Although functional nanoparticles, like fluorescent quantum dots and plasmonic Au nanoparticles (NPs), have been successfully applied for cancer cell imaging and photothermal therapy, they suffer from the main drawback of needing time-consuming targeting preparation for specific cancer cell detection and selective ablation. The lack of a generic and effective method therefore limits their potential high-throughput cancer cell preliminary screening and theranostic applications. We report herein a generic in vitro method for fast, targeting-free (avoiding time-consuming preparations of targeting moiety for specific cancer cells) visual screening and selective killing of cancer cells from normal cells, by using glucose-responsive/-sensitive glucose oxidase-modified Ag/Au nanoshells (Ag/Au-GOx NSs) as a smart plasmonic theranostic agent. The method is generic to some extent since it is based on the distinct localized surface plasmon resonance (LSPR) responses (and colors) of the smart nanoprobe with cancer cells (typically have a higher glucose uptake level) and normal cells.

Recent Progress of Bypass Surgery to the Dialysis-Dependent Patients with Critical Limb Ischemia

PubMed Central

Azuma, Nobuyoshi; Kikuchi, Shinsuke; Okuda, Hiroko; Miyake, Keisuke; Koya, Atsuhiro

2017-01-01

According to expansion of dialysis-dependent population, more than half of patients with critical ischemic limbs are dialysis-dependent in Japan. Although patients with end-staged renal disease are well-known as poor life prognosis, well-managed dialysis patients in Japan can survive much longer compared to dialysis patients in the United States and Europe. Therefore, some dialysis patients can enjoy the long-term benefits of bypass surgery. To decide the indication of bypass surgery, patient’s general condition, nutrition status, and vein availability are more important rather than arterial disease anatomy. Ultrasound guided nerve block anesthesia blocking both sciatic and femoral nerve is contributing greatly to quick postoperative recovery of high risk patients. Preoperative ultrasound examination also contribute to not only vein mapping but also find out the graftable segment of artery. The selection of distal target should be decided based on the degree of arterial disease (luminal surface as well as wall calcification), and arterial run-off. Several tips regarding anastomosis to heavily calcified artery have been established including how to create bloodless operative field without arterial clamps. Adequate wound management after bypass surgery is also important. Detection of deep infection such as osteomyelitis and the adequate treatment may avoid major amputation of salvageable limbs. In the era of endovascular treatment, the evidences guiding how to select dialysis patients suitable for bypass surgery are awaiting. (This is a translation of Jpn J Vasc Surg 2017; 26: 33–39.) PMID:29147171

Suspect screening of OH-PAHs and non-target screening of other organic compounds in wood smoke particles using HR-Orbitrap-MS.

PubMed

Avagyan, Rozanna; Åberg, Magnus; Westerholm, Roger

2016-11-01

Wood combustion has been shown to contribute significantly to emissions of polycyclic aromatic hydrocarbons and hydroxylated polycyclic aromatic hydrocarbons, compounds with toxic and carcinogenic properties. However, only a small number of hydroxylated polycyclic aromatic hydrocarbons have been determined in particles from wood combustion, usually compounds with available reference standards. In this present study, suspect and non-target screening strategies were applied to characterize the wood smoke particles from four different wood types and two combustion conditions with respect to hydroxylated polycyclic aromatic hydrocarbons and other organic compounds. In the suspect screening, 32 peaks corresponding to 12 monohydroxylated masses were tentatively identified by elemental composition assignments and matching of isotopic pattern and fragments. More than one structure was suggested for most of the measured masses. Statistical analysis was performed on the non-target screening data in order to single out significant peaks having intensities that depend on the wood type and/or combustion condition. Significant peaks were found in both negative and positive ionization modes, with unique peaks for each wood type and combustion condition, as well as a combination of both factors. Furthermore, structural elucidation of some peaks was done by comparing the spectra in the samples with spectra found in the spectral databases. Six compounds were tentatively identified in positive ionization mode, and 19 in negative ionization mode. The results in this present study demonstrate that there are significant overall differences in the chemistry of wood smoke particles that depends on both the wood type and the combustion condition used. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets.

PubMed

Krastev, Dragomir B; Pettitt, Stephen J; Campbell, James; Song, Feifei; Tanos, Barbara E; Stoynov, Stoyno S; Ashworth, Alan; Lord, Christopher J

2018-05-22

Poly (ADP-ribose)ylation is a dynamic protein modification that regulates multiple cellular processes. Here, we describe a system for identifying and characterizing PARylation events that exploits the ability of a PBZ (PAR-binding zinc finger) protein domain to bind PAR with high-affinity. By linking PBZ domains to bimolecular fluorescent complementation biosensors, we developed fluorescent PAR biosensors that allow the detection of temporal and spatial PARylation events in live cells. Exploiting transposon-mediated recombination, we integrate the PAR biosensor en masse into thousands of protein coding genes in living cells. Using these PAR-biosensor "tagged" cells in a genetic screen we carry out a large-scale identification of PARylation targets. This identifies CTIF (CBP80/CBP20-dependent translation initiation factor) as a novel PARylation target of the tankyrase enzymes in the centrosomal region of cells, which plays a role in the distribution of the centrosomal satellites.

Passage of downstream migrant American eels through an airlift-assisted deep bypass

USGS Publications Warehouse

Haro, Alexander J.; Watten, Barnaby J.; Noreika, John

2016-01-01

Traditional downstream guidance and bypass facilities for anadromous fishes (i.e., surface bypasses, surface guidance structures, and behavioral barriers) have frequently been ineffective for anguillid eels. Because eels typically spend the majority of their time near the bottom in the vicinity of intake structures, deep bypass structures with entrances near the bottom hold promise for increased effectiveness, thereby aiding in the recovery of this important species. A new design of a deep bypass system that uses airlift technology (the Conte Airlift Bypass) to induce flow in a bypass pipe was tested in a simulated intake entrance environment under controlled laboratory conditions. Water velocities of 0.9–1.5 m s−1 could be generated at the bypass entrance (opening with 0.073 m2 area), with corresponding flows through the bypass pipe of 0.07–0.11 m3 s−1. Gas saturation and hydrostatic pressure within the bypass pipe did not vary appreciably from a control (no air) condition under tested airflows. Migratory silver-phase American eels (Anguilla rostrata) tested during dark conditions readily located, entered, and passed through the bypass; initial avoidance rates (eels approaching but not entering the bypass entrance) were lower at higher entrance velocities. Eels that investigated the bypass pipe entrance tended to enter headfirst, but those that then exited the pipe upstream did so more frequently at lower entrance velocities. Eels appeared to swim against the flow while being transported downstream through the pipe; median transit times through the bypass for each test velocity ranged from 5.8 to 12.2 s, with transit time decreasing with increasing entrance velocity. Eels did not show strong avoidance of the vertical section of the pipe which contained injected air. No mortality or injury of bypassed eels was observed, and individual eels repeatedly passed through the bypass at rates of up to 40 passes per hour, suggesting that individuals do not

Coronary Artery Bypass Surgery: MedlinePlus Health Topic

MedlinePlus

... Coronary Artery Bypass (Texas Heart Institute) Also in Spanish Coronary Artery Bypass Graft Surgery (Beyond the Basics) ( ... Radiology, Radiological Society of North America) Also in Spanish Living With Cardiac Rehabilitation: MedlinePlus Health Topic (National ...

NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds

PubMed Central

Yu, Jun-lan; Chen, Tian-tian; Zhou, Chen; Lian, Fu-lin; Tang, Xu-long; Wen, Yi; Shen, Jing-kang; Xu, Ye-chun; Xiong, Bing; Zhang, Nai-xia

2016-01-01

Aim: Fragment-based lead discovery (FBLD) is a complementary approach in drug research and development. In this study, we established an NMR-based FBLD platform that was used to screen novel scaffolds targeting human bromodomain of BRD4, and investigated the binding interactions between hit compounds and the target protein. Methods: 1D NMR techniques were primarily used to generate the fragment library and to screen compounds. The inhibitory activity of hits on the first bromodomain of BRD4 [BRD4(I)] was examined using fluorescence anisotropy binding assay. 2D NMR and X-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. Results: An NMR-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8–10 compounds in each group). Eight hits with new scaffolds were found to inhibit BRD4(I). Four out of the 8 hits (compounds 1, 2, 8 and 9) had IC50 values of 100–260 μmol/L, demonstrating their potential for further BRD4-targeted hit-to-lead optimization. Analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to BRD4(I) in a non-acetylated lysine mimetic mode. Conclusion: An NMR-based platform for FBLD was established and used in discovery of BRD4-targeted compounds. Four potential hit-to-lead optimization candidates have been found, two of them bound to BRD4(I) in a non-acetylated lysine mimetic mode, being selective BRD4(I) inhibitors. PMID:27238211

A multiplex degenerate PCR analytical approach targeting to eight genes for screening GMOs.

PubMed

Guo, Jinchao; Chen, Lili; Liu, Xin; Gao, Ying; Zhang, Dabing; Yang, Litao

2012-06-01

Currently, the detection methods with lower cost and higher throughput are the major trend in screening genetically modified (GM) food or feed before specific identification. In this study, we developed a quadruplex degenerate PCR screening approach for more than 90 approved GMO events. This assay is consisted of four PCR systems targeting on nine DNA sequences from eight trait genes widely introduced into GMOs, such as CP4-EPSPS derived from Acetobacterium tumefaciens sp. strain CP4, phosphinothricin acetyltransferase gene derived from Streptomyceshygroscopicus (bar) and Streptomyces viridochromogenes (pat), and Cry1Ab, Cry1Ac, Cry1A(b/c), mCry3A, and Cry3Bb1 derived from Bacillus thuringiensis. The quadruplex degenerate PCR assay offers high specificity and sensitivity with the absolute limit of detection (LOD) of approximate 80targetcopies. Furthermore, the applicability of the quadruplex PCR assay was confirmed by screening either several artificially prepared samples or samples of Grain Inspection, Packers and Stockyards Administration (GIPSA) proficiency program. Copyright © 2011 Elsevier Ltd. All rights reserved.

21 CFR 870.4370 - Roller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Roller-type cardiopulmonary bypass blood pump. 870... Roller-type cardiopulmonary bypass blood pump. (a) Identification. A roller-type cardiopulmonary bypass blood pump is a device that uses a revolving roller mechanism to pump the blood through the...

21 CFR 870.4360 - Nonroller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Nonroller-type cardiopulmonary bypass blood pump... Nonroller-type cardiopulmonary bypass blood pump. (a) Identification. A nonroller-type cardiopulmonary bypass blood pump is a device that uses a method other than revolving rollers to pump the blood through...

21 CFR 870.4360 - Nonroller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Nonroller-type cardiopulmonary bypass blood pump... Nonroller-type cardiopulmonary bypass blood pump. (a) Identification. A nonroller-type cardiopulmonary bypass blood pump is a device that uses a method other than revolving rollers to pump the blood through...

21 CFR 870.4370 - Roller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Roller-type cardiopulmonary bypass blood pump. 870... Roller-type cardiopulmonary bypass blood pump. (a) Identification. A roller-type cardiopulmonary bypass blood pump is a device that uses a revolving roller mechanism to pump the blood through the...

21 CFR 870.4370 - Roller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Roller-type cardiopulmonary bypass blood pump. 870... Roller-type cardiopulmonary bypass blood pump. (a) Identification. A roller-type cardiopulmonary bypass blood pump is a device that uses a revolving roller mechanism to pump the blood through the...

21 CFR 870.4370 - Roller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Roller-type cardiopulmonary bypass blood pump. 870... Roller-type cardiopulmonary bypass blood pump. (a) Identification. A roller-type cardiopulmonary bypass blood pump is a device that uses a revolving roller mechanism to pump the blood through the...

21 CFR 870.4360 - Nonroller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Nonroller-type cardiopulmonary bypass blood pump... Nonroller-type cardiopulmonary bypass blood pump. (a) Identification. A nonroller-type cardiopulmonary bypass blood pump is a device that uses a method other than revolving rollers to pump the blood through...

21 CFR 870.4370 - Roller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Roller-type cardiopulmonary bypass blood pump. 870... Roller-type cardiopulmonary bypass blood pump. (a) Identification. A roller-type cardiopulmonary bypass blood pump is a device that uses a revolving roller mechanism to pump the blood through the...

21 CFR 870.4360 - Nonroller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Nonroller-type cardiopulmonary bypass blood pump... Nonroller-type cardiopulmonary bypass blood pump. (a) Identification. A nonroller-type cardiopulmonary bypass blood pump is a device that uses a method other than revolving rollers to pump the blood through...

21 CFR 870.4360 - Nonroller-type cardiopulmonary bypass blood pump.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Nonroller-type cardiopulmonary bypass blood pump... Nonroller-type cardiopulmonary bypass blood pump. (a) Identification. A nonroller-type cardiopulmonary bypass blood pump is a device that uses a method other than revolving rollers to pump the blood through...

21 CFR 870.4260 - Cardiopulmonary bypass arterial line blood filter.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass arterial line blood filter... Cardiopulmonary bypass arterial line blood filter. (a) Identification. A cardiopulmonary bypass arterial line blood filter is a device used as part of a gas exchange (oxygenator) system to filter nonbiologic...

21 CFR 870.4260 - Cardiopulmonary bypass arterial line blood filter.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass arterial line blood filter... Cardiopulmonary bypass arterial line blood filter. (a) Identification. A cardiopulmonary bypass arterial line blood filter is a device used as part of a gas exchange (oxygenator) system to filter nonbiologic...

21 CFR 870.4260 - Cardiopulmonary bypass arterial line blood filter.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass arterial line blood filter... Cardiopulmonary bypass arterial line blood filter. (a) Identification. A cardiopulmonary bypass arterial line blood filter is a device used as part of a gas exchange (oxygenator) system to filter nonbiologic...

21 CFR 870.4260 - Cardiopulmonary bypass arterial line blood filter.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass arterial line blood filter... Cardiopulmonary bypass arterial line blood filter. (a) Identification. A cardiopulmonary bypass arterial line blood filter is a device used as part of a gas exchange (oxygenator) system to filter nonbiologic...

21 CFR 870.4260 - Cardiopulmonary bypass arterial line blood filter.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass arterial line blood filter... Cardiopulmonary bypass arterial line blood filter. (a) Identification. A cardiopulmonary bypass arterial line blood filter is a device used as part of a gas exchange (oxygenator) system to filter nonbiologic...

Feasibility and safety of minimized cardiopulmonary bypass in major aortic surgery

PubMed Central

Momin, Aziz U.; Sharabiani, Mansour T. A.; Kidher, Emadin; Najefi, Ali; Mulholland, John W.; Reeves, Barnaby C.; Angelini, Gianni D.; Anderson, Jon R.

2013-01-01

OBJECTIVES Conventional cardiopulmonary bypass causes haemodilution and is a trigger of systemic inflammatory reactions, coagulopathy and organ failure. Miniaturized cardiopulmonary bypass has been proposed as a way to reduce these deleterious effects of conventional cardiopulmonary bypass and to promote a more physiological state. The use of miniaturized cardiopulmonary bypass has been reported in low-risk patients undergoing valve and coronary artery bypass graft (CABG) surgery. However, little is known about its application in major aortic surgery. METHODS From February 2007 to September 2010, 49 patients underwent major aortic surgery using the Hammersmith miniaturized cardiopulmonary bypass (ECCO, Sorin). Data were extracted from medical records to characterize preoperative comorbidities (EuroSCORE), perioperative complications and the use of blood products. The same data were collected and described for 328 consecutive patients having similar surgery with conventional cardiopulmonary bypass at the Bristol Heart Institute, our twinned centre, during the same period. RESULTS The miniaturized cardiopulmonary bypass group had a median EuroSCORE of 8 [inter-quartile range (IQR): 5–11], 13% had preoperative renal dysfunction and 20% of operations were classified as emergency or salvage. Thirty-day mortalities were 6.4; and 69, 67 and 74% had ≥1 unit of red cells, fresh frozen plasma (FFP) and platelets transfused, respectively. Eight percent of patients experienced a renal complication, and 8% a neurological complication. The conventional cardiopulmonary bypass group was similar, with a EuroSCORE of 8 (IQR: 6–10); 30-day mortalities were 9.4; and 68, 62 and 74% had ≥1 unit of red cells, FFP and platelets transfused, respectively. The proportions experiencing renal and neurological complications were 14 and 5%. CONCLUSIONS Our experience suggests that miniaturized cardiopulmonary bypass is safe and feasible for use in major aortic cardiac surgery. A

21 CFR 870.4220 - Cardiopulmonary bypass heart-lung machine console.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass heart-lung machine console... Cardiopulmonary bypass heart-lung machine console. (a) Identification. A cardiopulmonary bypass heart-lung machine... heart-lung machine. The console is designed to interface with the basic units used in a gas exchange...

21 CFR 870.4220 - Cardiopulmonary bypass heart-lung machine console.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass heart-lung machine console... Cardiopulmonary bypass heart-lung machine console. (a) Identification. A cardiopulmonary bypass heart-lung machine... heart-lung machine. The console is designed to interface with the basic units used in a gas exchange...

21 CFR 870.4220 - Cardiopulmonary bypass heart-lung machine console.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass heart-lung machine console... Cardiopulmonary bypass heart-lung machine console. (a) Identification. A cardiopulmonary bypass heart-lung machine... heart-lung machine. The console is designed to interface with the basic units used in a gas exchange...

21 CFR 870.4220 - Cardiopulmonary bypass heart-lung machine console.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass heart-lung machine console... Cardiopulmonary bypass heart-lung machine console. (a) Identification. A cardiopulmonary bypass heart-lung machine... heart-lung machine. The console is designed to interface with the basic units used in a gas exchange...

21 CFR 870.4220 - Cardiopulmonary bypass heart-lung machine console.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass heart-lung machine console... Cardiopulmonary bypass heart-lung machine console. (a) Identification. A cardiopulmonary bypass heart-lung machine... heart-lung machine. The console is designed to interface with the basic units used in a gas exchange...

Contrast MR of the brain after high-perfusion cardiopulmonary bypass

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simonson, T.M.; Yuh, W.T.C.; Hindman, B.J.

1994-01-01

To study the efficacy of contrast MR imaging in the evaluation of central nervous system complications in the cardiopulmonary bypass patient and attempt to explain their pathophysiology based on the MR appearance and the cardiopulmonary bypass protocol. Nineteen patients were prospectively studied with contrast MR examinations the day before and 3 to 7 days after cardiopulmonary bypass, to determine the nature, extent, and number of new postoperative MR abnormalities. Cardiopulmonary bypass parameters used in our institution included: membrane oxygenation, arterial filtration with a pore size of 25 [mu]m, and a relatively high perfusion rate to produce a cardiac index ofmore » 2.0 to 2.5 L min per m[sup 2]. The preoperative noncontrast MR examination showed age-related changes and/or signs of ischemia in 60% of patients on the day before surgery. However, there was no abnormal enhancement or new T2 abnormalities on any postoperative MR examination to suggest hypoperfusion or emboli. None of the 19 patients developed overt neurologic deficits postoperatively. Review of the cardiopulmonary bypass protocol used indicated significant variations in technique at different institutions. Contrast MR imaging demonstrated no new abnormalities in patients after cardiopulmonary bypass performed with strict in-line arterial filtration and relatively high perfusion. MR imaging is feasible in the early postoperative period after cardiopulmonary bypass and may offer a convenient method for evaluation of the neurologic impact of technical factors associated with cardiopulmonary bypass. 17 refs.« less

Li-Ion Battery By-Pass Removal Qualification

NASA Astrophysics Data System (ADS)

Borthomieu, Y.; Pasquier, E.

2005-05-01

The reasons of the by-pass use on Space batteries is to avoid open circuit, short-circuit and dramatic performances drift on the power system. By-pass diodes are currently used in NiH2 batteries due to the high probability of open circuit at cell level. This probability is mainly linked to the possibility to have a hydrogen leak within the pressure vessel due to the high operating pressure (70 bars) that can induce cell open circuit.For the Lithium-Ion batteries, first items had bypass implemented by similarity, but:All the cell failure cases have been analyzed at battery level:- Cell Open circuit:In contrast to NiCd and NiH2 cells, Li-Ion cells can be put in parallel due to the fact the open circuit voltage (OCV) is linked to the State Of Charge (SOC).With cells in parallel, a battery open circuit failure can never be encountered even with a cell in open circuit.- Cell Short circuit:In case of cell short, the entire cells within the module will be shorted.- Cell capacity spread:If the capacities of cells in series are strongly diverging, the worst module limits the battery. In case the battery is no more able to deliver the requested power for which it was designed, the worst module has to be reversed. In reversal, a Li-Ion cell is self-shorted. So, the strong capacity decrease in one module leads to the short of this module.These three failure cases cover all the possible Li-Ion failure root causes.Considering these three events, the analysis demonstrates that the Li-Ion battery still functions in any case without any by-pass system because the design of the battery size always takes into account the loss of one module.Nevertheless, the by-pass removal should allow to:- Improve the battery reliability as each bypass unit represents a single - Reduce by at least 30 % of the total price of the battery,- Reduce significant weight at battery level,- Shorten the battery manufacturing lead time (at least8 months for by-pass purchasing), - Avoid US export licenses

Attenuating the Systemic Inflammatory Response to Adult Cardiopulmonary Bypass: A Critical Review of the Evidence Base

PubMed Central

Landis, R. Clive; Brown, Jeremiah R.; Fitzgerald, David; Likosky, Donald S.; Shore-Lesserson, Linda; Baker, Robert A.; Hammon, John W.

2014-01-01

Abstract: A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically based review exists to cover the scope of anti-inflammatory interventions deployed. We therefore conducted an evidence-based review to capture “self-identified” anti-inflammatory interventions among adult cardiopulmonary bypass procedures. To be included, trials had to measure at least one inflammatory mediator and one clinical outcome, specified in the “Outcomes 2010” consensus statement. Ninety-eight papers satisfied inclusion criteria and formed the basis of the review. The review identified 33 different interventions and approaches to attenuate the systemic inflammatory response. However, only a minority of papers (35 of 98 [35.7%]) demonstrated any clinical improvement to one or more of the predefined outcome measures (most frequently myocardial protection or length of intensive care unit stay). No single intervention was supported by strong level A evidence (multiple randomized controlled trials [RCTs] or meta-analysis) for clinical benefit. Interventions at level A evidence included off-pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions at level B evidence (single RCT) for minimizing inflammation included nitric oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl-L-carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These observations are consistent with a “multiple hit” hypothesis, whereby clinically effective suppression of the systemic inflammatory response

Alterations of sucrose preference after Roux-en-Y gastric bypass.

PubMed

Bueter, M; Miras, A D; Chichger, H; Fenske, W; Ghatei, M A; Bloom, S R; Unwin, R J; Lutz, T A; Spector, A C; le Roux, C W

2011-10-24

Roux-en-Y gastric bypass (gastric bypass) patients reportedly have changes in perception and consumption of sweet-tasting foods. This study aimed to further investigate alterations in sweet food intake in rats and sucrose detection in humans after gastric bypass. Wistar rats were randomized to gastric bypass or sham-operations and preference for sucrose (sweet), sodium chloride (salty), citric acid (sour) and quinine hydrochloride (bitter) was assessed with standard two-bottle intake tests (vs. water). Intestinal T1R2 and T1R3 expression and plasma levels of glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) were measured. Furthermore, obese patients and normal weight controls were tested for sucrose taste detection thresholds pre- and postoperatively. Visual analogue scales measuring hedonic perception were used to determine the sucrose concentration considered by patients and controls as "just about right" pre- and postoperatively. Gastric bypass reduced the sucrose intake relative to water in rats (p<0.001). Preoperative sucrose exposure reduced this effect. Preference or aversion for compounds representative of other taste qualities in naïve rats remained unaffected. Intestinal T1R2 and T1R3 expression was significantly decreased in the alimentary limb while plasma levels of GLP-1 and PYY were elevated after bypass in rats (p=0.01). Bypass patients showed increased taste sensitivity to low sucrose concentrations compared with controls (p<0.05), but both groups considered the same sucrose concentration as "just about right" postoperatively. In conclusion, gastric bypass reduces sucrose intake relative to water in sucrose-naïve rats, but preoperative sucrose experience attenuates this effect. Changes in sucrose taste detection do not predict hedonic taste ratings of sucrose in bypass patients which remain unchanged. Thus, factors other than the unconditional affective value of the taste may also play a role in determining food preferences after gastric bypass

The impact of Relative Prevalence on dual-target search for threat items from airport X-ray screening.

PubMed

Godwin, Hayward J; Menneer, Tamaryn; Cave, Kyle R; Helman, Shaun; Way, Rachael L; Donnelly, Nick

2010-05-01

The probability of target presentation in visual search tasks influences target detection performance: this is known as the prevalence effect (Wolfe et al., 2005). Additionally, searching for several targets simultaneously reduces search performance: this is known as the dual-target cost (DTC: Menneer et al., 2007). The interaction between the DTC and prevalence effect was investigated in a single study by presenting one target in dual-target search at a higher level of prevalence than the other target (Target A: 45% Prevalence; Target B: 5% Prevalence). An overall DTC was found for both RTs and response accuracy. Furthermore, there was an effect of target prevalence in dual-target search, suggesting that, when one target is presented at a higher level of prevalence than the other, both the dual-target cost and the prevalence effect contribute to decrements in performance. The implications for airport X-ray screening are discussed. Copyright 2010 Elsevier B.V. All rights reserved.

International variation in the prevalence of preclinical colorectal cancer: Implications for predictive values of noninvasive screening tests and potential target populations for screening

PubMed Central

Stock, Christian; Brenner, Hermann

2017-01-01

Screening for colorectal cancer (CRC) is implemented in an increasing number of countries. We aimed to assess international variation in the prevalence of preclinical CRC and the resulting variation in positive and negative predictive values (PPVs, NPVs) of existing and potential CRC screening tests in various countries. Using age‐ and sex‐specific CRC incidence data and transition rates from preclinical to clinical CRC we estimated overall and age‐ and sex‐specific prevalence of preclinical CRC in the target population aged 50–74 years in different parts of the world. These prevalence estimates were used to derive PPVs and NPVs for existing and potential noninvasive screening tests with varying levels of sensitivity and specificity. Within all regions and countries, prevalence strongly increases with age and is higher in men than in women. In addition, major variation was seen between regions and countries, with overall prevalence varying between 1 and 0.1%. As a result, PPVs are expected to strongly vary between ∼10% for men in high incidence countries, such as Australia and Germany, and 1% for women in low incidence countries, whereas NPVs are expected to be consistently well above 99%. Variation in CRC prevalence profoundly affects expected PPVs of screening tests, and PPVs should be carefully considered when decisions on screening tests and strategies are made for specific populations and health care systems. Here, we provide estimates of preclinical CRC and expected PPVs and NPVs of noninvasive screening tests, which may enhance the empirical basis for planning of population‐based CRC screening strategies. PMID:28670788

Target discovery of cytotoxic withanolides from Physalis angulata var. villosa via reactivity-based screening.

PubMed

Zhang, Yi; Chen, Chen; Zhang, Ya-Long; Kong, Ling-Yi; Luo, Jian-Guang

2018-03-20

The reactivity-based screening (RBS) was developed for directed discovery of cytotoxic withanolides. In this study, a thiol probe, 4-chlorobenzenethiol, was used to selectively attack cytotoxic withanolides containing potential pharmacophore, 2(3)-en-1-one in ring A (AEO) and 5β,6β-epoxy in ring B (BE), from the plant extract of Physalis angulata var. villosa. The screening was performed based on the potential mechanism of 4-chlorobenzenethiol nucleophilic addition to AEO, followed by detection of adducts using liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-Q-TOF-MS). Guided by RBS, eleven target withanolides, including five new compounds, physagulides R-V (10-14) and six known ones (2, 7-9, 15, 16) were discovered. All of them exhibited cytotoxicity against the both tested cell lines, especially, compounds 2, 7, 8 and 14 showed potent activities with IC 50 values of 1.57-6.29 μM. The results suggested that RBS was efficient and accurate for rapid identification of cytotoxic withanolides and could guide isolation of target components from the complex medicinal plant extract. Copyright © 2018 Elsevier B.V. All rights reserved.

Intractable Electrical Storm After Coronary Artery Bypass Grafting Originating in Abnormal Purkinje Fibers.

PubMed

Tokunaga, Chiho; Tsukada, Toru; Sakamoto, Hiroaki; Naruse, Yoshihisa; Yoshida, Kentaro; Sekiguchi, Yukio; Imai, Akito; Aonuma, Kazutaka; Hiramatsu, Yuji

2016-01-01

Electrical storm is a rare but critical complication following revascularization in patients with ischemic heart disease. We report the case of a 67-year-old man who developed drug refractory intractable electrical storm after emergent coronary artery bypass grafting for ischemic cardiomyopathy. The electrical storm was successfully eliminated by percutaneous endocardial radiofrequency catheter ablation targeting the abnormal Purkinje-related triggering ventricular premature contractions in a low-voltage zone. © 2015 Wiley Periodicals, Inc.

Performance evaluation of structure based and ligand based virtual screening methods on ten selected anti-cancer targets.

PubMed

Ramasamy, Thilagavathi; Selvam, Chelliah

2015-10-15

Virtual screening has become an important tool in drug discovery process. Structure based and ligand based approaches are generally used in virtual screening process. To date, several benchmark sets for evaluating the performance of the virtual screening tool are available. In this study, our aim is to compare the performance of both structure based and ligand based virtual screening methods. Ten anti-cancer targets and their corresponding benchmark sets from 'Demanding Evaluation Kits for Objective In silico Screening' (DEKOIS) library were selected. X-ray crystal structures of protein-ligand complexes were selected based on their resolution. Openeye tools such as FRED, vROCS were used and the results were carefully analyzed. At EF1%, vROCS produced better results but at EF5% and EF10%, both FRED and ROCS produced almost similar results. It was noticed that the enrichment factor values were decreased while going from EF1% to EF5% and EF10% in many cases. Published by Elsevier Ltd.

Are patients bypassing paediatric cardiology outreach clinics?

PubMed

Fletcher, Alexander; Samson, Ray; McLeod, Karen

2017-07-01

Previous studies have identified that receiving specialist care close to home can positively influence patients' experience. Despite this, a review of cardiology outpatient appointments at the Royal Hospital for Children in Glasgow demonstrated that a large number of families are bypassing their local children's cardiology centre to attend cardiac clinics at the specialist children's surgical centre. We used patient questionnaire, audit of local facilities, and examined the relationship between diagnosis and bypass numbers to better understand factors influencing this trend. Our results suggest that patient preference, short travelling distance to specialist children's cardiac centre, a more severe cardiac diagnosis, and inconsistent local facilities, expertise, and support are likely to influence a family's decision to bypass their local children's cardiology centre.

Hyperammonemic syndrome after Roux-en-Y gastric bypass.

PubMed

Fenves, Andrew Z; Shchelochkov, Oleg A; Mehta, Ankit

2015-04-01

Hyperammonemic encephalopathy is an uncommon but severe complication of the Roux-en-Y gastric bypass surgery for obesity. Mechanisms underlying this complication are incompletely understood, resulting in delayed recognition and management. This study evaluated common laboratory findings and possible etiology of hyperammonemic encephalopathy after successful Roux-en-Y gastric bypass surgery. A retrospective review of 20 patients identified through our own clinical practice was conducted, with the addition of similar cases from other institutions identified through the review of literature. Patients presenting with hyperammonemic encephalopathy after Roux-en-Y gastric bypass surgery presented with overlapping clinical and laboratory findings. Common features included: (1) weight loss following successful Roux-en-Y gastric bypass for obesity; (2) hyperammonemic encephalopathy accompanied by elevated plasma glutamine levels; (3) absence of cirrhosis; (4) hypoalbuminemia; and (5) low plasma zinc levels. The mortality rate was 50%. Ninety-five percent of patients were women. Three patients were diagnosed with proximal urea cycle disorders. One patient experienced improvement in the hyperammonemia after surgical correction of spontaneous splenorenal shunt. Hyperammonemic encephalopathy after Roux-en-Y gastric bypass surgery is a newly recognized, potentially fatal syndrome with diverse pathophysiologic mechanisms encompassing genetic and nongenetic causes. © 2015 The Obesity Society.

Screening of missing proteins in the human liver proteome by improved MRM-approach-based targeted proteomics.

PubMed

Chen, Chen; Liu, Xiaohui; Zheng, Weimin; Zhang, Lei; Yao, Jun; Yang, Pengyuan

2014-04-04

To completely annotate the human genome, the task of identifying and characterizing proteins that currently lack mass spectrometry (MS) evidence is inevitable and urgent. In this study, as the first effort to screen missing proteins in large scale, we developed an approach based on SDS-PAGE followed by liquid chromatography-multiple reaction monitoring (LC-MRM), for screening of those missing proteins with only a single peptide hit in the previous liver proteome data set. Proteins extracted from normal human liver were separated in SDS-PAGE and digested in split gel slice, and the resulting digests were then subjected to LC-schedule MRM analysis. The MRM assays were developed through synthesized crude peptides for target peptides. In total, the expressions of 57 target proteins were confirmed from 185 MRM assays in normal human liver tissues. Among the proved 57 one-hit wonders, 50 proteins are of the minimally redundant set in the PeptideAtlas database, 7 proteins even have none MS-based information previously in various biological processes. We conclude that our SDS-PAGE-MRM workflow can be a powerful approach to screen missing or poorly characterized proteins in different samples and to provide their quantity if detected. The MRM raw data have been uploaded to ISB/SRM Atlas/PASSEL (PXD000648).

Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits.

PubMed

Blaazer, Antoni R; Orrling, Kristina M; Shanmugham, Anitha; Jansen, Chimed; Maes, Louis; Edink, Ewald; Sterk, Geert Jan; Siderius, Marco; England, Paul; Bailey, David; de Esch, Iwan J P; Leurs, Rob

2015-01-01

Methods to discover biologically active small molecules include target-based and phenotypic screening approaches. One of the main difficulties in drug discovery is elucidating and exploiting the relationship between drug activity at the protein target and disease modification, a phenotypic endpoint. Fragment-based drug discovery is a target-based approach that typically involves the screening of a relatively small number of fragment-like (molecular weight <300) molecules that efficiently cover chemical space. Here, we report a fragment screening on TbrPDEB1, an essential cyclic nucleotide phosphodiesterase (PDE) from Trypanosoma brucei, and human PDE4D, an off-target, in a workflow in which fragment hits and a series of close analogs are subsequently screened for antiparasitic activity in a phenotypic panel. The phenotypic panel contained T. brucei, Trypanosoma cruzi, Leishmania infantum, and Plasmodium falciparum, the causative agents of human African trypanosomiasis (sleeping sickness), Chagas disease, leishmaniasis, and malaria, respectively, as well as MRC-5 human lung cells. This hybrid screening workflow has resulted in the discovery of various benzhydryl ethers with antiprotozoal activity and low toxicity, representing interesting starting points for further antiparasitic optimization. © 2014 Society for Laboratory Automation and Screening.

Simultaneous screening of targeted and non-targeted contaminants using an LC-QTOF-MS system and automated MS/MS library searching.

PubMed

Herrera-Lopez, S; Hernando, M D; García-Calvo, E; Fernández-Alba, A R; Ulaszewska, M M

2014-09-01

Simultaneous high-resolution full-scan and tandem mass spectrometry (MS/MS) analysis using time of flight mass spectrometry brings an answer for increasing demand of retrospective and non-targeted data analysis. Such analysis combined with spectral library searching is a promising tool for targeted and untargeted screening of small molecules. Despite considerable extension of the panel of compounds of tandem mass spectral libraries, the heterogeneity of spectral data poses a major challenge against the effective usage of spectral libraries. Performance evaluation of available LC-MS/MS libraries will significantly increase credibility in the search results. The present work was aimed to evaluate fluctuation of MS/MS pattern, in the peak intensities distribution together with mass accuracy measurements, and in consequence, performance compliant with ion ratio and mass error criteria as principles in identification processes for targeted and untargeted contaminants at trace levels. Matrix effect and ultra-trace levels of concentration (from 50 ng l(-1) to 1000 ng l(-1) were evaluated as potential source of inaccuracy in the performance of spectral matching. Matrix-matched samples and real samples were screened for proof of applicability. By manual review of data and application of ion ratio and ppm error criteria, false negatives were obtained; this number diminished when in-house library was used, while with on-line MS/MS databases 100% of positive samples were found. In our experience, intensity of peaks across spectra was highly correlated to the concentration effect and matrix complexity. In turn, analysis of spectra acquired at trace concentrations and in different matrices results in better performance in providing correct and reliable identification. Copyright © 2014 John Wiley & Sons, Ltd.

Preservation of myocardium during coronary artery bypass surgery.

PubMed

Kinoshita, Takeshi; Asai, Tohru

2012-08-01

Myocardial protection aims to prevent reversible post-ischemic cardiac dysfunction (myocardial stunning) and irreversible myocardial cell death (myocardial infarction) that occur as a consequence of myocardial ischemia and/or ischemic-reperfusion injury. Although the mortality rate for isolated coronary artery bypass grafting has been markedly reduced during the past decade, myocardial death, as evidenced by elevation in creatine kinase-myocardial band and/or cardiac troponin, is common. This is ascribed to suboptimal myocardial protection during cardiopulmonary bypass or with off-pump technique, early graft failure, distal embolization, and regional or global myocardial ischemia during surgery. An unmet need in contemporary coronary bypass surgery is to find more effective cardioprotective strategies that have the potential for decreasing the morbidity and mortality associated with suboptimal cardioprotection. In the present review article on myocardial protection in contemporary coronary artery bypass surgery, we attempt to elucidate the clinical problems, summarize the outcomes of selected phase III trials, and introduce new perspectives.

Screening of phytochemicals against protease activated receptor 1 (PAR1), a promising target for cancer.

PubMed

Kakarala, Kavita Kumari; Jamil, Kaiser

2015-02-01

Drug resistance and drug-associated toxicity are the primary causes for withdrawal of many drugs, although patient recovery is satisfactory in many instances. Interestingly, the use of phytochemicals in the treatment of cancer as an alternative to synthetic drugs comes with a host of advantages; minimum side effects, good human absorption and low toxicity to normal cells. Protease activated receptor 1 (PAR1) has been established as a promising target in many diseases including various cancers. Strong evidences suggest its role in metastasis also. There are no natural compounds known to inhibit its activity, so we aimed to identify phytochemicals with antagonist activity against PAR1. We screened phytochemicals from Naturally Occurring Plant-based Anticancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/ ) against PAR1 using virtual screening workflow of Schrödinger software. It analyzes pharmaceutically relevant properties using Qikprop and calculates binding energy using Glide at three accuracy levels (high-throughput virtual screening, standard precision and extra precision). Our study led to the identification of phytochemicals, which showed interaction with at least one experimentally determined active site residue of PAR1, showed no violations to Lipinski's rule of five along with predicted high human absorption. Furthermore, structural interaction fingerprint analysis indicated that the residues H255, D256, E260, S344, V257, L258, L262, Y337 and S344 may play an important role in the hydrogen bond interactions of the phytochemicals screened. Of these residues, H255 and L258 residues were experimentally proved to be important for antagonist binding. The residues Y183, L237, L258, L262, F271, L332, L333, Y337, L340, A349, Y350, A352, and Y353 showed maximum hydrophobic interactions with the phytochemicals screened. The results of this work suggest that phytochemicals Reissantins D, 24,25-dihydro-27-desoxywithaferin A, Isoguaiacin

The Lung Screen Uptake Trial (LSUT): protocol for a randomised controlled demonstration lung cancer screening pilot testing a targeted invitation strategy for high risk and 'hard-to-reach' patients.

PubMed

Quaife, Samantha L; Ruparel, Mamta; Beeken, Rebecca J; McEwen, Andy; Isitt, John; Nolan, Gary; Sennett, Karen; Baldwin, David R; Duffy, Stephen W; Janes, Samuel M; Wardle, Jane

2016-04-20

Participation in low-dose CT (LDCT) lung cancer screening offered in the trial context has been poor, especially among smokers from socioeconomically deprived backgrounds; a group for whom the risk-benefit ratio is improved due to their high risk of lung cancer. Attracting high risk participants is essential to the success and equity of any future screening programme. This study will investigate whether the observed low and biased uptake of screening can be improved using a targeted invitation strategy. A randomised controlled trial design will be used to test whether targeted invitation materials are effective at improving engagement with an offer of lung cancer screening for high risk candidates. Two thousand patients aged 60-75 and recorded as a smoker within the last five years by their GP, will be identified from primary care records and individually randomised to receive either intervention invitation materials (which take a targeted, stepped and low burden approach to information provision prior to the appointment) or control invitation materials. The primary outcome is uptake of a nurse-led 'lung health check' hospital appointment, during which patients will be offered a spirometry test, an exhaled carbon monoxide (CO) reading, and an LDCT if eligible. Initial data on demographics (i.e. age, sex, ethnicity, deprivation score) and smoking status will be collected in primary care and analysed to explore differences between attenders and non-attenders with respect to invitation group. Those who attend the lung health check will have further data on smoking collected during their appointment (including pack-year history, nicotine dependence and confidence to quit). Secondary outcomes will include willingness to be screened, uptake of LDCT and measures of informed decision-making to ensure the latter is not compromised by either invitation strategy. If effective at improving informed uptake of screening and reducing bias in participation, this invitation

Laparoscopic Band-Separated One Anastomosis Gastric Bypass.

PubMed

Ospanov, Oral B

2016-09-01

This video demonstrates laparoscopic band-separated one anastomosis gastric bypass-combining the advantages of banding and gastric bypass without stapler and cutter use. This is basically a gastrojejunal loop bypass above an obstructive band in the upper stomach. An adjustable low pressure "Medsil" gastric band was introduced in the abdomen and retracted through the retrogastric tunnel. The front wall of the stomach below the band was displaced in the upward direction through the ring band, increasing the size of the anterior portion of the stomach pouch so that a gastroenteroanastomosis could be created at this point. Gastro-gastric sutures were placed to create a gastro-gastric plication around the band and hold it in position. The band tubing was exteriorized and connected to a special port, which was secured to the abdominal wall fascia. A jejunal loop was created about 200 cm from the ligament of Treitz and anastomosed to the gastric pouch by hand using Vicryl 2/0 sutures. Between November 2015 and February 2016, the study was performed on 10 patients. The average operating time for all cases was 75 min (range 63-87). There was no morbidity or mortality. No complications were observed, including band erosion and band infection. Operation costs were about $2000 lower with this method than with standard gastric bypass surgery. Postop the patients lost weight by 3-4 kg per month. Preliminary results show that laparoscopic band-separated one anastomosis gastric bypass have feasibility, safety, efficacy, and reduced operating costs.

21 CFR 870.4290 - Cardiopulmonary bypass adaptor, stopcock, manifold, or fitting.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass adaptor, stopcock, manifold... Devices § 870.4290 Cardiopulmonary bypass adaptor, stopcock, manifold, or fitting. (a) Identification. A cardiopulmonary bypass adaptor, stopcock, manifold, or fitting is a device used in cardiovascular diagnostic...

21 CFR 870.4290 - Cardiopulmonary bypass adaptor, stopcock, manifold, or fitting.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass adaptor, stopcock, manifold... Devices § 870.4290 Cardiopulmonary bypass adaptor, stopcock, manifold, or fitting. (a) Identification. A cardiopulmonary bypass adaptor, stopcock, manifold, or fitting is a device used in cardiovascular diagnostic...

Resurrection of the in situ saphenous vein bypass. 1000 cases later.

PubMed Central

Leather, R P; Shah, D M; Chang, B B; Kaufman, J L

1988-01-01

Distal bypasses for the terminal stages of atherosclerotic occlusive disease manifest by chronic limb-threatening ischemia are among the most challenging arterial reconstructive procedures of surgeons today. The length and low flow rates of distal bypasses often exceed the functional limits of synthetic and even free vein grafts. However, the saphenous vein, when used in situ, provides a unique, viable, physiologically active, and hence antithrombogenic endothelial flow surface that is ideally suited for such bypasses. This paper presents the experience of the Albany Medical Center Hospital with the first 1000 in situ bypasses performed by the valve incision method over a 12-year period. Limb-threatening ischemia was the most common indication for surgery (91%). An in situ bypass was attempted in over 95% of unselected limbs and were completed in situ and in toto in 94%. 66% of the bypasses were carried out to the infrapopliteal level, and in more than 50% of the limbs, the distal vein diameter was less than 3.5 mm. The 30-day patency rate was 95%, and the cumulative patency rates, by life table analysis at 1, 2, 3, 4, and 5 years, were 90%, 86%, 84%, 80%, and 76%, respectively. The vein diameter, specific outflow vessel, level of distal anastomosis (length of bypass), inguinal inflow source used, and instrumental evolution had no significant effect on immediate or long-term bypass performance. PMID:3178331

20 CFR 631.18 - Federal by-pass authority.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Federal by-pass authority. 631.18 Section 631.18 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR PROGRAMS UNDER... Secretary's intent to exercise by-pass authority and an opportunity to request and to receive a hearing...

Sodium thiopental and mean arterial pressure during cardiopulmonary bypass.

PubMed

Dabbagh, Ali; Rajaei, Samira; Ahani, Mohammad Reza

2011-06-01

Sodium thiopental is known to have a number of cardiovascular effects, but injection into the cardiopulmonary bypass reservoir has not been studied. The effect of sodium thiopental on mean arterial blood pressure during cardiopulmonary bypass was assessed in 150 patients undergoing elective coronary artery bypass grafting. Sodium thiopental 3 mg · kg(-1) was administered via the cardiopulmonary bypass reservoir. Mean arterial pressure was recorded just before drug administration and at 15-sec intervals up to 120 sec afterwards. Compared to the baseline value, mean arterial pressure was significantly higher at 30, 45, 60, and 75 sec after drug administration, and it was significantly lower at 90, 105, and 120 sec. Sodium thiopental, in addition to its effects on myocardial tissue, acts initially as a potent vasopressor, and shortly after, as a potent vasodilator.

A Phenotypic Based Target Screening Approach Delivers New Antitubercular CTP Synthetase Inhibitors.

PubMed

Esposito, Marta; Szadocka, Sára; Degiacomi, Giulia; Orena, Beatrice S; Mori, Giorgia; Piano, Valentina; Boldrin, Francesca; Zemanová, Júlia; Huszár, Stanislav; Barros, David; Ekins, Sean; Lelièvre, Joel; Manganelli, Riccardo; Mattevi, Andrea; Pasca, Maria Rosalia; Riccardi, Giovanna; Ballell, Lluis; Mikušová, Katarína; Chiarelli, Laurent R

2017-06-09

Despite its great potential, the target-based approach has been mostly unsuccessful in tuberculosis drug discovery, while whole cell phenotypic screening has delivered several active compounds. However, for many of these hits, the cellular target has not yet been identified, thus preventing further target-based optimization of the compounds. In this context, the newly validated drug target CTP synthetase PyrG was exploited to assess a target-based approach of already known, but untargeted, antimycobacterial compounds. To this purpose the publically available GlaxoSmithKline antimycobacterial compound set was assayed, uncovering a series of 4-(pyridin-2-yl)thiazole derivatives which efficiently inhibit the Mycobacterium tuberculosis PyrG enzyme activity, one of them showing low activity against the human CTP synthetase. The three best compounds were ATP binding site competitive inhibitors, with K i values ranging from 3 to 20 μM, but did not show any activity against a small panel of different prokaryotic and eukaryotic kinases, thus demonstrating specificity for the CTP synthetases. Metabolic labeling experiments demonstrated that the compounds directly interfere not only with CTP biosynthesis, but also with other CTP dependent biochemical pathways, such as lipid biosynthesis. Moreover, using a M. tuberculosis pyrG conditional knock-down strain, it was shown that the activity of two compounds is dependent on the intracellular concentration of the CTP synthetase. All these results strongly suggest a role of PyrG as a target of these compounds, thus strengthening the value of this kind of approach for the identification of new scaffolds for drug development.

21 CFR 870.4210 - Cardiopulmonary bypass vascular catheter, cannula, or tubing.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass vascular catheter, cannula... Devices § 870.4210 Cardiopulmonary bypass vascular catheter, cannula, or tubing. (a) Identification. A cardiopulmonary bypass vascular catheter, cannula, or tubing is a device used in cardiopulmonary surgery to...

21 CFR 870.4210 - Cardiopulmonary bypass vascular catheter, cannula, or tubing.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass vascular catheter, cannula... Devices § 870.4210 Cardiopulmonary bypass vascular catheter, cannula, or tubing. (a) Identification. A cardiopulmonary bypass vascular catheter, cannula, or tubing is a device used in cardiopulmonary surgery to...

Generation of an arrayed CRISPR-Cas9 library targeting epigenetic regulators: from high-content screens to in vivo assays

PubMed Central

2017-01-01

ABSTRACT The CRISPR-Cas9 system has revolutionized genome engineering, allowing precise modification of DNA in various organisms. The most popular method for conducting CRISPR-based functional screens involves the use of pooled lentiviral libraries in selection screens coupled with next-generation sequencing. Screens employing genome-scale pooled small guide RNA (sgRNA) libraries are demanding, particularly when complex assays are used. Furthermore, pooled libraries are not suitable for microscopy-based high-content screens or for systematic interrogation of protein function. To overcome these limitations and exploit CRISPR-based technologies to comprehensively investigate epigenetic mechanisms, we have generated a focused sgRNA library targeting 450 epigenetic regulators with multiple sgRNAs in human cells. The lentiviral library is available both in an arrayed and pooled format and allows temporally-controlled induction of gene knock-out. Characterization of the library showed high editing activity of most sgRNAs and efficient knock-out at the protein level in polyclonal populations. The sgRNA library can be used for both selection and high-content screens, as well as for targeted investigation of selected proteins without requiring isolation of knock-out clones. Using a variety of functional assays we show that the library is suitable for both in vitro and in vivo applications, representing a unique resource to study epigenetic mechanisms in physiological and pathological conditions. PMID:29327641

Abdominal Pain After Roux-En-Y Gastric Bypass for Morbid Obesity.

PubMed

Mala, Tom; Høgestøl, Ingvild

2018-05-01

Roux-en-Y gastric bypass is widely used as treatment of morbid obesity. Weight loss, effects on obesity-related co-morbidities and quality of life are well documented post Roux-en-Y gastric bypass. Other outcome measures are less well studied. This review explores aspects of prevalence, diagnostic evaluations, etiology, and treatment of abdominal pain specific to Roux-en-Y gastric bypass. The review is based on PubMed searches and clinical experience with Roux-en-Y gastric bypass. Symptoms in the early postoperative phase (<30 days) were not included. Based on limited evidence, up to about 30% of the patients may perceive recurrent abdominal pain post Roux-en-Y gastric bypass in the long term. A substantial subset of patients will need health-care evaluation for acute abdominal pain and hospital admission. The etiology of abdominal pain is heterogeneous and includes gallstone-related disease, intestinal obstruction, anastomotic ulcerations and strictures, intestinal dysmotility, dysfunctional eating, and food intolerance. Surgical treatment and guidance on diet and eating habits may allow symptom relief. The cause of pain remains undefined for a subset of patients. Impact of abdominal pain post Roux-en-Y gastric bypass on the perception of well-being, quality of life, and patient satisfaction with the procedure needs to be further evaluated and may be influenced by complex interactions between new symptoms post Roux-en-Y gastric bypass and relief of pre-existing symptoms. Abdominal pain should be part of follow-up consultations post Roux-en-Y gastric bypass. Future studies should focus on combined evaluations before and after surgery to enlighten potential casual relationships between abdominal pain and Roux-en-Y gastric bypass.

Pre-test CFD Calculations for a Bypass Flow Standard Problem

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rich Johnson

The bypass flow in a prismatic high temperature gas-cooled reactor (HTGR) is the flow that occurs between adjacent graphite blocks. Gaps exist between blocks due to variances in their manufacture and installation and because of the expansion and shrinkage of the blocks from heating and irradiation. Although the temperature of fuel compacts and graphite is sensitive to the presence of bypass flow, there is great uncertainty in the level and effects of the bypass flow. The Next Generation Nuclear Plant (NGNP) program at the Idaho National Laboratory has undertaken to produce experimental data of isothermal bypass flow between three adjacentmore » graphite blocks. These data are intended to provide validation for computational fluid dynamic (CFD) analyses of the bypass flow. Such validation data sets are called Standard Problems in the nuclear safety analysis field. Details of the experimental apparatus as well as several pre-test calculations of the bypass flow are provided. Pre-test calculations are useful in examining the nature of the flow and to see if there are any problems associated with the flow and its measurement. The apparatus is designed to be able to provide three different gap widths in the vertical direction (the direction of the normal coolant flow) and two gap widths in the horizontal direction. It is expected that the vertical bypass flow will range from laminar to transitional to turbulent flow for the different gap widths that will be available.« less

A new approach to data evaluation in the non-target screening of organic trace substances in water analysis.

PubMed

Müller, Alexander; Schulz, Wolfgang; Ruck, Wolfgang K L; Weber, Walter H

2011-11-01

Non-target screening via high performance liquid chromatography-mass spectrometry (HPLC-MS) has gained increasingly in importance for monitoring organic trace substances in water resources targeted for the production of drinking water. In this article a new approach for evaluating the data from non-target HPLC-MS screening in water is introduced and its advantages are demonstrated using the supply of drinking water as an example. The crucial difference between this and other approaches is the comparison of samples based on compounds (features) determined by their full scan data. In so doing, we take advantage of the temporal, spatial, or process-based relationships among the samples by applying the set operators, UNION, INTERSECT, and COMPLEMENT to the features of each sample. This approach regards all compounds, detectable by the used analytical method. That is the fundamental meaning of non-target screening, which includes all analytical information from the applied technique for further data evaluation. In the given example, in just one step, all detected features (1729) of a landfill leachate sample could be examined for their relevant influences on water purification respectively drinking water. This study shows that 1721 out of 1729 features were not relevant for the water purification. Only eight features could be determined in the untreated water and three of them were found in the final drinking water after ozonation. In so doing, it was possible to identify 1-adamantylamine as contamination of the landfill in the drinking water at a concentration in the range of 20 ng L(-1). To support the identification of relevant compounds and their transformation products, the DAIOS database (Database-Assisted Identification of Organic Substances) was used. This database concept includes some functions such as product ion search to increase the efficiency of the database query after the screening. To identify related transformation products the database function

Monsanto may bypass NIH in microbe test.

PubMed

Sun, Marjorie

1985-01-11

The Monsanto Company is planning to ask the Environmental Protection Agency for clearance to field test a genetically engineered microbial pesticide, bypassing the traditional approval process of the National Institutes of Health. Although only federally funded institutions are required to obtain NIH approval for genetic engineering tests, Monsanto is the first company to bypass the NIH regulatory process, which has become mired in a lawsuit brought by Jeremy Rifkin.

Narrative message targets within the decision-making process to undergo screening colonoscopy among Latinos: a qualitative study.

PubMed

Hennelly, Marie Oliva; Sly, Jamilia R; Villagra, Cristina; Jandorf, Lina

2015-06-01

Colorectal cancer (CRC) is a preventable yet leading cause of cancer mortality among Latinos in the USA. Cultural targeting and narrative messaging are two strategies to increase the low screening colonoscopy rates among Latinos. This study identifies key messages for educational interventions aiming to increase screening colonoscopy used among Latinos and proposes a model to understand the relationship between factors involved in colonoscopy decision-making. Individual in-depth interviews were conducted with 12 Latino participants primarily of Puerto Rican descent on the topics of CRC knowledge, barriers and facilitators to colonoscopy use, and the use of narrative in colorectal health messaging. Knowledge about colorectal anatomy and the anesthesia component of colonoscopy procedure is low. Fear of procedure-related pain and fear of treatment-related burden following a cancer diagnosis are significant barriers to colonoscopy. Fear of disease-related suffering and death following a cancer diagnosis and fear of regret are strong facilitators and can be augmented by cancer narratives. Storytelling is commonly used in Latino culture and is an acceptable method to educate the Latino community about CRC screening via colonoscopy. Machismo is a unique barrier to colonoscopy for Latino men via homophobia and reluctance to seek healthcare. A preliminary model to understand factors in colonoscopy decision-making among Latinos is presented. Counseling practices and educational interventions that use culturally targeted narrative health messaging to mediate fears and increase colonoscopy knowledge may increase screening colonoscopy use among Latinos.

Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools.

PubMed

Sugumar, Ramya; Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, Padmavathi Kannan

2016-03-01

Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski's Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the

Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools

PubMed Central

Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, Padmavathi Kannan

2016-01-01

Introduction Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. Aim To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. Materials and Methods The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski’s Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. Results Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin

Mitosis Is a Source of Potential Markers for Screening and Survival and Therapeutic Targets in Cervical Cancer

PubMed Central

Espinosa, Ana María; Alfaro, Ana; Roman-Basaure, Edgar; Guardado-Estrada, Mariano; Palma, Ícela; Serralde, Cyntia; Medina, Ingrid; Juárez, Eligia; Bermúdez, Miriam; Márquez, Edna; Borges-Ibáñez, Manuel; Muñoz-Cortez, Sergio; Alcántara-Vázquez, Avissai; Alonso, Patricia; Curiel-Valdez, José; Kofman, Susana; Villegas, Nicolas; Berumen, Jaime

2013-01-01

The effect of preventive human papillomavirus (HPV) vaccination on the reduction of the cervical cancer (CC) burden will not be known for 30 years. Therefore, it’s still necessary to improve the procedures for CC screening and treatment. The objective of this study was to identify and characterize cellular targets that could be considered potential markers for screening or therapeutic targets. A pyramidal strategy was used. Initially the expression of 8,638 genes was compared between 43 HPV16-positive CCs and 12 healthy cervical epitheliums using microarrays. A total of 997 genes were deregulated, and 21 genes that showed the greatest deregulation were validated using qRT-PCR. The 6 most upregulated genes (CCNB2, CDC20, PRC1, SYCP2, NUSAP1, CDKN3) belong to the mitosis pathway. They were further explored in 29 low-grade cervical intraepithelial neoplasias (CIN1) and 21 high-grade CIN (CIN2/3) to investigate whether they could differentiate CC and CIN2/3 (CIN2+) from CIN1 and controls. CCNB2, PRC1, and SYCP2 were mostly associated with CC and CDC20, NUSAP1, and CDKN3 were also associated with CIN2/3. The sensitivity and specificity of CDKN3 and NUSAP1 to detect CIN2+ was approximately 90%. The proteins encoded by all 6 genes were shown upregulated in CC by immunohistochemistry. The association of these markers with survival was investigated in 42 CC patients followed up for at least 42 months. Only CDKN3 was associated with poor survival and it was independent from clinical stage (HR = 5.9, 95%CI = 1.4–23.8, p = 0.01). CDKN3 and NUSAP1 may be potential targets for the development of screening methods. Nevertheless, further studies with larger samples are needed to define the optimal sensitivity and specificity. Inhibition of mitosis is a well-known strategy to combat cancers. Therefore, CDKN3 may be not only a screening and survival marker but a potential therapeutic target in CC. However, whether it’s indispensable for tumor growth remains to be

Prior failed ipsilateral percutaneous endovascular intervention in patients with critical limb ischemia predicts poor outcome after lower extremity bypass

PubMed Central

Nolan, Brian W.; De Martino, Randall R.; Stone, David H.; Schanzer, Andres; Goodney, Philip P.; Walsh, Daniel W.; Cronenwett, Jack L.

2017-01-01

had a prior ipsilateral bypass (1 year major amputation, 29% vs 20%; P = .022; 1 year graft occlusion, 33% vs 18%; P = .001). Independent multivariate predictors of higher 1-year amputation and graft occlusion rates were prior iPVI, prior ipsilateral bypass, dialysis dependence, prosthetic conduit and distal (tibial and pedal) bypass target. Conclusions Prior iPVI is highly predictive for poor outcome in patients undergoing LEB for CLI with higher 1-year amputation and graft occlusion rates than those without prior revascularization, similar to prior ipsilateral bypass These findings provide information, which may help with the complex decisions surrounding revascularization options in patients with CLI. PMID:21802888

An Experimental Design of Bypass Magneto-Rheological (MR) damper

NASA Astrophysics Data System (ADS)

Rashid, MM; Aziz, Mohammad Abdul; Raisuddin Khan, Md.

2017-11-01

The magnetorheological (MR) fluid bypass damper fluid flow through a bypass by utilizing an external channel which allows the controllability of MR fluid in the channel. The Bypass MR damper (BMRD) contains a rectangular bypass flow channel, current controlled movable piston shaft arrangement and MR fluid. The static piston coil case is winding by a coil which is used inside the piston head arrangement. The current controlled coil case provides a magnetic flux through the BMRD cylinder for controllability. The high strength of alloy steel materials are used for making piston shaft which allows magnetic flux propagation throughout the BMRD cylinder. Using the above design materials, a Bypass MR damper is designed and tested. An excitation of current is applied during the experiment which characterizes the BMRD controllability. It is shown that the BMRD with external flow channel allows a high controllable damping force using an excitation current. The experimental result of damping force-displacement characteristics with current excitation and without current excitation are compared in this research. The BMRD model is validated by the experimental result at various frequencies and applied excitation current.

Aortocoronary bypass in Jehovah's Witnesses: review of 46 patients.

PubMed

Sandiford, F M

1976-01-01

The hemodilution technique for cardiopulmonary bypass using blood substitutes for priming has permitted open heart operations in Jehovah's Witnesses who refuse to accept blood, and has reduced the need for massive blood transfusion in certain procedures including aortocoronary bypass. A series of 46 Jehovah's Witness patients underwent aortocoronary bypass procedures. Of these, two patients died, representing a mortality of 4.3 per cent. Neither patient's death was related to lack of blood transfusions. The hospital stay and recovery time of all the other patients was not affected by failure to transfuse blood. The excellent short- and long-term results of this particular group paralleled those observed in our larger series of over 2700 other patients who have undergone coronary bypass surgery since 1969. Among these patients not of the Jehovah's Witness religion, blood transfusion was not necessary in about 30 per cent, while the remainder averaged less than two units per patient. Our results with Jehovah's Witness patients encourage our policy of avoiding blood transfusions whenever possible in all operations. Further justification for our conservative attitude is provided by the current shortage of blood in relation to a projected continuous increase of aortocoronary bypass procedures in the future.

Gain versus loss-framed messaging and colorectal cancer screening among African Americans: A preliminary examination of perceived racism and culturally targeted dual messaging.

PubMed

Lucas, Todd; Hayman, Lenwood W; Blessman, James E; Asabigi, Kanzoni; Novak, Julie M

2016-05-01

This preliminary study examined the effect of gain versus loss-framed messaging as well as culturally targeted personal prevention messaging on African Americans' receptivity to colorectal cancer (CRC) screening. This research also examined mechanistic functions of perceived racism in response to message framing. Community samples of African Americans (N = 132) and White Americans (N = 50) who were non-compliant with recommended CRC screening completed an online education module about CRC, and were either exposed to a gain-framed or loss-framed message about CRC screening. Half of African Americans were exposed to an additional and culturally targeted self-control message about personal prevention of CRC. Theory of planned behavior measures of attitudes, normative beliefs, perceived behavioural control, and intentions to obtain a CRC screen served as primary outcomes. The effect of messaging on perceived racism was also measured as an outcome. Consistent with prior research, White Americans were more receptive to CRC screening when exposed to a loss-framed message. However, African Americans were more receptive when exposed to a gain-framed message. The contrary effect of loss-framed messaging on receptivity to screening among African Americans was mediated by an increase in perceived racism. However, including an additional and culturally targeted prevention message mitigated the adverse effect of a loss-framed message. This study identifies an important potential cultural difference in the effect of message framing on illness screening among African Americans, while also suggesting a culturally relevant linking mechanism. This study also suggests the potential for simultaneously presented and culturally targeted messaging to alter the effects of gain and loss-framed messaging on African Americans. What is already known on this subject? African Americans are at an increased risk of both developing and dying from colorectal cancer (CRC). These disparities can be

Long-term results of in situ saphenous vein bypass. Analysis of 2058 cases.

PubMed Central

Shah, D M; Darling, R C; Chang, B B; Fitzgerald, K M; Paty, P S; Leather, R P

1995-01-01

OBJECTIVE: The authors evaluated the long-term patency and outcome of patients undergoing infrainguinal reconstruction using the in situ saphenous vein. SUMMARY BACKGROUND DATA: The in situ saphenous vein bypass has demonstrated excellent patency and limb salvage rates in numerous studies. The authors previously reported their early results with these bypass procedures, and this article represents their long-term experience with 2058 in situ saphenous vein bypasses during a 20-year period. This comprises the largest series with long-term follow-up of in situ saphenous vein bypasses in the literature. METHODS: From 1975 to 1995, 3148 autogenous vein bypasses were performed at the authors' institution, of which 2058 used the saphenous vein in situ. The indication for operation was limb-threatening ischemia in 1875 of 2058 patients (91%). In 88% of patients with an intact ipsilateral saphenous vein, an in situ bypass was completed successfully. One thousand twenty-three bypasses (69%) were terminated at the infrapopliteal level. Of these bypasses, 1562 of 2058 (76%) were completed using the closed in situ technique. RESULTS: The 30-day patency rate was 96%, and the cumulative secondary patency was 91%, 81%, and 70% at 1, 5, and 10 years, respectively. Limb salvage rates using the in situ bypass were 97%, 95%, and 90% at 1, 5, and 10 years, respectively. CONCLUSION: The infrainguinal inflow source, length of bypass, specific outflow vessel, or vein diameter did not have a significant effect on immediate or long-term bypass performance. These data suggest that the in situ saphenous vein is an excellent conduit for femoropopliteal and femoral to infrageniculate bypasses for limb salvage. PMID:7574925

Carotid artery bypass in acute postendarterectomy thrombosis.

PubMed

Paty, P S; Darling, R C; Cordero, J A; Shah, D M; Chang, B B; Leather, R P

1996-08-01

Carotid endarterectomy has demonstrated excellent results over the past 2 decades with combined stroke mortality of < 4% in most active centers. However, the optimal technique for surgical reconstruction for patients with acute postoperative deficits is more controversial. In the last 10 years (1985 to 1995), we performed 1,267 carotid endarterectomies, with 17 strokes (1.3%) and 16 deaths (1.2%). Twenty-four patients developed acute (within 72 hours) postoperative neurologic deficits. In 10 patients, the carotid artery was confirmed patent by duplex scan or angiography, and the neurologic deficit resolved without further therapy. Early reexploration was performed in 14 cases for suspected thrombosis associated with a new neurologic deficit. In each case, resection of the endarterectomy site and an interposition bypass was performed with greater saphenous vein (11), jugular vein (2), or polytetrafluoroethylene (2) grafts. (One patient required a new bypass for acute occlusion of the initial vein bypass.) Postoperatively, 8 patients had complete resolution of their deficit, 3 had minimal residual deficits, and 3 suffered permanent stroke. However, 2 of these patients died. Carotid artery bypass with exclusion of the endarterectomy site resulted in improvement in symptoms in 79% (11 of 14) of the patients and complete resolution in 57% (8 of 14). In long-term follow up (1 to 41 months), there have been no occlusions and one restenosis requiring revision at 11 months. Carotid artery bypass can be performed safely with acceptable results. The use of autogenous venous conduits allows reconstruction with an endothelial lined conduit that may improve results in patients with acute postoperative neurologic deficit secondary to thrombosis of the endarterectomized carotid artery.

Cancer Screening Test Use - United States, 2015.

PubMed

White, Arica; Thompson, Trevor D; White, Mary C; Sabatino, Susan A; de Moor, Janet; Doria-Rose, Paul V; Geiger, Ann M; Richardson, Lisa C

2017-03-03

Healthy People 2020 (HP2020) includes objectives to increase screening for breast, cervical, and colorectal cancer (1) as recommended by the U.S. Preventive Services Task Force (USPSTF).* Progress toward meeting these objectives is monitored by measuring cancer screening test use against national targets using data from the National Health Interview Survey (NHIS) (1). Analysis of 2015 NHIS data indicated that screening test use remains substantially below HP2020 targets for selected cancer screening tests. Although colorectal cancer screening test use increased from 2000 to 2015, no improvements in test use were observed for breast and cervical cancer screening. Disparities exist in screening test use by race/ethnicity, socioeconomic status, and health care access indicators. Increased measures to implement evidence-based interventions and conduct targeted outreach are needed if the HP2020 targets for cancer screening are to be achieved and the disparities in screening test use are to be reduced.

21 CFR 870.4410 - Cardiopulmonary bypass in-line blood gas sensor.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass in-line blood gas sensor... Cardiopulmonary bypass in-line blood gas sensor. (a) Identification. A cardiopulmonary bypass in-line blood gas sensor is a transducer that measures the level of gases in the blood. (b) Classification. Class II...

21 CFR 870.4410 - Cardiopulmonary bypass in-line blood gas sensor.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass in-line blood gas sensor... Cardiopulmonary bypass in-line blood gas sensor. (a) Identification. A cardiopulmonary bypass in-line blood gas sensor is a transducer that measures the level of gases in the blood. (b) Classification. Class II...

21 CFR 870.4410 - Cardiopulmonary bypass in-line blood gas sensor.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass in-line blood gas sensor... Cardiopulmonary bypass in-line blood gas sensor. (a) Identification. A cardiopulmonary bypass in-line blood gas sensor is a transducer that measures the level of gases in the blood. (b) Classification. Class II...

21 CFR 870.4410 - Cardiopulmonary bypass in-line blood gas sensor.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass in-line blood gas sensor... Cardiopulmonary bypass in-line blood gas sensor. (a) Identification. A cardiopulmonary bypass in-line blood gas sensor is a transducer that measures the level of gases in the blood. (b) Classification. Class II...

21 CFR 870.4410 - Cardiopulmonary bypass in-line blood gas sensor.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass in-line blood gas sensor... Cardiopulmonary bypass in-line blood gas sensor. (a) Identification. A cardiopulmonary bypass in-line blood gas sensor is a transducer that measures the level of gases in the blood. (b) Classification. Class II...

Component analysis and target cell-based neuroactivity screening of Panax ginseng by ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

PubMed

Yuan, Jinbin; Chen, Yang; Liang, Jian; Wang, Chong-Zhi; Liu, Xiaofei; Yan, Zhihong; Tang, Yi; Li, Jiankang; Yuan, Chun-Su

2016-12-01

Ginseng is one of the most widely used natural medicines in the world. Recent studies have suggested Panax ginseng has a wide range of beneficial effects on aging, central nervous system disorders, and neurodegenerative diseases. However, knowledge about the specific bioactive components of ginseng is still limited. This work aimed to screen for the bioactive components in Panax ginseng that act against neurodegenerative diseases, using the target cell-based bioactivity screening method. Firstly, component analysis of Panax ginseng extracts was performed by UPLC-QTOF-MS, and a total of 54 compounds in white ginseng were characterized and identified according to the retention behaviors, accurate MW, MS characteristics, parent nucleus, aglycones, side chains, and literature data. Then target cell-based bioactivity screening method was developed to predict the candidate compounds in ginseng with SH-SY5Y cells. Four ginsenosides, Rg 2 , Rh 1 , Ro, and Rd, were observed to be active. The target cell-based bioactivity screening method coupled with UPLC-QTOF-MS technique has suitable sensitivity and it can be used as a screening tool for low content bioactive constituents in natural products. Copyright © 2016 Elsevier B.V. All rights reserved.

Quality of clinical care and bypassing of primary health centers in India.

PubMed

Rao, Krishna D; Sheffel, Ashley

2018-06-01

In many low and middle-income countries patients often bypass the nearest government health center offering free or subsidized services and seek more expensive care elsewhere. This study examines the role of quality of care, in particular clinician competence and structural quality of the health center, on bypassing behavior. Data for this study comes from a survey of 136 primary health centers (PHCs) and 3517 individuals living in the PHC's immediate vicinity in rural Chhattisgarh, India. Overall, the majority (67%) of patients bypassed the local PHC when seeking treatment. Bypassing decreased as provider competence increased, up to a point, after which, improvements in competency did not reduce bypassing. The clinical competence of the health care provider had a greater effect on reducing bypassing compared to PHC structural quality such as the building condition and drug stock-outs. However, the regular presence of clinical providers in the PHC was associated with lower bypassing. Patients that visited the local PHC spent half as much out-of-pocket as those that were treated at private clinics. Poor patients were less likely to bypass the local PHC compared to non-poor patients. These findings suggest that improving structural quality is not sufficient to reduce bypassing of PHCs. While better provider competency can substantially reduce bypassing, beyond a threshold competency level there is little effect. Efforts to strengthen facility-based primary care services need to go beyond simply focusing on improving infrastructure or quality of clinical care. There is a need to rethink how PHCs can be made more relevant to the health care needs of the communities they serve. Copyright © 2018 Elsevier Ltd. All rights reserved.

Leoligin, the major lignan from Edelweiss, inhibits intimal hyperplasia of venous bypass grafts

PubMed Central

Reisinger, Ute; Schwaiger, Stefan; Zeller, Iris; Messner, Barbara; Stigler, Robert; Wiedemann, Dominik; Mayr, Tobias; Seger, Christoph; Schachner, Thomas; Dirsch, Verena M.; Vollmar, Angelika M.; Bonatti, Johannes O.; Stuppner, Hermann; Laufer, Günther; Bernhard, David

2009-01-01

Aims Despite the lower patency of venous compared with arterial coronary artery bypass grafts, ∼50% of grafts used are saphenous vein conduits because of their easier accessibility. In a search for ways to increase venous graft patency, we applied the results of a previous pharmacological study screening for non-toxic compounds that inhibit intimal hyperplasia of saphenous vein conduits in organ cultures. Here we analyse the effects and mechanism of action of leoligin [(2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)tetrahydrofuran-3-yl]methyl (2Z)-2-methylbut-2-enoat, the major lignan from Edelweiss (Leontopodium alpinum Cass.). Methods and results We found that leoligin potently inhibits vascular smooth muscle cell (SMC) proliferation by inducing cell cycle arrest in the G1-phase. Leoligin induced cell death neither in SMCs nor, more importantly, in endothelial cells. In a human saphenous vein organ culture model for graft disease, leoligin potently inhibited intimal hyperplasia, and even reversed graft disease in pre-damaged vessels. Furthermore, in an in vivo mouse model for venous bypass graft disease, leoligin potently inhibited intimal hyperplasia. Conclusion Our data suggest that leoligin might represent a novel non-toxic, non-thrombogenic, endothelial integrity preserving candidate drug for the treatment of vein graft disease. PMID:19228707

CRISPR/Cas9-mediated gene knockout screens and target identification via whole-genome sequencing uncover host genes required for picornavirus infection.

PubMed

Kim, Heon Seok; Lee, Kyungjin; Bae, Sangsu; Park, Jeongbin; Lee, Chong-Kyo; Kim, Meehyein; Kim, Eunji; Kim, Minju; Kim, Seokjoong; Kim, Chonsaeng; Kim, Jin-Soo

2017-06-23

Several groups have used genome-wide libraries of lentiviruses encoding small guide RNAs (sgRNAs) for genetic screens. In most cases, sgRNA expression cassettes are integrated into cells by using lentiviruses, and target genes are statistically estimated by the readout of sgRNA sequences after targeted sequencing. We present a new virus-free method for human gene knockout screens using a genome-wide library of CRISPR/Cas9 sgRNAs based on plasmids and target gene identification via whole-genome sequencing (WGS) confirmation of authentic mutations rather than statistical estimation through targeted amplicon sequencing. We used 30,840 pairs of individually synthesized oligonucleotides to construct the genome-scale sgRNA library, collectively targeting 10,280 human genes ( i.e. three sgRNAs per gene). These plasmid libraries were co-transfected with a Cas9-expression plasmid into human cells, which were then treated with cytotoxic drugs or viruses. Only cells lacking key factors essential for cytotoxic drug metabolism or viral infection were able to survive. Genomic DNA isolated from cells that survived these challenges was subjected to WGS to directly identify CRISPR/Cas9-mediated causal mutations essential for cell survival. With this approach, we were able to identify known and novel genes essential for viral infection in human cells. We propose that genome-wide sgRNA screens based on plasmids coupled with WGS are powerful tools for forward genetics studies and drug target discovery. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Patient Bypass Behavior and Critical Access Hospitals: Implications for Patient Retention

ERIC Educational Resources Information Center

Liu, Jiexin (Jason); Bellamy, Gail R.; McCormick, Melissa

2007-01-01

Purpose: To assess the extent of bypass for inpatient care among patients living in Critical Access Hospital (CAH) service areas, and to determine factors associated with bypass, the reasons for bypass, and what CAHs can do to retain patients locally. Methods: Six hundred and forty-seven subjects, aged 18 years and older, who had been admitted to…

21 CFR 870.4330 - Cardiopulmonary bypass on-line blood gas monitor.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary bypass on-line blood gas monitor... Cardiopulmonary bypass on-line blood gas monitor. (a) Identification. A cardiopulmonary bypass on-line blood gas monitor is a device used in conjunction with a blood gas sensor to measure the level of gases in the blood...

21 CFR 870.4330 - Cardiopulmonary bypass on-line blood gas monitor.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary bypass on-line blood gas monitor... Cardiopulmonary bypass on-line blood gas monitor. (a) Identification. A cardiopulmonary bypass on-line blood gas monitor is a device used in conjunction with a blood gas sensor to measure the level of gases in the blood...

21 CFR 870.4330 - Cardiopulmonary bypass on-line blood gas monitor.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary bypass on-line blood gas monitor... Cardiopulmonary bypass on-line blood gas monitor. (a) Identification. A cardiopulmonary bypass on-line blood gas monitor is a device used in conjunction with a blood gas sensor to measure the level of gases in the blood...

21 CFR 870.4330 - Cardiopulmonary bypass on-line blood gas monitor.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Cardiopulmonary bypass on-line blood gas monitor. (a) Identification. A cardiopulmonary bypass on-line blood gas monitor is a device used in conjunction with a blood gas sensor to measure the level of gases in the blood... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass on-line blood gas monitor...

21 CFR 870.4330 - Cardiopulmonary bypass on-line blood gas monitor.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Cardiopulmonary bypass on-line blood gas monitor. (a) Identification. A cardiopulmonary bypass on-line blood gas monitor is a device used in conjunction with a blood gas sensor to measure the level of gases in the blood... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass on-line blood gas monitor...

3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions.

PubMed

Wenzel, Carsten; Riefke, Björn; Gründemann, Stephan; Krebs, Alice; Christian, Sven; Prinz, Florian; Osterland, Marc; Golfier, Sven; Räse, Sebastian; Ansari, Nariman; Esner, Milan; Bickle, Marc; Pampaloni, Francesco; Mattheyer, Christian; Stelzer, Ernst H; Parczyk, Karsten; Prechtl, Stefan; Steigemann, Patrick

2014-04-15

Cancer cells in poorly vascularized tumor regions need to adapt to an unfavorable metabolic microenvironment. As distance from supplying blood vessels increases, oxygen and nutrient concentrations decrease and cancer cells react by stopping cell cycle progression and becoming dormant. As cytostatic drugs mainly target proliferating cells, cancer cell dormancy is considered as a major resistance mechanism to this class of anti-cancer drugs. Therefore, substances that target cancer cells in poorly vascularized tumor regions have the potential to enhance cytostatic-based chemotherapy of solid tumors. With three-dimensional growth conditions, multicellular tumor spheroids (MCTS) reproduce several parameters of the tumor microenvironment, including oxygen and nutrient gradients as well as the development of dormant tumor regions. We here report the setup of a 3D cell culture compatible high-content screening system and the identification of nine substances from two commercially available drug libraries that specifically target cells in inner MCTS core regions, while cells in outer MCTS regions or in 2D cell culture remain unaffected. We elucidated the mode of action of the identified compounds as inhibitors of the respiratory chain and show that induction of cell death in inner MCTS core regions critically depends on extracellular glucose concentrations. Finally, combinational treatment with cytostatics showed increased induction of cell death in MCTS. The data presented here shows for the first time a high-content based screening setup on 3D tumor spheroids for the identification of substances that specifically induce cell death in inner tumor spheroid core regions. This validates the approach to use 3D cell culture screening systems to identify substances that would not be detectable by 2D based screening in otherwise similar culture conditions. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Cost-effectiveness of digital mammography breast cancer screening.

PubMed

Tosteson, Anna N A; Stout, Natasha K; Fryback, Dennis G; Acharyya, Suddhasatta; Herman, Benjamin A; Hannah, Lucy G; Pisano, Etta D

2008-01-01

The DMIST (Digital Mammography Imaging Screening Trial) reported improved breast cancer detection with digital mammography compared with film mammography in selected population subgroups, but it did not assess the economic value of digital relative to film mammography screening. To evaluate the cost-effectiveness of digital mammography screening for breast cancer. Validated, discrete-event simulation model. Data from DMIST and publicly available U.S. data. U.S. women age 40 years or older. Lifetime. Societal and Medicare. All-film mammography screening; all-digital mammography screening; and targeted digital mammography screening, which is age-targeted digital mammography (for women <50 years of age) and age- and density-targeted digital mammography (for women <50 years of age or women > or =50 years of age with dense breasts). Cost per quality-adjusted life-year (QALY) gained. All-digital mammography screening cost $331,000 (95% CI, $268,000 to $403,000) per QALY gained relative to all-film mammography screening but was more costly and less effective than targeted digital mammography screening. Targeted digital mammography screening resulted in more screen-detected cases of cancer and fewer deaths from cancer than either all-film or all-digital mammography screening, with cost-effectiveness estimates ranging from $26,500 (CI, $21,000 to $33,000) per QALY gained for age-targeted digital mammography to $84,500 (CI, $75,000 to $93,000) per QALY gained for age- and density-targeted digital mammography. In the Medicare population, the cost-effectiveness of density-targeted digital mammography screening varied from a base-case estimate of $97,000 (CI, $77,000 to $131,000) to $257,000 per QALY gained (CI, $91,000 to $536,000) in the alternative-case analyses, in which the sensitivity of film mammography was increased and the sensitivity of digital mammography in women with nondense breasts was decreased. Results were sensitive to the cost of digital mammography and to

Effect of a virtual reality-enhanced exercise protocol after coronary artery bypass grafting.

PubMed

Chuang, Tien-Yow; Sung, Wen-Hsu; Chang, Hwa-Ann; Wang, Ray-Yau

2006-10-01

Virtual reality (VR) technology has gained importance in many areas of medicine. Knowledge concerning the application and the influence of VR-enhanced exercise programs is limited for patients receiving coronary artery bypass grafting. The purpose of this study was to evaluate the effect of a virtual "country walk" on the number of sessions necessary to reach cardiac rehabilitation goals in patients undergoing coronary artery bypass grafting. Twenty subjects who were seen for cardiac rehabilitation between January and June 2004 comprised the study sample. The protocol for this study included an initial maximum graded exercise tolerance test, given to determine the subsequent training goals for the subject, followed by biweekly submaximal endurance training sessions. All subjects were assigned by lot to 1 of 2 submaximal endurance training programs, one (group 2) with and the other (group 1) without the added VR environment. In all other respects, the 2 programs were identical. Each training session lasted for 30 minutes and was carried out twice per week for about 3 months. The primary outcome measures were maximum load during the work sessions, target oxygen consumption, target heart rate (beats per minute), and number of training sessions required to reach rehabilitation goals. By the end of 20 training sessions, only 4 of the 10 control subjects had reached the heart rate target goal of 85% their maximum heart rate. In contrast, 9 of the 10 subjects in the VR program had attained this goal by 9 or fewer training sessions. When target metabolic cost (75% peak oxygen consumption) was used as the training goal, all 10 subjects in the VR program had reached this target after 2 training sessions (or, in some cases, 1 training session), but not until training session 15 did a cumulative number of 9 control subjects reach this goal. These study outcomes clearly support the notion that incorporating a VR environment into cardiac rehabilitation programs will accelerate

Isolated Human Pulmonary Artery Structure and Function Pre- and Post-Cardiopulmonary Bypass Surgery.

PubMed

Dora, Kim A; Stanley, Christopher P; Al Jaaly, Emad; Fiorentino, Francesca; Ascione, Raimondo; Reeves, Barnaby C; Angelini, Gianni D

2016-02-23

Pulmonary dysfunction is a known complication after cardiac surgery using cardiopulmonary bypass, ranging from subclinical functional changes to prolonged postoperative ventilation, acute lung injury, and acute respiratory distress syndrome. Whether human pulmonary arterial function is compromised is unknown. The aim of the present study was to compare the structure and function of isolated and cannulated human pulmonary arteries obtained from lung biopsies after the chest was opened (pre-cardiopulmonary bypass) to those obtained at the end of cardiopulmonary bypass (post-cardiopulmonary bypass) from patients undergoing coronary artery bypass graft surgery. Pre- and post-cardiopulmonary bypass lung biopsies were received from 12 patients undergoing elective surgery. Intralobular small arteries were dissected, cannulated, pressurized, and imaged using confocal microscopy. Functionally, the thromboxane mimetic U46619 produced concentration-dependent vasoconstriction in 100% and 75% of pre- and post-cardiopulmonary bypass arteries, respectively. The endothelium-dependent agonist bradykinin stimulated vasodilation in 45% and 33% of arteries pre- and post-cardiopulmonary bypass, respectively. Structurally, in most arteries smooth muscle cells aligned circumferentially; live cell viability revealed that although 100% of smooth muscle and 90% of endothelial cells from pre-cardiopulmonary bypass biopsies had intact membranes and were considered viable, only 60% and 58%, respectively, were viable from post-cardiopulmonary bypass biopsies. We successfully investigated isolated pulmonary artery structure and function in fresh lung biopsies from patients undergoing heart surgery. Pulmonary artery contractile tone and endothelium-dependent dilation were significantly reduced in post-cardiopulmonary bypass biopsies. The decreased functional responses were associated with reduced cell viability. URL: http://www.isrctn.com/ISRCTN34428459. Unique identifier: ISRCTN 34428459. �

Airway bypass treatment of severe homogeneous emphysema: taking advantage of collateral ventilation.

PubMed

Choong, Cliff K; Cardoso, Paulo F G; Sybrecht, Gerhard W; Cooper, Joel D

2009-05-01

Airway bypass is being investigated as a new form of minimally invasive therapy for the treatment of homogeneous emphysema. It is a bronchoscopic catheter-based procedure that creates transbronchial extra-anatomic passages at the bronchial segmental level. The passages are expanded, supported with the expectation that the patency is maintained by paclitaxel drug-eluting airway bypass stents. The concept of airway bypass has been demonstrated in two separate experimental studies. These studies have shown that airway bypass takes advantage of collateral ventilation present in homogeneous emphysema to allow trapped gas to escape and reduce hyperinflation. It improves lung mechanics, expiratory flow, and volume. Airway bypass stent placements have been shown to be feasible and safe in both animal and human studies. Paclitaxel-eluting airway bypass stents were found to prolong stent patency and were adopted for clinical studies. A study evaluating the early results of the clinical application of airway bypass with paclitaxel-eluting stents found that airway bypass procedures reduced hyperinflation and improved pulmonary function and dyspnea in selected subjects who have severe emphysema. The duration of benefit appeared to correlate with the degree of pretreatment hyperinflation. These preliminary clinical results supported further evaluation of the procedure and led to the EASE Trial. The EASE Trial is a prospective, multicenter, randomized, double-blind, sham-controlled study. The trial aims to evaluate the safety and effectiveness of the airway bypass to improve pulmonary function and reduce dyspnea in homogeneous emphysema subjects who have severe hyperinflation. The trial is presently ongoing worldwide, though enrollment was completed.

Thermal activation of dislocations in large scale obstacle bypass

NASA Astrophysics Data System (ADS)

Sobie, Cameron; Capolungo, Laurent; McDowell, David L.; Martinez, Enrique

2017-08-01

Dislocation dynamics simulations have been used extensively to predict hardening caused by dislocation-obstacle interactions, including irradiation defect hardening in the athermal case. Incorporating the role of thermal energy on these interactions is possible with a framework provided by harmonic transition state theory (HTST) enabling direct access to thermally activated reaction rates using the Arrhenius equation, including rates of dislocation-obstacle bypass processes. Moving beyond unit dislocation-defect reactions to a representative environment containing a large number of defects requires coarse-graining the activation energy barriers of a population of obstacles into an effective energy barrier that accurately represents the large scale collective process. The work presented here investigates the relationship between unit dislocation-defect bypass processes and the distribution of activation energy barriers calculated for ensemble bypass processes. A significant difference between these cases is observed, which is attributed to the inherent cooperative nature of dislocation bypass processes. In addition to the dislocation-defect interaction, the morphology of the dislocation segments pinned to the defects play an important role on the activation energies for bypass. A phenomenological model for activation energy stress dependence is shown to describe well the effect of a distribution of activation energies, and a probabilistic activation energy model incorporating the stress distribution in a material is presented.

Oxygen delivery during cardiopulmonary bypass (and renal outcome) using two systems of extracorporeal circulation: a retrospective review.

PubMed

Bennett, Mark J; Rajakaruna, Cha; Bazerbashi, Samer; Webb, Gerry; Gomez-Cano, Mayam; Lloyd, Clinton

2013-06-01

To investigate the combined influence of blood flow and haemodilution with either a miniaturized (Mini-CPB) or a conventional cardiopulmonary bypass (C-CPB) circuit on average oxygen delivery during bypass. The influence of this on clinical outcome, particularly renal dysfunction after routine coronary artery bypass surgery (CABG), was measured. Retrospective analysis in two groups of 160 patients based on the surgeon's preference for bypass circuit. We compared consecutive patients undergoing isolated CABG surgery by two surgeons using Mini-CPB with a matched cohort of patients, from the same period, undergoing isolated CABG surgery by four other surgeons using a C-CPB. No trial-related intervention occurred. Data on bypass circuit parameters and clinical outcomes were acquired from routinely collected data sources. Average cardiopulmonary bypass pump flow was significantly lower with Mini-CPB compared with C-CPB. Mini-CPB resulted in significantly less haemodilution. The resultant calculated average oxygen delivery provided by the two systems was the same. Percentage change in plasma creatinine was significantly and inversely related to the oxygen delivery during CPB. There was no difference in percentage change in plasma creatinine between groups. The risk of having Acute Kidney Injury Network (AKIN) score ≥ 1 increased 1% for every 1 ml min(-1) m(-2) decrease in oxygen delivery (P = 0.0001, OR 0.990, 95% CI 0.984-0.995). Despite aiming for the same target pump flow, periodic limitations of venous return to the pump resulted in a significant reduction in average flow delivered to the patient by Mini-CPB. Less haemodilution compensated for this reduction, so that the average oxygen delivery was the same. The association between oxygen delivery and postoperative change in plasma creatinine was evident in both groups. Further work to understand whether there is a particular cohort of patients who benefit (or are put at risk) by one method of CPB vs the other is

Detection and identification of 700 drugs by multi-target screening with a 3200 Q TRAP LC-MS/MS system and library searching.

PubMed

Dresen, S; Ferreirós, N; Gnann, H; Zimmermann, R; Weinmann, W

2010-04-01

The multi-target screening method described in this work allows the simultaneous detection and identification of 700 drugs and metabolites in biological fluids using a hybrid triple-quadrupole linear ion trap mass spectrometer in a single analytical run. After standardization of the method, the retention times of 700 compounds were determined and transitions for each compound were selected by a "scheduled" survey MRM scan, followed by an information-dependent acquisition using the sensitive enhanced product ion scan of a Q TRAP hybrid instrument. The identification of the compounds in the samples analyzed was accomplished by searching the tandem mass spectrometry (MS/MS) spectra against the library we developed, which contains electrospray ionization-MS/MS spectra of over 1,250 compounds. The multi-target screening method together with the library was included in a software program for routine screening and quantitation to achieve automated acquisition and library searching. With the help of this software application, the time for evaluation and interpretation of the results could be drastically reduced. This new multi-target screening method has been successfully applied for the analysis of postmortem and traffic offense samples as well as proficiency testing, and complements screening with immunoassays, gas chromatography-mass spectrometry, and liquid chromatography-diode-array detection. Other possible applications are analysis in clinical toxicology (for intoxication cases), in psychiatry (antidepressants and other psychoactive drugs), and in forensic toxicology (drugs and driving, workplace drug testing, oral fluid analysis, drug-facilitated sexual assault).

Smokers' rights to coronary artery bypass graft surgery.

PubMed

Heath, Janie; Braun, Mary Ann; Brindle, Margaret

2002-06-01

Imagine a health maintenance organization creating a policy to deny all smokers access to nonemergent coronary artery bypass graft surgery. The cost savings to the organization and society would be potentially significant. Now envision the smoker, a hardworking father with daily angina, and the provider, writing costly prescriptions to manage the angina. What ethical and legal questions do you suppose would present in that setting? Now imagine how you would respond if given this scenario of denying smokers access to nonemergent coronary artery bypass graft. This article discusses the implications of resource allocation with self-inflicted health behaviors such as smoking. Tough questions are raised that explore both the pros and the cons of smokers' rights to coronary artery bypass graft.

Bypass flow computations on the LOFA transient in a VHTR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tung, Yu-Hsin; Johnson, Richard W.; Ferng, Yuh-Ming

2014-01-01

Bypass flow in the prismatic gas-cooled very high temperature reactor (VHTR) is not intentionally designed to occur, but is present in the gaps between graphite blocks. Previous studies of the bypass flow in the core indicated that the cooling provided by flow in the bypass gaps had a significant effect on temperature and flow distributions for normal operating conditions. However, the flow and heat transports in the core are changed significantly after a Loss of Flow Accident (LOFA). This study aims to study the effect and role of the bypass flow after a LOFA in terms of the temperature andmore » flow distributions and for the heat transport out of the core by natural convection of the coolant for a 1/12 symmetric section of the active core which is composed of images and mirror images of two sub-region models. The two sub-region models, 9 x 1/12 and 15 x 1/12 symmetric sectors of the active core, are employed as the CFD flow models using computational grid systems of 70.2 million and 117 million nodes, respectively. It is concluded that the effect of bypass flow is significant for the initial conditions and the beginning of LOFA, but the bypass flow has little effect after a long period of time in the transient computation of natural circulation.« less

Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk.

PubMed

Lim, Regine M; Silver, Ari J; Silver, Maxwell J; Borroto, Carlos; Spurrier, Brett; Petrossian, Tanya C; Larson, Jessica L; Silver, Lee M

2016-02-01

Carrier screening for mutations contributing to cystic fibrosis (CF) is typically accomplished with panels composed of variants that are clinically validated primarily in patients of European descent. This approach has created a static genetic and phenotypic profile for CF. An opportunity now exists to reevaluate the disease profile of CFTR at a global population level. CFTR allele and genotype frequencies were obtained from a nonpatient cohort with more than 60,000 unrelated personal genomes collected by the Exome Aggregation Consortium. Likely disease-contributing mutations were identified with the use of public database annotations and computational tools. We identified 131 previously described and likely pathogenic variants and another 210 untested variants with a high probability of causing protein damage. None of the current genetic screening panels or existing CFTR mutation databases covered a majority of deleterious variants in any geographical population outside of Europe. Both clinical annotation and mutation coverage by commercially available targeted screening panels for CF are strongly biased toward detection of reproductive risk in persons of European descent. South and East Asian populations are severely underrepresented, in part because of a definition of disease that preferences the phenotype associated with European-typical CFTR alleles.

Screening the receptorome to discover the molecular targets for plant-derived psychoactive compounds: a novel approach for CNS drug discovery.

PubMed

Roth, Bryan L; Lopez, Estela; Beischel, Scott; Westkaemper, Richard B; Evans, Jon M

2004-05-01

Because psychoactive plants exert profound effects on human perception, emotion, and cognition, discovering the molecular mechanisms responsible for psychoactive plant actions will likely yield insights into the molecular underpinnings of human consciousness. Additionally, it is likely that elucidation of the molecular targets responsible for psychoactive drug actions will yield validated targets for CNS drug discovery. This review article focuses on an unbiased, discovery-based approach aimed at uncovering the molecular targets responsible for psychoactive drug actions wherein the main active ingredients of psychoactive plants are screened at the "receptorome" (that portion of the proteome encoding receptors). An overview of the receptorome is given and various in silico, public-domain resources are described. Newly developed tools for the in silico mining of data derived from the National Institute of Mental Health Psychoactive Drug Screening Program's (NIMH-PDSP) K(i) Database (K(i) DB) are described in detail. Additionally, three case studies aimed at discovering the molecular targets responsible for Hypericum perforatum, Salvia divinorum, and Ephedra sinica actions are presented. Finally, recommendations are made for future studies.

Genome wide interactions of wild-type and activator bypass forms of σ54

PubMed Central

Schaefer, Jorrit; Engl, Christoph; Zhang, Nan; Lawton, Edward; Buck, Martin

2015-01-01

Enhancer-dependent transcription involving the promoter specificity factor σ54 is widely distributed amongst bacteria and commonly associated with cell envelope function. For transcription initiation, σ54-RNA polymerase yields open promoter complexes through its remodelling by cognate AAA+ ATPase activators. Since activators can be bypassed in vitro, bypass transcription in vivo could be a source of emergent gene expression along evolutionary pathways yielding new control networks and transcription patterns. At a single test promoter in vivo bypass transcription was not observed. We now use genome-wide transcription profiling, genome-wide mutagenesis and gene over-expression strategies in Escherichia coli, to (i) scope the range of bypass transcription in vivo and (ii) identify genes which might alter bypass transcription in vivo. We find little evidence for pervasive bypass transcription in vivo with only a small subset of σ54 promoters functioning without activators. Results also suggest no one gene limits bypass transcription in vivo, arguing bypass transcription is strongly kept in check. Promoter sequences subject to repression by σ54 were evident, indicating loss of rpoN (encoding σ54) rather than creating rpoN bypass alleles would be one evolutionary route for new gene expression patterns. Finally, cold-shock promoters showed unusual σ54-dependence in vivo not readily correlated with conventional σ54 binding-sites. PMID:26082500

RNA interference as a method for target-site screening in the Western Corn Rootworm, Diabrotica virgifera virgifera

USDA-ARS?s Scientific Manuscript database

RNA interference (RNAi) is one of the most powerful and extraordinarily-specific means by which to silence genes. The ability of RNAi to silence genes makes it possible to ascertain function from genomic data, thereby making it an excellent choice for target-site screening. To test the efficacy of...

Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.

PubMed

Kobayashi, Masakazu; Retra, Kim; Figaroa, Francis; Hollander, Johan G; Ab, Eiso; Heetebrij, Robert J; Irth, Hubertus; Siegal, Gregg

2010-09-01

Fragment-based drug discovery (FBDD) has become a widely accepted tool that is complementary to high-throughput screening (HTS) in developing small-molecule inhibitors of pharmaceutical targets. Because a fragment campaign can only be as successful as the hit matter found, it is critical that the first stage of the process be optimized. Here the authors compare the 3 most commonly used methods for hit discovery in FBDD: high concentration screening (HCS), solution ligand-observed nuclear magnetic resonance (NMR), and surface plasmon resonance (SPR). They selected the commonly used saturation transfer difference (STD) NMR spectroscopy and the proprietary target immobilized NMR screening (TINS) as representative of the array of possible NMR methods. Using a target typical of FBDD campaigns, the authors find that HCS and TINS are the most sensitive to weak interactions. They also find a good correlation between TINS and STD for tighter binding ligands, but the ability of STD to detect ligands with affinity weaker than 1 mM K(D) is limited. Similarly, they find that SPR detection is most suited to ligands that bind with K(D) better than 1 mM. However, the good correlation between SPR and potency in a bioassay makes this a good method for hit validation and characterization studies.

Gastric bypass surgeries in New Hampshire, 1996-2007.

PubMed

Cherala, Sai S

2012-01-01

Obesity is a national epidemic. Gastric bypass surgery may be the only option that provides significant long-term weight loss for people who are morbidly obese (body mass index [BMI] ≥ 40 kg/m²) or for people who have a BMI of 35 or higher and have an obesity-related comorbidity. The objective of this study was to assess trends in gastric bypass surgery in New Hampshire. Data from 1996 to 2007 from the New Hampshire Inpatient Hospital Discharge data set were analyzed. Records for patients with a gastric bypass surgery code were identified, and data on patients and hospitalizations were collected. A joinpoint regression model was used to analyze trends in surgery rates. Differences between patients and payer types were analyzed by using the Cochran-Mantel-Haenszel χ² test. The annual rate of gastric bypass surgery increased significantly from 3.3 to 22.4 per 100,000 adults between 1996 and 2007. The in-hospital death rate decreased significantly from 11% in 1996 to 1% in 2007. A greater proportion of women (78.1% during the study period) than men had this surgery. The average charge of a surgery decreased significantly from $44,484 in 1996 to $43,907 in 2007; by 2007, total annual charges were $13.9 million. Since 1996, private or "other" payers have been charged for nearly 80% of the total discharges. The number of gastric bypass surgeries has increased in New Hampshire, and so have their cost. These increases may reflect a shortage in effective primary care and preventive measures to address the obesity epidemic.

Bypass of a nick by the replisome of bacteriophage T7.

PubMed

Zhu, Bin; Lee, Seung-Joo; Richardson, Charles C

2011-08-12

DNA polymerase and DNA helicase are essential components of DNA replication. The helicase unwinds duplex DNA to provide single-stranded templates for DNA synthesis by the DNA polymerase. In bacteriophage T7, movement of either the DNA helicase or the DNA polymerase alone terminates upon encountering a nick in duplex DNA. Using a minicircular DNA, we show that the helicase · polymerase complex can bypass a nick, albeit at reduced efficiency of 7%, on the non-template strand to continue rolling circle DNA synthesis. A gap in the non-template strand cannot be bypassed. The efficiency of bypass synthesis depends on the DNA sequence downstream of the nick. A nick on the template strand cannot be bypassed. Addition of T7 single-stranded DNA-binding protein to the complex stimulates nick bypass 2-fold. We propose that the association of helicase with the polymerase prevents dissociation of the helicase upon encountering a nick, allowing the helicase to continue unwinding of the duplex downstream of the nick.

Outcomes of lower extremity bypass performed for acute limb ischemia

PubMed Central

Baril, Donald T.; Patel, Virendra I.; Judelson, Dejah R.; Goodney, Philip P.; McPhee, James T.; Hevelone, Nathanael D.; Cronenwett, Jack L.; Schanzer, Andres

2013-01-01

Objective Acute limb ischemia remains one of the most challenging emergencies in vascular surgery. Historically, outcomes following interventions for acute limb ischemia have been associated with high rates of morbidity and mortality. The purpose of this study was to determine contemporary outcomes following lower extremity bypass performed for acute limb ischemia. Methods All patients undergoing infrainguinal lower extremity bypass between 2003 and 2011 within hospitals comprising the Vascular Study Group of New England were identified. Patients were stratified according to whether or not the indication for lower extremity bypass was acute limb ischemia. Primary end points included bypass graft occlusion, major amputation, and mortality at 1 year postoperatively as determined by Kaplan-Meier life table analysis. Multivariable Cox proportional hazards models were constructed to evaluate independent predictors of mortality and major amputation at 1 year. Results Of 5712 lower extremity bypass procedures, 323 (5.7%) were performed for acute limb ischemia. Patients undergoing lower extremity bypass for acute limb ischemia were similar in age (66 vs 67; P = .084) and sex (68% male vs 69% male; P = .617) compared with chronic ischemia patients, but were less likely to be on aspirin (63% vs 75%; P < .0001) or a statin (55% vs 68%; P < .0001). Patients with acute limb ischemia were more likely to be current smokers (49% vs 39%; P < .0001), to have had a prior ipsilateral bypass (33% vs 24%; P = .004) or a prior ipsilateral percutaneous intervention (41% vs 29%; P = .001). Bypasses performed for acute limb ischemia were longer in duration (270 vs 244 minutes; P = .007), had greater blood loss (363 vs 272 mL; P < .0001), and more commonly utilized prosthetic conduits (41% vs 33%; P = .003). Acute limb ischemia patients experienced increased in-hospital major adverse events (20% vs 12%; P < .0001) including myocardial infarction, congestive heart failure exacerbation

Outcomes of lower extremity bypass performed for acute limb ischemia.

PubMed

Baril, Donald T; Patel, Virendra I; Judelson, Dejah R; Goodney, Philip P; McPhee, James T; Hevelone, Nathanael D; Cronenwett, Jack L; Schanzer, Andres

2013-10-01

Acute limb ischemia remains one of the most challenging emergencies in vascular surgery. Historically, outcomes following interventions for acute limb ischemia have been associated with high rates of morbidity and mortality. The purpose of this study was to determine contemporary outcomes following lower extremity bypass performed for acute limb ischemia. All patients undergoing infrainguinal lower extremity bypass between 2003 and 2011 within hospitals comprising the Vascular Study Group of New England were identified. Patients were stratified according to whether or not the indication for lower extremity bypass was acute limb ischemia. Primary end points included bypass graft occlusion, major amputation, and mortality at 1 year postoperatively as determined by Kaplan-Meier life table analysis. Multivariable Cox proportional hazards models were constructed to evaluate independent predictors of mortality and major amputation at 1 year. Of 5712 lower extremity bypass procedures, 323 (5.7%) were performed for acute limb ischemia. Patients undergoing lower extremity bypass for acute limb ischemia were similar in age (66 vs 67; P = .084) and sex (68% male vs 69% male; P = .617) compared with chronic ischemia patients, but were less likely to be on aspirin (63% vs 75%; P < .0001) or a statin (55% vs 68%; P < .0001). Patients with acute limb ischemia were more likely to be current smokers (49% vs 39%; P < .0001), to have had a prior ipsilateral bypass (33% vs 24%; P = .004) or a prior ipsilateral percutaneous intervention (41% vs 29%; P = .001). Bypasses performed for acute limb ischemia were longer in duration (270 vs 244 minutes; P = .007), had greater blood loss (363 vs 272 mL; P < .0001), and more commonly utilized prosthetic conduits (41% vs 33%; P = .003). Acute limb ischemia patients experienced increased in-hospital major adverse events (20% vs 12%; P < .0001) including myocardial infarction, congestive heart failure exacerbation, deterioration in renal function

Impact of angiosome- and nonangiosome-targeted peroneal bypass on limb salvage and healing in patients with chronic limb-threatening ischemia.

PubMed

Ricco, Jean-Baptiste; Gargiulo, Mauro; Stella, Andrea; Abualhin, Mohammad; Gallitto, Enrico; Desvergnes, Mathieu; Belmonte, Romain; Schneider, Fabrice

2017-11-01

Direct (DIR) or indirect (IND) revascularization of pedal angiosomes in patients with chronic limb-threatening ischemia (CLTI) has an unclear impact on limb salvage and healing. The aim of this study was to evaluate the outcomes of DIR and IND revascularization in patients with a peroneal bypass and tissue loss. We conducted a retrospective study of a prospectively maintained database in two European university centers from 2004 to 2015. We extracted from this database all patients with CLTI and tissue loss who had received a bypass to the peroneal artery. All patients underwent angiography before bypass. Revascularization was considered DIR if the wound was in a peroneal angiosome. Wounds, ischemia, and infection were categorized according to the Wound, Ischemia, and foot Infection (WIfI) classification. Limb salvage and amputation-free survival were calculated using the Kaplan-Meier method. Cox regression was used to compare the role of patient characteristics, including diabetes, peroneal runoff, pedal arch angiosome, WIfI grade, chronic kidney disease, and diabetes, in amputation-free-survival. From January 2004 through October 2015, there were 120 peroneal bypasses performed in 120 patients with CLTI and foot tissue loss. Only 55 wounds (46%) could be ascribed to a peroneal angiosome. At 3 years, amputation-free survival in patients with DIR revascularization was 54.9% ± 7.3% compared with 56.5% ± 6.3% in patients with IND revascularization (P = .44), with no significant difference in wound healing. Amputation-free survival at 3 years in patients with two patent peroneal branches was 74.8% ± 6.9% compared with 45.0% ± 6.0% in patients with one patent peroneal branch (P = .003). Amputation-free survival at 3 years in patients with a patent pedal arch (Rutherford 0-1) was 73.0% ± 7.0% vs 45.7% ± 6.0% in patients with incomplete pedal arch (Rutherford 2-3; P = .0002). Amputation-free survival at 3 years in patients with grade 1 or grade 2 WIf

Laparoscopic Conversion of One Anastomosis Gastric Bypass to a Standard Roux-en-Y Gastric Bypass.

PubMed

Amor, Imed Ben; Petrucciani, Niccolo; Kassir, Radwan; Al Munifi, Abdullah; Piche, Thierry; Debs, Tarek; Gugenheim, Jean

2017-05-01

One anastomosis gastric bypass (OAGB) demonstrated results similar to traditional Roux-en-Y procedures [1-3], in terms of weight loss and resolution of obesity-related comorbidities. The main controversy regarding OAGB is the concern for an association between biliary alkaline gastritis and esophageal or gastric cancer raised by some studies [4]. We present the case of a 51-year-old woman with a BMI of 41 kg/m2 who underwent a laparoscopic OAGB in 2014. One year later, she consulted for recurrent heartburns. An upper GI endoscopy showed pouchitis and bile reflux in the esophagus. Medical treatment of gastroesophageal reflux disease was ineffective. We decided to convert the OAGB to a Roux-en-Y gastric bypass (RYGB). In this video, we show how to revise an OAGB to treat chronic bile reflux, by converting the procedure to a standard RYGB. The intervention starts by restoring the normal anatomy of the small bowel, with the resection of the gastrojejunal anastomosis, which was located at 250-cm du Treitz's ligament. Then, the gastric pouch is created. A standard Roux-en-Y gastric bypass is performed. The resection of the gastrojejunal anastomosis allows fashioning the Roux-en-Y limb with the classical measures. This technique allows a conversion to a standard RYGB and is effective in treating the biliary reflux.

Hemodynamic effect of bypass geometry on intracranial aneurysm: A numerical investigation.

PubMed

Kurşun, Burak; Uğur, Levent; Keskin, Gökhan

2018-05-01

Hemodynamic analyzes are used in the clinical investigation and treatment of cardiovascular diseases. In the present study, the effect of bypass geometry on intracranial aneurysm hemodynamics was investigated numerically. Pressure, wall shear stress (WSS) and velocity distribution causing the aneurysm to grow and rupture were investigated and the best conditions were tried to be determined in case of bypassing between basilar (BA) and left/right posterior arteries (LPCA/RPCA) for different values of parameters. The finite volume method was used for numerical solutions and calculations were performed with the ANSYS-Fluent software. The SIMPLE algorithm was used to solve the discretized conservation equations. Second Order Upwind method was preferred for finding intermediate point values in the computational domain. As the blood flow velocity changes with time, the blood viscosity value also changes. For this reason, the Carreu model was used in determining the viscosity depending on the velocity. Numerical study results showed that when bypassed, pressure and wall shear stresses reduced in the range of 40-70% in the aneurysm. Numerical results obtained are presented in graphs including the variation of pressure, wall shear stress and velocity streamlines in the aneurysm. Considering the numerical results for all parameter values, it is seen that the most important factors affecting the pressure and WSS values in bypassing are the bypass position on the basilar artery (L b ) and the diameter of the bypass vessel (d). Pressure and wall shear stress reduced in the range of 40-70% in the aneurysm in the case of bypass for all parameters. This demonstrates that pressure and WSS values can be greatly reduced in aneurysm treatment by bypassing in cases where clipping or coil embolization methods can not be applied. Copyright © 2018 Elsevier B.V. All rights reserved.

Stress analysis method for clearance-fit joints with bearing-bypass loads

NASA Technical Reports Server (NTRS)

Naik, R. A.; Crews, J. H., Jr.

1989-01-01

Within a multi-fastener joint, fastener holes may be subjected to the combined effects of bearing loads and loads that bypass the hole to be reacted elsewhere in the joint. The analysis of a joint subjected to search combined bearing and bypass loads is complicated by the usual clearance between the hole and the fastener. A simple analysis method for such clearance-fit joints subjected to bearing-bypass loading has been developed in the present study. It uses an inverse formulation with a linear elastic finite-element analysis. Conditions along the bolt-hole contact arc are specified by displacement constraint equations. The present method is simple to apply and can be implemented with most general purpose finite-element programs since it does not use complicated iterative-incremental procedures. The method was used to study the effects of bearing-bypass loading on bolt-hole contact angles and local stresses. In this study, a rigid, frictionless bolt was used with a plate having the properties of a quasi-isotropic graphite/epoxy laminate. Results showed that the contact angle as well as the peak stresses around the hole and their locations were strongly influenced by the ratio of bearing and bypass loads. For single contact, tension and compression bearing-bypass loading had opposite effects on the contact angle. For some compressive bearing-bypass loads, the hole tended to close on the fastener leading to dual contact. It was shown that dual contact reduces the stress concentration at the fastener and would, therefore, increase joint strength in compression. The results illustrate the general importance of accounting for bolt-hole clearance and contact to accurately compute local bolt-hole stresses for combined bearings and bypass loading.

[Coronary artery bypass surgery: methods of performance monitoring and quality control].

PubMed

Albert, A; Sergeant, P; Ennker, J

2009-10-01

The strength of coronary bypass operations depends on the preservation of their benefits regarding freedom of symptoms, quality of life and survival, over decades. Significant variability of the results of an operative intervention according to the hospital or the operating surgeon is considered a weakness in the procedure. The external quality insurance tries to reach a transparent service providing market through hospital ranking comparability. Widely available information and competition will promote the improvement of the whole quality. The structured dialog acts as a control instrument for the BQS (Federal Quality Insurance). It is launched in case of deviations from the standard references or statistically significant differences between the results of the operations in any hospital and the average notational results. In comparison to the external control the hospital internal control has greater ability to reach a medically useful statement regarding the results of the treatment and to correct the mistakes in time. An online information portal based on a departmental databank (DataWarehouse, DataMart) is an attractive solution for the physician in order to get transparently and timely informed about the variability in the performance.The individual surgeon significantly influences the short- and long-term treatment results. Accordingly, selection, targeted training and performance measurements are necessary.Strict risk management and failure analysis of individual cases are included in the methods of internal quality control aiming to identify and correct the inadequacies in the system and the course of treatment. According to the international as well as our own experience, at least 30% of the mortalities after bypass operations are avoidable. A functioning quality control is especially important in minimally invasive interventions because they are often technically more demanding in comparison to the conventional procedures. In the field of OPCAB surgery

Genome wide interactions of wild-type and activator bypass forms of σ54.

PubMed

Schaefer, Jorrit; Engl, Christoph; Zhang, Nan; Lawton, Edward; Buck, Martin

2015-09-03

Enhancer-dependent transcription involving the promoter specificity factor σ(54) is widely distributed amongst bacteria and commonly associated with cell envelope function. For transcription initiation, σ(54)-RNA polymerase yields open promoter complexes through its remodelling by cognate AAA+ ATPase activators. Since activators can be bypassed in vitro, bypass transcription in vivo could be a source of emergent gene expression along evolutionary pathways yielding new control networks and transcription patterns. At a single test promoter in vivo bypass transcription was not observed. We now use genome-wide transcription profiling, genome-wide mutagenesis and gene over-expression strategies in Escherichia coli, to (i) scope the range of bypass transcription in vivo and (ii) identify genes which might alter bypass transcription in vivo. We find little evidence for pervasive bypass transcription in vivo with only a small subset of σ(54) promoters functioning without activators. Results also suggest no one gene limits bypass transcription in vivo, arguing bypass transcription is strongly kept in check. Promoter sequences subject to repression by σ(54) were evident, indicating loss of rpoN (encoding σ(54)) rather than creating rpoN bypass alleles would be one evolutionary route for new gene expression patterns. Finally, cold-shock promoters showed unusual σ(54)-dependence in vivo not readily correlated with conventional σ(54) binding-sites. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

A remote augmentor lift system with a turbine bypass engine

NASA Technical Reports Server (NTRS)

Fishbach, L. H.; Franciscus, L. C.

1982-01-01

Two supersonic vertical takeoff or landing (VTOL) aircraft engine types, a conventional medium bypass ratio turbofan, and a turbine bypass turbojet were studied. The aircraft assumed was a clipped delta wing with canard configuration. A VTOL deck launched intercept, DLI, mission with Mach 1.6 dash and cruise segments was used as the design mission. Several alternate missions requiring extended subsonic capabilities were analyzed. Comparisons were made between the turbofan (TF) and the turbine bypass turbojet (TBE) engines in airplane types using a Remote Augmented Lift Systems, RALS and a Lift plus Lift Cruise system (L+LC). The figure of merit was takeoff gross weight for the VTOL DLI mission. The results of the study show that the turbine bypass turbojet and the conventional turbofan are competitive engines for both type of aircraft in terms of takeoff gross weight and range. However, the turbine bypass turbojet would be a simpler engine and may result in more attractive life cycle costs and reduced maintenance. The RALS and L+LC airplane types with either TBE or TF engines have approximately the same aircraft takeoff gross weight.

A new strategy to identify hepatitis B virus entry inhibitors by AlphaScreen technology targeting the envelope-receptor interaction.

PubMed

Saso, Wakana; Tsukuda, Senko; Ohashi, Hirofumi; Fukano, Kento; Morishita, Ryo; Matsunaga, Satoko; Ohki, Mio; Ryo, Akihide; Park, Sam-Yong; Suzuki, Ryosuke; Aizaki, Hideki; Muramatsu, Masamichi; Sureau, Camille; Wakita, Takaji; Matano, Tetsuro; Watashi, Koichi

2018-06-22

Current anti-hepatitis B virus (HBV) agents have limited effect in curing HBV infection, and thus novel anti-HBV agents with different modes of action are in demand. In this study, we applied AlphaScreen assay to high-throughput screening of small molecules inhibiting the interaction between HBV large surface antigen (LHBs) and the HBV entry receptor, sodium taurocholate cotransporting polypeptide (NTCP). From the chemical screening, we identified that rapamycin, an immunosuppressant, strongly inhibited the LHBs-NTCP interaction. Rapamycin inhibited hepatocyte infection with HBV without significant cytotoxicity. This activity was due to impaired attachment of the LHBs preS1 domain to cell surface. Pretreatment of target cells with rapamycin remarkably reduced their susceptibility to preS1 attachment, while rapamycin pretreatment to preS1 did not affect its attachment activity, suggesting that rapamycin targets the host side. In support of this, a surface plasmon resonance analysis showed a direct interaction of rapamycin with NTCP. Consistently, rapamycin also prevented hepatitis D virus infection, whose entry into cells is also mediated by NTCP. We also identified two rapamycin derivatives, everolimus and temsirolimus, which possessed higher anti-HBV potencies than rapamycin. Thus, this is the first report for application of AlphaScreen technology that monitors a viral envelope-receptor interaction to identify viral entry inhibitors. Copyright © 2018 Elsevier Inc. All rights reserved.

Posttraumatic growth in post-surgical coronary artery bypass graft patients

PubMed Central

Waight, Catherine A; Sheridan, Judith; Tesar, Peter

2015-01-01

Recent research in posttraumatic growth has been applied to people with life-threatening illnesses to optimise recovery. There is a lack of research exploring posttraumatic growth in coronary artery bypass graft patients. This article describes the recovery experience of 14 coronary artery bypass graft patients (13 males and 1 female) at their first outpatient review post-surgery. Grounded theory analysis was used to develop a model of distinct and shared pathways to growth depending on whether patients were symptomatic or asymptomatic pre-coronary artery bypass graft. Outcomes of posttraumatic growth in this sample included action-based healthy lifestyle growth and two forms of cognitive growth: appreciation of life and new possibilities. The model of posttraumatic growth developed in this study may be helpful in guiding future research into promoting posttraumatic growth and behaviour change in coronary artery bypass graft patients. PMID:28070351

Efficacy of aprotinin with various anticoagulant agents in cardiopulmonary bypass.

PubMed

Terrell, M R; Walenga, J M; Koza, M J; Pifarré, R

1996-08-01

Aprotinin has recently been approved for clinical use in cardiopulmonary bypass. Although unfractionated heparin has been the only anticoagulant widely used for cardiopulmonary bypass, disadvantages involving heparin have led to ongoing investigations of alternative anticoagulant agents. The objective of this study was to evaluate the efficacy of aprotinin in combination with other anticoagulant agents, specifically low molecular weight heparin and recombinant hirudin, using a dog model of cardiopulmonary bypass. The blood conservation resulting from the use of aprotinin was observed only with unfractionated heparin. Efficacy of anticoagulation as measured by protein deposits in the bypass circuit filter revealed an unexpected reduction in the quantity of deposits when aprotinin was used in combination with low molecular weight heparin. As alternative anticoagulant agents are sought, the potential benefits of aprotinin in the reduction of operative blood loss must be evaluated independently for each anticoagulant agent.

40 CFR 63.307 - Standards for bypass/bleeder stacks.

Code of Federal Regulations, 2014 CFR

2014-07-01

... National Emission Standards for Coke Oven Batteries § 63.307 Standards for bypass/bleeder stacks. (a)(1.... (2) Coke oven emissions shall not be vented to the atmosphere through bypass/bleeder stacks, except.... (3) The owner or operator of a brownfield coke oven battery or a padup rebuild shall install such a...

40 CFR 63.307 - Standards for bypass/bleeder stacks.

Code of Federal Regulations, 2013 CFR

2013-07-01

... National Emission Standards for Coke Oven Batteries § 63.307 Standards for bypass/bleeder stacks. (a)(1.... (2) Coke oven emissions shall not be vented to the atmosphere through bypass/bleeder stacks, except.... (3) The owner or operator of a brownfield coke oven battery or a padup rebuild shall install such a...

40 CFR 63.307 - Standards for bypass/bleeder stacks.

Code of Federal Regulations, 2012 CFR

2012-07-01

... National Emission Standards for Coke Oven Batteries § 63.307 Standards for bypass/bleeder stacks. (a)(1.... (2) Coke oven emissions shall not be vented to the atmosphere through bypass/bleeder stacks, except.... (3) The owner or operator of a brownfield coke oven battery or a padup rebuild shall install such a...

Aerodynamic/acoustic performance of YJ101/double bypass VCE with coannular plug nozzle

NASA Technical Reports Server (NTRS)

Vdoviak, J. W.; Knott, P. R.; Ebacker, J. J.

1981-01-01

Results of a forward Variable Area Bypass Injector test and a Coannular Nozzle test performed on a YJ101 Double Bypass Variable Cycle Engine are reported. These components are intended for use on a Variable Cycle Engine. The forward Variable Area Bypass Injector test demonstrated the mode shifting capability between single and double bypass operation with less than predicted aerodynamic losses in the bypass duct. The acoustic nozzle test demonstrated that coannular noise suppression was between 4 and 6 PNdB in the aft quadrant. The YJ101 VCE equipped with the forward VABI and the coannular exhaust nozzle performed as predicted with exhaust system aerodynamic losses lower than predicted both in single and double bypass modes. Extensive acoustic data were collected including far field, near field, sound separation/ internal probe measurements as Laser Velocimeter traverses.

Tandem application of ligand-based virtual screening and G4-OAS assay to identify novel G-quadruplex-targeting chemotypes.

PubMed

Musumeci, Domenica; Amato, Jussara; Zizza, Pasquale; Platella, Chiara; Cosconati, Sandro; Cingolani, Chiara; Biroccio, Annamaria; Novellino, Ettore; Randazzo, Antonio; Giancola, Concetta; Pagano, Bruno; Montesarchio, Daniela

2017-05-01

G-quadruplex (G4) structures are key elements in the regulation of cancer cell proliferation and their targeting is deemed to be a promising strategy in anticancer therapy. A tandem application of ligand-based virtual screening (VS) calculations together with the experimental G-quadruplex on Oligo Affinity Support (G4-OAS) assay was employed to discover novel G4-targeting compounds. The interaction of the selected compounds with the investigated G4 in solution was analysed through a series of biophysical techniques and their biological activity investigated by immunofluorescence and MTT assays. A focused library of 60 small molecules, designed as putative G4 groove binders, was identified through the VS. The G4-OAS experimental screening led to the selection of 7 ligands effectively interacting with the G4-forming human telomeric DNA. Evaluation of the biological activity of the selected compounds showed that 3 ligands of this sub-library induced a marked telomere-localized DNA damage response in human tumour cells. The combined application of virtual and experimental screening tools proved to be a successful strategy to identify new bioactive chemotypes able to target the telomeric G4 DNA. These compounds may represent useful leads for the development of more potent and selective G4 ligands. Expanding the repertoire of the available G4-targeting chemotypes with improved physico-chemical features, in particular aiming at the discovery of novel, selective G4 telomeric ligands, can help in developing effective anti-cancer drugs with fewer side effects. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Copyright © 2017 Elsevier B.V. All rights reserved.

Isolation, Characterization and Identification of Environmental Bacterial Isolates with Screening for Antagonism Against Three Bacterial Targets

DTIC Science & Technology

2017-04-01

treatments. This report summarizes work conducted to identify microorganisms that exhibit narrow-spectrum activity through the secretion of...induced activity against three target strains of interest to the DoD: Bacillus anthracis Sterne, Staphylococcus aureus and Pseudomonas aeruginosa. The...percentage of environmental isolates that demonstrated activity against Bacillus anthracis Sterne was 15% (9 of 62 isolates screened), while 2% of

Virtual screening using combinatorial cyclic peptide libraries reveals protein interfaces readily targetable by cyclic peptides.

PubMed

Duffy, Fergal J; O'Donovan, Darragh; Devocelle, Marc; Moran, Niamh; O'Connell, David J; Shields, Denis C

2015-03-23

Protein-protein and protein-peptide interactions are responsible for the vast majority of biological functions in vivo, but targeting these interactions with small molecules has historically been difficult. What is required are efficient combined computational and experimental screening methods to choose among a number of potential protein interfaces worthy of targeting lead macrocyclic compounds for further investigation. To achieve this, we have generated combinatorial 3D virtual libraries of short disulfide-bonded peptides and compared them to pharmacophore models of important protein-protein and protein-peptide structures, including short linear motifs (SLiMs), protein-binding peptides, and turn structures at protein-protein interfaces, built from 3D models available in the Protein Data Bank. We prepared a total of 372 reference pharmacophores, which were matched against 108,659 multiconformer cyclic peptides. After normalization to exclude nonspecific cyclic peptides, the top hits notably are enriched for mimetics of turn structures, including a turn at the interaction surface of human α thrombin, and also feature several protein-binding peptides. The top cyclic peptide hits also cover the critical "hot spot" interaction sites predicted from the interaction crystal structure. We have validated our method by testing cyclic peptides predicted to inhibit thrombin, a key protein in the blood coagulation pathway of important therapeutic interest, identifying a cyclic peptide inhibitor with lead-like activity. We conclude that protein interfaces most readily targetable by cyclic peptides and related macrocyclic drugs may be identified computationally among a set of candidate interfaces, accelerating the choice of interfaces against which lead compounds may be screened.

Gastric bypass: why Roux-en-Y? A review of experimental data.

PubMed

Collins, Brendan J; Miyashita, Tomoharu; Schweitzer, Michael; Magnuson, Thomas; Harmon, John W

2007-10-01

To highlight the clinical and experimental rationales that support why the Roux-en-Y limb is an important surgical principle for bariatric gastric bypass. We reviewed PubMed citations for open Roux-en-Y gastric bypass (RYGBP), laparoscopic RYGBP, loop gastric bypass, chronic alkaline reflux gastritis, and duodenoesophageal reflux. We reviewed clinical and experimental articles. Clinical articles included prospective, retrospective, and case series of patients undergoing RYGBP, laparoscopic RYGBP, or loop gastric bypass. Experimental articles that were reviewed included in vivo and in vitro models of chronic duodenoesophageal reflux and its effect on carcinogenesis. No formal data extraction was performed. We reviewed published operative times, lengths of stay, and anastomotic leak rates for laparoscopic RYGBP and loop gastric bypass. For in vivo and in vitro experimental models of duodenoesophageal reflux, we reviewed the kinetics and potential molecular mechanisms of carcinogenesis. Recent data suggest that laparoscopic loop gastric bypass, performed without the creation of a Roux-en-Y gastroenterostomy, is a faster surgical technique that confers similarly robust weight loss compared with RYGBP or laparoscopic RYGBP. In the absence of a Roux limb, the long-term effects of chronic alkaline reflux are unknown. Animal models and in vitro analyses of chronic alkaline reflux suggest a carcinogenic effect.

Protein Interactions in T7 DNA Replisome Facilitate DNA Damage Bypass.

PubMed

Zou, Zhenyu; Chen, Ze; Xue, Qizhen; Xu, Ying; Xiong, Jingyuan; Yang, Ping; Le, Shuai; Zhang, Huidong

2018-06-14

DNA replisome inevitably encounters DNA damage during DNA replication. T7 DNA replisome contains DNA polymerase (gp5), the processivity factor thioredoxin (trx), helicase-primase (gp4), and ssDNA binding protein (gp2.5). T7 protein interactions mediate this DNA replication. However, whether the protein interactions could promote DNA damage bypass is still little addressed. In this study, we investigated the strand-displacement DNA synthesis past 8-oxoG or O6-MeG at the synthetic DNA fork by T7 DNA replisome. DNA damage does not obviously affect the binding affinities among helicase, polymerase, and DNA fork. Relative to unmodified G, both 8-oxoG and O6-MeG, as well as GC-rich template sequence clusters, inhibit the strand-displacement DNA synthesis and produce partial extension products. Relative to gp4 ΔC-tail, gp4 promotes the DNA damage bypass. The presence of gp2.5 further promotes this bypass. Thus, the interactions of polymerase with helicase and ssDNA binidng protein faciliate the DNA damage bypass. Similarly, accessory proteins in other complicated DNA replisomes also facilitate the DNA damage bypass. This work provides the novel mechanism information of DNA damage bypass by DNA replisome. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multi-target screening mines hesperidin as a multi-potent inhibitor: Implication in Alzheimer's disease therapeutics.

PubMed

Chakraborty, Sandipan; Bandyopadhyay, Jaya; Chakraborty, Sourav; Basu, Soumalee

2016-10-04

Alzheimer's disease (AD) is the most frequent form of neurodegenerative disorder in elderly people. Involvement of several pathogenic events and their interconnections make this disease a complex disorder. Therefore, designing compounds that can inhibit multiple toxic pathways is the most attractive therapeutic strategy in complex disorders like AD. Here, we have designed a multi-tier screening protocol combining ensemble docking to mine BACE1 inhibitor, as well as 2-D QSAR models for anti-amyloidogenic and antioxidant activities. An in house developed phytochemical library of 200 phytochemicals has been screened through this multi-target procedure which mine hesperidin, a flavanone glycoside commonly found in citrus food items, as a multi-potent phytochemical in AD therapeutics. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of hesperidin to the active site of BACE1 induces a conformational transition of the protein from open to closed form. Hesperidin docks close to the catalytic aspartate residues and orients itself in a way that blocks the cavity opening thereby precluding substrate binding. Hesperidin is a high affinity BACE1 inhibitor and only 500 nM of the compound shows complete inhibition of the enzyme activity. Furthermore, ANS and Thioflavin-T binding assay show that hesperidin completely inhibits the amyloid fibril formation which is further supported by atomic force microscopy. Hesperidin exhibits moderate ABTS(+) radical scavenging assay but strong hydroxyl radical scavenging ability, as evident from DNA nicking assay. Present study demonstrates the applicability of a novel multi-target screening procedure to mine multi-potent agents from natural origin for AD therapeutics. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Reverse bias protected solar array with integrated bypass battery

NASA Technical Reports Server (NTRS)

Landis, Geoffrey A (Inventor)

2012-01-01

A method for protecting the photovoltaic cells in a photovoltaic (PV) array from reverse bias damage by utilizing a rechargeable battery for bypassing current from a shaded photovoltaic cell or group of cells, avoiding the need for a bypass diode. Further, the method mitigates the voltage degradation of a PV array caused by shaded cells.

Travel burden and dentist bypass among dentally insured children.

PubMed

McKernan, Susan C; Pooley, Mark J; Momany, Elizabeth T; Kuthy, Raymond A

2016-06-01

Using administrative data from Iowa Medicaid and a large private dental insurer, we compared distance to the nearest primary care dentist for children ages 6-15 in 2012. Additionally, we examined rates of provider bypass in both populations as an indicator of spatial accessibility to dental care. We calculated measures of travel burden, including distance to the nearest primary care dentist and distance to current primary care dentist. Distance outcomes and rates of bypass, traveling beyond the nearest dentist for care, were compared by insurance type. We found that Medicaid-enrolled children lived farther from the nearest dentist and farther from their current dentist than privately insured children. However, rates of bypass were higher among the privately insured population. These results were consistent among urban and rural residents; additionally, both rural populations demonstrated greater travel distances than urban dwellers. Travel burden was greater among Medicaid-enrolled children. Lower rates of bypass, in conjunction with lower rates of dental utilization in this population, may indicate a distance threshold beyond which dental care becomes unattainable. © 2016 American Association of Public Health Dentistry.

Postoperative enlargement and prognostic effects of portal venous bypass grafts in children undergoing Rex shunt.

PubMed

Zhang, Jin-Shan; Li, Long; Cheng, Wei

2018-05-22

Patency of the bypass vein after a Rex shunt is an important indicator of prognosis. However, there is no report about the change of caliber of the bypass vein after a Rex shunt. The aim of this study was to identify postoperative changes of the bypass vein and to assess the relationship with prognosis. Between October 2008 and October 2016 in our center, 114 children were diagnosed with extrahepatic portal venous obstruction. The portal cavernoma-portal bypass with interposition of grafted portal vessels was performed in 31 children, the gastroportal shunt was performed in 54 children, and other Rex shunts were performed in another 29 children. At follow-up, the patency and diameter of the bypass vein were assessed with ultrasound and computed tomography. The intraoperative and postoperative diameters of the bypass vein were compared to identify postoperative changes of the bypass vein. Prognosis was compared between children with and children without an enlarged bypass vein. The caliber of the bypass vein was enlarged in 50% of children (40/80) at 6 months postoperatively. The postoperative incidences of rebleeding and esophageal varices were significantly lower in children with an enlarged bypass vein than in those without (P < .05). Postoperatively, the reduced splenic size was significantly higher in children with an enlarged bypass vein than in those without (P < .05). The postoperative increase in platelet count in children with an enlarged bypass vein was significantly higher than in those without (P = .006). There was no significant difference in the flow velocity of the bypass vein between children with and children without an enlarged bypass vein (P = .133). The portal pressure was significantly reduced after surgery in children with an enlarged bypass vein than in children without an enlarged bypass vein (P = .017). The caliber of the bypass vein increases in 50% of children after a Rex shunt using a grafted portal vessel, which is related to a

Rankine cycle condenser pressure control using an energy conversion device bypass valve

DOEpatents

Ernst, Timothy C; Nelson, Christopher R; Zigan, James A

2014-04-01

The disclosure provides a waste heat recovery system and method in which pressure in a Rankine cycle (RC) system of the WHR system is regulated by diverting working fluid from entering an inlet of an energy conversion device of the RC system. In the system, an inlet of a controllable bypass valve is fluidly coupled to a working fluid path upstream of an energy conversion device of the RC system, and an outlet of the bypass valve is fluidly coupled to the working fluid path upstream of the condenser of the RC system such that working fluid passing through the bypass valve bypasses the energy conversion device and increases the pressure in a condenser. A controller determines the temperature and pressure of the working fluid and controls the bypass valve to regulate pressure in the condenser.

Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass.

PubMed

Nguyen, Bao; Luong, Le; Naase, Hatam; Vives, Marc; Jakaj, Gentjan; Finch, Jonathan; Boyle, Joseph; Mulholland, John W; Kwak, Jong-hwan; Pyo, Suhkneung; de Luca, Amalia; Athanasiou, Thanos; Angelini, Gianni; Anderson, Jon; Haskard, Dorian O; Evans, Paul C

2014-08-01

Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood. A porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells. Surgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury. Systemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Immobilized magnetic beads-based multi-target affinity selection coupled with HPLC-MS for screening active compounds from traditional Chinese medicine and natural products.

PubMed

Chen, Yaqi; Chen, Zhui; Wang, Yi

2015-01-01

Screening and identifying active compounds from traditional Chinese medicine (TCM) and other natural products plays an important role in drug discovery. Here, we describe a magnetic beads-based multi-target affinity selection-mass spectrometry approach for screening bioactive compounds from natural products. Key steps and parameters including activation of magnetic beads, enzyme/protein immobilization, characterization of functional magnetic beads, screening and identifying active compounds from a complex mixture by LC/MS, are illustrated. The proposed approach is rapid and efficient in screening and identification of bioactive compounds from complex natural products.

Blood glucose screening among elderly Malaysians: Who to target?

PubMed

Cheah, Yong Kang; Goh, Kim-Leng

2017-01-01

Early detection of raised blood glucose can reduce the risk of developing diabetes. Despite being a high-risk group, a significant proportion of the elderly population does not undergo blood glucose screening. The aim of the present study was to examine the factors affecting blood glucose screening among the elderly. Data from a sample of 2463 respondents in the National Health and Morbidity Survey 2011 were used. Pearson Chi-squared tests were conducted to find factors associated with screening behavior. A logit model was used to analyze the likelihood of screening. Income, age, education, ethnicity, employment status, availability of medical coverage, and smoking behavior were significantly associated with blood glucose screening. The likelihood of blood glucose screening was positively correlated with available monthly income and was higher in those aged 60-69 years, those attaining higher education, Malays, and elderly who are medically covered. The findings of the present study provide insights for health policy formulation for the elderly. As part of their efforts to reduce national health costs, governments should pay particular attention to the elderly, who are likely to be unscreened for blood glucose levels, because they face even larger risk exposure. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Cost-utility analysis comparing laparoscopic vs open aortobifemoral bypass surgery.

PubMed

Krog, Anne Helene; Sahba, Mehdi; Pettersen, Erik M; Wisløff, Torbjørn; Sundhagen, Jon O; Kazmi, Syed Sh

2017-01-01

Laparoscopic aortobifemoral bypass has become an established treatment option for symptomatic aortoiliac obstructive disease at dedicated centers. Minimally invasive surgical techniques like laparoscopic surgery have often been shown to reduce expenses and increase patients' health-related quality of life. The main objective of our study was to measure quality-adjusted life years (QALYs) and costs after totally laparoscopic and open aortobifemoral bypass. This was a within trial analysis in a larger ongoing randomized controlled prospective multicenter trial, Norwegian Laparoscopic Aortic Surgery Trial. Fifty consecutive patients suffering from symptomatic aortoiliac occlusive disease suitable for aortobifemoral bypass surgery were randomized to either totally laparoscopic (n=25) or open surgical procedure (n=25). One patient dropped out of the study before surgery. We measured health-related quality of life using the EuroQol (EQ-5D-5L) questionnaire at 4 different time points, before surgery and for 6 months during follow-up. We calculated the QALYs gained by using the area under the curve for both groups. Costs were calculated based on prices for surgical equipment, vascular prosthesis and hospital stay. We found a significantly higher increase in QALYs after laparoscopic vs open aortobifemoral bypass surgery, with a difference of 0.07 QALYs, ( p =0.001) in favor of laparoscopic aortobifemoral bypass. The total cost of surgery, equipment and hospital stay after laparoscopic surgery (9,953 €) was less than open surgery (17,260 €), ( p =0.001). Laparoscopic aortobifemoral bypass seems to be cost-effective compared with open surgery, due to an increase in QALYs and lower procedure-related costs.

Cerebroprotective effect of piracetam in patients undergoing coronary bypass burgery.

PubMed

Holinski, Sebastian; Claus, Benjamin; Alaaraj, Nour; Dohmen, Pascal Maria; Kirilova, Kremena; Neumann, Konrad; Uebelhack, Ralf; Konertz, Wolfgang

2008-11-01

Reduction of cognitive function is a possible side effect after cardiac surgery using cardiopulmonary bypass. We investigated the cerebroprotective effect of piracetam on cognitive performance in patients undergoing coronary artery bypass surgery under cardiopulmonary bypass. Patients scheduled for elective, primary and isolated coronary bypass surgery were randomised either to piracetam or placebo group. The study was performed in a double blind fashion. Patients received either 12 g piracetam or placebo at the beginning of the operation. Six neuropsychological subtests from the Syndrom Kurz Test and the Alzheimer's Disease Assessment Scale were performed preoperatively and on the third postoperative day. To assess the overall cognitive function and the degree of cognitive decline across all tests after surgery we combined the six test-scores by principal component analysis. A total number of 120 patients were enrolled into the study. Preoperative overall cognitive function were not significantly different between the groups. The postoperative combined score of the neuropsychological tests showed a deterioration of cognitive function in both groups (placebo-pre: -0.06+/-0.99 vs placebo-post: -1.38+/-1.11; p<0.0005 and piracetam-pre: 0.06+/-1.02 vs piracetam-post: -0.65+/-0.93; p<0.0005). However, the piracetam patients performed significantly better compared to the placebo patients after the operation and had a less decline of overall cognitive function (p<0.0005). Piracetam has a cerebroprotective effect in patients undergoing coronary artery bypass surgery with the use of cardiopulmonary bypass. It reduces an early postoperative substantial decline of neuropsychological abilities.

Biliary bypass surgery - Analysis of indications & outcome of different procedures.

PubMed

Hussain Talpur, K Altaf; Mahmood Malik, Arshad; Iqbal Memon, Amir; Naeem Qureshi, Jawed; Khan Sangrasi, Ahmed; Laghari, Abdul Aziz

2013-05-01

This study reports the indications and outcome of various biliary bypass surgical procedures from a single centre over a period of 10 years. This is a prospective observational study conducted over a period of 10 years (January 2001-december 2010). A total of 1500 patients were included, who underwent pancreatico-biliary surgery due to common bile duct (CBD) stones, congenital anomalies of biliary tree, unoperable pancreatico-biliary malignancies, CBD strictures and cases who developed iatrogenic biliary injuries during cholecystectomy (both open & laproscopic) during this period of time. The patients who required biliary bypass surgery were further analysed for indications and outcome. Out of 1500 patients 83(5.53%) required biliary bypass surgical procedures. The CBD stones were observed as the most common indication (25.3%), followed by CBD injuries after open(10.84%) or laproscopic-cholecystectomy (14.46%), carcinoma head of pancreas (12.05%) and CBD obstruction(14.46%) either due to CBD strictures or unknown distal obstruction. Roux-en-Y-hepatico-jejunostomy (26.51%) was the most frequently performed procedure, followed by choledochoduodenostomy and Roux-en-Y choledocho-jejunostomy (i.e. 25.3% and 12.05% respectively). Roux-en-Y biliary bypass procedure was observed to be associated with better outcome in terms of rate of complications as well duration of hospital stay. Biliary bypass surgical procedures are the better options to restore the continuity of biliary system in patients with iatrogenic biliary tree injuries and un-operable pancreatico-biliary malignancy. Roux-en-Y biliary bypass procedure is safe and problem solving method in these cases.

Robust Bayesian Algorithm for Targeted Compound Screening in Forensic Toxicology.

PubMed

Woldegebriel, Michael; Gonsalves, John; van Asten, Arian; Vivó-Truyols, Gabriel

2016-02-16

As part of forensic toxicological investigation of cases involving unexpected death of an individual, targeted or untargeted xenobiotic screening of post-mortem samples is normally conducted. To this end, liquid chromatography (LC) coupled to high-resolution mass spectrometry (MS) is typically employed. For data analysis, almost all commonly applied algorithms are threshold-based (frequentist). These algorithms examine the value of a certain measurement (e.g., peak height) to decide whether a certain xenobiotic of interest (XOI) is present/absent, yielding a binary output. Frequentist methods pose a problem when several sources of information [e.g., shape of the chromatographic peak, isotopic distribution, estimated mass-to-charge ratio (m/z), adduct, etc.] need to be combined, requiring the approach to make arbitrary decisions at substep levels of data analysis. We hereby introduce a novel Bayesian probabilistic algorithm for toxicological screening. The method tackles the problem with a different strategy. It is not aimed at reaching a final conclusion regarding the presence of the XOI, but it estimates its probability. The algorithm effectively and efficiently combines all possible pieces of evidence from the chromatogram and calculates the posterior probability of the presence/absence of XOI features. This way, the model can accommodate more information by updating the probability if extra evidence is acquired. The final probabilistic result assists the end user to make a final decision with respect to the presence/absence of the xenobiotic. The Bayesian method was validated and found to perform better (in terms of false positives and false negatives) than the vendor-supplied software package.

Pharmacokinetics of ε-Aminocaproic Acid in Neonates Undergoing Cardiac Surgery with Cardiopulmonary Bypass.

PubMed

Eaton, Michael P; Alfieris, George M; Sweeney, Dawn M; Angona, Ronald E; Cholette, Jill M; Venuto, Charles; Anderson, Brian

2015-05-01

Antifibrinolytic medications such as ε-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h × (WT/70). Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg · kg · h, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults.

Forensic investigation of concrete pavement : U.S. 460, Appomattox Bypass.

DOT National Transportation Integrated Search

2005-01-01

This report describes the investigation of structural failure in a section of the Appomattox Bypass along U.S. 460 in the town of Appomattox, Virginia. The bypass is a four-lane divided highway. The section that was investigated is an 11-year-old sec...

Bypass of a Nick by the Replisome of Bacteriophage T7*

PubMed Central

Zhu, Bin; Lee, Seung-Joo; Richardson, Charles C.

2011-01-01

DNA polymerase and DNA helicase are essential components of DNA replication. The helicase unwinds duplex DNA to provide single-stranded templates for DNA synthesis by the DNA polymerase. In bacteriophage T7, movement of either the DNA helicase or the DNA polymerase alone terminates upon encountering a nick in duplex DNA. Using a minicircular DNA, we show that the helicase·polymerase complex can bypass a nick, albeit at reduced efficiency of 7%, on the non-template strand to continue rolling circle DNA synthesis. A gap in the non-template strand cannot be bypassed. The efficiency of bypass synthesis depends on the DNA sequence downstream of the nick. A nick on the template strand cannot be bypassed. Addition of T7 single-stranded DNA-binding protein to the complex stimulates nick bypass 2-fold. We propose that the association of helicase with the polymerase prevents dissociation of the helicase upon encountering a nick, allowing the helicase to continue unwinding of the duplex downstream of the nick. PMID:21701044

Rural health care bypass behavior: how community and spatial characteristics affect primary health care selection.

PubMed

Sanders, Scott R; Erickson, Lance D; Call, Vaughn R A; McKnight, Matthew L; Hedges, Dawson W

2015-01-01

(1) To assess the prevalence of rural primary care physician (PCP) bypass, a behavior in which residents travel farther than necessary to obtain health care, (2) To examine the role of community and non-health-care-related characteristics on bypass behavior, and (3) To analyze spatial bypass patterns to determine which rural communities are most affected by bypass. Data came from the Montana Health Matters survey, which gathered self-reported information from Montana residents on their health care utilization, satisfaction with health care services, and community and demographic characteristics. Logistic regression and spatial analysis were used to examine the probability and spatial patterns of bypass. Overall, 39% of respondents bypass local health care. Similar to previous studies, dissatisfaction with local health care was found to increase the likelihood of bypass. Dissatisfaction with local shopping also increases the likelihood of bypass, while the number of friends in a community, and commonality with community reduce the likelihood of bypass. Other significant factors associated with bypass include age, income, health, and living in a highly rural community or one with high commuting flows. Our results suggest that outshopping theory, in which patients bundle services and shopping for added convenience, extends to primary health care selection. This implies that rural health care selection is multifaceted, and that in addition to perceived satisfaction with local health care, the quality of local shopping and levels of community attachment also influence bypass behavior. © 2014 National Rural Health Association.

Intraoperative sonographic assessment of graft patency during extracranial-intracranial bypass.

PubMed

Badie, B; Lee, F T; Pozniak, M A; Strother, C M

2000-09-01

Extracranial-intracranial (EC-IC) bypass may be necessary to facilitate treatment of unclippable posterior circulation fusiform aneurysms. Although intraoperative digital subtraction angiography (DSA) allows assessment of graft patency, this technique, because of difficulties inherent in performing selective catheterization and angiography in the operating room, has limitations. Duplex sonography, in contrast, is easily performed, and provides information regarding graft patency and blood flow direction during EC-IC bypass procedures. This latter information proved useful in determining the time of parent artery occlusion after two EC-IC bypass procedures performed for treatment of a fusiform midbasilar artery aneurysm.

Cardiopulmonary bypass with bivalirudin in type II heparin-induced thrombocytopenia.

PubMed

Clayton, Stephanie B; Acsell, Jeffrey R; Crumbley, Arthur J; Uber, Walter E

2004-12-01

Cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia poses significant challenges. Inadequate pharmacokinetic profiles, monitoring, reversibility, and availability often limit alternative anticoagulation strategies. Bivalirudin, a semisynthetic direct thrombin inhibitor, was recently approved for use in patients undergoing percutaneous coronary interventions. Its unique properties, including a relatively short half-life, an anticoagulation effect that closely correlates with activated clotting time, and an alternate metabolic pathway for elimination, make bivalirudin an attractive agent for cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia. We report our experience using bivalirudin in 2 patients undergoing coronary artery bypass grafting.

[Targeted newborn screening for sickle-cell anemia: Sickling test (Emmel test) boundaries in the prenatal assessment in West African area].

PubMed

Diallo, D A; Guindo, A; Touré, B A; Sarro, Y S; Sima, M; Tessougué, O; Baraika, M A; Guindo, P; Traoré, M; Diallo, M; Dorie, A

2018-05-01

Newborn screening for sickle cell anemia is necessary in Africa where the disease is more frequent. Hemoglobin electrophoresis is used for screening, but is limited by a high cost and difficult access. Sickling test (Emmel test), which is more affordable and technically more accessible, is often requested for prenatal assessment of pregnant women in West African areas to reserve screening for newborns from mothers in whom the positive sickling test attests the presence of hemoglobin S. This study aims to evaluate the number of undetected sickle cell anemia newborns by a screening policy targeting only newborns from mothers in whom a sickling test would have been positive. From 2010 to 2012, in Bamako, Mali, West Africa, 2489 newborns were routinely screened for sickle cell anemia at the umbilical cord or heel by isoelectrofocusing and, if necessary, by high-performance liquid chromatography. These newborns were born from 2420 mothers whose hemoglobin was studied by isoelectrofocusing. The data was recorded and processed using Excel software version 14.0.0. We calculated the frequency of the sickle cell gene in mothers and newborns as well as the number of SCA newborns from heterozygous or C homozygous mothers. Of the 2489 newborns, 16 had sickle cell anemia (6 SS and 10 SC); 198 had the sickle cell trait; 139 were AC and 1 was CC. Of the 10 newborns with SC profile, 3 were born from mothers not carrying the S gene but the C gene of hemoglobin and in which an Emmel test would have been negative. Targeted newborn screening, based on the results of sickling test in pregnant women, would misdiagnose more than one of six sickle cell anemia newborns who would not benefit from early care. Cost-effectiveness studies of routine newborn screening for sickle cell anemia should lead to a better screening strategy in contexts where hemoglobin S and other hemoglobin defect genes coexist. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Role of cytokine hemoadsorption in cardiopulmonary bypass-induced ventricular dysfunction in a porcine model.

PubMed

Vocelka, Craig R; Jones, Krystal M; Mikhova, Krasimira M; Ebisu, Ryan M; Shar, Ashley; Kellum, John A; Verrier, Edward D; Rabkin, David G

2013-12-01

Little is known about the effect of cardiopulmonary bypass alone on cardiac function; in an attempt to illuminate this relationship and test a possible mechanism, we used Cytosorb, a device capable of removing virtually all types of circulating cytokines to test the hypothesis that hemoadsorption of cytokines during bypass attenuates bypass-induced acute organ dysfunction. Twelve Yorkshire pigs (50-65 kg) were instrumented with a left ventricular conductance catheter. Baseline mechanics and cytokine expression (tumor necrosis factor [TNF], interleukin-6 [IL-6], and interleukin-10) were measured before and hourly after 1 hour of normothermic cardiopulmonary bypass. Animals underwent bypass without (cardiopulmonary bypass [CPB], n = 6) or with (CPB+HA, n = 6) the CytosorbTM device. Data were compared with "historical" controls (n = 6) that were similarly instrumented but underwent observation instead of bypass. Five hours after separation from bypass (or observation), animals were euthanized. Myocardial water content was determined postmortem. Neither TNF nor IL-6 was significantly elevated in either experimental group versus controls at any time point. Preload recruitable stroke work and dP/dtmax were significantly depressed immediately after separation from bypass in both CPB+HA and CPB and remained depressed for the duration of the experiment. Although Tau remained unchanged, dP/dTmin was significantly diminished in both bypass groups at all time points after separation from bypass. Cytokine hemoadsorption had no effect on any measurable index of function. Differences in postmortem data were not evident between groups. One hour of normothermic CPB results in a significant and sustained decline in left ventricular function that appears unrelated to changes in cytokine expression. Because we did not appreciate a significant change in cytokine concentrations postbypass, the capacity of cytokine hemoadsorption to attenuate CPB-induced ventricular dysfunction could not

Active bypass flow control for a seal in a gas turbine engine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ebert, Todd A.; Kimmel, Keith D.

An active bypass flow control system for controlling bypass compressed air based upon leakage flow of compressed air flowing past an outer balance seal between a stator and rotor of a first stage of a gas turbine in a gas turbine engine is disclosed. The active bypass flow control system is an adjustable system in which one or more metering devices may be used to control the flow of bypass compressed air as the flow of compressed air past the outer balance seal changes over time as the outer balance seal between the rim cavity and the cooling cavity wears.more » In at least one embodiment, the metering device may include a valve formed from one or more pins movable between open and closed positions in which the one pin at least partially bisects the bypass channel to regulate flow.« less

Screening of broad spectrum natural pesticides against conserved target arginine kinase in cotton pests by molecular modeling.

PubMed

Sakthivel, Seethalakshmi; Habeeb, S K M; Raman, Chandrasekar

2018-03-12

Cotton is an economically important crop and its production is challenged by the diversity of pests and related insecticide resistance. Identification of the conserved target across the cotton pest will help to design broad spectrum insecticide. In this study, we have identified conserved sequences by Expressed Sequence Tag profiling from three cotton pests namely Aphis gossypii, Helicoverpa armigera, and Spodoptera exigua. One target protein arginine kinase having a key role in insect physiology and energy metabolism was studied further using homology modeling, virtual screening, molecular docking, and molecular dynamics simulation to identify potential biopesticide compounds from the Zinc natural database. We have identified four compounds having excellent inhibitor potential against the identified broad spectrum target which are highly specific to invertebrates.

Heart bypass surgery - minimally invasive - discharge

MedlinePlus

... thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2 ... bypass surgery - minimally invasive Heart failure - overview High blood cholesterol ...

Is phonology bypassed in normal or dyslexic development?

PubMed

Pennington, B F; Lefly, D L; Van Orden, G C; Bookman, M O; Smith, S D

1987-01-01

A pervasive assumption in most accounts of normal reading and spelling development is that phonological coding is important early in development but is subsequently superseded by faster, orthographic coding which bypasses phonology. We call this assumption, which derives from dual process theory, the developmental bypass hypothesis. The present study tests four specific predictions of the developmental bypass hypothesis by comparing dyslexics and nondyslexics from the same families in a cross-sectional design. The four predictions are: 1) That phonological coding skill develops early in normal readers and soon reaches asymptote, whereas orthographic coding skill has a protracted course of development; 2) that the correlation of adult reading or spelling performance with phonological coding skill is considerably less than the correlation with orthographic coding skill; 3) that dyslexics who are mainly deficient in phonological coding skill should be able to bypass this deficit and eventually close the gap in reading and spelling performance; and 4) that the greatest differences between dyslexics and developmental controls on measures of phonological coding skill should be observed early rather than late in development.None of the four predictions of the developmental bypass hypothesis were upheld. Phonological coding skill continued to develop in nondyslexics until adulthood. It accounted for a substantial (32-53 percent) portion of the variance in reading and spelling performance in adult nondyslexics, whereas orthographic coding skill did not account for a statistically reliable portion of this variance. The dyslexics differed little across age in phonological coding skill, but made linear progress in orthographic coding skill, surpassing spelling-age (SA) controls by adulthood. Nonetheless, they didnot close the gap in reading and spelling performance. Finally, dyslexics were significantly worse than SA (and Reading Age [RA]) controls in phonological coding skill

Fragment Screening and HIV Therapeutics

PubMed Central

Bauman, Joseph D.; Patel, Disha; Arnold, Eddy

2013-01-01

Fragment screening has proven to be a powerful alternative to traditional methods for drug discovery. Biophysical methods, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance, are used to screen a diverse library of small molecule compounds. Although compounds identified via this approach have relatively weak affinity, they provide a good platform for lead development and are highly efficient binders with respect to their size. Fragment screening has been utilized for a wide-range of targets, including HIV-1 proteins. Here, we review the fragment screening studies targeting HIV-1 proteins using X-ray crystallography or surface plasmon resonance. These studies have successfully detected binding of novel fragments to either previously established or new sites on HIV-1 protease and reverse transcriptase. In addition, fragment screening against HIV-1 reverse transcriptase has been used as a tool to better understand the complex nature of ligand binding to a flexible target. PMID:21972022

Femorofemoral bypass grafting in high-risk patients.

PubMed

Deruyter, L; Caes, F; Van den Brande, P; Cham, B; Welch, W

1986-01-01

A total of 37 extra-anatomic femorofemoral bypasses were inserted for severe unilateral iliac artery stenosis or a thrombosed graft limb of an aorto-bifemoral bifurcation graft. All patients were severely debilitated and at high risk for direct aorto-iliac reconstruction. 30% suffered severe claudication; 70% had ischemic restpain or trophic lesions. 43% died during a mean follow-up period of 17 months. This study demonstrates that the extra-anatomic femoro-femoral bypass procedure is an effective alternative therapeutic modality for high-risk patients with an acceptable operative mortality (5.4%) and morbidity to improve the quality of life.

The Development of Target-Specific Pose Filter Ensembles To Boost Ligand Enrichment for Structure-Based Virtual Screening.

PubMed

Xia, Jie; Hsieh, Jui-Hua; Hu, Huabin; Wu, Song; Wang, Xiang Simon

2017-06-26

Structure-based virtual screening (SBVS) has become an indispensable technique for hit identification at the early stage of drug discovery. However, the accuracy of current scoring functions is not high enough to confer success to every target and thus remains to be improved. Previously, we had developed binary pose filters (PFs) using knowledge derived from the protein-ligand interface of a single X-ray structure of a specific target. This novel approach had been validated as an effective way to improve ligand enrichment. Continuing from it, in the present work we attempted to incorporate knowledge collected from diverse protein-ligand interfaces of multiple crystal structures of the same target to build PF ensembles (PFEs). Toward this end, we first constructed a comprehensive data set to meet the requirements of ensemble modeling and validation. This set contains 10 diverse targets, 118 well-prepared X-ray structures of protein-ligand complexes, and large benchmarking actives/decoys sets. Notably, we designed a unique workflow of two-layer classifiers based on the concept of ensemble learning and applied it to the construction of PFEs for all of the targets. Through extensive benchmarking studies, we demonstrated that (1) coupling PFE with Chemgauss4 significantly improves the early enrichment of Chemgauss4 itself and (2) PFEs show greater consistency in boosting early enrichment and larger overall enrichment than our prior PFs. In addition, we analyzed the pairwise topological similarities among cognate ligands used to construct PFEs and found that it is the higher chemical diversity of the cognate ligands that leads to the improved performance of PFEs. Taken together, the results so far prove that the incorporation of knowledge from diverse protein-ligand interfaces by ensemble modeling is able to enhance the screening competence of SBVS scoring functions.

Esophageal bypass operation prior to definitive chemoradiotherapy in advanced esophageal cancer with tracheobronchial invasion.

PubMed

Hihara, Jun; Hamai, Yoichi; Emi, Manabu; Aoki, Yoshiro; Taomoto, Junya; Miyata, Yoshihiro; Okada, Morihito

2014-01-01

In T4 esophageal cancer with tracheobronchial invasion, an esophagorespiratory fistula (ERF) often occurs during or after chemoradiotherapy. We have performed esophageal bypass operations prior to definitive chemoradiotherapy for these patients to increase the chemoradiotherapy completion rate by minimizing the potential effect of an ERF. The aim of this study was to examine the clinical outcome of esophageal bypass surgery prior to chemoradiotherapy. Between 1997 and 2010, 17 patients underwent esophageal bypass surgery followed by definitive chemoradiotherapy for esophageal cancer with tracheobronchial invasion (bypass group). Ten patients in the same circumstances were treated with chemoradiotherapy alone (control group). Overall survival, the clinical effect of chemoradiotherapy, the ERF incidence rate, and the safety of esophageal bypass surgery were assessed. The overall response rate to chemoradiotherapy was 64.7% in the bypass group and 90.0% in the control group. Except for 2 patients with ERF at initial diagnosis, 4 (26.7%) of the 15 patients developed ERF in the bypass group, and 3 (30.0%) of the 10 patients developed ERF in the control group during or after chemoradiotherapy. The 2-year and 3-year overall survival rates were 17.6% and 17.6% in the bypass group and 20.0% and 0% in the control group, respectively (p = 0.924); long-term survival of more than 3 years was seen only in the bypass group. Esophageal bypass surgery prior to definitive chemoradiotherapy could be performed safely, and this strategy contributed to long-term survival in the patients who achieved a good response to chemoradiotherapy but developed an ERF. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Cost-utility analysis comparing laparoscopic vs open aortobifemoral bypass surgery

PubMed Central

Krog, Anne Helene; Sahba, Mehdi; Pettersen, Erik M; Wisløff, Torbjørn; Sundhagen, Jon O; Kazmi, Syed SH

2017-01-01

Objectives Laparoscopic aortobifemoral bypass has become an established treatment option for symptomatic aortoiliac obstructive disease at dedicated centers. Minimally invasive surgical techniques like laparoscopic surgery have often been shown to reduce expenses and increase patients’ health-related quality of life. The main objective of our study was to measure quality-adjusted life years (QALYs) and costs after totally laparoscopic and open aortobifemoral bypass. Patients and methods This was a within trial analysis in a larger ongoing randomized controlled prospective multicenter trial, Norwegian Laparoscopic Aortic Surgery Trial. Fifty consecutive patients suffering from symptomatic aortoiliac occlusive disease suitable for aortobifemoral bypass surgery were randomized to either totally laparoscopic (n=25) or open surgical procedure (n=25). One patient dropped out of the study before surgery. We measured health-related quality of life using the EuroQol (EQ-5D-5L) questionnaire at 4 different time points, before surgery and for 6 months during follow-up. We calculated the QALYs gained by using the area under the curve for both groups. Costs were calculated based on prices for surgical equipment, vascular prosthesis and hospital stay. Results We found a significantly higher increase in QALYs after laparoscopic vs open aortobifemoral bypass surgery, with a difference of 0.07 QALYs, (p=0.001) in favor of laparoscopic aortobifemoral bypass. The total cost of surgery, equipment and hospital stay after laparoscopic surgery (9,953 €) was less than open surgery (17,260 €), (p=0.001). Conclusion Laparoscopic aortobifemoral bypass seems to be cost-effective compared with open surgery, due to an increase in QALYs and lower procedure-related costs. PMID:28670132

Heart bypass surgery - minimally invasive

MedlinePlus

... MIDCAB; Robot-assisted coronary artery bypass; RACAB; Keyhole heart surgery; CAD - MIDCAB; Coronary artery disease - MIDCAB ... To perform this surgery: The heart surgeon will make a 3- to 5-inch (8 to 13 centimeters) surgical cut in the left part of your chest ...

Autologous alternative veins may not provide better outcomes than prosthetic conduits for below-knee bypass when great saphenous vein is unavailable.

PubMed

Avgerinos, Efthymios D; Sachdev, Ulka; Naddaf, Abdallah; Doucet, Dannielle R; Mohapatra, Abhisekh; Leers, Steven A; Chaer, Rabih A; Makaroun, Michel S

2015-08-01

There is a need to better define the role of alternative autologous vein (AAV) segments over contemporary prosthetic conduits in patients with critical limb ischemia when great saphenous vein (GSV) is not available for use as the bypass conduit. Consecutive patients who underwent bypass to infrageniculate targets between 2007 and 2011 were categorized in three groups: GSV, AAV, and prosthetic. The primary outcome was graft patency. The secondary outcome was limb salvage. Cox proportional hazards regression was used to adjust for baseline confounding variables. A total of 407 infrainguinal bypasses to below-knee targets were analyzed; 255 patients (63%) received a single-segment GSV, 106 patients (26%) received an AAV, and 46 patients (11%) received a prosthetic conduit. Baseline characteristics were similar among groups, with the exception of popliteal targets and anticoagulation use being more frequent in the prosthetic group. Primary patency at 2 and 5 years was estimated at 47% and 32%, respectively, for the GSV group; 24% and 23% for the AAV group; and 43% and 38% for the prosthetic group. Primary assisted patency at 2 and 5 years was estimated at 71% and 55%, respectively, for the GSV group; 53% and 51% for the AAV group; and 45% and 40% for the prosthetic group. Secondary patency at 2 and 5 years was estimated at 75% and 60%, respectively, for the GSV group; 57% and 55% for the AAV group; and 46% and 41% for the prosthetic group. In Cox analysis, primary patency (hazard ratio [HR], 0.55; P < .001; 95% confidence interval [CI], 0.404-0.758), primary assisted patency (HR, 0.57; P = .004; 95% CI, 0.388-0.831), and secondary patency (HR, 0.56; P = .005; 95% CI, 0.372-0.840) were predicted by GSV compared with AAV, but there was no difference between AAV and prosthetic grafts except for the primary patency, for which prosthetic was protective (HR, 0.38; P < .001; 95% CI, 0.224-0.629). Limb salvage was similar among groups. AAV conduits may not offer a significant

Applications of chemogenomic library screening in drug discovery.

PubMed

Jones, Lyn H; Bunnage, Mark E

2017-04-01

The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

PubMed Central

Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

2012-01-01

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID:21814200

Bypass transition in boundary layers including curvature and favorable pressure gradient effects

NASA Technical Reports Server (NTRS)

Volino, R. J.; Simon, T. W.

1991-01-01

Recent studies of 2-D boundary layers undergoing bypass transition were reviewed. Bypass transition is characterized by the sudden appearance of turbulent spots in boundary layer without first the regular, observable growth of disturbances predicted by linear stability theory. There are no standard criteria or parameters for defining bypass transition, but it is known to be the mode of transition when the flow is disturbed by perturbations of sufficient amplitude.

Temporary diabetes insipidus in 2 men after on-pump coronary artery bypass grafting.

PubMed

Uyar, Ihsan Sami; Sahin, Veysel; Akpinar, Besir; Yurtman, Volkan; Abacilar, Feyzi; Okur, Faik Fevzi; Ates, Mehmet

2013-01-01

Many complications have been reported after cardiopulmonary bypass. A common physiologic change during the early postoperative period after cardiopulmonary bypass is increased diuresis. In patients whose urine output is increased, postoperative diabetes insipidus can develop, although reports of this are rare. We present the cases of 2 patients who underwent on-pump coronary artery bypass grafting (with cardiopulmonary bypass). Each was diagnosed with diabetes insipidus postoperatively: a 54-year-old man on the 3rd day, and a 66-year-old man on the 4th day. Each patient recovered from the condition after 6 hours of intranasal therapy with synthetic vasopressin (antidiuretic hormone). The diagnosis of diabetes insipidus should be considered in patients who produce excessive urine early after cardiac surgery in which cardiopulmonary bypass has been used.

The Golden bypass landslide, Golden, Colorado

USGS Publications Warehouse

Highland, L.M.; Brown, W. M.

1993-01-01

Slope instability along a new highway bypass in Golden, Colorado, became a major concern in 1993. Rains and snowmelt accelerated movement of a landslide that had begun to develop before the bypass was opened to traffic in July of 1991. The downslope movement of earth materials increased significantly in 1993. During the first few months of the year, the landslide pushed onto the west shoulder of the road and crumpled the pavement beneath the south-bound lane. As we prepare this article (September, 1993), the slide continues to encroach onto the highway, posing a persistent problem despite repeated efforts to slow or stop its movement. As this article will show, permanent solutions to landslide problems of this kind are difficult to obtain. 

Outcomes of Mini vs Roux-en-Y gastric bypass: A meta-analysis and systematic review.

PubMed

Wang, Fu-Gang; Yan, Wen-Mao; Yan, Ming; Song, Mao-Min

2018-05-10

Mini gastric bypass has been proved to be capable of achieving excellent metabolic results by numerous published studies. Compared to Roux-en-Y gastric bypass, mini gastric bypass is a technically simpler and reversible procedure. However, comparative outcomes of the effectiveness between Mini gastric bypass and Roux-en-Y gastric bypass remain unclear. A systematic literature search was performed in Pubmed, Embase, Cochrane library from inception to February 9, 2018. For assessment of method quality, NOS (Newcastle-Ottawa Scale) and Cochrane Collaboration's tool for assessing risk of bias were used for cohort study and randomized controlled trials, respectively. The meta-analysis was performed by RevMan 5.3 software. 10 cohort studies and 1 randomized controlled trial was included in our meta-analysis. The method quality of the 10 cohort studies was proved as high quality according to the Newcastle-Ottawa Scale. The randomized controlled trial was proved to have a low risk of bias according to Cochrane Collaboration's assessment. Patients receiving mini-gastric bypass had multiple advantageous indexes as compared with patients receiving Roux-en-Y gastric bypass. Examples include: a higher 1-year EWL% (P < 0.05), higher 2-year EWL% (P < 0.05), higher type 2 diabetes mellitus remission rate, as well as a shorter operation time (P < 0.05). No significant statistical difference was observed in hypertension remission rate, mortality, leakage rate, GERD rate, or hospital stay between mini gastric bypass and Roux-en-Y gastric bypass. Mini gastric bypass seems to be a simpler procedure with a better weight reduction effect. This seems to also be the case regarding remission rates of type 2 diabetes mellitus when using Mini gastric bypass in comparison to Roux-en-Y gastric bypass. A small sample size and biased data may have influenced the stability of our results. In light of this, surgeons should treat our results in a conservative way. Larger sample size and

Targeted population screening of late onset Pompe disease in unspecified myopathy patients for Korean population.

PubMed

Lee, Jung Hwan; Shin, Jin-Hong; Park, Hyung Jun; Kim, Sook Za; Jeon, Young Mi; Kim, Hye Kyoung; Kim, Dae-Seong; Choi, Young-Chul

2017-06-01

We performed targeted population screening of late onset Pompe disease (LOPD) in unspecified myopathy patients, because early diagnosis is difficult due to its heterogeneous clinical features. We prospectively enrolled 90 unrelated myopathic patients who had one or more signs out of five LOPD-like clinical findings (proximal weakness, axial weakness, lingual weakness, respiratory difficulty, idiopathic hyperCKemia). Acid alpha glucosidase activity was evaluated with dried blood spot and mixed leukocyte simultaneously. For a final diagnosis of LOPD, 16 patients with decreased enzyme activity were genotyped by GAA molecular analysis. We found two patients with LOPD (2.2%), and the remaining 14 patients had at least one G576S or E689K mutation, known as the pseudodeficiency allele. Acid alpha glucosidase activity of LOPD patients was significantly lower than that of patients with at least one pseudodeficiency allele (p = 0.017). This study is the first LOPD screening study for targeted Korean population, and more generally, an Asian population. Our findings suggest that for diagnosis of LOPD in Asian population, modified cutoff value of acid alpha glucosidase activity with dry blood spot considering that of patients having heterozygote pathogenic variants or pseudodeficiency alleles may reduce time and cost requirements and increase the comfort of patients. Copyright © 2017 Elsevier B.V. All rights reserved.

A Fluorescent Protein Scaffold for Presenting Structurally Constrained Peptides Provides an Effective Screening System to Identify High Affinity Target-Binding Peptides

PubMed Central

Kadonosono, Tetsuya; Yabe, Etsuri; Furuta, Tadaomi; Yamano, Akihiro; Tsubaki, Takuya; Sekine, Takuya; Kuchimaru, Takahiro; Sakurai, Minoru; Kizaka-Kondoh, Shinae

2014-01-01

Peptides that have high affinity for target molecules on the surface of cancer cells are crucial for the development of targeted cancer therapies. However, unstructured peptides often fail to bind their target molecules with high affinity. To efficiently identify high-affinity target-binding peptides, we have constructed a fluorescent protein scaffold, designated gFPS, in which structurally constrained peptides are integrated at residues K131–L137 of superfolder green fluorescent protein. Molecular dynamics simulation supported the suitability of this site for presentation of exogenous peptides with a constrained structure. gFPS can present 4 to 12 exogenous amino acids without a loss of fluorescence. When gFPSs presenting human epidermal growth factor receptor type 2 (HER2)-targeting peptides were added to the culture medium of HER2-expressing cells, we could easily identify the peptides with high HER2-affinity and -specificity based on gFPS fluorescence. In addition, gFPS could be expressed on the yeast cell surface and applied for a high-throughput screening. These results demonstrate that gFPS has the potential to serve as a powerful tool to improve screening of structurally constrained peptides that have a high target affinity, and suggest that it could expedite the one-step identification of clinically applicable cancer cell-binding peptides. PMID:25084350

Health and performance of calves with forestomach-bypass fed milk replacer.

PubMed

McKinstry, D M; Cason, J L; Albert, T F; Sass, B

1976-02-01

Ten male Holstein calves were placed in groups of two calves each on similarity of age. On calf in each group was subjected to forestomach-bypass surgery at about 1 mo of age. Fortified commercial milk replacer with added minerals and vitamins was fed as the sole diet. The calves were housed indoors on slatted platforms. Weight gain was determined biweekly. Feed intake was determined daily. Necropsies were performed upon termination of the study. Recurrent ruminal bloat, fever, and anorexia of varying degrees and combinations occurred in four of the calves with forestomach bypass. Two of these calves showed slow weight gain. One of the four calves died following acute bloat while the other three calves were sacrificed following repeated episodes of bloat. The time of termination varied between 3 and 10 mo. One calf with forestomach bypass and all control calves appeared healthy throughout the experiment. Necropsies indicated that the ruminal bloat, seen in most of the forestomach-bypass calves, could be attributed to the back-flow of ingesta via the omasal-abomasal orifice. This ingesta appeared to produce gas which became trapped in the bypassed rumen.

Multislice Computed Tomography Accurately Detects Stenosis in Coronary Artery Bypass Conduits

PubMed Central

Duran, Cihan; Sagbas, Ertan; Caynak, Baris; Sanisoglu, Ilhan; Akpinar, Belhhan; Gulbaran, Murat

2007-01-01

The aim of this study was to evaluate the accuracy of multislice computed tomography in detecting graft stenosis or occlusion after coronary artery bypass grafting, using coronary angiography as the standard. From January 2005 through May 2006, 25 patients (19 men and 6 women; mean age, 54 ± 11.3 years) underwent diagnostic investigation of their bypass grafts by multislice computed tomography within 1 month of coronary angiography. The mean time elapsed after coronary artery bypass grafting was 6.2 years. In these 25 patients, we examined 65 bypass conduits (24 arterial and 41 venous) and 171 graft segments (the shaft, proximal anastomosis, and distal anastomosis). Compared with coronary angiography, the segment-based sensitivity, specificity, and positive and negative predictive values of multislice computed tomography in the evaluation of stenosis were 89%, 100%, 100%, and 99%, respectively. The patency rate for multislice compu-ted tomography was 85% (55/65: 3 arterial and 7 venous grafts were occluded), with 100% sensitivity and specificity. From these data, we conclude that multislice computed tomography can accurately evaluate the patency and stenosis of bypass grafts during outpatient follow-up. PMID:17948078

Investigation of bypass fluid flow in an active magnetic regenerative liquefier

DOE PAGES

Holladay, Jamelyn; Teyber, Reed; Meinhardt, Kerry; ...

2018-05-19

Active magnetic regenerators (AMR) with second order magnetocaloric materials operating below the Curie temperature have a unique property where the magnetized specific heat is lower than the demagnetized specific heat. The associated thermal mass imbalance allows a fraction of heat transfer fluid in the cold heat exchanger to bypass the magnetized regenerator. This cold bypassed fluid can precool a process stream as it returns to the hot side, thereby increasing the efficiency of liquefaction and reducing the cost of liquid cryogens. In the present work, the net cooling power of an active magnetic regenerative liquefier is investigated as a functionmore » of the bypass flow fraction. In conclusion, experiments are performed at a fixed temperature span yielding a 30% improvement in net cooling power, affirming the potential of bypass flow in active magnetic regenerative liquefiers.« less

Investigation of bypass fluid flow in an active magnetic regenerative liquefier

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holladay, Jamelyn; Teyber, Reed; Meinhardt, Kerry

Active magnetic regenerators (AMR) with second order magnetocaloric materials operating below the Curie temperature have a unique property where the magnetized specific heat is lower than the demagnetized specific heat. The associated thermal mass imbalance allows a fraction of heat transfer fluid in the cold heat exchanger to bypass the magnetized regenerator. This cold bypassed fluid can precool a process stream as it returns to the hot side, thereby increasing the efficiency of liquefaction and reducing the cost of liquid cryogens. In the present work, the net cooling power of an active magnetic regenerative liquefier is investigated as a functionmore » of the bypass flow fraction. Experiments are performed at a fixed temperature span yielding a 30% improvement in net cooling power, affirming the potential of bypass flow in active magnetic regenerative liquefiers.« less

Investigation of bypass fluid flow in an active magnetic regenerative liquefier

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holladay, Jamelyn; Teyber, Reed; Meinhardt, Kerry

Active magnetic regenerators (AMR) with second order magnetocaloric materials operating below the Curie temperature have a unique property where the magnetized specific heat is lower than the demagnetized specific heat. The associated thermal mass imbalance allows a fraction of heat transfer fluid in the cold heat exchanger to bypass the magnetized regenerator. This cold bypassed fluid can precool a process stream as it returns to the hot side, thereby increasing the efficiency of liquefaction and reducing the cost of liquid cryogens. In the present work, the net cooling power of an active magnetic regenerative liquefier is investigated as a functionmore » of the bypass flow fraction. In conclusion, experiments are performed at a fixed temperature span yielding a 30% improvement in net cooling power, affirming the potential of bypass flow in active magnetic regenerative liquefiers.« less

Environmental Assessment: Johnson County Road F-20 Bypass, Johnson County, Iowa.

DTIC Science & Technology

1986-08-01

D-A184 328 ENVIRONMENTAL ASSESSMENT- JOHNSON COUNTY ROAD F-20 vil BYPASS JOHNSON COUNTY’ IOWA (U) ARMY ENGINEER DISTRICT ROCK ISLAND IL AUG 86...BYPASS JOHNSON COUNTY, IOWA DTIC SELECTEI AUG 24 198D AUGUST 1986 -’"Thn; c>, .. i ’, been p ore i Icr publj rJlxaje aid sale; ii ,,. I distibu on is...2004 19 EPLY TO ATTENTION OP NCRPD-E ENVIRONMENTAL ASSE SSMENT JOHNSON COUNTY ROAD F-20 BYPASS JOHNSON COUNTY, IOWA Acce3siofl For NTIS MR& QUA~rTY

A screen of cell-surface molecules identifies leucine-rich repeat proteins as key mediators of synaptic target selection in the Drosophila neuromuscular system

PubMed Central

Kurusu, Mitsuhiko; Cording, Amy; Taniguchi, Misako; Menon, Kaushiki; Suzuki, Emiko; Zinn, Kai

2008-01-01

Summary In Drosophila embryos and larvae, a small number of identified motor neurons innervate body wall muscles in a highly stereotyped pattern. Although genetic screens have identified many proteins that are required for axon guidance and synaptogenesis in this system, little is known about the mechanisms by which muscle fibers are defined as targets for specific motor axons. To identify potential target labels, we screened 410 genes encoding cell-surface and secreted proteins, searching for those whose overexpression on all muscle fibers causes motor axons to make targeting errors. Thirty such genes were identified, and a number of these were members of a large gene family encoding proteins whose extracellular domains contain leucine-rich repeat (LRR) sequences, which are protein interaction modules. By manipulating gene expression in muscle 12, we showed that four LRR proteins participate in the selection of this muscle as the appropriate synaptic target for the RP5 motor neuron. PMID:18817735

A multi-element screening method to identify metal targets for blood biomonitoring in green sea turtles (Chelonia mydas).

PubMed

Villa, C A; Finlayson, S; Limpus, C; Gaus, C

2015-04-15

Biomonitoring of blood is commonly used to identify and quantify occupational or environmental exposure to chemical contaminants. Increasingly, this technique has been applied to wildlife contaminant monitoring, including for green turtles, allowing for the non-lethal evaluation of chemical exposure in their nearshore environment. The sources, composition, bioavailability and toxicity of metals in the marine environment are, however, often unknown and influenced by numerous biotic and abiotic factors. These factors can vary considerably across time and space making the selection of the most informative elements for biomonitoring challenging. This study aimed to validate an ICP-MS multi-element screening method for green turtle blood in order to identify and facilitate prioritisation of target metals for subsequent fully quantitative analysis. Multi-element screening provided semiquantitative results for 70 elements, 28 of which were also determined through fully quantitative analysis. Of the 28 comparable elements, 23 of the semiquantitative results had an accuracy between 67% and 112% relative to the fully quantified values. In lieu of any available turtle certified reference materials (CRMs), we evaluated the use of human blood CRMs as a matrix surrogate for quality control, and compared two commonly used sample preparation methods for matrix related effects. The results demonstrate that human blood provides an appropriate matrix for use as a quality control material in the fully quantitative analysis of metals in turtle blood. An example for the application of this screening method is provided by comparing screening results from blood of green turtles foraging in an urban and rural region in Queensland, Australia. Potential targets for future metal biomonitoring in these regions were identified by this approach. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthetic metabolic bypass for a metabolic toggle switch enhances acetyl-CoA supply for isopropanol production by Escherichia coli.

PubMed

Soma, Yuki; Yamaji, Taiki; Matsuda, Fumio; Hanai, Taizo

2017-05-01

Almost all synthetic pathways for biofuel production are designed to require endogenous metabolites in glycolysis, such as phosphoenolpyruvate, pyruvate, and acetyl-CoA. However, such metabolites are also required for bacterial cell growth. To reduce the metabolic imbalance between cell growth and target chemical production, we previously constructed a metabolic toggle switch (MTS) as a conditional flux redirection tool controlling metabolic flux of TCA cycle toward isopropanol production. This approach succeeded to improve the isopropanol production titer and yield while ensuring sufficient cell growth. However, excess accumulation of pyruvate, the precursor for acetyl-CoA synthesis, was also observed. In this study, for efficient conversation of pyruvate to acetyl-CoA (pyruvate oxidation), we designed a synthetic metabolic bypass composed of poxB and acs with the MTS for acetyl-CoA supply from the excess pyruvate. When this designed bypass was expressed at the appropriate expression level associated with the conditional metabolic flux redirection, pyruvate accumulation was prevented, and the isopropanol production titer and yield were improved. Final isopropanol production titer of strain harboring MTS with the synthetic metabolic bypass improved 4.4-fold compared with strain without metabolic flux regulation, and it was 1.3-fold higher than that of strain harboring the conventional MTS alone. Additionally, glucose consumption was also improved 1.7-fold compared with strain without metabolic flux regulation. On the other hand, introduction of the synthetic metabolic bypass alone showed no improvement in isopropanol production and glucose consumption. These results showed that the improvement in bio-production process caused by synergy between the MTS and the synthetic metabolic bypass. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Endovascular Treatments in Combination with Extracranial-Intracranial Bypass for Complex Intracranial Aneurysms.

PubMed

Sato, Kenichi; Endo, Hidenori; Fujimura, Miki; Endo, Toshiki; Matsumoto, Yasushi; Shimizu, Hiroaki; Tominaga, Teiji

2018-05-01

Although most intracranial aneurysms can be treated with microsurgery or endovascular procedure alone, a subset of aneurysms may require a combined approach. The purpose of this study was to assess the efficacy of endovascular interventions combined with bypass surgery for the treatment of complex intracranial aneurysms. We retrospectively reviewed medical records from a prospectively maintained patient database to identify patients who underwent endovascular treatment of an intracranial aneurysm at our institutes between 2007 and 2017. We recruited patients who received a preplanned combination of endovascular treatment and extracranial-intracranial bypass surgery. Forty-four patients (44 aneurysms) were treated with a combined approach. Twenty-four patients presented with subarachnoid hemorrhage. Treatment strategies included endovascular parent artery occlusion with the bypass surgery to restore cerebral blood flow (n = 12), endovascular trapping with bypass surgery to isolate incorporated branches (n = 12), and intra-aneurysmal coil embolization with bypass surgery to isolate incorporated branches (n = 20). During a mean period of 35.6 months, follow-up catheter angiography was performed in 35 of 44 patients (79.5%) and demonstrated complete aneurysm obliteration in 29 patients (82.9%) and bypass patency in 33 (94.3%). The postoperative aneurysm-related mortality and morbidity rates were 6.8% and 13.6%, respectively. Combined endovascular and surgical bypass procedures are useful for the treatment of complex intracranial aneurysms when conventional surgical or endovascular techniques are not feasible and show acceptable rates of morbidity and mortality. Copyright © 2018 Elsevier Inc. All rights reserved.

Lipid Nanoparticles: A novel approach for brain targeting.

PubMed

Shankar, Ravi; Joshi, Monika; Pathak, Kamla

2018-06-10

Brain is a delicate organ, separated from general circulation and is characterized by the presence of relatively impermeable Blood Brain Barrier (BBB). The BBB maintains homeostasis in the brain thus restricting the entrance of foreign bodies and several molecules from reaching the brain. As a result several promising molecules do not reach the target site and fail to produce in vivo response. Nevertheless, lipid nanoparticles are taken up readily by the brain because of their lipophilic nature. The bioacceptable and biodegradable nature of lipid nanoparticles makes them less toxic and suited for brain targeting. In the present review the BBB, mechanism of transport across the BBB, strategies to bypass the blood-brain barrier have been presented. The aptness of lipid nanoparticles for brain targeting has been highlighted. The proposed mechanism of uptake of the lipid nanoparticles, methods of prolonging the plasma retention and various methods of preparation for formulation of effective delivery systems for brain targeting have been included and dealt in this review. Lipid based formulations can be designated as the current and future generation of drug delivery systems as these possess tremendous potential to bypass BBB and reach the target site due to their small size and ability to dodge the reticular endothelial system. However, these nanostructures need to be investigated intensively to successfully reach the clinical trials stage. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Editor’s Highlight: A Genome-wide Screening of Target Genes Against Silver Nanoparticles in Fission Yeast

PubMed Central

Lee, Sook-Jeong; Lee, Minho; Nam, Miyoung; Lee, Sol; Choi, Jian; Lee, Hye-Jin; Kim, Dong-Uk; Hoe, Kwang-Lae

2018-01-01

Abstract To identify target genes against silver nanoparticles (AgNPs), we screened a genome-wide gene deletion library of 4843 fission yeast heterozygous mutants covering 96% of all protein encoding genes. A total of 33 targets were identified by a microarray and subsequent individual confirmation. The target pattern of AgNPs was more similar to those of AgNO3 and H2O2, followed by Cd and As. The toxic effect of AgNPs on fission yeast was attributed to the intracellular uptake of AgNPs, followed by the subsequent release of Ag+, leading to the generation of reactive oxygen species (ROS). Next, we focused on the top 10 sensitive targets for further studies. As described previously, 7 nonessential targets were associated with detoxification of ROS, because their heterozygous mutants showed elevated ROS levels. Three novel essential targets were related to folate metabolism or cellular component organization, resulting in cell cycle arrest and no induction in the transcriptional level of antioxidant enzymes such as Sod1 and Gpx1 when 1 of the 2 copies was deleted. Intriguingly, met9 played a key role in combating AgNP-induced ROS generation via NADPH production and was also conserved in a human cell line. PMID:29294138

Screen-Time Weight-loss Intervention Targeting Children at Home (SWITCH): a randomized controlled trial.

PubMed

Maddison, Ralph; Marsh, Samantha; Foley, Louise; Epstein, Leonard H; Olds, Timothy; Dewes, Ofa; Heke, Ihirangi; Carter, Karen; Jiang, Yannan; Mhurchu, Cliona Ni

2014-09-10

Screen-based activities, such as watching television (TV), playing video games, and using computers, are common sedentary behaviors among young people and have been linked with increased energy intake and overweight. Previous home-based sedentary behaviour interventions have been limited by focusing primarily on the child, small sample sizes, and short follow-up periods. The SWITCH (Screen-Time Weight-loss Intervention Targeting Children at Home) study aimed to determine the effect of a home-based, family-delivered intervention to reduce screen-based sedentary behaviour on body composition, sedentary behaviour, physical activity, and diet over 24 weeks in overweight and obese children. A two-arm, parallel, randomized controlled trial was conducted. Children and their primary caregiver living in Auckland, New Zealand were recruited via schools, community centres, and word of mouth. The intervention, delivered over 20 weeks, consisted of a face-to-face meeting with the parent/caregiver and the child to deliver intervention content, which focused on training and educating them to use a wide range of strategies designed to reduce their child's screen time. Families were given Time Machine TV monitoring devices to assist with allocating screen time, activity packages to promote alternative activities, online support via a website, and monthly newsletters. Control participants were given the intervention material on completion of follow-up. The primary outcome was change in children's BMI z-score from baseline to 24 weeks. Children (n = 251) aged 9-12 years and their primary caregiver were randomized to receive the SWITCH intervention (n = 127) or no intervention (controls; n = 124). There was no significant difference in change of zBMI between the intervention and control groups, although a favorable trend was observed (-0.016; 95% CI: -0.084, 0.051; p = 0.64). There were also no significant differences on secondary outcomes, except for a trend towards

Novel screening techniques for ion channel targeting drugs

PubMed Central

Obergrussberger, Alison; Stölzle-Feix, Sonja; Becker, Nadine; Brüggemann, Andrea; Fertig, Niels; Möller, Clemens

2015-01-01

Ion channels are integral membrane proteins that regulate the flux of ions across the cell membrane. They are involved in nearly all physiological processes, and malfunction of ion channels has been linked to many diseases. Until recently, high-throughput screening of ion channels was limited to indirect, e.g. fluorescence-based, readout technologies. In the past years, direct label-free biophysical readout technologies by means of electrophysiology have been developed. Planar patch-clamp electrophysiology provides a direct functional label-free readout of ion channel function in medium to high throughput. Further electrophysiology features, including temperature control and higher-throughput instruments, are continually being developed. Electrophysiological screening in a 384-well format has recently become possible. Advances in chip and microfluidic design, as well as in cell preparation and handling, have allowed challenging cell types to be studied by automated patch clamp. Assays measuring action potentials in stem cell-derived cardiomyocytes, relevant for cardiac safety screening, and neuronal cells, as well as a large number of different ion channels, including fast ligand-gated ion channels, have successfully been established by automated patch clamp. Impedance and multi-electrode array measurements are particularly suitable for studying cardiomyocytes and neuronal cells within their physiological network, and to address more complex physiological questions. This article discusses recent advances in electrophysiological technologies available for screening ion channel function and regulation. PMID:26556400

Novel screening techniques for ion channel targeting drugs.

PubMed

Obergrussberger, Alison; Stölzle-Feix, Sonja; Becker, Nadine; Brüggemann, Andrea; Fertig, Niels; Möller, Clemens

2015-01-01

Ion channels are integral membrane proteins that regulate the flux of ions across the cell membrane. They are involved in nearly all physiological processes, and malfunction of ion channels has been linked to many diseases. Until recently, high-throughput screening of ion channels was limited to indirect, e.g. fluorescence-based, readout technologies. In the past years, direct label-free biophysical readout technologies by means of electrophysiology have been developed. Planar patch-clamp electrophysiology provides a direct functional label-free readout of ion channel function in medium to high throughput. Further electrophysiology features, including temperature control and higher-throughput instruments, are continually being developed. Electrophysiological screening in a 384-well format has recently become possible. Advances in chip and microfluidic design, as well as in cell preparation and handling, have allowed challenging cell types to be studied by automated patch clamp. Assays measuring action potentials in stem cell-derived cardiomyocytes, relevant for cardiac safety screening, and neuronal cells, as well as a large number of different ion channels, including fast ligand-gated ion channels, have successfully been established by automated patch clamp. Impedance and multi-electrode array measurements are particularly suitable for studying cardiomyocytes and neuronal cells within their physiological network, and to address more complex physiological questions. This article discusses recent advances in electrophysiological technologies available for screening ion channel function and regulation.

Totally Endoscopic Coronary Artery Bypass for Anomalous Origin of Right Coronary Artery.

PubMed

Kuo, Chia-Cheng; Hsing, Chung-Hsi; Cheng, Bor-Chih

2017-01-01

Anomalous origin of the right coronary artery (ARCA) from the left Valsalva sinus is a rare but known cause of sudden cardiac death. Surgical revascularization techniques include coronary artery bypass grafting, unroofing, and reimplantation. We report 4 patients who underwent robot-assisted totally endoscopic coronary artery bypass (TECAB) for ARCA as an alternative surgical option. In 3 patients, a single aortocoronary saphenous vein bypass was performed, and in 1 patient the right internal mammary artery was used. All grafts are patent as shown by computed tomographic angiography or cardiac catheterization. We claim that totally endoscopic coronary artery bypass is feasible and safe for anomalous origin of the right coronary artery. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Apico-brachiocephalic artery bypass for aortic stenosis with porcelain aorta.

PubMed

Shimizu, Shuji; Nakai, Mikizo; Itoh, Atsushi; Yoshizumi, Ko; Ochi, Yoshiki; Okada, Masahiro; Sano, Shunji

2010-02-01

Apicoaortic bypass for left ventricular outflow tract obstruction has been performed with acceptable mid-term mortality. However, sometimes it is difficult to anastomose the distal end of the conduit to the calcified descending aorta in patients with a porcelain aorta. We report an aortic non-touch modification of the apicoaortic bypass in an 80-year-old woman with valvular aortic stenosis and a porcelain aorta extending from the ascending to abdominal aorta. We performed apico-brachiocephalic artery bypass under circulatory arrest with deep hypothermia. This procedure may become a useful surgical option for patients with a severe porcelain aorta. 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

A Bayesian assessment of the effect of highway bypasses in Iowa on crashes and crash rate.

PubMed

Cena, Lorenzo G; Keren, Nir; Li, Wen; Carriquiry, Alicia L; Pawlovich, Michael D; Freeman, Steven A

2011-08-01

A common contention is that the construction of highway bypasses negatively impacts the economy of local communities by reducing pass-by traffic for businesses. However, as access to specific business' account records is limited, this impact is difficult to quantify. Another common contention is that bypasses contribute to a reduction in overall crashes in the community and in the surrounding areas. Even though a large number of bypasses have been constructed in the State of Iowa over the past several years, their actual impact in terms of traffic safety has not been quantified. This study seeks answers to the following questions: (a) Are bypasses in Iowa associated with a reduction in crash frequencies and crash rates on the bypassed highway? (b) Do bypasses in Iowa introduce a reduction of overall crash frequencies and rates or do they merely shift crashes from the highways through the communities to the bypasses with no significant overall reduction? We obtained crash information from the Iowa DOT at 19 sites on which a bypass was constructed sometime during the past 23 years. We also obtained the same information at six sites used as comparison sites on which no bypasses were constructed at least until 2005. We them employed a Bayesian approach to estimating the association between the construction of the bypass and crash rates, while also accounting for other factors. The construction of bypasses in Iowa is associated with a significant increase in traffic safety both on the main road through town and on the combined main road and bypass roadway. Copyright © 2011 National Safety Council and Elsevier Ltd. All rights reserved.

Genetic therapy for vein bypass graft disease: current perspectives.

PubMed

Simosa, Hector F; Conte, Michael S

2004-01-01

Although continued progress in endovascular technology holds promise for less invasive approaches to arterial diseases, surgical bypass grafting remains the mainstay of therapy for patients with advanced coronary and peripheral ischemia. In the United States, nearly 400,000 coronary and 100,000 lower extremity bypass procedures are performed annually. The autogenous vein, particularly the greater saphenous vein, has proven to be a durable and versatile arterial substitute, with secondary patency rates at 5 years of 70 to 80% in the extremity. However, vein graft failure is a common occurrence that incurs significant morbidity and mortality, and, to date, pharmacologic approaches to prolong vein graft patency have produced limited results. Dramatic advances in genetics, coupled with a rapidly expanding knowledge of the molecular basis of vascular diseases, have set the stage for genetic interventions. The attraction of a genetic approach to vein graft failure is based on the notion that the tissue at risk is readily accessible to the clinician prior to the onset of the pathologic process and the premise that genetic reprogramming of cells in the wall of the vein can lead to an improved healing response. Although the pathophysiology of vein graft failure is incompletely understood, numerous relevant molecular targets have been elucidated. Interventions designed to influence cell proliferation, thrombosis, inflammation, and matrix remodeling at the genetic level have been described, and many have been tested in animal models. Both gene delivery and gene blockade strategies have been investigated, with the latter reaching the stage of advanced clinical trials.

Evaluation of a Prototype Surface Flow Bypass for Juvenile Salmon and Steelhead at the Powerhouse of Lower Granite Dam, Snake River, Washington, 1996-2000

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Gary E.; Anglea, Steven M.; Adams, Noah S.

2005-02-28

A surface flow bypass provides a route in the upper water column for naturally, surface-oriented juvenile salmonids to safely migrate through a hydroelectric dam. Surface flow bypasses were recommended in several regional salmon recovery plans as a means to increase passage survival of juvenile salmonids at Columbia and Snake River dams. A prototype surface flow bypass, called the SBC, was retrofit on Lower Granite Dam and evaluated from 1996 to 2000 using biotelemetry and hydroacoustic techniques. In terms of passage efficiency, the best SBC configurations were a surface skimmer (99 m3/s [3,500 cfs], three entrances 5 m wide, 5 mmore » deep and one entrance 5 m wide, 15 m deep) and a single chute (99 m3/s, one entrance 5 m wide, 8.5 m deep). They each passed 62 ? 3% (95% confidence interval) of the total juvenile fish population that entered the section of the dam with the SBC entrances (Turbine Units 4-5). Smooth entrance shape and concentrated surface flow characteristics of these configurations are worth pursuing in designs for future surface flow bypasses. In addition, a guidance wall in the Lower Granite Dam forebay diverted the following percentages of juvenile salmonids away from Turbine Units 1-3 toward other passage routes, including the SBC: run-at-large 79 ? 18%; hatchery steelhead 86%; wild steelhead 65%; and yearling chinook salmon 66%. When used in combination with spill or turbine intake screens, a surface flow bypass with a guidance wall can produce a high level (> 90% of total project passage) of non-turbine passage and provide operational flexibility to fisheries managers and dam operators responsible for enhancing juvenile salmonid survival.« less

Bile acid malabsorption after intestinal bypass surgery for obesity. A comparison between jejunoileal shunt and biliointestinal bypass.

PubMed

Nyhlin, H; Brydon, G; Danielsson, A; Eriksson, F

1990-01-01

Seventeen patients were operated on with intestinal shunts for morbid obesity, in eight a biliointestinal bypass (BI) was constructed and in the rest a conventional jejunoileal (JI)-shunt. The reduction in weight was similar in both groups, and so was malabsorption of fat, but the BI-group had significantly less bowel motions with less watery diarrhoea. Bile acid malabsorption was measured both chemically by estimating the total amount of faecal bile acids excreted, as well as indirectly by using a 75Se-labelled synthetic bile acid (SeHCAT). Both techniques revealed a substantial loss of bile acid after both types of operation, but patients with BI bypass surgery had significantly lower elimination time of the bile acid than those with JI-shunts. There was a significant negative correlation between SeHCAT retention and total faecal bile acids. However, some patients with low SeHCAT retention had normal or even reduced output of faecal bile acids. Estimation of faecal bile acids may display false negative results when the bile acid pool is decreased. The SeHCAT-test seems to be a better technique for measuring bile acid losses. The study suggests that BI bypass surgery for obesity seems to be advantageous over the JI shunt in reducing the postoperative loss of bile acids and choleretic diarrhoea, without influencing the weight loss.

Target analysis of primary aromatic amines combined with a comprehensive screening of migrating substances in kitchen utensils by liquid chromatography-high resolution mass spectrometry.

PubMed

Sanchis, Yovana; Coscollà, Clara; Roca, Marta; Yusà, Vicent

2015-06-01

An analytical strategy including both the quantitative target analysis of 8 regulated primary aromatic amines (PAAs), as well as a comprehensive post-run target screening of 77 migrating substances, was developed for nylon utensils, using liquid chromatography-orbitrap-high resolution mass spectrometry (LC-HRMS) operating in full scan mode. The accurate mass data were acquired with a resolving power of 50,000 FWHM (scan speed, 2 Hz), and by alternating two acquisition events, ESI+ with and without fragmentation. The target method was validated after statistical optimization of the main ionization and fragmentation parameters. The quantitative method presented appropriate performance to be used in official monitoring with recoveries ranging from 78% to 112%, precision in terms of Relative Standard Deviation (RSD) was less than 15%, and the limits of quantification were between 2 and 2.5 µg kg(-1). For post-target screening, a customized theoretical database was built for food contact material migrants, including bisphenols, phthalates, and other amines. For identification purposes, accurate exact mass (<5 ppm) and some diagnostic ions including fragments were used. The strategy was applied to 10 real samples collected from different retailers in the Valencian Region (Spain) during 2014. Six out of eight target PAAs were detected in at least one sample in the target analysis. The most frequently detected compounds were 4,4'-methylenedianiline and aniline, with concentrations ranging from 2.4 to 19,715 µg kg(-1) and 2.5 to 283 µg kg(-1), respectively. Two phthalates were identified and confirmed in the post-run target screening analysis. Copyright © 2015 Elsevier B.V. All rights reserved.

Biliary bypass surgery – Analysis of indications & outcome of different procedures

PubMed Central

Hussain Talpur, K.Altaf; Mahmood Malik, Arshad; Iqbal Memon, Amir; Naeem Qureshi, Jawed; Khan Sangrasi, Ahmed; Laghari, Abdul Aziz

2013-01-01

Objectives: This study reports the indications and outcome of various biliary bypass surgical procedures from a single centre over a period of 10 years. Methods: This is a prospective observational study conducted over a period of 10 years (January 2001-december 2010). A total of 1500 patients were included, who underwent pancreatico-biliary surgery due to common bile duct (CBD) stones, congenital anomalies of biliary tree, unoperable pancreatico-biliary malignancies, CBD strictures and cases who developed iatrogenic biliary injuries during cholecystectomy (both open & laproscopic) during this period of time. The patients who required biliary bypass surgery were further analysed for indications and outcome. Results: Out of 1500 patients 83(5.53%) required biliary bypass surgical procedures. The CBD stones were observed as the most common indication (25.3%), followed by CBD injuries after open(10.84%) or laproscopic-cholecystectomy (14.46%), carcinoma head of pancreas (12.05%) and CBD obstruction(14.46%) either due to CBD strictures or unknown distal obstruction. Roux-en-Y-hepatico-jejunostomy (26.51%) was the most frequently performed procedure, followed by choledochoduodenostomy and Roux-en-Y choledocho-jejunostomy (i.e. 25.3% and 12.05% respectively). Roux-en-Y biliary bypass procedure was observed to be associated with better outcome in terms of rate of complications as well duration of hospital stay. Conclusion: Biliary bypass surgical procedures are the better options to restore the continuity of biliary system in patients with iatrogenic biliary tree injuries and un-operable pancreatico-biliary malignancy. Roux-en-Y biliary bypass procedure is safe and problem solving method in these cases. PMID:24353631

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass.

PubMed

Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-01

The purpose of this study was to investigate the population pharmacokinetics (PK) of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix (version 4.4) software. Pharmacokinetic-pharmacodynamic (PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples from 78 patients were analyzed. The PK for cefuroxime were best described by a two-compartment model with between-subject variability on clearance, the volume of distribution of the central compartment, and the volume of distribution of the peripheral compartment. The clearance of cefuroxime was related to creatinine clearance (CL CR ). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of the percentage of the time that the free concentration is maintained above the MIC during a dosing interval ( fT MIC ) of 65% for an MIC of 8 mg/liter in patients with a CL CR of 30, 60, or 90 ml/min, whereas this dosing regimen failed to achieve the PK-PD target in patients with a CL CR of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CL CR values required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CL CR values (≤30 ml/min). Copyright © 2018 American Society for Microbiology.

Development of a suspect and non-target screening approach to detect veterinary antibiotic residues in a complex biological matrix using liquid chromatography/high-resolution mass spectrometry.

PubMed

Solliec, Morgan; Roy-Lachapelle, Audrey; Sauvé, Sébastien

2015-12-30

Swine manure can contain a wide range of veterinary antibiotics, which could enter the environment via manure spreading on agricultural fields. A suspect and non-target screening method was applied to swine manure samples to attempt to identify veterinary antibiotics and pharmaceutical compounds for a future targeted analysis method. A combination of suspect and non-target screening method was developed to identify various veterinary antibiotic families using liquid chromatography coupled with high-resolution mass spectrometry (LC/HRMS). The sample preparation was based on the physicochemical parameters of antibiotics for the wide scope extraction of polar compounds prior to LC/HRMS analysis. The amount of data produced was processed by applying restrictive thresholds and filters to significantly reduce the number of compounds found and eliminate matrix components. The suspect and non-target screening was applied on swine manure samples and revealed the presence of seven common veterinary antibiotics and some of their relative metabolites, including tetracyclines, β-lactams, sulfonamides and lincosamides. However, one steroid and one analgesic were also identified. The occurrence of the identified compounds was validated by comparing their retention times, isotopic abundance patterns and fragmentation patterns with certified standards. This identification method could be very useful as an initial step to screen for and identify emerging contaminants such as veterinary antibiotics and pharmaceuticals in environmental and biological matrices prior to quantification. Copyright © 2015 John Wiley & Sons, Ltd.

Cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal anti-D prophylaxis in RhD-negative pregnant women: a model-based analysis.

PubMed

Neovius, M; Tiblad, E; Westgren, M; Kublickas, M; Neovius, K; Wikman, A

2016-07-01

To estimate the cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal versus no routine antenatal anti-D prophylaxis (RAADP) or versus non-targeted RAADP. Model based on a population-based cohort study. The Swedish health service. Intervention subjects in the underlying cohort study were RhD-negative pregnant women receiving first trimester fetal RHD screening followed by targeted anti-D in 2010-2011 (n = 6723). Historical comparators were RhD-negative women who delivered in 2008-2009 when standard care did not include RAADP (n = 7099). Healthcare costs for the three strategies were included for the first and subsequent pregnancies. For the comparison with non-targeted RAADP, the immunisation rate was based on the observed rate for targeted therapy and adjusted downwards by removing the influence of false negatives. Additional cost per RhD immunisation averted. Compared with RAADP, targeted prophylaxis was associated with fewer immunisations (0.19 versus 0.46% per pregnancy) and lower costs (cost-savings of €32 per RhD-negative woman). The savings were from lower costs during pregnancy and delivery, and lower costs of future pregnancies through fewer immunisations. Non-targeted anti-D was estimated to result in 0.06% fewer immunisations and an additional €16 in cost-savings per mother, compared with targeted anti-D. Based on effect data from a population-based cohort study, targeted prophylaxis was associated with lower immunisation risk and costs versus no RAADP. Based on effect data from theoretical calculations, non-targeted RAADP was predicted to result in lower costs and immunisation risk compared with targeted prophylaxis. Fetal RHD screening and targeted prophylaxis resulted in lower immunisation risk and costs compared with no RAADP. © 2015 Royal College of Obstetricians and Gynaecologists.

Bypassing birthing centres for child birth: a community-based study in rural Chitwan Nepal.

PubMed

Shah, Rajani

2016-10-21

Child delivery in a health facility is important to reduce maternal mortality. Bypassing nearby birthing facility to deliver at a hospital is common in developing countries including Nepal. Very little is known about the extent and determinants of bypassing the birthing centres in Nepal. This study measures the status of bypassing, characteristics of bypassers and their reasons for bypassing. A community-based cross-sectional study was carried out in six rural village development committees of Chitwan district of Nepal. Structured interviews were conducted with 263 mothers who had given birth at a health facility and whose nearest facility was a birthing centre. Descriptive statistics, univariate and multivariable logistic regression analysis were performed. More than half of the mothers had bypassed the nearer birthing centres to deliver at hospital. Living in plain area [aOR: 2.467; 95 % CI: 1.005-6.058], higher wealth index [aOR: 4.981; 95 % CI: 2.482-9.999], advantaged caste/ethnicity [aOR: 2.172; 95 % CI: 1.153-4.089], older age [aOR: 2.222; 95 % CI: 1.050-4.703] and first birth [aOR: 2.032; 95 % CI: 1.060-3.894] were associated with higher likelihood of bypassing. Among the reasons of bypassing as reported by the bypassers, lack of operation, video x-ray, and blood test facilities were the most common ones, followed by the lack of medicines/drugs and equipment, lack of skilled service provider, and inadequate physical facilities, among others. Quality of service at the birthing centres needs to be given a high consideration to increase their use as well as to ensure an equitable access to the quality care by all.

Clevidipine compared with nitroglycerin for blood pressure control in coronary artery bypass grafting: a randomized double-blind study.

PubMed

Merry, Alan F; Avery, Edwin G; Nussmeier, Nancy A; Playford, Hugh R; Warman, Guy R; Wang, Yamei; Sladen, Robert N

2014-05-01

We tested the hypothesis that clevidipine, a rapidly acting dihydropyridine calcium channel blocker, is not inferior to nitroglycerin (NTG) in controlling blood pressure before cardiopulmonary bypass (CPB) during coronary artery bypass grafting (CABG). In this double-blind study from October 4, 2003 to April 26, 2004, 100 patients undergoing CABG with CPB were randomized at four centres to receive intravenous infusions of clevidipine (0.2-8 μg·kg(-1)·min(-1)) or NTG (0.4 μg·kg(-1)·min(-1) to a clinician-determined maximum dose rate) from induction of anesthesia through 12 hr postoperatively. The study drug was titrated in the pre-CPB period with the aim of maintaining mean arterial pressure (MAP) within ± 5 mmHg of a clinician-predetermined target. The primary endpoint was the area under the curve (AUC) for the total time each patient's MAP was outside the target range from drug initiation to the start of CPB, normalized per hour (AUCMAP-D). The predefined non-inferiority criterion for the primary endpoint was a 95% confidence interval (CI) upper limit no greater than 1.50 for the geometric means ratio between clevidipine and NTG. Total mean [standard deviation (SD)] dose pre-bypass was 4.5 (4.7) mg for clevidipine and 6.9 (5.4) mg for NTG (P < 0.05). The geometric mean AUCMAP-D for clevidipine was 283 mmHg·min·hr(-1) (n = 45) and for NTG was 292 mmHg·min·hr(-1) (n = 48); the geometric means ratio was 0.97 (95% CI 0.74 to 1.27). The geometric mean AUCMAP-D during aortic cannulation was 357.7 mmHg·min·hr(-1) for clevidipine compared with 190.5 mmHg·min·hr(-1) for NTG. Mean (SD) heart rate with clevidipine was 76.0 (13.8) beats·min(-1) compared with 81.5 (14.4) beats·min(-1) for NTG. There were no clinically important differences between groups in adverse events. During CABG, clevidipine was not inferior to NTG for blood pressure control pre-bypass.

The effects of gastric bypass surgery on drug absorption and pharmacokinetics.

PubMed

Brocks, Dion R; Ben-Eltriki, Mohamed; Gabr, Raniah Q; Padwal, Raj S

2012-12-01

Being overweight is widespread in most societies and represents a major health threat. Gastric bypass surgery offers a highly effective mode of treatment for the morbidly obese patients. The procedures cause an alteration in normal gastrointestinal anatomy and physiology, with consequences not only on nutrient absorption, but also possibly on orally administered drugs. Bypass of the acidic environment of the stomach, partial impairment of bile salts-drug interactions and reduced absorptive surface, all create the potential for reduced absorption of drugs. This article provides an overview of the effects of obesity and the most prevalent type of gastric bypass (Roux-en-Y) on pharmacokinetics. Articles for review were searched using Pubmed. The absorption of those drugs with known bioavailability issues generally seem to be most affected by bypass surgery. It is important to consider the effect of obesity on pharmacokinetics independent of the bypass procedure, because it leads to a dramatic drop in body mass over a relatively short period of time. This may be associated with reversals in the influence of obesity on drug disposition to characteristics more in line with leaner patients. Drugs will differ in their pharmacokinetic response to surgery, limiting any general conclusions regarding the impact of the surgery on drug disposition.

High-Content Surface and Total Expression siRNA Kinase Library Screen with VX-809 Treatment Reveals Kinase Targets that Enhance F508del-CFTR Rescue.

PubMed

Perkins, Lydia A; Fisher, Gregory W; Naganbabu, Matharishwan; Schmidt, Brigitte F; Mun, Frederick; Bruchez, Marcel P

2018-03-05

The most promising F508del-CFTR corrector, VX-809, has been unsuccessful as an effective, stand-alone treatment for CF patients, but the rescue effect in combination with other drugs may confer an acceptable level of therapeutic benefit. Targeting cellular factors that modify trafficking may act to enhance the cell surface density of F508-CFTR with VX-809 correction. Our goal is to identify druggable kinases that enhance F508del-CFTR rescue and stabilization at the cell surface beyond that achievable with the VX-809 corrector alone. To achieve this goal, we implemented a new high-throughput screening paradigm that quickly and quantitatively measures surface density and total protein in the same cells. This allowed for rapid screening for increased surface targeting and proteostatic regulation. The assay utilizes fluorogen-activating-protein (FAP) technology with cell excluded and cell permeant fluorogenic dyes in a quick, wash-free fluorescent plate reader format on live cells to first measure F508del-CFTR expressed on the surface and then the total amount of F508del-CFTR protein present. To screen for kinase targets, we used Dharmacon's ON-TARGET plus SMARTpool siRNA Kinase library (715 target kinases) with and without 10 μM VX-809 treatment in triplicate at 37 °C. We identified several targets that had a significant interaction with VX-809 treatment in enhancing surface density with siRNA knockdown. Select small-molecule inhibitors of the kinase targets demonstrated augmented surface expression with VX-809 treatment.

Predictors of contemporary coronary artery bypass grafting outcomes.

PubMed

Weisel, Richard D; Nussmeier, Nancy; Newman, Mark F; Pearl, Ronald G; Wechsler, Andrew S; Ambrosio, Giuseppe; Pitt, Bertram; Clare, Robert M; Pieper, Karen S; Mongero, Linda; Reece, Tammy L; Yau, Terrence M; Fremes, Stephen; Menasché, Philippe; Lira, Armando; Harrington, Robert A; Ferguson, T Bruce

2014-12-01

The study objective was to identify the predictors of outcomes in a contemporary cohort of patients from the Reduction in cardiovascular Events by acaDesine in patients undergoing CABG (RED-CABG) trial. Despite the increasing risk profile of patients who undergo coronary artery bypass grafting, morbidity and mortality have remained low, and identification of the current predictors of adverse outcomes may permit new treatments to further improve outcomes. The RED-CABG trial was a multicenter, randomized, double-blind, placebo-controlled study that determined that acadesine did not reduce adverse events in moderately high-risk patients undergoing nonemergency coronary artery bypass grafting. The primary efficacy end point was a composite of all-cause death, nonfatal stroke, or the need for mechanical support for severe left ventricular dysfunction through postoperative day 28. Logistic regression modeling with stepwise variable selection identified which prespecified baseline characteristics were associated with the primary outcome. A second logistic model included intraoperative variables as potential covariates. The 4 independent preoperative risk factors predictive of the composite end point were (1) a history of heart failure (odds ratio, 2.9); (2) increasing age (odds ratio, 1.033 per decade); (3) a history of peripheral vascular disease (odds ratio, 1.6); and (4) receiving aspirin before coronary artery bypass grafting (odds ratio, 0.5), which was protective. The duration of the cardiopulmonary bypass (odds ratio, 1.8) was the only intraoperative variable that contributed to adverse outcomes. Patients who had heart failure and preserved systolic function had a similar high risk of adverse outcomes as those with low ejection fractions, and new approaches may mitigate this risk. Recognition of patients with excessive atherosclerotic burden may permit perioperative interventions to improve their outcomes. The contemporary risks of coronary artery bypass grafting

Postoperative Dysphagia in Debranching Thoracic Endovascular Aortic Repair with Retroesophageal Carotid-Carotid Bypass.

PubMed

Yoneyama, Fumiya; Sato, Fujio; Tokunaga, Chiho; Sakamoto, Hiroaki; Enomoto, Yoshiharu; Watanabe, Yutaka; Hiramatsu, Yuji

2017-08-01

A carotid-carotid bypass is commonly used in debranching thoracic endovascular aortic repair. When the bypass graft is placed in the retroesophageal position, the esophagus may be compressed by the graft from behind. Therefore, dysphagia may occur postoperatively as a serious complication. To avoid this issue, we recommend placing the bypass graft below the cricoid cartilage. Copyright © 2017 Elsevier Inc. All rights reserved.

Early superficial temporal artery to middle cerebral artery bypass in acute ischemic stroke.

PubMed

Lee, Sang-Bok; Huh, Pil-Woo; Kim, Dal-Soo; Yoo, Do-Sung; Lee, Tae-Gyu; Cho, Kyoung-Suok

2013-08-01

To evaluate the effects and safety of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis in the early stage after an acute ischemic event and the improvement of present symptoms in patients with intracranial atherosclerotic occlusive disease with stroke/stroke in progress. From 2006 to 2010, 20 patients (15 males and five females) with atherosclerotic cerebrovascular disease were treated with an STA-MCA bypass. All of the patients presented with an acute ischemic stroke or stroke in progress despite maximal medical treatment. The patients underwent an STA-MCA bypass within 7 days from symptom onset. The clinical outcome and hemodynamic study of the 20 patients were preoperatively and postoperatively investigated. A pooled analysis was performed, and the results were compared with those obtained from other delayed STA-MCA bypass studies. Among the 20 patients who underwent an early STA-MCA bypass, fourteen (70%) patients achieved a good functional outcome (mRS 0, n=3; mRS 1, n=9; mRS 2, n=2). Prior to surgery, the mean basal regional cerebral blood flow (rCBF) and cerebrovascular reserve capacity (CVR) in the symptomatic hemisphere were 37.3±4.3 ml/100 g/min and -1.68±2.9%. The mean basal rCBF and CVR had significantly increased postoperatively, and no reperfusion-induced hemorrhage had occurred. In the pooled analysis, no significant differences were observed in the clinical outcome (P=0.328) or in the incidence of postoperative complications (P=0.516) between patients who underwent an early STA-MCA bypass and in patients who underwent a delayed STA-MCA bypass in previous studies. In this study, which consisted of 20 carefully selected patients with acute ischemic stroke, an early STA-MCA bypass was safely and effectively performed, and in some cases, an early STA-MCA bypass resulted in rapid neurological improvement. An early STA-MCA bypass was beneficial in select patients who had acute ischemic stroke with imaging evidence of a small

Environmental impact case study : Martinsville bypass.

DOT National Transportation Integrated Search

1971-01-01

At the request of the Environmental Quality Division, the Environmental and Economics Section of the Virginia Highway Research Council conducted an environmental impact study of the proposed Route 220 bypass around Martinsville. This evaluation of th...

Network modeling of kinase inhibitor polypharmacology reveals pathways targeted in chemical screens

PubMed Central

Ursu, Oana; Gosline, Sara J. C.; Beeharry, Neil; Fink, Lauren; Bhattacharjee, Vikram; Huang, Shao-shan Carol; Zhou, Yan; Yen, Tim; Fraenkel, Ernest

2017-01-01

Small molecule screens are widely used to prioritize pharmaceutical development. However, determining the pathways targeted by these molecules is challenging, since the compounds are often promiscuous. We present a network strategy that takes into account the polypharmacology of small molecules in order to generate hypotheses for their broader mode of action. We report a screen for kinase inhibitors that increase the efficacy of gemcitabine, the first-line chemotherapy for pancreatic cancer. Eight kinase inhibitors emerge that are known to affect 201 kinases, of which only three kinases have been previously identified as modifiers of gemcitabine toxicity. In this work, we use the SAMNet algorithm to identify pathways linking these kinases and genetic modifiers of gemcitabine toxicity with transcriptional and epigenetic changes induced by gemcitabine that we measure using DNaseI-seq and RNA-seq. SAMNet uses a constrained optimization algorithm to connect genes from these complementary datasets through a small set of protein-protein and protein-DNA interactions. The resulting network recapitulates known pathways including DNA repair, cell proliferation and the epithelial-to-mesenchymal transition. We use the network to predict genes with important roles in the gemcitabine response, including six that have already been shown to modify gemcitabine efficacy in pancreatic cancer and ten novel candidates. Our work reveals the important role of polypharmacology in the activity of these chemosensitizing agents. PMID:29023490

The Benefits of Photorespiratory Bypasses: How Can They Work?1[OPEN

PubMed Central

Xin, Chang-Peng; Tholen, Danny; Devloo, Vincent; Zhu, Xin-Guang

2015-01-01

Bypassing the photorespiratory pathway is regarded as a way to increase carbon assimilation and, correspondingly, biomass production in C3 crops. Here, the benefits of three published photorespiratory bypass strategies are systemically explored using a systems-modeling approach. Our analysis shows that full decarboxylation of glycolate during photorespiration would decrease photosynthesis, because a large amount of the released CO2 escapes back to the atmosphere. Furthermore, we show that photosynthesis can be enhanced by lowering the energy demands of photorespiration and by relocating photorespiratory CO2 release into the chloroplasts. The conductance of the chloroplast membranes to CO2 is a key feature determining the benefit of the relocation of photorespiratory CO2 release. Although our results indicate that the benefit of photorespiratory bypasses can be improved by increasing sedoheptulose bisphosphatase activity and/or increasing the flux through the bypass, the effectiveness of such approaches depends on the complex regulation between photorespiration and other metabolic pathways. PMID:25516604

Intraoperative Evaluation of Reverse Bypass Using a Naturally Formed "Bonnet" Superficial Temporal Artery: Technical Note.

PubMed

Nagm, Alhusain; Horiuchi, Tetsuyoshi; Hasegawa, Takatoshi; Hongo, Kazuhiro

2016-04-01

In reverse bypass that used a naturally formed "bonnet" superficial temporal artery, intraoperative volume flow measurement quantifies flow augmentation after revascularization, confirms flow preservation, and identifies inadvertent vessel compromise. A 75-year-old man presented with transient ischemic attacks attributed to right internal carotid artery stenosis. He underwent successful reverse bypass via a naturally formed "bonnet" superficial temporal artery middle cerebral artery bypass. As the result of proper intraoperative volume flow evaluation, a successful reverse bypass was achieved. Modification of the intraoperative stroke risk and prediction of the long-term patency after reverse bypass can be achieved by meticulous intraoperative blood flow evaluation. Copyright © 2016 Elsevier Inc. All rights reserved.

Minimally invasive entero-enteral dual-path bypass using self-assembling magnets.

PubMed

Ryou, Marvin; Aihara, Hiroyuki; Thompson, Christopher C

2016-10-01

A minimally invasive method of entero-enteral bypass may be desirable for treatment of obstruction, obesity, or metabolic syndrome. We have developed a technology based on miniature self-assembling magnets which create large-caliber anastomoses (incisionless anastomosis system or IAS). The aim of this study was to assess (a) procedural characteristics of IAS deployment and (b) long-term integrity and patency of the resulting jejuno-ileal dual-path bypass. Endoscopic jejuno-ileal bypass creation using IAS magnets was performed in 8 Yorkshire pigs survived 3 months. The jejunal magnet was endoscopically deployed. However, the ileal magnet required surgical delivery given restraints of porcine anatomy. A 5-mm enterotomy was created through which the ileal magnet was inserted using a modified laparoscopic delivery tool. Magnets were manually coupled. Pigs underwent serial endoscopies for anastomosis assessment. Three-month necropsies were performed, followed by pressure testing of anastomoses and histological analysis. Jejuno-ileal bypass creation using self-assembling IAS magnets was successful in all 8 pigs (100 %). Patent, leak-free bypasses formed in all animals by day 10. All IAS magnets were expelled by day 12. Anastomoses were widely patent at 3 months, with mean maximal diameter of 30 mm. At necropsy, adhesions were minimal. Pressure testing confirmed superior integrity of anastomotic tissue. Histology showed full epithelialization across the anastomosis with no evidence of submucosal fibrosis or inflammation. Entero-enteral bypass using self-assembling IAS magnets is safe and technically feasible in the porcine model. IAS magnets can be rapidly delivered endoscopically or through a modified laparoscopic device. Expulsion of fused magnets avoids retention of prosthetic material. Anastomoses are widely patent and fully re-epithelialized. Three-month pressure testing reveals anastomotic tissue to be as robust as native tissue, while necropsy and histology

Rankine cycle load limiting through use of a recuperator bypass

DOEpatents

Ernst, Timothy C.

2011-08-16

A system for converting heat from an engine into work includes a boiler coupled to a heat source for transferring heat to a working fluid, a turbine that transforms the heat into work, a condenser that transforms the working fluid into liquid, a recuperator with one flow path that routes working fluid from the turbine to the condenser, and another flow path that routes liquid working fluid from the condenser to the boiler, the recuperator being configured to transfer heat to the liquid working fluid, and a bypass valve in parallel with the second flow path. The bypass valve is movable between a closed position, permitting flow through the second flow path and an opened position, under high engine load conditions, bypassing the second flow path.

Preschool vision screening.

PubMed Central

Jarvis, S N; Tamhne, R C; Thompson, L; Francis, P M; Anderson, J; Colver, A F

1991-01-01

Although a good case for preschool screening for vision defects can be made there is very little evidence that existing programmes are effective in practice. A comparative trial of three different methods of preschool vision screening is described. Some 7000 children initially aged 5 months (younger cohorts) and 30 months (older cohorts) in three matched areas entered the trial during 1987. During 18 months of follow up new visual and ocular defects among these children were ascertained through ophthalmology outpatients and from optician records. Screening at 35 months by an orthoptist based in the community is superior to conventional health visitor surveillance at 30 months and to an agreed programme of primary care screening for squint at 30-36 months as judged by screening sensitivity (100% v 50% v 50%) and the incidence of treated target conditions (17 v 3 v 5 per 1000 person years). A notable feature in the area served by the orthoptist is that 13 children received treatment for straight eyed visual acuity loss from among 1000 children whereas there were no such cases among 2500 in the comparison areas. In the younger cohorts (that is, screening at age 5-9 months) all three programmes showed equally poor results, only one of the eight treated target conditions arising from all 3500 younger children being screen detected. PMID:2025002

Right Internal Mammary Artery Use in 140 Robotic Totally Endoscopic Coronary Bypass Cases: Toward Multiarterial Grafting.

PubMed

Balkhy, Husam H; Nathan, Sandeep; Arnsdorf, Susan E; Krienbring, Dorothy J

Benefits of adding a second arterial graft in coronary bypass are well documented. In patients requiring mulitvessel grafting robotic totally endoscopic coronary bypass (TECAB) has allowed for routine harvesting and use of the right internal mammary artery (RIMA). We retrospectively reviewed the technical considerations and target choice in 140 cases of beating heart TECAB where a RIMA graft was used. In 2008, we introduced beating heart TECAB with anastomotic connectors into our practice, first with single IMA and then with bilateral internal mammary artery. A robotic stabilizer was used not only to facilitate exposure of the coronary targets but also to aid the RIMA harvest using a skeletonized approach. Flow measurements were obtained routinely. We reviewed the technical aspects, target choice, and intraoperative flows in our TECAB patients who underwent grafting with RIMA grafts. From February 2008 to January 2015, a total of 404 patients underwent beating heart TECAB with anastomotic connectors, of which 194 (48%) were mulitvessel procedures. One hundred forty patients (35%) had a RIMA graft and constitute the patient population for this review. One hundred thirty-one RIMA grafts were harvested via left-sided ports and grafted to left coronary targets, and nine RIMA grafts were harvested via right-sided ports and grafted to the right coronary artery. Flow was greater than 25 mL/min (pulsatility index < 2) in 95% of grafts. Perioperative mortality was 0.7% and mean ± standard deviation length of hospital stay was 3.1 (1.5) days. The RIMA was used as an in situ graft in 124 cases (84%) and as a free T-graft in 24 cases (16%) cases. Right internal mammary artery graft use in all TECABS increased from 23% in the first 5 years to 53% in the last 2 years. Robotic TECAB allows the routine harvesting and use of the RIMA graft in a safe and reproducible manner. Skeletonization and sternal sparing allow the RIMA to reach various coronary targets. Further studies are

21 CFR 870.4270 - Cardiopulmonary bypass cardiotomy suction line blood filter.

Code of Federal Regulations, 2014 CFR

2014-04-01

... blood filter. 870.4270 Section 870.4270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Devices § 870.4270 Cardiopulmonary bypass cardiotomy suction line blood filter. (a) Identification. A cardiopulmonary bypass cardiotomy suction line blood filter is a device used as part of a gas exchange (oxygenator...

21 CFR 870.4270 - Cardiopulmonary bypass cardiotomy suction line blood filter.

Code of Federal Regulations, 2010 CFR

2010-04-01

... blood filter. 870.4270 Section 870.4270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Devices § 870.4270 Cardiopulmonary bypass cardiotomy suction line blood filter. (a) Identification. A cardiopulmonary bypass cardiotomy suction line blood filter is a device used as part of a gas exchange (oxygenator...

21 CFR 870.4270 - Cardiopulmonary bypass cardiotomy suction line blood filter.

Code of Federal Regulations, 2011 CFR

2011-04-01

... blood filter. 870.4270 Section 870.4270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Devices § 870.4270 Cardiopulmonary bypass cardiotomy suction line blood filter. (a) Identification. A cardiopulmonary bypass cardiotomy suction line blood filter is a device used as part of a gas exchange (oxygenator...

21 CFR 870.4270 - Cardiopulmonary bypass cardiotomy suction line blood filter.

Code of Federal Regulations, 2012 CFR

2012-04-01

... blood filter. 870.4270 Section 870.4270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Devices § 870.4270 Cardiopulmonary bypass cardiotomy suction line blood filter. (a) Identification. A cardiopulmonary bypass cardiotomy suction line blood filter is a device used as part of a gas exchange (oxygenator...

21 CFR 870.4270 - Cardiopulmonary bypass cardiotomy suction line blood filter.

Code of Federal Regulations, 2013 CFR

2013-04-01

... blood filter. 870.4270 Section 870.4270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Devices § 870.4270 Cardiopulmonary bypass cardiotomy suction line blood filter. (a) Identification. A cardiopulmonary bypass cardiotomy suction line blood filter is a device used as part of a gas exchange (oxygenator...

Roux-en-Y gastric bypass reversal: a systematic review.

PubMed

Shoar, Saeed; Nguyen, Thu; Ona, Mel A; Reddy, Madhavi; Anand, Sury; Alkuwari, Mohammed J; Saber, Alan A

2016-08-01

Due to the large number of Roux-en-Y gastric bypass surgeries performed over the last decade, reversal of the bypass to normal anatomy has been increasingly reported. University affiliated Teaching Hospital, United States. The aim of this systematic review was to summarize the literature data regarding the indications, technical considerations, and outcomes of gastric bypass reversal. PubMed/MEDLINE search was conducted for articles reporting reversal of gastric bypass to normal anatomy. Patients' demographic characteristics, primary reason for reversal, reversal technique, and postreversal events were retrieved and categorized from each eligible paper. Thirty-five articles encompassing a total of 100 patients were eligible. Malnutrition was the most common indication for reversal (12.3%), followed by severe dumping syndrome (9.4%), postprandial hypoglycemia (8.5%), and excessive weight loss (8.5%). Techniques for gastrogastrostomy were available in 42 patients, with the hand-sewn technique as the most common (67.4%) followed by the linear stapler (23.2%) and the end-to-end anastomosis stapler used in 3 patients (6.9%). The reversal technique was performed endoscopically and described in 3 studies (3 patients). Techniques for handling the Roux limb were described in 56 patients (56%); the limb was reconnected in 32 patients (57.2%) and resected in 24 patients (42.8%). Weight regain was the most prevalent postreversal event (28.8%), followed by severe gastroesophageal reflux diseases (10.2%) and persistent abdominal pain (6.8%). There was no reported mortality. Gastric bypass reversal is indicated for excessive weight loss, dumping syndrome, and postprandial hypoglycemia. The procedure is well tolerated and feasible when performed laparoscopically and has no reported mortality. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Investigation on the Core Bypass Flow in a Very High Temperature Reactor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hassan, Yassin

2013-10-22

Uncertainties associated with the core bypass flow are some of the key issues that directly influence the coolant mass flow distribution and magnitude, and thus the operational core temperature profiles, in the very high-temperature reactor (VHTR). Designers will attempt to configure the core geometry so the core cooling flow rate magnitude and distribution conform to the design values. The objective of this project is to study the bypass flow both experimentally and computationally. Researchers will develop experimental data using state-of-the-art particle image velocimetry in a small test facility. The team will attempt to obtain full field temperature distribution using racksmore » of thermocouples. The experimental data are intended to benchmark computational fluid dynamics (CFD) codes by providing detailed information. These experimental data are urgently needed for validation of the CFD codes. The following are the project tasks: • Construct a small-scale bench-top experiment to resemble the bypass flow between the graphite blocks, varying parameters to address their impact on bypass flow. Wall roughness of the graphite block walls, spacing between the blocks, and temperature of the blocks are some of the parameters to be tested. • Perform CFD to evaluate pre- and post-test calculations and turbulence models, including sensitivity studies to achieve high accuracy. • Develop the state-of-the art large eddy simulation (LES) using appropriate subgrid modeling. • Develop models to be used in systems thermal hydraulics codes to account and estimate the bypass flows. These computer programs include, among others, RELAP3D, MELCOR, GAMMA, and GAS-NET. Actual core bypass flow rate may vary considerably from the design value. Although the uncertainty of the bypass flow rate is not known, some sources have stated that the bypass flow rates in the Fort St. Vrain reactor were between 8 and 25 percent of the total reactor mass flow rate. If bypass flow rates are

Extended use of cardiopulmonary bypass in a multidisciplinary hospital

PubMed Central

Shahabuddin, Syed; Habib, Nabeel

2015-01-01

Objective To share our experience highlighting the additional use of cardiopulmonary bypass (CPB) in cases other than the conventional ischemic, congenital and valvular heart diseases. Methodology All patients undergoing non-traditional cardiac surgery utilizing the cardiopulmonary bypass during a period from 1999 to 2009 reviewed. Their preoperative presentation, operative strategy and immediate postoperative status were assessed. Results A total of six such cases were identified including three female and three male patients. Two patients presented with road traffic accident having aortic transection along with other injuries. They underwent repair utilizing partial cardiopulmonary bypass. One patient presented with large PDA aneurysm and symptoms related to its pressure effect on respiratory system. He underwent repair under hypothermic circulatory arrest. These three patients were done via left thoracotomy. Three patients underwent deep hypothermic circulatory arrest, one for removal of thrombus from right atrium after complicated liver abscess, one patient required vascular graft interposition in left internal carotid artery for aneurysm extending into cranium and the third one underwent resection of vascular tumor of posterior cranial fossa. One patient required exploration for bleeding. One patient died after prolonged hospitalization. Rest of the patient had unremarkable postoperative course and were discharged home. Conclusion Our short experience highlights the extended use of cardiopulmonary bypass in a multidisciplinary hospital, facilitating to perform complex, technically challenging non cardiac procedures which otherwise may not be possible. PMID:26309443

The SPORTSMART study: a pilot randomised controlled trial of sexually transmitted infection screening interventions targeting men in football club settings

PubMed Central

Fuller, Sebastian S; Mercer, Catherine H; Copas, Andrew J; Saunders, John; Sutcliffe, Lorna J; Cassell, Jackie A; Hart, Graham; Johnson, Anne M; Roberts, Tracy E; Jackson, Louise J; Muniina, Pamela; Estcourt, Claudia S

2015-01-01

Background Uptake of chlamydia screening by men in England has been substantially lower than by women. Non-traditional settings such as sports clubs offer opportunities to widen access. Involving people who are not medically trained to promote screening could optimise acceptability. Methods We developed two interventions to explore the acceptability and feasibility of urine-based sexually transmitted infection (STI) screening interventions targeting men in football clubs. We tested these interventions in a pilot cluster randomised control trial. Six clubs were randomly allocated, two to each of three trial arms: team captain-led and poster STI screening promotion; sexual health adviser-led and poster STI screening promotion; and poster-only STI screening promotion (control/comparator). Primary outcome was test uptake. Results Across the three arms, 153 men participated in the trial and 90 accepted the offer of screening (59%, 95% CI 35% to 79%). Acceptance rates were broadly comparable across the arms: captain-led: 28/56 (50%); health professional-led: 31/46 (67%); and control: 31/51 (61%). However, rates varied appreciably by club, precluding formal comparison of arms. No infections were identified. Process evaluation confirmed that interventions were delivered in a standardised way but the control arm was unintentionally ‘enhanced’ by some team captains actively publicising screening events. Conclusions Compared with other UK-based community screening models, uptake was high but gaining access to clubs was not always easy. Use of sexual health advisers and team captains to promote screening did not appear to confer additional benefit over a poster-promoted approach. Although the interventions show potential, the broader implications of this strategy for UK male STI screening policy require further investigation. PMID:25512674

Endothelin and vasopressin influence splanchnic blood flow distribution during and after cardiopulmonary bypass.

PubMed

Bomberg, Hagen; Bierbach, Benjamin; Flache, Stephan; Wagner, Isabell; Gläser, Lena; Groesdonk, Heinrich V; Menger, Michael D; Schäfers, Hans-Joachim

2013-02-01

Gastrointestinal blood flow can be compromised during and after cardiopulmonary bypass. Endothelin has been shown to be involved in the intestinal microcirculatory disturbance of sepsis. The aim of the present study was to analyze the involvement of the endothelin system on intestinal blood flow regulation during cardiopulmonary bypass and the effect of vasopressin given during cardiopulmonary bypass. A total of 24 pigs were studied in 4 groups (n = 6): group I, sham; group II, ischemia/reperfusion with 1 hour of superior mesenteric artery occlusion; group III, cardiopulmonary bypass for 1 hour; and group IV, 1 hour of cardiopulmonary bypass plus vasopressin administration, maintaining the baseline arterial pressure. All the pigs were reperfused for 90 minutes. During the experiment, the hemodynamics and jejunal microcirculation were measured continuously. The jejunal mucosal expression of endothelin-1 and its receptor subtypes A and B were determined using polymerase chain reaction. During cardiopulmonary bypass, superior mesenteric artery flow was preserved but marked jejunal microvascular impairment occurred compared with baseline (mucosal capillary density, 192.2 ± 5.4 vs 150.8 ± 5.1 cm/cm(2); P = .005; tissue blood flow, 501.7 ± 39.3 vs 332.3 ± 27.9 AU; P = .025). The expression of endothelin-1 after cardiopulmonary bypass (3.2 ± 0.4 vs 12.2 ± 0.8 RQ, P = .006) and endothelin subtype A (0.7 ± 0.2 vs 2.4 ± 0.6 RQ; P = .01) was significantly increased compared to the sham group. Vasopressin administration during cardiopulmonary bypass led to normal capillary density (189.9 ± 3.9 vs 178.0 ± 6.3; P = .1) and tissue blood flow (501.7 ± 39.3 vs 494.7 ± 44.4 AU; P = .4) compared with baseline. The expression of endothelin-1 (3.2 ± 0.4 vs 1.8 ± 0.3 RQ; P = .3) and endothelin subtype A (0.7 ± 0.2 vs 0.9 ± 0.2 RQ; P = .5) was not different from the sham group. Cardiopulmonary bypass leads to microvascular impairment of jejunal microcirculation, which is