Development and Validation of an Empiric Tool to Predict Favorable Neurologic Outcomes Among PICU Patients.

PubMed

Gupta, Punkaj; Rettiganti, Mallikarjuna; Gossett, Jeffrey M; Daufeldt, Jennifer; Rice, Tom B; Wetzel, Randall C

2018-01-01

To create a novel tool to predict favorable neurologic outcomes during ICU stay among children with critical illness. Logistic regression models using adaptive lasso methodology were used to identify independent factors associated with favorable neurologic outcomes. A mixed effects logistic regression model was used to create the final prediction model including all predictors selected from the lasso model. Model validation was performed using a 10-fold internal cross-validation approach. Virtual Pediatric Systems (VPS, LLC, Los Angeles, CA) database. Patients less than 18 years old admitted to one of the participating ICUs in the Virtual Pediatric Systems database were included (2009-2015). None. A total of 160,570 patients from 90 hospitals qualified for inclusion. Of these, 1,675 patients (1.04%) were associated with a decline in Pediatric Cerebral Performance Category scale by at least 2 between ICU admission and ICU discharge (unfavorable neurologic outcome). The independent factors associated with unfavorable neurologic outcome included higher weight at ICU admission, higher Pediatric Index of Morality-2 score at ICU admission, cardiac arrest, stroke, seizures, head/nonhead trauma, use of conventional mechanical ventilation and high-frequency oscillatory ventilation, prolonged hospital length of ICU stay, and prolonged use of mechanical ventilation. The presence of chromosomal anomaly, cardiac surgery, and utilization of nitric oxide were associated with favorable neurologic outcome. The final online prediction tool can be accessed at https://soipredictiontool.shinyapps.io/GNOScore/. Our model predicted 139,688 patients with favorable neurologic outcomes in an internal validation sample when the observed number of patients with favorable neurologic outcomes was among 139,591 patients. The area under the receiver operating curve for the validation model was 0.90. This proposed prediction tool encompasses 20 risk factors into one probability to predict favorable neurologic outcome during ICU stay among children with critical illness. Future studies should seek external validation and improved discrimination of this prediction tool.

Vision and Vestibular System Dysfunction Predicts Prolonged Concussion Recovery in Children.

PubMed

Master, Christina L; Master, Stephen R; Wiebe, Douglas J; Storey, Eileen P; Lockyer, Julia E; Podolak, Olivia E; Grady, Matthew F

2018-03-01

Up to one-third of children with concussion have prolonged symptoms lasting beyond 4 weeks. Vision and vestibular dysfunction is common after concussion. It is unknown whether such dysfunction predicts prolonged recovery. We sought to determine which vision or vestibular problems predict prolonged recovery in children. A retrospective cohort of pediatric patients with concussion. A subspecialty pediatric concussion program. Four hundred thirty-two patient records were abstracted. Presence of vision or vestibular dysfunction upon presentation to the subspecialty concussion program. The main outcome of interest was time to clinical recovery, defined by discharge from clinical follow-up, including resolution of acute symptoms, resumption of normal physical and cognitive activity, and normalization of physical examination findings to functional levels. Study subjects were 5 to 18 years (median = 14). A total of 378 of 432 subjects (88%) presented with vision or vestibular problems. A history of motion sickness was associated with vestibular dysfunction. Younger age, public insurance, and presence of headache were associated with later presentation for subspecialty concussion care. Vision and vestibular problems were associated within distinct clusters. Provocable symptoms with vestibulo-ocular reflex (VOR) and smooth pursuits and abnormal balance and accommodative amplitude (AA) predicted prolonged recovery time. Vision and vestibular problems predict prolonged concussion recovery in children. A history of motion sickness may be an important premorbid factor. Public insurance status may represent problems with disparities in access to concussion care. Vision assessments in concussion must include smooth pursuits, saccades, near point of convergence (NPC), and accommodative amplitude (AA). A comprehensive, multidomain assessment is essential to predict prolonged recovery time and enable active intervention with specific school accommodations and targeted rehabilitation.

Surgical problems and complex procedures: issues for operative time in robotic totally endoscopic coronary artery bypass grafting.

PubMed

Wiedemann, Dominik; Bonaros, Nikolaos; Schachner, Thomas; Weidinger, Felix; Lehr, Eric J; Vesely, Mark; Bonatti, Johannes

2012-03-01

Robotically assisted totally endoscopic coronary artery bypass grafting (TECAB) is a viable option for closed chest coronary surgery, but it requires learning curves and longer operative times. This study evaluated the effect of extended operation times on the outcome of patients undergoing TECAB. From 2001 to 2009, 325 patients underwent TECAB with the da Vinci telemanipulation system. Correlations between operative times and preoperative, intraoperative, and early postoperative parameters were investigated. Receiver operating characteristic analysis was used to define the threshold of the procedure duration above which intensive care unit stay and ventilation time were prolonged. Demographic data, intraoperative and postoperative parameters, and survival data were compared. Patients with prolonged operative times more often underwent multivessel revascularization (P < .001) and beating-heart TECAB (P =.023). Other preoperative parameters were not associated with longer operative times. Incidences of technical difficulties and conversions (P < .001) were higher among patients with longer operative times. Prolonged intensive care unit stay, mechanical ventilation, hospital stay, and with requirement of blood products were associated with longer operative times. Receiver operating characteristic analysis showed operative times >445 minutes and >478 minutes to predict prolonged (>48 hours) intensive care unit stay and mechanical ventilation, respectively. Patients with procedures >478 minutes had longer hospital stays and higher perioperative morbidity and mortality. Kaplan-Meier analysis revealed decreased survival among patients with operative times >478 minutes. Multivessel revascularization and conversions lead to prolonged operative times in totally endoscopic coronary artery bypass grafting. Longer operative times significantly influence early postoperative and midterm outcomes. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Grading of Emphysema Is Indispensable for Predicting Prolonged Air Leak After Lung Lobectomy.

PubMed

Murakami, Junichi; Ueda, Kazuhiro; Tanaka, Toshiki; Kobayashi, Taiga; Hamano, Kimikazu

2018-04-01

The aim of this study was to assess the utility of quantitative computed tomography-based grading of emphysema for predicting prolonged air leak after thoracoscopic lobectomy. A consecutive series of 284 patients undergoing thoracoscopic lobectomy for lung cancer was retrospectively reviewed. Prolonged air leak was defined as air leaks lasting 7 days or longer. The grade of emphysema (emphysema index) was defined by the proportion of the emphysematous lung volume (less than -910 HU) to the total lung volume (-600 to -1,024 HU) by a computer-assisted histogram analysis of whole-lung computed tomography scans. The mean length of chest tube drainage was 1.5 days. Fifteen patients (5.3%) presented with prolonged air leak. According to a receiver-operating characteristics curve analysis, the emphysema index was the best predictor of prolonged air leak, with an area under the curve of 0.85 (95% confidence interval: 0.73 to 0.98). An emphysema index of 35% or greater was the best cutoff value for predicting prolonged air leak, with a negative predictive value of 0.99. The emphysema index was the only significant predictor for the length of postoperative chest tube drainage among conventional variables, including the pulmonary function and resected lobe, in both univariate and multivariate analyses. Prolonged air leak resulted in an increased duration of hospitalization (p < 0.001) and was frequently accompanied by pneumonia or empyema (p < 0.001). The grade of emphysema on computed tomography scan is the best predictor of prolonged air leak that adversely influences early postoperative outcomes. We must take new measures against prolonged air leak in quantitative computed tomography-based high-risk patients. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model

PubMed Central

Yao, X; Anderson, D L; Ross, S A; Lang, D G; Desai, B Z; Cooper, D C; Wheelan, P; McIntyre, M S; Bergquist, M L; MacKenzie, K I; Becherer, J D; Hashim, M A

2008-01-01

Background and purpose: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. Experimental approach: Sixteen marketed drugs from various pharmacological classes with a known incidence—or lack thereof—of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. Key results: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. Conclusions and implications: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization. PMID:18587422

Central aortic systolic blood pressure can predict prolonged QTc duration better than brachial artery systolic blood pressure in rural community residents.

PubMed

Huang, Yuqing; Tang, Songtao; Chen, Ji-Yan; Huang, Cheng; Li, Jie; Cai, An-Ping; Feng, Yingqing

2018-01-01

Previous studies have suggested that prolonged electrocardiogram QTc duration was independent risk factor for both increased cardiovascular and all-cause mortality, but there was no dating about the relationship between central aortic systolic blood pressure (CASP) and QTc duration. The aim of this study was to analyze the relationship between CASP and QTc duration, and assess whether CASP can predict prolonged QTc duration more than BSBP. A total of 500 patients were enrolled in this study, central and brachial aortic blood pressure and electrocardiogram QTc duration were measured. Pearson correlation was assessed for determining the associations of QTc duration with clinical conditions. Multivariate logistic regression analyses were performed to determine the independent predictor of prolonged QTc duration. Receiver operating characteristic (ROC) curve was used to evaluate the utility of blood pressure for prolonged QTc duration. We found QTc durations were significantly positive with CASP (r = 0.308, p < 0.001), BSBP (r = 0.227, p < 0.001), and age (r = 0.154, p = 0.010), but negatively related to heart rate (r = -440, p < 0.001). A multiple logistic regression analysis demonstrated that the CASP was an independent determinant of prolonged QTc (OR = 1.648; 95%CI: 1.032, 2.101; p < 0.001). CASP had a better predictive value for prolonged QTc duration than (AUC: 0.771 vs. 0.646, p < 0.001) BSBP. Our results suggested that the non-invasive CASP is independently correlated with QTc duration, and CASP can predict prolonged QTc duration more than BSBP.

Prolonged Mechanical Ventilation as a Predictor of Mortality After Cardiac Surgery.

PubMed

Fernandez-Zamora, Maria Dolores; Gordillo-Brenes, Antonio; Banderas-Bravo, Esther; Arboleda-Sánchez, José Andrés; Hinojosa-Pérez, Rafael; Aguilar-Alonso, Eduardo; Herruzo-Aviles, Ángel; Curiel-Balsera, Emilio; Sánchez-Rodríguez, Ángel; Rivera-Fernández, Ricardo

2018-05-01

Mortality among the small percentage of cardiac surgery patients receiving prolonged mechanical ventilation is high, but this issue appears to be inadequately addressed in guidelines. This study is a retrospective analysis of prospective, multi-center, and observational study in Spain including all adults undergoing cardiac surgery in 3 Andalusian hospitals between June 2008 and December 2012. The study included 3,588 adults with mean ± SD age of 63.5 ± 12.8 y and with median (interquartile range) EuroSCORE of 5 (3-7) points. Prolonged mechanical ventilation (> 24 h) was required by 415 subjects (11.6%), with ICU mortality of 44.3% (184 subjects), and was not required by 3,173 subjects (88.4%), with ICU mortality of 3.1% (99 subjects, P < .001). Prolonged mechanical ventilation was associated with more complications and was required by 4.5% of subjects with a EuroSCORE <5, 11.2% with a score of 5-7, 27.2% with a score of 8-10, and 32.2% with a score > 10. In the multivariable analysis, ICU mortality was associated with illness severity, duration of bypass surgery, surgery type, and prolonged mechanical ventilation (odds ratio 15.19, 95% CI 11.56-22.09). The main cause of death was multiple organ failure and sepsis in subjects who required prolonged mechanical ventilation (50.3%) and cardiogenic shock in those who did not (59.2%). Prolonged postoperative mechanical ventilation was required by 10-20% of cardiac surgery subjects, who constitute a specific group that represents most of the postoperative mortality, which is associated with multiple organ failure and sepsis. Copyright © 2018 by Daedalus Enterprises.

Studying the Power of the Integrative Weaning Index in Predicting the Success Rate of the Spontaneous Breathing Trial in Patients under Mechanical Ventilation.

PubMed

Ebrahimabadi, Sahar; Moghadam, Ahmad Bagheri; Vakili, Mohammadali; Modanloo, Mahnaz; Khoddam, Homeira

2017-08-01

The use of weaning predictive indicators can avoid early extubation and wrongful prolonged mechanical ventilation. This study aimed to determine the power of the integrative weaning index (IWI) in predicting the success rate of the spontaneous breathing trial (SBT) in patients under mechanical ventilation. In this prospective study, 105 patients undergoing mechanical ventilation for over 48 h were enrolled. Before weaning initiation, the IWI was calculated and based on the defined cutoff point (≥25), the success rate of the SBT was predicted. In case of weaning from the device, 2-h SBT was performed and the physiologic and respiratory indices were continuously studied while being intubated. If they were in the normal range besides the patient's tolerance, the test was considered as a success. The result was then compared with the IWI and further analyzed. The SBT was successful in 90 (85.7%) and unsuccessful in 15 (14.3%) cases. The difference between the true patient outcome after SBT, and the IWI prediction was 0.143 according to the Kappa agreement coefficient ( P < 0.001). Moreover, regarding the predictive power, IWI had high sensitivity (95.6%), specificity (40%), positive and negative predictive values (90.5% and 60), positive and negative likelihood ratios (1.59 and 0.11), and accuracy (86.7%). The IWI as a more objective indicator has acceptable accuracy and power for predicting the 2-h SBT result. Therefore, in addition to the reliable prediction of the final weaning outcome, it has favorable power to predict if the patient is ready to breathe spontaneously as the first step to weaning.

Studying the Power of the Integrative Weaning Index in Predicting the Success Rate of the Spontaneous Breathing Trial in Patients under Mechanical Ventilation

PubMed Central

Ebrahimabadi, Sahar; Moghadam, Ahmad Bagheri; Vakili, Mohammadali; Modanloo, Mahnaz; Khoddam, Homeira

2017-01-01

Background and Aims: The use of weaning predictive indicators can avoid early extubation and wrongful prolonged mechanical ventilation. This study aimed to determine the power of the integrative weaning index (IWI) in predicting the success rate of the spontaneous breathing trial (SBT) in patients under mechanical ventilation. Materials and Methods: In this prospective study, 105 patients undergoing mechanical ventilation for over 48 h were enrolled. Before weaning initiation, the IWI was calculated and based on the defined cutoff point (≥25), the success rate of the SBT was predicted. In case of weaning from the device, 2-h SBT was performed and the physiologic and respiratory indices were continuously studied while being intubated. If they were in the normal range besides the patient's tolerance, the test was considered as a success. The result was then compared with the IWI and further analyzed. Results: The SBT was successful in 90 (85.7%) and unsuccessful in 15 (14.3%) cases. The difference between the true patient outcome after SBT, and the IWI prediction was 0.143 according to the Kappa agreement coefficient (P < 0.001). Moreover, regarding the predictive power, IWI had high sensitivity (95.6%), specificity (40%), positive and negative predictive values (90.5% and 60), positive and negative likelihood ratios (1.59 and 0.11), and accuracy (86.7%). Conclusion: The IWI as a more objective indicator has acceptable accuracy and power for predicting the 2-h SBT result. Therefore, in addition to the reliable prediction of the final weaning outcome, it has favorable power to predict if the patient is ready to breathe spontaneously as the first step to weaning. PMID:28904477

The vestibulo-ocular reflex and its possible roles in space motion sickness

NASA Technical Reports Server (NTRS)

Watt, Douglas G. D.

1987-01-01

Prolonged exposure to an inappropriate vestibulo-ocular reflex (VOR) will usually lead to motion sickness, and it has been predicted on theoretical grounds that VOR gain may be decreased in weightlessness. While experiments during parabolic flight in aircraft tend to confirm this prediction, experiments during orbital spaceflight have led to apparently contradictory results. It is suggested that VOR gain is reduced initially, but that rapid compensatory mechanisms restore it to normal within minutes of reaching weightlessness. However, even though this process may lead to the rapid return of functionally normal gaze stability, it may not protect against the development of motion sickness.

Can Creatinine Height Index Predict Weaning and Survival Outcomes in Patients on Prolonged Mechanical Ventilation After Critical Illness?

PubMed

Datta, Debapriya; Foley, Raymond; Wu, Rong; Grady, James; Scalise, Paul

2018-02-01

Malnutrition is common in chronic critically ill patients on prolonged mechanical ventilation (PMV) and may affect weaning. The creatinine height index (CHI), which reflects lean muscle mass, is regarded as the most accurate indicator of malnutrition. The objective of this study was to determine the impact of CHI in comparison with other traditional nutritional indices on successful weaning and survival in patients on PMV after critical illness. Records of 167 patients on PMV following critical illness, admitted for weaning, were reviewed. Parameters studied included age, gender, body mass index (BMI), percentage ideal body weight (%IBW), total protein, albumin, prealbumin, hemoglobin (Hb), and cause of respiratory failure. Number successfully weaned and number discharged alive and time to wean and time to discharge alive were determined from records. The CHI was calculated from 24-hour urine creatinine using a standard formula. Unpaired 2-sample t test was performed to determine the association between the studied nutritional parameters and outcomes. Predictive value of studied parameters for successful weaning and survival was determined by multivariate logistic regression analysis to model dichotomous outcome of successful weaning and survival. Mean age was 68 ± 14 years, 49% were males, 64% were successfully weaned, and 65.8% survived. Total protein, Hb, and CHI had a significant impact on successful weaning. Weight, %IBW, BMI, and CHI had a significant effect on survival. Of all parameters, CHI was most strongly predictive of successful weaning and survival. The CHI is a strong predictor of successful weaning and survival in patients on PMV.

Coexistence of Ureaplasma and chorioamnionitis is associated with prolonged mechanical ventilation.

PubMed

Jung, Euiseok; Choi, Chang Won; Kim, Su Yeong; Sung, Tae-Jung; Kim, Haeryoung; Park, Kyoung Un; Kim, Han-Suk; Kim, Beyong Il; Choi, Jung-Hwan

2017-01-01

Both histologic chorioamnionitis (HCAM) and Ureaplasma infection are considered important contributors to perinatal lung injury. We tested the hypothesis that coexistence of maternal HCAM and perinatal Ureaplasma exposure increases the risk of prolonged mechanical ventilation in extremely low-birthweight (ELBW) infants. A retrospective cohort study was carried out of all ELBW infants born between January 2008 and December 2013 at a single academic center. Placental pathology and gastric fluid Ureaplasma data were available for all infants. Culture and polymerase chain reaction were used to detect Ureaplasma in gastric fluid. Prolonged mechanical ventilation was defined as mechanical ventilation that began within 28 days after birth and continued. Of 111 ELBW infants enrolled, 84 survived beyond 36 weeks of postmenstrual age (PMA) and were included in the analysis. Eighteen infants (21.4%) had both HCAM and Ureaplasma exposure. Seven infants (8.3%) required mechanical ventilation beyond 36 weeks of PMA. Coexistence of HCAM and Ureaplasma in gastric fluid was significantly associated with prolonged mechanical ventilation after adjustment for gestational age, sex, mode of delivery, and use of macrolide antibiotics (OR, 8.7; 95%CI: 1.1-67.2). Coexistence of maternal HCAM and perinatal Ureaplasma exposure significantly increases the risk of prolonged mechanical ventilation in ELBW infants. © 2016 Japan Pediatric Society.

Identifying QT prolongation from ECG impressions using a general-purpose Natural Language Processor

PubMed Central

Denny, Joshua C.; Miller, Randolph A.; Waitman, Lemuel Russell; Arrieta, Mark; Peterson, Joshua F.

2009-01-01

Objective Typically detected via electrocardiograms (ECGs), QT interval prolongation is a known risk factor for sudden cardiac death. Since medications can promote or exacerbate the condition, detection of QT interval prolongation is important for clinical decision support. We investigated the accuracy of natural language processing (NLP) for identifying QT prolongation from cardiologist-generated, free-text ECG impressions compared to corrected QT (QTc) thresholds reported by ECG machines. Methods After integrating negation detection to a locally-developed natural language processor, the KnowledgeMap concept identifier, we evaluated NLP-based detection of QT prolongation compared to the calculated QTc on a set of 44,318 ECGs obtained from hospitalized patients. We also created a string query using regular expressions to identify QT prolongation. We calculated sensitivity and specificity of the methods using manual physician review of the cardiologist-generated reports as the gold standard. To investigate causes of “false positive” calculated QTc, we manually reviewed randomly selected ECGs with a long calculated QTc but no mention of QT prolongation. Separately, we validated the performance of the negation detection algorithm on 5,000 manually-categorized ECG phrases for any medical concept (not limited to QT prolongation) prior to developing the NLP query for QT prolongation. Results The NLP query for QT prolongation correctly identified 2,364 of 2,373 ECGs with QT prolongation with a sensitivity of 0.996 and a positive predictive value of 1.000. There were no false positives. The regular expression query had a sensitivity of 0.999 and positive predictive value of 0.982. In contrast, the positive predictive value of common QTc thresholds derived from ECG machines was 0.07–0.25 with corresponding sensitivities of 0.994–0.046. The negation detection algorithm had a recall of 0.973 and precision of 0.982 for 10,490 concepts found within ECG impressions. Conclusions NLP and regular expression queries of cardiologists’ ECG interpretations can more effectively identify QT prolongation than the automated QTc intervals reported by ECG machines. Future clinical decision support could employ NLP queries to detect QTc prolongation and other reported ECG abnormalities. PMID:18938105

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

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

Nozaki, Yumiko, E-mail: yumiko-nozaki@ds-pharma.co.jp; Honda, Yayoi, E-mail: yayoi-honda@ds-pharma.co.jp; Tsujimoto, Shinji, E-mail: shinji-tsujimoto@ds-pharma.co.jp

2014-07-01

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min formore » 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.« less

Attachment style dimensions can affect prolonged grief risk in caregivers of terminally ill patients with cancer.

PubMed

Lai, Carlo; Luciani, Massimiliano; Galli, Federico; Morelli, Emanuela; Cappelluti, Roberta; Penco, Italo; Aceto, Paola; Lombardo, Luigi

2015-12-01

The aim of the present study was to evaluate the predictive role of attachment dimensions on the risk of prolonged grief. Sixty caregivers of 51 terminally ill patients with cancer who had been admitted in a hospice were selected. Caregivers were interviewed using Attachment Scale Questionnaire, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Prolonged Grief Disorder 12 (PG-12). The consort caregivers showed higher PG-12 level compared to the sibling caregivers. Anxiety, depression, need for approval, and preoccupation with relationships levels were significantly correlated with PG-12 scores. Female gender, high levels of depression, and preoccupation with relationships significantly predicted higher levels of prolonged grief risk. © The Author(s) 2014.

Basic mechanisms of gabitril (tiagabine) and future potential developments.

PubMed

Meldrum, B S; Chapman, A G

1999-01-01

Gabitril (tiagabine) is a potent selective inhibitor of the principal neuronal gamma-aminobutyric acid (GABA) transporter (GAT-1) in the cortex and hippocampus. By slowing the reuptake of synaptically-released GABA, it prolongs inhibitory postsynaptic potentials. In animal models of epilepsy, tiagabine is particularly effective against kindled (limbic) seizures and against reflexly-induced generalized convulsive seizures. These data are predictive of its efficacy in complex partial seizures in humans. Possible clinical applications outside the field of epilepsy include bipolar disorder and pain.

Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

PubMed Central

Park, Eunjung; Gintant, Gary A; Bi, Daoqin; Kozeli, Devi; Pettit, Syril D; Skinner, Matthew; Willard, James; Wisialowski, Todd; Koerner, John; Valentin, Jean‐Pierre

2018-01-01

Background and Purpose Translation of non‐clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non‐clinical in vitro IKr current human ether‐à‐go‐go‐related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. Experimental Approach The predictive performance of three non‐clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). Key Results Non‐clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low‐intermediate (1×–30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post‐test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. Conclusions and Implications The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay. PMID:29181850

Computer mouse use predicts acute pain but not prolonged or chronic pain in the neck and shoulder.

PubMed

Andersen, J H; Harhoff, M; Grimstrup, S; Vilstrup, I; Lassen, C F; Brandt, L P A; Kryger, A I; Overgaard, E; Hansen, K D; Mikkelsen, S

2008-02-01

Computer use may have an adverse effect on musculoskeletal outcomes. This study assessed the risk of neck and shoulder pain associated with objectively recorded professional computer use. A computer programme was used to collect data on mouse and keyboard usage and weekly reports of neck and shoulder pain among 2146 technical assistants. Questionnaires were also completed at baseline and at 12 months. The three outcome measures were: (1) acute pain (measured as weekly pain); (2) prolonged pain (no or minor pain in the neck and shoulder region over four consecutive weeks followed by three consecutive weeks with a high pain score); and (3) chronic pain (reported pain or discomfort lasting more than 30 days and "quite a lot of trouble" during the past 12 months). Risk for acute neck pain and shoulder pain increased linearly by 4% and 10%, respectively, for each quartile increase in weekly mouse usage time. Mouse and keyboard usage time did not predict the onset of prolonged or chronic pain in the neck or shoulder. Women had higher risks for neck and shoulder pain. Number of keystrokes and mouse clicks, length of the average activity period, and micro-pauses did not influence reports of acute or prolonged pain. A few psychosocial factors predicted the risk of prolonged pain. Most computer workers have no or minor neck and shoulder pain, few experience prolonged pain, and even fewer, chronic neck and shoulder pain. Moreover, there seems to be no relationship between computer use and prolonged and chronic neck and shoulder pain.

Factors associated with prolonged length of stay following cardiac surgery in a major referral hospital in Oman: a retrospective observational study.

PubMed

Almashrafi, Ahmed; Alsabti, Hilal; Mukaddirov, Mirdavron; Balan, Baskaran; Aylin, Paul

2016-06-08

Two objectives were set for this study. The first was to identify factors influencing prolonged postoperative length of stay (LOS) following cardiac surgery. The second was to devise a predictive model for prolonged LOS in the cardiac intensive care unit (CICU) based on preoperative factors available at admission and to compare it against two existing cardiac stratification systems. Observational retrospective study. A tertiary hospital in Oman. All adult patients who underwent cardiac surgery at a major referral hospital in Oman between 2009 and 2013. 30.5% of the patients had prolonged LOS (≥11 days) after surgery, while 17% experienced prolonged ICU LOS (≥5 days). Factors that were identified to prolong CICU LOS were non-elective surgery, current congestive heart failure (CHF), renal failure, combined coronary artery bypass graft (CABG) and valve surgery, and other non-isolated valve or CABG surgery. Patients were divided into three groups based on their scores. The probabilities of prolonged CICU LOS were 11%, 26% and 28% for group 1, 2 and 3, respectively. The predictive model had an area under the curve of 0.75. Factors associated with prolonged overall postoperative LOS included the body mass index, the type of surgery, cardiopulmonary bypass machine use, packed red blood cells use, non-elective surgery and number of complications. The latter was the most important determinant of postoperative LOS. Patient management can be tailored for individual patient based on their treatments and personal attributes to optimise resource allocation. Moreover, a simple predictive score system to enable identification of patients at risk of prolonged CICU stay can be developed using data that are routinely collected by most hospitals. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Does endometrial integrin expression in endometriosis patients predict enhanced in vitro fertilization cycle outcomes after prolonged GnRH agonist therapy?

PubMed

Surrey, Eric S; Lietz, Annette K; Gustofson, Robert L; Minjarez, Debra A; Schoolcraft, William B

2010-02-01

To determine whether endometrial expression of the integrin alpha(v)beta(3) vitronectin can predict which endometriosis patient subgroup will benefit from pre-IVF cycle prolonged GnRH agonist (GnRHa) therapy. Prospective randomized institutional review board approved pilot trial. Private assisted reproductive technology program. IVF candidates with regular menses, surgically confirmed endometriosis, and normal ovarian reserve. All patients underwent endometrial biopsy 9 to 11 days post-LH surge to evaluate alpha(v)beta(3) integrin expression. Patients were randomized either to receive depot leuprolide acetate 3.75 mg every 28 days for three doses before controlled ovarian hyperstimulation (COH) or to proceed directly to COH and IVF. Group 1: integrin-positive controls (N = 12); group 2: integrin-positive administered prolonged GnRHa (N = 8). Group A: integrin-negative controls (N = 7); group B: integrin-negative administered prolonged GnRHa (N = 9). COH responses, ongoing pregnancy and implantation rates. There were no significant effects of GnRH agonist treatment in either of the integrin expression strata regarding ongoing pregnancy or implantation rates, although these outcomes were more frequent in group 2 vs. 1 (62.5% vs. 41.6% and 35% vs. 20.6%, respectively). This effect may have because of limited sample size. The value of a negative integrin biopsy in predicting an ongoing pregnancy after prolonged GnRH agonist therapy was only 44.4%. Endometrial alpha(v)beta(3) integrin expression did not predict which endometriosis patients would benefit from prolonged GnRHa therapy before IVF. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Prolonged pain and disability are common after rib fractures.

PubMed

Fabricant, Loic; Ham, Bruce; Mullins, Richard; Mayberry, John

2013-05-01

The contribution of rib fractures to prolonged pain and disability may be underappreciated and undertreated. Clinicians are traditionally taught that the pain and disability of rib fractures resolves in 6 to 8 weeks. This study was a prospective observation of 203 patients with rib fractures at a level 1 trauma center. Chest wall pain was evaluated by the McGill Pain Questionnaire (MPQ) pain rating index (PRI) and present pain intensity (PPI). Prolonged pain was defined as a PRI of 8 or more at 2 months after injury. Prolonged disability was defined as a decrease in 1 or more levels of work or functional status at 2 months after injury. Predictors of prolonged pain and disability were determined by multivariate analysis. One hundred forty-five male patients and 58 female patients with a mean injury severity score (ISS) of 20 (range, 1 to 59) had a mean of 5.4 rib fractures (range, 1 to 29). Forty-four (22%) patients had bilateral fractures, 15 (7%) had flail chest, and 92 (45%) had associated injury. One hundred eighty-seven patients were followed 2 months or more. One hundred ten (59%) patients had prolonged chest wall pain and 142 (76%) had prolonged disability. Among 111 patients with isolated rib fractures, 67 (64%) had prolonged chest wall pain and 69 (66%) had prolonged disability. MPQ PPI was predictive of prolonged pain (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.4 to 2.5), and prolonged disability (OR, 2.2; 95% CI, 1.5 to 3.4). The presence of significant associated injuries was predictive of prolonged disability (OR, 5.9; 95% CI, 1.4 to 29). Prolonged chest wall pain is common, and the contribution of rib fractures to disability is greater than traditionally expected. Further investigation into more effective therapies that prevent prolonged pain and disability after rib fractures is needed. Copyright © 2013 Elsevier Inc. All rights reserved.

Course of Weaning from Prolonged Mechanical Ventilation after Cardiac Surgery

PubMed Central

Herlihy, James P.; Koch, Stephen M.; Jackson, Robert; Nora, Hope

2006-01-01

In order to determine the temporal pattern of weaning from mechanical ventilation for patients undergoing prolonged mechanical ventilation after cardiac surgery, we performed a retrospective review of 21 patients' weaning courses at our long-term acute care hospital. Using multiple regression analysis of an estimate of individual patients' percentage of mechanical ventilator support per day (%MVSD), we determined that 14 of 21 patients (67%) showed a statistically significant quadratic or cubic relationship between time and %MVSD. These patients showed little or no improvement in their ventilator dependence until a point in time when, abruptly, they began to make rapid progress (a “wean turning point”), after which they progressed to discontinuation of mechanical ventilation in a relatively short period of time. The other 7 patients appeared to have a similar weaning pattern, although the data were not statistically significant. Most patients in the study group weaned from the ventilator through a specific temporal pattern that is newly described herein. Data analysis suggested that the mechanism for the development of a wean turning point was improvement of pulmonary mechanics rather than improvement in gas exchange or respiratory load. Although these observations need to be confirmed by a prospective trial, they may have implications for weaning cardiac surgery patients from prolonged mechanical ventilation, and possibly for weaning a broader group of patients who require prolonged mechanical ventilation. PMID:16878611

hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.

PubMed

Nogawa, Hisashi; Kawai, Tomoyuki

2014-10-15

Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. Copyright © 2014 Elsevier B.V. All rights reserved.

Morphofunctional alterations in ventral tegmental area dopamine neurons in acute and prolonged opiates withdrawal. A computational perspective.

PubMed

Enrico, P; Migliore, M; Spiga, S; Mulas, G; Caboni, F; Diana, M

2016-05-13

Dopamine (DA) neurons of the ventral tegmental area (VTA) play a key role in the neurobiological basis of goal-directed behaviors and addiction. Morphine (MOR) withdrawal induces acute and long-term changes in the morphology and physiology of VTA DA cells, but the mechanisms underlying these modifications are poorly understood. Because of their predictive value, computational models are a powerful tool in neurobiological research, and are often used to gain further insights and deeper understanding on the molecular and physiological mechanisms underlying the development of various psychiatric disorders. Here we present a biophysical model of a DA VTA neuron based on 3D morphological reconstruction and electrophysiological data, showing how opiates withdrawal-driven morphological and electrophysiological changes could affect the firing rate and discharge pattern. The model findings suggest how and to what extent a change in the balance of GABA/GLU inputs can take into account the experimentally observed hypofunction of VTA DA neurons during acute and prolonged withdrawal, whereas morphological changes may play a role in the increased excitability of VTA DA cell to opiate administration observed during opiate withdrawal. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Methods And Systms For Analyzing The Degradation And Failure Of Mechanical Systems

DOEpatents

Jarrell, Donald B.; Sisk, Daniel R.; Hatley, Darrel D.; Kirihara, Leslie J.; Peters, Timothy J.

2005-02-08

Methods and systems for identifying, understanding, and predicting the degradation and failure of mechanical systems are disclosed. The methods include measuring and quantifying stressors that are responsible for the activation of degradation mechanisms in the machine component of interest. The intensity of the stressor may be correlated with the rate of physical degradation according to some determinable function such that a derivative relationship exists between the machine performance, degradation, and the underlying stressor. The derivative relationship may be used to make diagnostic and prognostic calculations concerning the performance and projected life of the machine. These calculations may be performed in real time to allow the machine operator to quickly adjust the operational parameters of the machinery in order to help minimize or eliminate the effects of the degradation mechanism, thereby prolonging the life of the machine. Various systems implementing the methods are also disclosed.

A clinical prediction model for prolonged air leak after pulmonary resection.

PubMed

Attaar, Adam; Winger, Daniel G; Luketich, James D; Schuchert, Matthew J; Sarkaria, Inderpal S; Christie, Neil A; Nason, Katie S

2017-03-01

Prolonged air leak increases costs and worsens outcomes after pulmonary resection. We aimed to develop a clinical prediction tool for prolonged air leak using pretreatment and intraoperative variables. Patients who underwent pulmonary resection for lung cancer/nodules (from January 2009 to June 2014) were stratified by prolonged parenchymal air leak (>5 days). Using backward stepwise logistic regression with bootstrap resampling for internal validation, candidate variables were identified and a nomogram risk calculator was developed. A total of 2317 patients underwent pulmonary resection for lung cancer/nodules. Prolonged air leak (8.6%, n = 200) was associated with significantly longer hospital stay (median 10 vs 4 days; P < .001). Final model variables associated with increased risk included low percent forced expiratory volume in 1 second, smoking history, bilobectomy, higher annual surgeon caseload, previous chest surgery, Zubrod score >2, and interaction terms for right-sided thoracotomy and wedge resection by thoracotomy. Wedge resection, higher body mass index, and unmeasured percent forced expiratory volume in 1 second were protective. Derived nomogram discriminatory accuracy was 76% (95% confidence interval [CI], 0.72-0.79) and facilitated patient stratification into low-, intermediate- and high-risk groups with monotonic increase in observed prolonged air leaks (2.0%, 8.9%, and 19.2%, respectively; P < .001). Patients at intermediate and high risk were 4.80 times (95% CI, 2.86-8.07) and 11.86 times (95% CI, 7.21-19.52) more likely to have prolonged air leak compared with patients at low risk. Using readily available candidate variables, our nomogram predicts increasing risk of prolonged air leak with good discriminatory ability. Risk stratification can support surgical decision making, and help initiate proactive, patient-specific surgical management. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Longitudinal changes and predictors of prolonged grief for bereaved family caregivers over the first 2 years after the terminally ill cancer patient's death.

PubMed

Tsai, Wei-I; Prigerson, Holly G; Li, Chung-Yi; Chou, Wen-Chi; Kuo, Su-Ching; Tang, Siew Tzuh

2016-05-01

A significant minority of bereaved caregivers experience prolonged grief. However, few longitudinal studies have examined prolonged grief, especially in an Asian context. We explored longitudinal changes and factors predicting prolonged grief in bereaved caregivers of terminally ill Taiwanese cancer patients. Observational, prospective, and longitudinal. Prolonged grief symptoms were measured with the PG-13 at 6, 13, 18, and 24 months postloss. A convenience sample of 493 caregivers (83.3% participation rate) of terminally ill cancer patients was recruited from a medical center in Taiwan. The prevalence of prolonged grief decreased significantly over time from the patient's death (7.73%, 1.80%, 2.49%, and 1.85% at 6, 13, 18, and 24 months postloss, respectively, p < 0.05 at all times in reference to 6 months postloss). Caregivers' likelihood of prolonged grief was significantly higher if they had severe preloss depressive symptoms, negatively perceived their relative's dying situation, and were poorly prepared for the patient's death. However, the likelihood of prolonged grief decreased significantly with greater perceived concurrent social support and subjective caregiving burden right before the patient's death. Prolonged grief in bereavement diminished over time and was predicted by modifiable factors before, during, and after bereavement. To facilitate bereavement adjustment and avoid prolonged grief, healthcare professionals should develop and provide at-risk caregivers with effective interventions starting when patients are still alive to improve their dying experience, to facilitate preparedness for the patient's forthcoming death, to alleviate caregivers' preloss depressive symptoms, and to enhance their perceived postloss social support. © The Author(s) 2015.

Symptom Severity Predicts Prolonged Recovery after Sport-Related Concussion: Age and Amnesia Do Not

PubMed Central

Meehan, William P.; Mannix, Rebekah C.; Stracciolini, Andrea; Elbin, R.J.; Collins, Michael W.

2013-01-01

Objective To identify predictors of prolonged symptoms for athletes who sustain concussions. Study design We conducted a multi-center, prospective, cohort study of patients in 2 sport concussion clinics. Possible predictors of prolonged symptoms from concussion were compared between two groups: those whose symptoms resolved within 28 days and those whose symptoms persisted beyond 28 days. Candidate predictor variables were entered into a logistic regression model that was used to generate adjusted odds ratios. Results During the study period, 182 patients met inclusion criteria. The mean age was 15.2 years (SD 3.04 years). Over a third (N=65) of patients underwent computerized neurocognitive testing on their initial visit. In univariate analyses, Post Concussion Symptom Scale (PCSS) score and all composite scores on computerized neurocognitive testing appeared to be associated with prolonged symptom duration. Sex, age, loss of consciousness at time of injury and amnesia at time of injury were not associated with prolonged symptom duration. After adjusting for potential confounding, however, only total score on the PCSS score was associated with the odds of suffering prolonged symptoms. Conclusions After adjusting for other potential confounding variables, only total score on the PCSS was associated with the odds of suffering prolonged symptoms from sport-related concussions; age and amnesia were not. Further efforts to develop clinical tools for predicting which athletes will suffer prolonged recoveries after concussion should focus on initial symptom score. PMID:23628374

Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective.

PubMed

Pollard, C E; Valentin, J-P; Hammond, T G

2008-08-01

Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression

PubMed Central

Andrews, Paul W.; Kornstein, Susan G.; Halberstadt, Lisa J.; Gardner, Charles O.; Neale, Michael C.

2011-01-01

Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings. PMID:21779273

Predicting prolonged length of hospital stay in older emergency department users: use of a novel analysis method, the Artificial Neural Network.

PubMed

Launay, C P; Rivière, H; Kabeshova, A; Beauchet, O

2015-09-01

To examine performance criteria (i.e., sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV], likelihood ratios [LR], area under receiver operating characteristic curve [AUROC]) of a 10-item brief geriatric assessment (BGA) for the prediction of prolonged length hospital stay (LHS) in older patients hospitalized in acute care wards after an emergency department (ED) visit, using artificial neural networks (ANNs); and to describe the contribution of each BGA item to the predictive accuracy using the AUROC value. A total of 993 geriatric ED users admitted to acute care wards were included in this prospective cohort study. Age >85years, gender male, polypharmacy, non use of formal and/or informal home-help services, history of falls, temporal disorientation, place of living, reasons and nature for ED admission, and use of psychoactive drugs composed the 10 items of BGA and were recorded at the ED admission. The prolonged LHS was defined as the top third of LHS. The ANNs were conducted using two feeds forward (multilayer perceptron [MLP] and modified MLP). The best performance was reported with the modified MLP involving the 10 items (sensitivity=62.7%; specificity=96.6%; PPV=87.1; NPV=87.5; positive LR=18.2; AUC=90.5). In this model, presence of chronic conditions had the highest contributions (51.3%) in AUROC value. The 10-item BGA appears to accurately predict prolonged LHS, using the ANN MLP method, showing the best criteria performance ever reported until now. Presence of chronic conditions was the main contributor for the predictive accuracy. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Duration of division-related events in cleaving sand dollar eggs.

PubMed

Rappaport, R; Rappaport, B N

1993-07-01

A minimal mechanism for cytokinesis comprises a stimulus-to-surface contraction, a receptive surface, and a localized surface contractile mechanism. Duration of each is brief and times when they function are predictable. The processes that begin and end the functional period of each component were investigated. Sand dollar blastomeres from the completion of first cleavage to the beginning of fourth cleavage were used. By changing a cell's shape, it was possible to determine whether its capacity to accomplish an activity is restricted to its usual time frame. The first appearance of the furrow was advanced about 5 min by confining the mitotic apparatus in a narrow cytoplasmic cylinder. The period when the mitotic apparatus induces furrowing was prolonged about 18 min by moving the mitotic apparatus in an elongate cell each time the furrow appeared. The period of active furrowing was prolonged to about 21.8 min by pushing the mitotic apparatus close to the cell margin and then stretching the region through which the unilateral furrow must pass. In relation to normal division cycle events, results showed that each event of cytokinesis can operate both before and after its normal active period. Components of the mechanism are capable of functioning for about half the period of the division cycle. Normal timing of events may be determined by geometrical factors and the normal consequences of each activity.

A prospective study of prolonged stay in the intensive care unit: predictors and impact on resource utilization.

PubMed

Arabi, Yaseen; Venkatesh, S; Haddad, Samir; Al Shimemeri, Abdullah; Al Malik, Salim

2002-10-01

To evaluate the predictors of prolonged Intensive Care Unit (ICU) stay and the impact on resource utilization. Prospective study. Adult medical/surgical ICU in a tertiary-care teaching hospital. All admissions to the ICU (numbering 947) over a 20-month period were enrolled. Data on demographic and clinical profile, length of stay, and outcome were collected prospectively. The ICU length of stay and mechanical ventilation days were used as surrogate parameters for resource utilization. Potential predictors were analyzed for possible association with prolonged ICU stay (length of stay > 14 days). Patients with prolonged ICU stay formed only 11% of patients, but utilized 45.1% of ICU days and 55.5% of mechanical ventilation days. Non-elective admissions, readmissions, respiratory or trauma-related reasons for admission, and first 24-hour evidence of infection, oliguria, coagulopathy, and the need for mechanical ventilation or vasopressor therapy had significant association with prolonged ICU stay. Mean APACHE II and SAPS II were slightly higher in patients with prolonged stay. ICU outcome was comparable to patients with < or = 14 days ICU stay. Patients with prolonged ICU stay form a small proportion of ICU patients, yet they consume a significant share of the ICU resources. The outcome of this group of patients is comparable to that of shorter stay patients. The predictors identified in the study can be used in targeting this group to improve resource utilization and efficiency of ICU care.

Hemodynamic changes during weaning: can we assess and predict cardiac-related weaning failure by transthoracic echocardiography?

PubMed Central

2010-01-01

Cardiac-related failure of weaning from mechanical ventilation is an important reason for prolonged mechanical ventilation, intensive care unit treatment, and increased morbidity and mortality. When transthoracic echocardiography (TTE) is routinely performed before a weaning trial, patients at high risk of cardiac-related failure can be detected by low left ventricular (LV) ejection fraction, diastolic dysfunction, and elevated LV filling pressure. During the weaning trial, a further increase of LV filling pressure and progression of diastolic failure can be observed by repeated TTE. Owing to certain limitations concerning patients and methodology, TTE cannot be employed in every patient and invasive hemodynamic monitoring is still mandatory in selected patients with repetitive weaning failure. PMID:20619005

Hemodynamic changes during weaning: can we assess and predict cardiac-related weaning failure by transthoracic echocardiography?

PubMed

Voga, Gorazd

2010-01-01

Cardiac-related failure of weaning from mechanical ventilation is an important reason for prolonged mechanical ventilation, intensive care unit treatment, and increased morbidity and mortality. When transthoracic echocardiography (TTE) is routinely performed before a weaning trial, patients at high risk of cardiac-related failure can be detected by low left ventricular (LV) ejection fraction, diastolic dysfunction, and elevated LV filling pressure. During the weaning trial, a further increase of LV filling pressure and progression of diastolic failure can be observed by repeated TTE. Owing to certain limitations concerning patients and methodology, TTE cannot be employed in every patient and invasive hemodynamic monitoring is still mandatory in selected patients with repetitive weaning failure.

Hydrodynamic Trapping of Swimming Bacteria by Convex Walls

NASA Astrophysics Data System (ADS)

Sipos, O.; Nagy, K.; Di Leonardo, R.; Galajda, P.

2015-06-01

Swimming bacteria display a remarkable tendency to move along flat surfaces for prolonged times. This behavior may have a biological importance but can also be exploited by using microfabricated structures to manipulate bacteria. The main physical mechanism behind the surface entrapment of swimming bacteria is, however, still an open question. By studying the swimming motion of Escherichia coli cells near microfabricated pillars of variable size, we show that cell entrapment is also present for convex walls of sufficiently low curvature. Entrapment is, however, markedly reduced below a characteristic radius. Using a simple hydrodynamic model, we predict that trapped cells swim at a finite angle with the wall and a precise relation exists between the swimming angle at a flat wall and the critical radius of curvature for entrapment. Both predictions are quantitatively verified by experimental data. Our results demonstrate that the main mechanism for wall entrapment is hydrodynamic in nature and show the possibility of inhibiting cell adhesion, and thus biofilm formation, using convex features of appropriate curvature.

Outcome of ventilated infants born at term without major congenital abnormalities.

PubMed

Ramadan, Ghada; Paul, Nicola; Morton, Margaret; Peacock, Janet L; Greenough, Anne

2012-02-01

The longer-term outcome of term-born infants without congenital anomalies requiring ventilation in the first 24 h after birth has rarely been reported. Our aims were to determine the mortality and long-term morbidity of such infants and identify risk factors for adverse outcome. The outcomes of 43 of 45 infants born at term consecutively requiring mechanical ventilation were reviewed. The infants had: meconium aspiration syndrome (n = 11), hypoxic ischaemic encephalopathy (HIE) (n = 11), respiratory depression (n = 12), sepsis (n = 5), persistent pulmonary hypertension of the newborn (n = 3) and middle cerebral artery infarction (n = 1). Eleven infants developed seizures (26%), 13 (30%) had abnormal electroencephalograms and 11 (26%) had abnormal MRI scans; 26% had an adverse outcome: six died, and five had severe neurodisability at 2 years. The infants with congenital toxoplasmosis and a middle cerebral artery infarction were excluded from the prediction analysis. In the remaining 41 patients, requirement for anticonvulsants (relative risk, RR = 4.44, 95% CI = 1.48 to 12.70; p = 0.014) and prolonged ventilation (longer than 3 days) (RR 4.83, 95% CI 1.51 to 15.64) predicted adverse outcome. Infants with HIE had an increased risk of adverse outcome (relative risk 5.45, 95% CI 1.01 to 33.85), but an adverse outcome occurred in infants with other diagnoses. Mortality and neurodisability at follow-up were common in infants born at term without major congenital anomalies who required mechanical ventilation in the first 24 h after birth, particularly in those who developed seizures requiring treatment and prolonged ventilation.

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

Gandhi, Adarsh, E-mail: adarsh.gandhi@nih.gov; Guo, Tao, E-mail: tguo4@jhu.edu; Shah, Pranav

Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZmore » by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP{sup +/+} and TIRAP{sup −/−} mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP{sup +/+} mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP{sup −/−} mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies provide novel mechanistic insights into idiosyncratic hepatotoxicity.« less

Comprehensive Analyses of Ventricular Myocyte Models Identify Targets Exhibiting Favorable Rate Dependence

PubMed Central

Bugana, Marco; Severi, Stefano; Sobie, Eric A.

2014-01-01

Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs. PMID:24675446

Comprehensive analyses of ventricular myocyte models identify targets exhibiting favorable rate dependence.

PubMed

Cummins, Megan A; Dalal, Pavan J; Bugana, Marco; Severi, Stefano; Sobie, Eric A

2014-03-01

Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.

Increased Late Sodium Current Contributes to the Electrophysiological Effects of Chronic, but Not Acute, Dofetilide Administration.

PubMed

Qiu, Xiaoliang S; Chauveau, Samuel; Anyukhovsky, Evgeny P; Rahim, Tania; Jiang, Ya-Ping; Harleton, Erin; Feinmark, Steven J; Lin, Richard Z; Coronel, Ruben; Janse, Michiel J; Opthof, Tobias; Rosen, Tove S; Cohen, Ira S; Rosen, Michael R

2016-04-01

Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some IKr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (INa-L) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. We continuously infused dofetilide (6-9 μg/kg bolus+6-9 μg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. INa-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an IKr blocker with no effects on phosphoinositide 3-kinase and INa-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. Increased INa-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and INa-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome. © 2016 American Heart Association, Inc.

National Trends (2009-2013) for Palliative Care Utilization for Patients Receiving Prolonged Mechanical Ventilation.

PubMed

Chatterjee, Kshitij; Goyal, Abhinav; Kakkera, Krishna; Harrington, Sarah; Corwin, Howard L

2018-05-04

Patients requiring mechanical ventilation have high morbidity and mortality. Providing palliative care services has been suggested as a way to improve comprehensive management of critically ill patients. We examined the trend in the utilization of palliative care among adults who require prolonged mechanical ventilation. Primary objectives were to determine the trend in palliative care utilization over time, predictors for palliative care utilization, and palliative care impact on hospital length of stay. Retrospective, cross-sectional study. The National Inpatient Sample data between 2009 and 2013 was used for this study. Adults (age ≥ 18 yr) who underwent prolonged mechanical ventilation (≥ 96 consecutive hr) were studied. Palliative care and mechanical ventilation were identified using the corresponding International Classification of Diseases, 9th revision, Clinical Modification, codes. A total of 1,751,870 hospitalizations with prolonged mechanical ventilation were identified between 2009 and 2013. The utilization of palliative care increased yearly from 6.5% in 2009 to 13.1% in 2013 (p < 0.001). Among the mechanically ventilated patients who died, palliative care increased from 15.9% in 2009 to 33.3% in 2013 (p < 0.001). Median hospital length of stay for patients with and without palliative care was 13 and 17 days, respectively (p < 0.001). Patients discharged to either short- or long-term care facilities had a shorter length of stay if palliative care was provided (15 vs 19 d; p < 0.001). The factors associated with a higher palliative care utilization included older age, malignancy, larger hospitals in urban areas, and teaching hospitals. Non-Caucasian race was associated with lower palliative care utilization. Among patients who undergo prolonged mechanical ventilation, palliative care utilization is increasing, particularly in patients who die during hospitalization. Using palliative care for mechanically ventilated patients who are discharged to either short- or long-term care facilities is associated with a shorter hospital length of stay.

Emotional attentional control predicts changes in diurnal cortisol secretion following exposure to a prolonged psychosocial stressor.

PubMed

Lenaert, Bert; Barry, Tom J; Schruers, Koen; Vervliet, Bram; Hermans, Dirk

2016-01-01

Hypothalamic-pituitary-adrenal (HPA) axis irregularities have been associated with several psychological disorders. Hence, the identification of individual difference variables that predict variations in HPA-axis activity represents an important challenge for psychiatric research. We investigated whether self-reported attentional control in emotionally demanding situations prospectively predicted changes in diurnal salivary cortisol secretion following exposure to a prolonged psychosocial stressor. Low ability to voluntarily control attention has previously been associated with anxiety and depressive symptomatology. Attentional control was assessed using the Emotional Attentional Control Scale. In students who were preparing for academic examination, salivary cortisol was assessed before (time 1) and after (time 2) examination. Results showed that lower levels of self-reported emotional attentional control at time 1 (N=90) predicted higher absolute diurnal cortisol secretion and a slower decline in cortisol throughout the day at time 2 (N=71). Difficulty controlling attention during emotional experiences may lead to chronic HPA-axis hyperactivity after prolonged exposure to stress. These results indicate that screening for individual differences may foster prediction of HPA-axis disturbances, paving the way for targeted disorder prevention. Copyright © 2015 Elsevier Ltd. All rights reserved.

Phonological neighborhood and word frequency effects on the stuttered disfluencies of children who stutter: comments on Anderson (2007).

PubMed

Howell, Peter

2010-10-01

This letter comments on a study by Anderson (2007) that compared the effects of word frequency, neighborhood density, and phonological neighborhood frequency on part-word repetitions, prolongations, and single-syllable word repetitions produced by children who stutter. Anderson discussed her results with respect to 2 theories about stuttering: the covert repair hypothesis and execution planning (EXPLAN) theory. Her remarks about EXPLAN theory are examined. Anderson considered that EXPLAN does not predict the relationship between word and neighborhood frequency and stuttering for part-word repetitions and prolongations (she considered that EXPLAN predicts that stuttering occurs on simple words for children). The actual predictions that EXPLAN makes are upheld by her results. She also considered that EXPLAN cannot account for why stuttering is affected by the same variables that lead to speech errors, and it is shown that this is incorrect. The effects of word frequency, neighborhood density, and phonological neighborhood frequency on part-word repetitions, prolongations, and single-syllable word repetitions reported by Anderson (2007) are consistent with the predictions of the EXPLAN model.

Preoperative Plasma Aldosterone Levels and Postoperative Atrial Fibrillation Occurrence Following Cardiac Surgery: A Review of Literature and Design of the ALDO-POAF Study (ALDOsterone for Prediction of Post-Operative Atrial Fibrillation).

PubMed

Chequel, Mathieu; Ollitrault, Pierre; Saloux, Eric; Parienti, Jean-Jacques; Fischer, Marc-Olivier; Desgué, Julien; Allouche, Stéphane; Milliez, Paul; Alexandre, Joachim

2016-01-01

Post-operative atrial fibrillation (POAF) is a major and frequent complication occurring after cardiac surgery, contributing to prolonged intensive care and hospital stays and is associated with several cardiovascular complications. The exact mechanisms and signaling pathways involved in the development of POAF seem to be multifactorial and remain to date incompletely understood. β-blockers and amiodarone are the first line preventive drugs but are partially effective and near 30% of POAF resist to these strategies. In this work, we review the current knowledge about pathophysiological POAF mechanisms and preventive pharmacological strategies. We also discuss the rational for the use of pre-operative plasma aldosterone and galectin-3 (Gal-3) levels as predictive biomarkers of POAF and the potential role of aldosterone antagonists in the POAF preventive strategy. POAF is a major complication occurring after cardiac surgery. In this context, there is some evidence indicating that renin-angiotensin-aldosterone system and Gal-3 could be very useful predictive biomarkers of POAF and potentially interesting therapeutic target to prevent POAF occurrence. We present the rationale and the design of the ALDO-POAF trial (ALDOsterone for prediction of Post- Operative Atrial Fibrillation, NCT 02814903).

Predicting prolonged dose titration in patients starting warfarin.

PubMed

Finkelman, Brian S; French, Benjamin; Bershaw, Luanne; Brensinger, Colleen M; Streiff, Michael B; Epstein, Andrew E; Kimmel, Stephen E

2016-11-01

Patients initiating warfarin therapy generally experience a dose-titration period of weeks to months, during which time they are at higher risk of both thromboembolic and bleeding events. Accurate prediction of prolonged dose titration could help clinicians determine which patients might be better treated by alternative anticoagulants that, while more costly, do not require dose titration. A prediction model was derived in a prospective cohort of patients starting warfarin (n = 390), using Cox regression, and validated in an external cohort (n = 663) from a later time period. Prolonged dose titration was defined as a dose-titration period >12 weeks. Predictor variables were selected using a modified best subsets algorithm, using leave-one-out cross-validation to reduce overfitting. The final model had five variables: warfarin indication, insurance status, number of doctor's visits in the previous year, smoking status, and heart failure. The area under the ROC curve (AUC) in the derivation cohort was 0.66 (95%CI 0.60, 0.74) using leave-one-out cross-validation, but only 0.59 (95%CI 0.54, 0.64) in the external validation cohort, and varied across clinics. Including genetic factors in the model did not improve the area under the ROC curve (0.59; 95%CI 0.54, 0.65). Relative utility curves indicated that the model was unlikely to provide a clinically meaningful benefit compared with no prediction. Our results suggest that prolonged dose titration cannot be accurately predicted in warfarin patients using traditional clinical, social, and genetic predictors, and that accurate prediction will need to accommodate heterogeneities across clinical sites and over time. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

PubMed

Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

2016-05-01

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Health, Enterprise, and Labor Complementarity in the Household*

PubMed Central

Adhvaryu, Achyuta; Nyshadham, Anant

2017-01-01

We study the role of household enterprise as a coping mechanism after health shocks. Using variation in the cost of traveling to formal sector health facilities to predict recovery from acute illness in Tanzania, we show that individuals with prolonged illness switch from farm labor to enterprise activity. This response occurs along both the extensive (entry) and intensive (capital stock and labor supply) margins. Family members who are not ill exhibit exactly the same pattern of responses. Deriving a simple extension to the canonical agricultural household model, we show that our results suggest complementarities in household labor. PMID:28943705

Variation in Definition of Prolonged Mechanical Ventilation.

PubMed

Rose, Louise; McGinlay, Michael; Amin, Reshma; Burns, Karen Ea; Connolly, Bronwen; Hart, Nicholas; Jouvet, Philippe; Katz, Sherri; Leasa, David; Mawdsley, Cathy; McAuley, Danny F; Schultz, Marcus J; Blackwood, Bronagh

2017-10-01

Consistency of definitional criteria for terminology applied to describe subject cohorts receiving mechanical ventilation within ICU and post-acute care settings is important for understanding prevalence, risk stratification, effectiveness of interventions, and projections for resource allocation. Our objective was to quantify the application and definition of terms for prolonged mechanical ventilation. We conducted a scoping review of studies (all designs except single-case study) reporting a study population (adult and pediatric) using the term prolonged mechanical ventilation or a synonym. We screened 5,331 references, reviewed 539 full-text references, and excluded 120. Of the 419 studies (representing 38 countries) meeting inclusion criteria, 297 (71%) reported data on a heterogeneous subject cohort, and 66 (16%) included surgical subjects only (46 of those 66, 70% cardiac surgery). Other studies described COPD (16, 4%), trauma (22, 5%), neuromuscular (17, 4%), and sepsis (1, 0.2%) cohorts. A total of 741 terms were used to refer to the 419 study cohorts. The most common terms were: prolonged mechanical ventilation (253, 60%), admission to specialized unit (107, 26%), and long-term mechanical ventilation (79, 19%). Some authors (282, 67%) defined their cohorts based on duration of mechanical ventilation, with 154 studies (55%) using this as the sole criterion. We identified 37 different durations of ventilation ranging from 5 h to 1 y, with > 21 d being the most common (28 of 282, 7%). For studies describing a surgical cohort, minimum ventilation duration required for inclusion was ≥ 24 h for 20 of 66 studies (30%). More than half of all studies (237, 57%) did not provide a reason/rationale for definitional criteria used, with only 28 studies (7%) referring to a consensus definition. We conclude that substantial variation exists in the terminology and definitional criteria for cohorts of subjects receiving prolonged mechanical ventilation. Standardization of terminology and definitional criteria is required for study data to be maximally informative. Copyright © 2017 by Daedalus Enterprises.

Prolonged weaning: from the intensive care unit to home.

PubMed

Navalesi, P; Frigerio, P; Patzlaff, A; Häußermann, S; Henseke, P; Kubitschek, M

2014-01-01

Weaning is the process of withdrawing mechanical ventilation which starts with the first spontaneous breathing trial (SBT). Based on the degree of difficulty and duration, weaning is classified as simple, difficult and prolonged. Prolonged weaning, which includes patients who fail 3 SBTs or are still on mechanical ventilation 7 days after the first SBT, affects a relatively small fraction of mechanically ventilated ICU patients but these, however, requires disproportionate resources. There are several potential causes which can lead to prolonged weaning. It is nonetheless important to understand the problem from the point of view of each individual patient in order to adopt appropriate treatment and define precise prognosis. An otherwise stable patient who remains on mechanical ventilation will be considered for transfer to a specialized weaning unit (SWU). Though there is not a precise definition, SWU can be considered as highly specialized and protected environments for patients requiring mechanical ventilation despite resolution of the acute disorder. Proper staffing, well defined short-term and long-term goals, attention to psychological and social problems represent key determinants of SWU success. Some patients cannot be weaned, either partly or entirely, and may require long-term home mechanical ventilation. In these cases the logistics relating to caregivers and the equipment must be carefully considered and addressed. Copyright © 2014 Sociedade Portuguesa de Pneumologia. Published by Elsevier España. All rights reserved.

Simulation and in situ measurement of stress distribution in a polymer electrolyte membrane fuel cell stack

NASA Astrophysics Data System (ADS)

de la Cruz, Javier; Cano, Ulises; Romero, Tatiana

2016-10-01

A critical parameter for PEM fuel cell's electric contact is the nominal clamping pressure. Predicting the mechanical behavior of all components in a fuel cell stack is a very complex task due to the diversity of materials properties. Prior to the integration of a 3 kW PEMFC power plant, a numerical simulation was performed in order to obtain the mechanical stress distribution for two of the most pressure sensitive components of the stack: the membrane, and the graphite plates. The stress distribution of the above mentioned components was numerically simulated by finite element analysis and the stress magnitude for the membrane was confirmed using pressure films. Stress values were found within the elastic zone which guarantees mechanical integrity of fuel cell components. These low stress levels particularly for the membrane will allow prolonging the life and integrity of the fuel cell stack according to its design specifications.

Human spaceflight and space adaptations: Computational simulation of gravitational unloading on the spine

NASA Astrophysics Data System (ADS)

Townsend, Molly T.; Sarigul-Klijn, Nesrin

2018-04-01

Living in reduced gravitational environments for a prolonged duration such, as a fly by mission to Mars or an extended stay at the international space station, affects the human body - in particular, the spine. As the spine adapts to spaceflight, morphological and physiological changes cause the mechanical integrity of the spinal column to be compromised, potentially endangering internal organs, nervous health, and human body mechanical function. Therefore, a high fidelity computational model and simulation of the whole human spine was created and validated for the purpose of investigating the mechanical integrity of the spine in crew members during exploratory space missions. A spaceflight exposed spine has been developed through the adaptation of a three-dimensional nonlinear finite element model with the updated Lagrangian formulation of a healthy ground-based human spine in vivo. Simulation of the porohyperelastic response of the intervertebral disc to mechanical unloading resulted in a model capable of accurately predicting spinal swelling/lengthening, spinal motion, and internal stress distribution. The curvature of this space adaptation exposed spine model was compared to a control terrestrial-based finite element model, indicating how the shape changed. Finally, the potential of injury sites to crew members are predicted for a typical 9 day mission.

Development of models to predict early post-transplant recurrence of hepatocellular carcinoma that also integrate the quality and characteristics of the liver graft: A national registry study in China.

PubMed

Ling, Qi; Liu, Jimin; Zhuo, Jianyong; Zhuang, Runzhou; Huang, Haitao; He, Xiangxiang; Xu, Xiao; Zheng, Shusen

2018-04-27

Donor characteristics and graft quality were recently reported to play an important role in the recurrence of hepatocellular carcinoma after liver transplantation. Our aim was to establish a prognostic model by using both donor and recipient variables. Data of 1,010 adult patients (training/validation: 2/1) undergoing primary liver transplantation for hepatocellular carcinoma were extracted from the China Liver Transplant Registry database and analyzed retrospectively. A multivariate competing risk regression model was developed and used to generate a nomogram predicting the likelihood of post-transplant hepatocellular carcinoma recurrence. Of 673 patients in the training cohort, 70 (10.4%) had hepatocellular carcinoma recurrence with a median recurrence time of 6 months (interquartile range: 4-25 months). Cold ischemia time was the only independent donor prognostic factor for predicting hepatocellular carcinoma recurrence (hazard ratio = 2.234, P = .007). The optimal cutoff value was 12 hours when patients were grouped according to cold ischemia time at 2-hour intervals. Integrating cold ischemia time into the Milan criteria (liver transplantation candidate selection criteria) improved the accuracy for predicting hepatocellular carcinoma recurrence in both training and validation sets (P < .05). A nomogram composed of cold ischemia time, tumor burden, differentiation, and α-fetoprotein level proved to be accurate and reliable in predicting the likelihood of 1-year hepatocellular carcinoma recurrence after liver transplantation. Additionally, donor anti-hepatitis B core antibody positivity, prolonged cold ischemia time, and anhepatic time were linked to the intrahepatic recurrence, whereas older donor age, prolonged donor warm ischemia time, cold ischemia time, and ABO incompatibility were relevant to the extrahepatic recurrence. The graft quality integrated models exhibited considerable predictive accuracy in early hepatocellular carcinoma recurrence risk assessment. The identification of donor risks can further help understand the mechanism of different patterns of recurrence. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of prolonged isothermal heat treatment on the mechanical behavior of advanced NANOBAIN steel

NASA Astrophysics Data System (ADS)

Avishan, Behzad

2017-09-01

The microstructural evolution and consequent changes in strength and ductility of advanced NANOBAIN steel during prolonged isothermal heat-treatment stages were investigated. The microstructure and mechanical properties of nanostructured bainite were not expected to be influenced by extending the heat-treatment time beyond the optimum value because of the autotempering phenomenon and high tempering resistance. However, experimental results indicated that the microstructure was thermodynamically unstable and that prolonged austempering resulted in carbon depletion from high-carbon retained austenite and carbide precipitations. Therefore, austenite became thermally less stable and partially transformed into martensite during cooling to room temperature. Prolonged austempering did not lead to the typical tempering sequence of bainite, and the sizes of the microstructural constituents were independent of the extended heat-treatment times. This independence, in turn, resulted in almost constant ultimate tensile strength values. However, microstructural variations enhanced the yield strength and the hardness of the material at extended isothermal heat-treatment stages. Finally, although microstructural changes decreased the total elongation and impact toughness, considerable combinations of mechanical properties could still be achieved.

Substantia nigra activity level predicts trial-to-trial adjustments in cognitive control

PubMed Central

Boehler, C.N.; Bunzeck, N.; Krebs, R.M.; Noesselt, T.; Schoenfeld, M.A.; Heinze, H.-J.; Münte, T.F.; Woldorff, M.G.; Hopf, J.-M.

2011-01-01

Effective adaptation to the demands of a changing environment requires flexible cognitive control. The medial and lateral frontal cortices are involved in such control processes, putatively in close interplay with the basal ganglia. In particular, dopaminergic projections from the midbrain (i.e., from the substantia nigra (SN) and the ventral tegmental area (VTA)) have been proposed to play a pivotal role in modulating the activity in these areas for cognitive control purposes. In that dopaminergic involvement has been strongly implicated in reinforcement learning, these ideas suggest functional links between reinforcement learning, where the outcome of actions shapes behavior over time, and cognitive control in a more general context, where no direct reward is involved. Here, we provide evidence from functional MRI in humans that activity in the SN predicts systematic subsequent trial-to-trial response time (RT) prolongations that are thought to reflect cognitive control in a Stop-signal paradigm. In particular, variations in the activity level of the SN in one trial predicted the degree of RT prolongation on the subsequent trial, consistent with a modulating output signal from the SN being involved in enhancing cognitive control. This link between SN activity and subsequent behavioral adjustments lends support to theoretical accounts that propose dopaminergic control signals that shape behavior both in the presence and absence of direct reward. This SN-based modulatory mechanism is presumably mediated via a wider network that determines response speed in this task, including frontal and parietal control regions, along with the basal ganglia and the associated subthalamic nucleus. PMID:20465358

Cost containment and mechanical ventilation in the United States.

PubMed

Cohen, I L; Booth, F V

1994-08-01

In many ICUs, admission and discharge hinge on the need for intubation and ventilatory support. As few as 5% to 10% of ICU patients require prolonged mechanical ventilation, and this patient group consumes > or = 50% of ICU patient days and ICU resources. Prolonged ventilatory support and chronic ventilator dependency, both in the ICU and non-ICU settings, have a significant and growing impact on healthcare economics. In the United States, the need for prolonged mechanical ventilation is increasingly recognized as separate and distinct from the initial diagnosis and/or procedure that leads to hospitalization. This distinction has led to improved reimbursement under the prospective diagnosis-related group (DRG) system, and demands more precise accounting from healthcare providers responsible for these patients. Using both published and theoretical examples, mechanical ventilation in the United States is discussed, with a focus on cost containment. Included in the discussion are ventilator teams, standards of care, management protocols, stepdown units, rehabilitation units, and home care. The expanding role of total quality management (TQM) is also presented.

Clinical outcome of Guillain-Barré syndrome after prolonged mechanical ventilation.

PubMed

van den Berg, Bianca; Storm, Eline F; Garssen, Marcel J P; Blomkwist-Markens, Patricia H; Jacobs, Bart C

2018-04-07

Patients with Guillain-Barré syndrome (GBS) may suffer from respiratory failure for months or longer. The aim of this study was to determine the frequency, clinical course and outcome of patients with GBS requiring prolonged mechanical ventilation (MV). Prospectively collected data from 526 patients with GBS participating in previous trials were analysed to determine the frequency and duration of prolonged MV (longer than 2 months). In addition, a cross-sectional study was conducted in patients with GBS requiring MV to determine the clinical course and long-term outcome with the ability to walk unaided as primary endpoint. In the cohort study, 145 of 526 patients with GBS (28%) required MV, including 33 (6%) patients with prolonged MV. Patients requiring prolonged MV had a lower Medical Research Council sum score and more frequent bulbar involvement and inexcitable nerves compared with shorter ventilated patients. At 6 months, 18% of patients with prolonged MV were able to walk unaided compared with 76% of patients requiring shorter MV (P<0.001). In the cross-sectional study, 63 patients requiring MV were included with a median follow-up of 11 years (range 2-44 years). Twenty-six (41%) of these patients needed prolonged MV (median 93 days, range 62-261). Fifteen (58%) of these patients were able to walk unaided at maximum follow-up and eight (31%) reached this endpoint more than 1 year after diagnosis. Prolonged ventilation in GBS is associated with poor prognosis, yet patients requiring prolonged ventilation may show slow but persistent recovery for years and even reach the ability to walk and live independently. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Physiologic mechanisms of circulatory and body fluid losses in weightlessness identified by mathematical modeling

NASA Technical Reports Server (NTRS)

Simanonok, K. E.; Srinivasan, R. S.; Charles, J. B.

1993-01-01

Central volume expansion due to fluid shifts in weightlessness is believed to activate adaptive reflexes which ultimately result in a reduction of the total circulating blood volume. However, the flight data suggests that a central volume overdistention does not persist, in which case some other factor or factors must be responsible for body fluid losses. We used a computer simulation to test the hypothesis that factors other than central volume overdistention are involved in the loss of blood volume and other body fluid volumes observed in weightlessness and in weightless simulations. Additionally, the simulation was used to identify these factors. The results predict that atrial volumes and pressures return to their prebedrest baseline values within the first day of exposure to head down tilt (HDT) as the blood volume is reduced by an elevated urine formation. They indicate that the mechanisms for large and prolonged body fluid losses in weightlessness is red cell hemoconcentration that elevates blood viscosity and peripheral resistance, thereby lowering capillary pressure. This causes a prolonged alteration of the balance of Starling forces, depressing the extracellular fluid volume until the hematocrit is returned to normal through a reduction of the red cell mass, which also allows some restoration of the plasma volume. We conclude that the red cell mass becomes the physiologic driver for a large 'undershoot' of the body fluid volumes after the normalization of atrial volumes and pressures.

Three-dimensional Simulation and Prediction of Solenoid Valve Failure Mechanism Based on Finite Element Model

NASA Astrophysics Data System (ADS)

Li, Jianfeng; Xiao, Mingqing; Liang, Yajun; Tang, Xilang; Li, Chao

2018-01-01

The solenoid valve is a kind of basic automation component applied widely. It’s significant to analyze and predict its degradation failure mechanism to improve the reliability of solenoid valve and do research on prolonging life. In this paper, a three-dimensional finite element analysis model of solenoid valve is established based on ANSYS Workbench software. A sequential coupling method used to calculate temperature filed and mechanical stress field of solenoid valve is put forward. The simulation result shows the sequential coupling method can calculate and analyze temperature and stress distribution of solenoid valve accurately, which has been verified through the accelerated life test. Kalman filtering algorithm is introduced to the data processing, which can effectively reduce measuring deviation and restore more accurate data information. Based on different driving current, a kind of failure mechanism which can easily cause the degradation of coils is obtained and an optimization design scheme of electro-insulating rubbers is also proposed. The high temperature generated by driving current and the thermal stress resulting from thermal expansion can easily cause the degradation of coil wires, which will decline the electrical resistance of coils and result in the eventual failure of solenoid valve. The method of finite element analysis can be applied to fault diagnosis and prognostic of various solenoid valves and improve the reliability of solenoid valve’s health management.

Prediction of Thorough QT study results using action potential simulations based on ion channel screens.

PubMed

Mirams, Gary R; Davies, Mark R; Brough, Stephen J; Bridgland-Taylor, Matthew H; Cui, Yi; Gavaghan, David J; Abi-Gerges, Najah

2014-01-01

Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development. Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms - IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration-effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration. Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1Hz and running to steady state, for a range of concentrations. We compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥5ms was predicted with up to 79% sensitivity and 100% specificity. This study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety assessment. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Alternating high and low climate variability: The context of natural selection and speciation in Plio-Pleistocene hominin evolution.

PubMed

Potts, Richard; Faith, J Tyler

2015-10-01

Interaction of orbital insolation cycles defines a predictive model of alternating phases of high- and low-climate variability for tropical East Africa over the past 5 million years. This model, which is described in terms of climate variability stages, implies repeated increases in landscape/resource instability and intervening periods of stability in East Africa. It predicts eight prolonged (>192 kyr) eras of intensified habitat instability (high variability stages) in which hominin evolutionary innovations are likely to have occurred, potentially by variability selection. The prediction that repeated shifts toward high climate variability affected paleoenvironments and evolution is tested in three ways. In the first test, deep-sea records of northeast African terrigenous dust flux (Sites 721/722) and eastern Mediterranean sapropels (Site 967A) show increased and decreased variability in concert with predicted shifts in climate variability. These regional measurements of climate dynamics are complemented by stratigraphic observations in five basins with lengthy stratigraphic and paleoenvironmental records: the mid-Pleistocene Olorgesailie Basin, the Plio-Pleistocene Turkana and Olduvai Basins, and the Pliocene Tugen Hills sequence and Hadar Basin--all of which show that highly variable landscapes inhabited by hominin populations were indeed concentrated in predicted stages of prolonged high climate variability. Second, stringent null-model tests demonstrate a significant association of currently known first and last appearance datums (FADs and LADs) of the major hominin lineages, suites of technological behaviors, and dispersal events with the predicted intervals of prolonged high climate variability. Palynological study in the Nihewan Basin, China, provides a third test, which shows the occupation of highly diverse habitats in eastern Asia, consistent with the predicted increase in adaptability in dispersing Oldowan hominins. Integration of fossil, archeological, sedimentary, and paleolandscape evidence illustrates the potential influence of prolonged high variability on the origin and spread of critical adaptations and lineages in the evolution of Homo. The growing body of data concerning environmental dynamics supports the idea that the evolution of adaptability in response to climate and overall ecological instability represents a unifying theme in hominin evolutionary history. Published by Elsevier Ltd.

Predictive Associations of Music, Anxiety, and Sedative Exposure on Mechanical Ventilation Weaning Trials

PubMed Central

Hetland, Breanna; Lindquist, Ruth; Weinert, Craig R.; Peden-McAlpine, Cynthia; Savik, Kay; Chlan, Linda

2017-01-01

Background Weaning from mechanical ventilation requires increased respiratory effort, which can heighten anxiety and later prolong the need for mechanical ventilation. Objectives To examine the predictive associations of music intervention, anxiety, sedative exposure, and patients’ characteristics on time to initiation and duration of weaning trials of patients receiving mechanical ventilation. Methods A descriptive, correlational design was used for a secondary analysis of data from a randomized trial. Music listening was defined as self-initiated, patient-directed music via headphones. Anxiety was measured daily with a visual analog scale. Sedative exposure was operationalized as a daily sedation intensity score and a sedative dose frequency. Analyses consisted of descriptive statistics, graphing, survival analysis, Cox proportional hazards regression, and linear regression. Results Of 307 patients, 52% were women and 86% were white. Mean age was 59.3 (SD, 14.4) years, mean Acute Physiology and Chronic Health Evaluation III score was 62.9 (SD, 21.6), mean duration of ventilatory support was 8 (range, 1–52) days, and mean stay in the intensive care unit was 18 (range, 2–71) days. Music listening, anxiety levels, and sedative exposure did not influence time to initial weaning trial or duration of trials. Clinical factors of illness severity, days of weaning trials, and tracheostomy placement influenced weaning patterns in this sample. Conclusions Prospective studies of music intervention and other psychophysiological factors during weaning from mechanical ventilation are needed to better understand factors that promote successful weaning. PMID:28461543

Religious Coping and Behavioral Disengagement: Opposing Influences on Advance Care Planning and Receipt of Intensive Care Near Death

PubMed Central

Maciejewski, Paul K.; Phelps, Andrea C.; Kacel, Elizabeth L.; Balboni, Tracy A.; Balboni, Michael; Wright, Alexi A.; Pirl, William; Prigerson, Holly G.

2011-01-01

Objective This study examines the relationships between methods of coping with advanced cancer, completion of advance care directives, and receipt of intensive, life-prolonging care near death. Methods The analysis is based on a sample of 345 patients interviewed between January 1, 2003, and August 31, 2007, and followed until death as part of the Coping with Cancer Study, an NCI/NIMH-funded, multi-site, prospective, longitudinal, cohort study of patients with advanced cancer. The Brief COPE was used to assess active coping, use of emotional-support, and behavioral disengagement. The Brief RCOPE was used to assess positive and negative religious coping. The main outcome was intensive, life-prolonging care near death, defined as receipt of ventilation or resuscitation in the last week of life. Results Positive religious coping was associated with lower rates of having a living will (AOR=0.39, p=0.003) and predicted higher rates of intensive, life-prolonging care near death (AOR, 5.43; p<0.001), adjusting for other coping methods and potential socio-demographic and health status confounds. Behavioral disengagement was associated with higher rates of DNR order completion (AOR, 2.78; p=0.003) and predicted lower rates of intensive life-prolonging care near death (AOR, 0.20; p=0.036). Not having a living will partially mediated the influence of positive religious coping on receipt of intensive, life-prolonging care near death. Conclusion Positive religious coping and behavioral disengagement are important determinants of completion of advance care directives and receipt of intensive, life-prolonging care near death. PMID:21449037

Prolonged secretion of cortisol as a possible mechanism underlying stress and depressive behaviour

PubMed Central

Qin, Dong-dong; Rizak, Joshua; Feng, Xiao-li; Yang, Shang-chuan; Lü, Long-bao; Pan, Lei; Yin, Yong; Hu, Xin-tian

2016-01-01

Stress is associated with the onset of depressive episodes, and cortisol hypersecretion is considered a biological risk factor of depression. However, the possible mechanisms underlying stress, cortisol and depressive behaviours are inconsistent in the literature. This study examined the interrelationships among stress, cortisol and observed depressive behaviours in female rhesus macaques for the first time and explored the possible mechanism underlying stress and depressive behaviour. Female monkeys were video-recorded, and the frequencies of life events and the duration of huddling were analysed to measure stress and depressive behaviour. Hair samples were used to measure chronic cortisol levels, and the interactions between stress and cortisol in the development of depressive behaviour were further evaluated. Significant correlations were found between stress and depressive behaviour measures and between cortisol levels and depressive behaviour. Stress was positively correlated with cortisol levels, and these two factors interacted with each other to predict the monkeys’ depressive behaviours. This finding extends the current understanding of stress/cortisol interactions in depression, especially pertaining to females. PMID:27443987

Critical care nurses management of prolonged weaning: an interview study.

PubMed

Cederwall, Carl-Johan; Plos, Kaety; Rose, Louise; Dübeck, Amanda; Ringdal, Mona

2014-09-01

For most critically ill patients requiring mechanical ventilation in the intensive care unit (ICU) weaning is uncomplicated. For the remainder, weaning is a challenge and may result in further complications and increased risk of mortality. Critical care nurses (CCNs) require substantial knowledge and experience to manage patients experiencing prolonged weaning. The aim of this study was to explore CCNs approach for management of patients experiencing prolonged weaning in the ICU. A descriptive qualitative design. Semi-structured interviews with 19 experienced CCNs were conducted. Data were analysed using content analysis. Participants used various strategies for weaning that were grouped into four categories: individualized planning for the weaning process, assessing patient's capacity, managing the process and team interaction. The overall theme that emerged was: CCNs drive the weaning process using both a patient centred and targeted approach. CCNs in these ICUs performed weaning using a patient centred approach to plan, initiate, assess and establish a holistic weaning process. Team collaboration among all health care practitioners was important. CCNs have a key role in prioritizing weaning and driving the process forward. Closeness to the patient and a key role in management of the mechanical ventilated patient in ICU gives the CCN unique potential to develop and create models and tools for prolonged weaning. These tools, specially designed for patients undergoing prolonged weaning, would give focus on continuous planning, collaborating, managing and evaluation in the process of liberating patients from mechanical ventilation. © 2014 British Association of Critical Care Nurses.

Tolerability to prolonged lifting tasks. A validation of the recommended limits.

PubMed

Capodaglio, P; Bazzini, G

1997-01-01

Prolonged physical exertion is subjectively regulated by the perception of effort. This preliminary study was conducted to validate the use of subjective perceptions of effort in assessing objectively tolerable workloads for prolonged lifting tasks. Ten healthy male subjects tested their maximal lifting capacity (MLC) on a lift dynamometer (LidoLift, Loredan Biomed., West Sacramento, CA) and underwent incremental and 30-minute endurance lifting tests. Cardiorespiratory parameters were monitored with an oxygen uptake analyzer, mechanical parameters were calculated using a computerized dynamometer. Ratings of perceived exertion were given on Borg's 10-point scale. Physiological responses to repetitive lifting were matched with subjective perceptions. A single-variable statistical regression for power functions was performed to obtain the individual "iso-perception" curves as functions of the mechanical work exerted. We found that the "iso-perception" curve corresponding to a "moderate" perception of effort may represent the individual "tolerance threshold" for prolonged lifting tasks, since physiological responses at this level of intensity did not change significantly and the respiratory exchange ratio was less than one. The individually tolerable weight for lifting tasks lasting 30 min has been expressed as a percentage of the isoinertial MLC value and compared with the currently recommended limits for prolonged lifting tasks (Italian legislation D.L. 626/94). On the basis of our preliminary results a "tolerance threshold" of 20% MLC has been proposed for prolonged lifting tasks.

Electromechanical heterogeneity in the heart : A key to long QT syndrome?

PubMed

Dressler, F F; Brado, J; Odening, K E

2018-03-01

In the healthy heart, physiological heterogeneities in structure and in electrical and mechanical activity are crucial for normal, efficient excitation and pumping. Alterations of heterogeneity have been linked to arrhythmogenesis in various cardiac disorders such as long QT syndrome (LQTS). This inherited arrhythmia disorder is caused by mutations in different ion channel genes and is characterized by (heterogeneously) prolonged cardiac repolarization and increased risk for ventricular tachycardia, syncope and sudden cardiac death. Cardiac electrical and mechanical function are not independent of each other but interact in a bidirectional manner by electromechanical and mechano-electrical coupling. Therefore, changes in either process will affect the other. Recent experimental and clinical evidence suggests that LQTS, which is primarily considered an "electrical" disorder, also exhibits features of disturbed mechanical function and heterogeneity, which in turn appears to correlate with the risk of arrhythmia in the individual patient. In this review, we give a short overview of the current knowledge about physiological and pathological, long QT-related electrical and mechanical heterogeneity in the heart. Also, their respective roles for future risk prediction approaches in LQTS are discussed.

Return to Work After Lumbar Microdiscectomy - Personalizing Approach Through Predictive Modeling.

PubMed

Papić, Monika; Brdar, Sanja; Papić, Vladimir; Lončar-Turukalo, Tatjana

2016-01-01

Lumbar disc herniation (LDH) is the most common disease among working population requiring surgical intervention. This study aims to predict the return to work after operative treatment of LDH based on the observational study including 153 patients. The classification problem was approached using decision trees (DT), support vector machines (SVM) and multilayer perception (MLP) combined with RELIEF algorithm for feature selection. MLP provided best recall of 0.86 for the class of patients not returning to work, which combined with the selected features enables early identification and personalized targeted interventions towards subjects at risk of prolonged disability. The predictive modeling indicated at the most decisive risk factors in prolongation of work absence: psychosocial factors, mobility of the spine and structural changes of facet joints and professional factors including standing, sitting and microclimate.

System identification of dynamic closed-loop control of total peripheral resistance by arterial and cardiopulmonary baroreceptors

NASA Astrophysics Data System (ADS)

Nikolai Aljuri, A.; Bursac, Nenad; Marini, Robert; Cohen, Richard J.

2001-08-01

Prolonged exposure to microgravity in space flight missions (days) impairs the mechanisms responsible for defense of arterial blood pressure (ABP) and cardiac output (CO) against orthostatic stress in the post-flight period. The mechanisms responsible for the observed orthostatic intolerance are not yet completely understood. Additionally, effective counter measures to attenuate this pathophysiological response are not available. The aim of this study was to investigate the ability of our proposed system identification method to predict closed-loop dynamic changes in TPR induced by changes in mean arterial pressure (MAP) and right atrial pressure (RAP). For this purpose we designed and employed a novel experimental animal model for the examination of arterial and cardiopulmonary baroreceptors in the dynamic closed-loop control of total peripheral resistance (TPR), and applied system identification to the analysis of beat-to-beat fluctuations in the measured signals.

Prolonged longevity of hypopituitary dwarf mice.

PubMed

Bartke, A; Brown-Borg, H; Mattison, J; Kinney, B; Hauck, S; Wright, C

2001-01-01

In two types of mutant dwarf mice, congenital deficiencies in pituitary function are associated with remarkably increased life expectancy. In this review, we will describe the key phenotypic characteristics of these animals, the evidence that they exhibit delayed aging, and the mechanisms that are suspected to account for their prolonged longevity.

Does a 'tight' hamstring predict low back pain reporting during prolonged standing?

PubMed

Raftry, Sean M; Marshall, Paul W M

2012-06-01

The purpose of this study was to investigate the relationship between hamstring passive stiffness and extensibility in asymptomatic individuals with the reporting of low back pain during 2-h prolonged standing. Twenty healthy participants with no history of low back pain (mean±SD, age 22.6±2.7 years, height 1.74±0.09 m, weight 76.2±14.8 kg). Low back pain (VAS score; mm) was continuously monitored during 2-h prolonged standing. Hamstring extensibility, passive stiffness, and stretch tolerance were measured before and after prolonged standing using an instrumented straight leg raise (iSLR). Ten participants reported a clinically relevant increase (Δ VAS>10mm) in low back pain during prolonged standing. Hamstring extensiblity (leg°(max)), passive stiffness (Nm.°(-1)), and stretch tolerance (VAS; mm) were no different between pain developers and non-pain developers. No changes in hamstring measures were observed following 2-h prolonged standing. No relationship was observed in this study between measures of hamstring extensibility and the reporting of low back pain during prolonged standing. There is no evidence to recommend hamstring extensibility interventions (i.e. passive stretching) as a means of reducing pain reporting in occupations requiring prolonged standing. Copyright © 2012 Elsevier Ltd. All rights reserved.

Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial.

PubMed

Dixon, Barry; Schultz, Marcus J; Smith, Roger; Fink, James B; Santamaria, John D; Campbell, Duncan J

2010-01-01

Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation. Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization. Nebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events. Nebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings. The Australian Clinical Trials Registry (ACTR-12608000121369).

Prolonged persistent patent ductus arteriosus: potential perdurable anomalies in premature infants.

PubMed

Saldeño, Y P; Favareto, V; Mirpuri, J

2012-12-01

Patent ductus arteriosus (PDA) is a common condition among preterm infants. Controversy exists regarding the risk-benefit ratio of early closure of PDAs by either medical or surgical treatments. On the other hand, potential morbidities associated with no or delayed closure has not been well studied. The objective of the study was to determine if there is an association of prolonged persistent PDA (PP-PDA) with various morbidities in infants ≤28 weeks or 1250 g. This matched case-control analysis includes preterm infants with a diagnosis of PDA over a period of 28 months in a single level III center in the USA. The predictive variable was the presence of a PP-PDA (PDA>3 weeks). Cases were infants with PP-PDA and controls were those with PDA but not PP-PDA (two controls for each case). Outcome variables included days on mechanical ventilation and with oxygen treatment, length of hospital stay, bronchopulmonary dysplasia (BPD), retinopathy of prematurity stage III-V (ROP) necrotizing enterocolitis grade II or more (NEC), delayed growth, direct hyperbilirubinemia >4 mg dl(-1) and osteopenia of prematurity. Data was obtained from database collected prospectively and from the review of clinical records when necessary. Statistics included ANOVA, Kaplan-Meier curves and χ (2). Significance was set at P<0.05. PP-PDA was associated with a significant increase in the number of days of mechanical ventilation, oxygen treatment and length of hospital stay, and in the rates of BPD (60% vs 4.5%), NEC (29% vs 5%), ROP (43% vs 5%), direct hyperbilirubinemia (41% vs 3%), osteopenia (44% vs 6%), parenteral nutrition for >40 days (70% vs 21%), tracheostomy during the hospitalization (15% vs 0%) and delayed growth (70% vs 21%), were also significantly higher in babies with PP-PDA. A prolonged exposure to PDA does not seem to be inconsequential for some infants and is associated with an increase prevalence of severe morbidities with potential long lasting effects.

Seasonal changes in the assembly mechanisms structuring tropical fish communities.

PubMed

Fitzgerald, Daniel B; Winemiller, Kirk O; Sabaj Pérez, Mark H; Sousa, Leandro M

2017-01-01

Despite growing interest in trait-based approaches to community assembly, little attention has been given to seasonal variation in trait distribution patterns. Mobile animals can rapidly mediate influences of environmental factors and species interactions through dispersal, suggesting that the relative importance of different assembly mechanisms can vary over short time scales. This study analyzes seasonal changes in functional trait distributions of tropical fishes in the Xingu River, a major tributary of the Amazon with large predictable temporal variation in hydrologic conditions and species density. Comparison of observed functional diversity revealed that species within wet-season assemblages were more functionally similar than those in dry-season assemblages. Further, species within wet-season assemblages were more similar than random expectations based on null model predictions. Higher functional richness within dry season communities is consistent with increased niche complementarity during the period when fish densities are highest and biotic interactions should be stronger; however, null model tests suggest that stochastic factors or a combination of assembly mechanisms influence dry-season assemblages. These results demonstrate that the relative influence of community assembly mechanisms can vary seasonally in response to changing abiotic conditions, and suggest that studies attempting to infer a single dominant mechanism from functional patterns may overlook important aspects of the assembly process. During the prolonged flood pulse of the wet season, expanded habitat and lower densities of aquatic organisms likely reduce the influence of competition and predation. This temporal shift in the influence of different assembly mechanisms, rather than any single mechanism, may play a large role in maintaining the structure and diversity of tropical rivers and perhaps other dynamic and biodiverse systems. © 2016 by the Ecological Society of America.

A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation derived from the effects of terfenadine, cisapride and E-4031 in the conscious chronic av node--ablated, His bundle-paced dog.

PubMed

Nolan, Emily R; Feng, Meihua Rose; Koup, Jeffrey R; Liu, Jing; Turluck, Daniel; Zhang, Yiqun; Paulissen, Jerome B; Olivier, N Bari; Miller, Teresa; Bailie, Marc B

2006-01-01

Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node--ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundle-pacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid E(max) model with an effect site. Maximum RT change (E(max)), free drug concentration at half of the maximum effect (EC(50)), and free drug concentration associated with a 10 ms RT prolongation (EC(10 ms)) were estimated. A linear correlation between EC(10 ms) and HERG IC(50) values was identified. The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to I(Kr) inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.

Ambulatory assessment of skin conductivity during first thesis presentation: lower self-confidence predicts prolonged stress response.

PubMed

Elfering, Achim; Grebner, Simone

2011-06-01

In this field study self-confidence was tested to predict the course of galvanic electrodermal stress response prior, during and after public speaking. Ten graduate students initially rated their self-confidence and afterwards presented their thesis proposals orally in a 10-min presentation to their supervisor and peers. Galvanic skin response level was measured throughout and analysed for 10 min prior to, during, and 10 min after the presentation. Two major galvanic electrodermal stress response types were observed. Five students showed a 'healthy response', i.e. an anticipatory increase in electrodermal conductance, followed by a decrease after termination of the presentation. The other five students showed a steady increase of skin conductance during and after their presentation ('prolonged response'). In line with the allostatic load model the 'prolonged response' group reported significantly lower self-confidence before presentation than the 'healthy response' group (p < 0.01). Self-confidence is a resource in novices facing an unfamiliar stressor.

Impact of Prolonged Mechanical Ventilation in Very Low Birth Weight Infants: Results From a National Cohort Study.

PubMed

Choi, Young-Bin; Lee, Juyoung; Park, Jisun; Jun, Yong Hoon

2018-03-01

To evaluate the in-hospital consequences of prolonged respiratory support with invasive mechanical ventilation in very low birth weight infants. A cohort study was performed using prospectively collected data from 69 neonatal intensive care units participating in the Korean national registry. In total, 3508 very low birth weight infants born between January 1, 2013 and December 31, 2014 were reviewed. The adjusted hazard ratio for death increased significantly for infants who received mechanical ventilation for more than 2 weeks compared with those were mechanically ventilated for 7 days or less. The individual mortality rate increased after 8 weeks, reaching 50% and 60% at 14 and 16 weeks of cumulative mechanical ventilation, respectively. After adjusting for potential confounders, the cumulative duration of mechanical ventilation was associated with a clinically significant increase in the odds of bronchopulmonary dysplasia and pulmonary hypertension. Mechanical ventilation exposure for longer than 2 weeks, compared with 7 days or less, was associated with retinopathy of prematurity requiring laser coagulation and periventricular leukomalacia. The odds of abnormal auditory screening test results were significantly increased in infants who needed mechanical ventilation for more than 4 weeks. A longer cumulative duration of mechanical ventilation was associated with increased lengths of hospitalization and parenteral nutrition and a higher probability of discharge with poor achievement of physical growth. Although mechanical ventilation is a life-saving intervention for premature infants, these results indicate that it is associated with negative consequences when applied for prolonged periods. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term outcome and quality of life of patients requiring prolonged mechanical ventilation after cardiac surgery.

PubMed

Pappalardo, Federico; Franco, Annalisa; Landoni, Giovanni; Cardano, Paola; Zangrillo, Alberto; Alfieri, Ottavio

2004-04-01

To study the long-term survival and quality of life of patients with a complicated post-operative course after cardiac surgery requiring prolonged (>or=7 days) mechanical ventilation (MV), since they represent a heavy burden on hospital resources and their outcome has never been adequately evaluated. Out of 4827 consecutive cardiac surgical patients, 148 (3%) required prolonged post-operative MV: their hospital course was analysed and factors affecting prolonged MV and mortality were identified using multivariate analysis. Long-term survival was assessed using Cox proportional hazard method. Long-term (36+/-12 months) follow-up information was collected and quality of life was assessed by an ad hoc questionnaire. Overall mortality in the study group was 45.3 versus 2% in the control population (P<0.0001). Predictors of death in the prolonged MV group were age (odds ratio, OR 1.049) and diabetes (OR 3.459). Long-term survival was significantly worse in those patients who were extubated after 21 days: 88.9 versus 70.9% at 1 year (P=0.03) and 80.9 versus 64.5% at 5 years (P=0.05). Mild or no limitation in daily living was referred by 69% of the survivors. The hospital mortality of patients requiring prolonged MV is high. The long-term survival of patients who are weaned from MV after 21 days is significantly lower. The great majority of the survivors can enjoy a good quality of life.

Thermoregulatory, Cardiovascular, and Metabolic Responses to Mild Caloric Restriction in the Brown Norway Rat

EPA Science Inventory

Caloric restriction (CR) has been demonstrated to prolong the life span of a variety of species. CR-induced reduction in core temperature (Tc) is considered a key mechanism responsible for prolonging life span in rodents; however, little is known on the regulation of CR-induced h...

Ever at the ready for events that never happen

PubMed Central

Brosschot, Jos F.

2017-01-01

ABSTRACT Stress, whether daily stress, work stress or traumatic stress, is unhealthy. This lecture covers three recent theoretical approaches in explaining the mechanisms underlying the influence of psychological stress on somatic health. It is argued that stress research should focus less on stressors themselves and put more emphasis on prolonged stress responses. Three mechanisms are identified that cause this unhealthy prolonged stress response: first, the partly-proven mechanism of perseverative cognition; second, the mechanism of unconscious stress, which is currently being explored; and third, the notion of the stress response being a default response that is inhibited only when safety is perceived. All three mechanisms are deeply rooted in millions of years of our evolution. Although the dangers of the past have virtually disappeared, many of us remain ever at the ready for events that never happen. PMID:28451075

The effect of energy accumulation and boundary slip on laminar flow between rotating plates

NASA Astrophysics Data System (ADS)

Wu, Zhenpeng; Zeng, Liangcai; Chen, Keying; Jin, Xiaohong; Wu, Shiqian

2018-02-01

The poor operating conditions of fluid lubrication equipment during the start-up process are due to the resistance of the high-viscosity lubricating liquid. Moreover, the excessive reduction in fluid viscosity due to the elevated temperature resulting from power consumption during prolonged operation is not conducive to the generation of dynamic pressure. In this study, we examine the effect of energy accumulation and boundary slip on the laminar flow of a liquid between a pair of rotating plates. The experiments are conducted using a rotary rheometer, with polymethyl methacrylate (PMMA) as the thermal insulation material and polytetrafluoroethylene (PTFE) as the slip drag reduction material, and a three-dimensional simulation model is established. This model is derived by combining the energy equation including the slip length and the heat conduction equation. Thus, the temperature changes over time are predicted by this model, and the model accuracy is verified by experiments. The results reveal the following points: 1) boundary slips function as a drag reduction mechanism for short-time continuous operation; 2) under prolonged operation, the slip reduces the extent of the oil viscosity decrease and clear control of the elevated temperature by the boundary slip is observed.

Coupling of rainfall-induced landslide triggering model with predictions of debris flow runout distances

NASA Astrophysics Data System (ADS)

Lehmann, Peter; von Ruette, Jonas; Fan, Linfeng; Or, Dani

2014-05-01

Rapid debris flows initiated by rainfall induced shallow landslides present a highly destructive natural hazard in steep terrain. The impact and run-out paths of debris flows depend on the volume, composition and initiation zone of released material and are requirements to make accurate debris flow predictions and hazard maps. For that purpose we couple the mechanistic 'Catchment-scale Hydro-mechanical Landslide Triggering (CHLT)' model to compute timing, location, and landslide volume with simple approaches to estimate debris flow runout distances. The runout models were tested using two landslide inventories obtained in the Swiss Alps following prolonged rainfall events. The predicted runout distances were in good agreement with observations, confirming the utility of such simple models for landscape scale estimates. In a next step debris flow paths were computed for landslides predicted with the CHLT model for a certain range of soil properties to explore its effect on runout distances. This combined approach offers a more complete spatial picture of shallow landslide and subsequent debris flow hazards. The additional information provided by CHLT model concerning location, shape, soil type and water content of the released mass may also be incorporated into more advanced models of runout to improve predictability and impact of such abruptly-released mass.

Risk factors of prolonged mechanical ventilation following open heart surgery: what has changed over the last decade?

PubMed

Siddiqui, Muhammad-Mujtaba Ali; Paras, Iftikhar; Jalal, Anjum

2012-09-01

To identify the risk factors for prolonged invasive mechanical ventilation after open heart surgery in Pakistan. This study is based on retrospective analysis of database. We conducted study of all patients who underwent open heart surgery at CPE Institute of Cardiology, Multan from March 2009 to May 2011. The data was retrieved from the database in the form of electronic spreadsheet which was then analyzed using SPSS software. The patients with incomplete data entries were removed from the analysis resulting in a set of 1,617 patients. The data of each patient consisted of 65 preoperative, operative and postoperative variables. The data was summarized as means, medians and standard deviations for numeric variables and frequencies and percentages or categoric variables. These risk factors were compared using Chi-sqaure test. Their ODDs ratios and 95% confidence intervals of ODD's Ratios and P values were calculated. Out of a total of 1,617 patients, 77 patients (4.76%) had prolonged ventilation for a cumulated duration of more than over 24 hours. Preoperative renal failure, emphysema, low EF (<30%), urgent operation, preoperative critical state, prolonged bypass time, prolonged cross clamp time, complex surgical procedures and peri-operative myocardial infarction were found to be risk factors for PIMV. Old age, female gender, advanced ASA class, advanced NYHA class, diabetes mellitus, smoking, history of COPD, redo surgery, left main stenosis, obesity and use of intra-aortic balloon pump were not found to have significant ODDs ratios for PIMV. The patients with prolonged ventilation had significantly high mortality i.e. 32.47% while the normal ventilation group had 0.32% overall mortality. Many of the previously considered risk factors for prolonged ventilation after open heart study are no more significant risk factors. However, prolonged ventilation continues to be associated with very high mortality.

Mechanical process for enhancing metal hydride for the anode of a Ni-MH secondary battery

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

Ikeya, T.; Kumai, K.; Iwahori, T.

1993-11-01

This study attempted to find a simpler method for modifying hydrogen storage alloys that are used as anodes in Ni-MH batteries to prolong their cycle life. The alloy was modified by mechanical grinding with cobalt metal powder. A short grinding time yielded samples with a higher discharge capacity and longer cycle life than those of the alloy which was mixed with the cobalt powder without the mechanical treatment. However, prolonged grinding caused a decrease in the discharge capacity because of amorphization of the alloy by mechanical stress. The authors believed the formation of a cobalt compound on the alloy surfacemore » plus closer contact between particle enhanced the cyclic durability and discharge capacity of metal hydride anodes.« less

Improving Cardiometabolic Health with Diet, Physical Activity, and Breaking Up Sitting: What about Sleep?

PubMed Central

Vincent, Grace E.; Jay, Sarah M.; Sargent, Charli; Vandelanotte, Corneel; Ridgers, Nicola D.; Ferguson, Sally A.

2017-01-01

Cardiometabolic disease poses a serious health and economic burden worldwide and its prevalence is predicted to increase. Prolonged sitting, lack of physical activity, poor diet, and short sleep duration are ubiquitous behaviors in modern society, and all are independent risk factors in the development of cardiometabolic disease. Existing evidence demonstrates that breaking up prolonged periods of sitting is beneficial for cardiometabolic health, however, studies have not controlled for prior sleep duration. This article examines how prolonged sitting and short sleep duration independently contribute to cardiometabolic risk, and how breaking up sitting and obtaining adequate sleep may reduce this risk. We suggest that as prolonged sitting and short sleep duration influence the same cardiometabolic parameters, there is potential for short sleep to attenuate the positive impact of breaking up prolonged sitting with physical activity. Likewise, breaking up prolonged sitting and obtaining adequate sleep together could improve predictors of cardiometabolic disease, i.e., the combined effect may be stronger than either alone. To explore these perspectives, we propose a research agenda to investigate the relationship between breaking up prolonged sitting with physical activity and short sleep duration. This will provide an evidence-base for informing the design of interventions to reduce the burden of cardiometabolic disease on communities worldwide. PMID:29167645

Mechanisms of force depression caused by different types of physical exercise studied by direct electrical stimulation of human quadriceps muscle.

PubMed

Skurvydas, Albertas; Mamkus, Gediminas; Kamandulis, Sigitas; Dudoniene, Vilma; Valanciene, Dovile; Westerblad, Håkan

2016-12-01

Force production frequently remains depressed for several hours or even days after various types of strenuous physical exercise. We hypothesized that the pattern of force changes during the first hour after exercise can be used to reveal muscular mechanisms likely to underlie the decline in muscle performance during exercise as well as factors involved in the triggering the prolonged force depression after exercise. Nine groups of recreationally active male volunteers performed one of the following types of exercise: single prolonged or repeated short maximum voluntary contractions (MVCs); single or repeated all-out cycling bouts; repeated drop jumps. The isometric force of the right quadriceps muscle was measured during stimulation with brief 20 and 100 Hz trains of electrical pulses given before and at regular intervals for 60 min after exercise. All exercises resulted in a prolonged force depression, which was more marked at 20 Hz than at 100 Hz. Short-lasting (≤2 min) MVC and all-out cycling exercises showed an initial force recovery (peak after ~ 5 min) followed by a secondary force depression. The repeated drop jumps, which involve eccentric contractions, resulted in a stable force depression with the 20 Hz force being markedly more decreased after 100 than 10 jumps. In accordance with our hypothesis, the results propose at least three different mechanisms that influence force production after exercise: (1) a transiently recovering process followed by (2) a prolonged force depression after metabolically demanding exercise, and (3) a stable force depression after mechanically demanding contractions.

Test-retest paradigm of the forced swimming test in female mice is not valid for predicting antidepressant-like activity: participation of acetylcholine and sigma-1 receptors.

PubMed

Su, Jing; Hato-Yamada, Noriko; Araki, Hiroaki; Yoshimura, Hiroyuki

2013-01-01

The forced swimming test (FST) in mice is widely used to predict the antidepressant activity of a drug, but information describing the immobility of female mice is limited. We investigated whether a prior swimming experience affects the immobility duration in a second FST in female mice and whether the test-retest paradigm is a valid screening tool for antidepressants. Female ICR mice were exposed to the FST using two experimental paradigms: a single FST and a double FST in which mice had experienced FST once 24 h prior to the second trail. The initial FST experience reliably prolonged immobility duration in the second FST. The antidepressants imipramine and paroxetine significantly reduced immobility duration in the single FST, but not in the double FST. Scopolamine and the sigma-1 (σ1) antagonist NE-100 administered before the second trial significantly prevented the prolongation of immobility. Neither a 5-HT1A nor a 5-HT2A receptor agonist affected immobility duration. We suggest that the test-retest paradigm in female mice is not adequate for predicting antidepressant-like activity of a drug; the prolongation of immobility in the double FST is modulated through acetylcholine and σ1 receptors.

Neural Circuits via Which Single Prolonged Stress Exposure Leads to Fear Extinction Retention Deficits

ERIC Educational Resources Information Center

Knox, Dayan; Stanfield, Briana R.; Staib, Jennifer M.; David, Nina P.; Keller, Samantha M.; DePietro, Thomas

2016-01-01

Single prolonged stress (SPS) has been used to examine mechanisms via which stress exposure leads to post-traumatic stress disorder symptoms. SPS induces fear extinction retention deficits, but neural circuits critical for mediating these deficits are unknown. To address this gap, we examined the effect of SPS on neural activity in brain regions…

Physiological responses to prolonged bed rest in humans: A compendium of research, 1981-1988

NASA Technical Reports Server (NTRS)

Luu, Phuong B.; Ortiz, Vanessa; Barnes, Paul R.; Greenleaf, John E.

1990-01-01

Clinical observations and results form more basic studies that help to elucidate the physiological mechanisms of the adaptation of humans to prolonged bed rest. If the authors' abstract or summary was appropriate, it was included. In some cases a more detailed synopsis was provided under the subheadings of purpose, methods, results, and conclusions.

Criteria for Postoperative Mechanical Ventilation After Thymectomy in Patients With Myasthenia Gravis: A Retrospective Analysis.

PubMed

Chigurupati, Keerthi; Gadhinglajkar, Shrinivas; Sreedhar, Rupa; Nair, Muraleedharan; Unnikrishnan, Madathipat; Pillai, Manjusha

2018-02-01

To determine the criteria for postoperative mechanical ventilation after thymectomy in patients with Myasthenia Gravis. Retrospective study. Teritiary care centre. 77 Myasthenia gravis patients operated for thymectomy were studied. After obtaining clearance from Institutional ethics committee, medical records of 77 patients with MG, who were operated for thymectomy between January 2005 and December 2015 were reviewed in a retrospective manner. Perioperative variables collected from the patient records were demographic data, duration of the disease, Osserman and Genkin classification, Anti-acetylcholine antibody (AChR) positivity, preoperative daily dose of drug, history of preoperative myasthenic crisis, preoperative vital capacity, technique of anesthesia, drugs used for anesthesia, perioperative complications, and duration of postoperative mechanical ventilation. The patients were divided into two groups, group I and group II consisting of those who required postoperative ventilation for < 300 minutes and > 300 minutes, respectively. The determinants of prolonged postoperative ventilation were studied. The requirement of mechanical ventilation was higher in patients with higher Osserman's grade of myasthenia gravis. Duration of the disease had no effect on the duration of mechanical ventilation in myasthenic patients post thymectomy (p = 0.89). The patients with a preoperative history of myasthenic crisis had a requirement for prolonged mechanical ventilation (p=0.03). Patients with preoperative vital capacity < 2.9 litres and preoperative CT scan showing thymoma had a requirement for prolonged mechanical ventilation with p values < 0.001 and 0.035, respectively. Patients who showed positivity for anti-acetylcholine antibodies had a prolonged mechanical ventilation (p=0.026). Preoperative dose of pyridostigmine and the choice of continuation or discontinuation of antcholinesterases on the day of surgery had no influence on the duration of mechanical ventilation (p value of 0.19 and 0.36 respectively). Epidural analgesia intra and postoperatively significantly reduced the requirement of mechanical ventilation (p=0.006). The predictors of postoperative ventilation in myasthenic patients undergoing thymectomy as per our study are: 1. Grade of myasthenia; 2. History of preoperative myasthenic crisis; 3. Anti-acetylcholine antibodies positivity; 4. Presence of thymoma; and 5. a vital capacity < 2.9 litres. Use of thoracic epidural as a part of combined anesthetic technique helps to reduce the need of mechanical ventilation in these patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of exercise training on pulmonary mechanics and functional status in patients with prolonged mechanical ventilation.

PubMed

Chen, Yen-Huey; Lin, Hui-Ling; Hsiao, Hsiu-Feng; Chou, Lan-Ti; Kao, Kuo-Chin; Huang, Chung-Chi; Tsai, Ying-Huang

2012-05-01

The functional status and outcomes in patients with prolonged mechanical ventilation (PMV) are often limited by poor endurance and pulmonary mechanics, which result from the primary diseases or prolonged time bedridden. We evaluate the impact of exercise training on pulmonary mechanics, physical functional status, and hospitalization outcomes in PMV patients. Twenty-seven subjects with PMV in our respiratory care center (RCC) were divided randomly into an exercise training group (n = 12) and a control group (n = 15). The exercise program comprised 10 sessions of exercise training. The measurement of pulmonary mechanics and physical functional status (Functional Independence Measurement and Barthel index) were performed pre-study and post-study. The hospitalization outcomes included: days of mechanical ventilation, hospitalization days, and weaning and mortality rates during RCC stay. The training group had significant improvement in tidal volume (143.6 mL vs 192.5 mL, P = .02) and rapid shallow breathing index after training (162.2 vs 110.6, P = .009). No significant change was found in the control group except respiratory rate. Both groups had significant improvement in functional status during the study. However, the training group had greater changes in FIM score than the control group (44.6 vs 34.2, P = .024). The training group also had shorter RCC stay and higher weaning and survival rates than the control group, although no statistical difference was found. Subjects with PMV in our RCC demonstrated significant improvement in pulmonary mechanics and functional status after exercise training. The application of exercise training may be helpful for PMV patients to improve hospitalization outcomes.

Predicting failure to return to work.

PubMed

Mills, R

2012-08-01

The research question is: is it possible to predict, at the time of workers' compensation claim lodgement, which workers will have a prolonged return to work (RTW) outcome? This paper illustrates how a traditional analytic approach to the analysis of an existing large database can be insufficient to answer the research question, and suggests an alternative data management and analysis approach. This paper retrospectively analyses 9018 workers' compensation claims from two different workers' compensation jurisdictions in Australia (two data sets) over a 4-month period in 2007. De-identified data, submitted at the time of claim lodgement, were compared with RTW outcomes for up to 3 months. Analysis consisted of descriptive, parametric (analysis of variance and multiple regression), survival (proportional hazards) and data mining (partitioning) analysis. No significant associations were found on parametric analysis. Multiple associations were found between the predictor variables and RTW outcome on survival analysis, with marked differences being found between some sub-groups on partitioning--where diagnosis was found to be the strongest discriminator (particularly neck and shoulder injuries). There was a consistent trend for female gender to be associated with a prolonged RTW outcome. The supplied data were not sufficient to enable the development of a predictive model. If we want to predict early who will have a prolonged RTW in Australia, workers' compensation claim forms should be redesigned, data management improved and specialised analytic techniques used. © 2011 The Author. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale?

PubMed

Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C

2013-12-01

Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes.

Percutaneous dilatational tracheostomy following total artificial heart implantation.

PubMed

Spiliopoulos, Sotirios; Dimitriou, Alexandros Merkourios; Serrano, Maria Rosario; Guersoy, Dilek; Autschbach, Ruediger; Goetzenich, Andreas; Koerfer, Reiner; Tenderich, Gero

2015-07-01

Coagulation disorders and an immune-altered state are common among total artificial heart patients. In this context, we sought to evaluate the safety of percutaneous dilatational tracheostomy in cases of prolonged need for mechanical ventilatory support. We retrospectively analysed the charts of 11 total artificial heart patients who received percutaneous dilatational tracheostomy. We focused on early and late complications. We observed no major complications and no procedure-related deaths. Early minor complications included venous oozing (45.4%) and one case of local infection. Late complications, including subglottic stenosis, stomal infection or infections of the lower respiratory tract, were not observed. In conclusion, percutaneous dilatational tracheostomy in total artificial heart patients is safe. Considering the well-known benefits of early tracheotomy over prolonged translaryngeal intubation, we advocate early timing of therapy in cases of prolonged mechanical ventilation. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

High-temperature Tensile Properties and Creep Life Assessment of 25Cr35NiNb Micro-alloyed Steel

NASA Astrophysics Data System (ADS)

Ghatak, Amitava; Robi, P. S.

2016-05-01

Reformer tubes in petrochemical industries are exposed to high temperatures and gas pressure for prolonged period. Exposure of these tubes at severe operating conditions results in change in the microstructure and degradation of mechanical properties which may lead to premature failure. The present work highlights the high-temperature tensile properties and remaining creep life prediction using Larson-Miller parametric technique of service exposed 25Cr35NiNb micro-alloyed reformer tube. Young's modulus, yield strength, and ultimate tensile strength of the steel are lower than the virgin material and decreases with the increase in temperature. Ductility continuously increases with the increase in temperature up to 1000 °C. Strain hardening exponent increases up to 600 °C, beyond which it starts decreasing. The tensile properties are discussed with reference to microstructure and fractographs. Based on Larson-Miller technique, a creep life of at least 8.3 years is predicted for the service exposed material at 800 °C and 5 MPa.

One-year trajectories of care and resource utilization for recipients of prolonged mechanical ventilation: a cohort study.

PubMed

Unroe, Mark; Kahn, Jeremy M; Carson, Shannon S; Govert, Joseph A; Martinu, Tereza; Sathy, Shailaja J; Clay, Alison S; Chia, Jessica; Gray, Alice; Tulsky, James A; Cox, Christopher E

2010-08-03

Growing numbers of critically ill patients receive prolonged mechanical ventilation. Little is known about the patterns of care as patients transition from acute care hospitals to postacute care facilities or about the associated resource utilization. To describe 1-year trajectories of care and resource utilization for patients receiving prolonged mechanical ventilation. 1-year prospective cohort study. 5 intensive care units at Duke University Medical Center, Durham, North Carolina. 126 patients receiving prolonged mechanical ventilation (defined as ventilation for >or=4 days with tracheostomy placement or ventilation for >or=21 days without tracheostomy), as well as their 126 surrogates and 54 intensive care unit physicians, enrolled consecutively over 1 year. Patients and surrogates were interviewed in the hospital, as well as 3 and 12 months after discharge, to determine patient survival, functional status, and facility type and duration of postdischarge care. Physicians were interviewed in the hospital to elicit prognoses. Institutional billing records were used to assign costs for acute care, outpatient care, and interfacility transportation. Medicare claims data were used to assign costs for postacute care. 103 (82%) hospital survivors had 457 separate transitions in postdischarge care location (median, 4 transitions [interquartile range, 3 to 5 transitions]), including 68 patients (67%) who were readmitted at least once. Patients spent an average of 74% (95% CI, 68% to 80%) of all days alive in a hospital or postacute care facility or receiving home health care. At 1 year, 11 patients (9%) had a good outcome (alive with no functional dependency), 33 (26%) had a fair outcome (alive with moderate dependency), and 82 (65%) had a poor outcome (either alive with complete functional dependency [4 patients; 21%] or dead [56 patients; 44%]). Patients with poor outcomes were older, had more comorbid conditions, and were more frequently discharged to a postacute care facility than patients with either fair or good outcomes (P < 0.05 for all). The mean cost per patient was $306,135 (SD, $285,467), and total cohort cost was $38.1 million, for an estimated $3.5 million per independently functioning survivor at 1 year. The results of this single-center study may not be applicable to other centers. Patients receiving prolonged mechanical ventilation have multiple transitions of care, resulting in substantial health care costs and persistent, profound disability. The optimism of surrogate decision makers should be balanced by discussions of these outcomes when considering a course of prolonged life support. None.

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

PubMed Central

Flagel, Shelly B.; Chaudhury, Sraboni; Waselus, Maria; Kelly, Rebeca; Sewani, Salima; Clinton, Sarah M.; Thompson, Robert C.; Watson, Stanley J.; Akil, Huda

2016-01-01

This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with “temperament,” including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor. PMID:27114539

FATIGUE OF DENTAL CERAMICS

PubMed Central

Zhang, Yu; Sailer, Irena; Lawn, Brian R

2013-01-01

Objectives Clinical data on survival rates reveal that all-ceramic dental prostheses are susceptible to fracture from repetitive occlusal loading. The objective of this review is to examine the underlying mechanisms of fatigue in current and future dental ceramics. Data/sources The nature of various fatigue modes is elucidated using fracture test data on ceramic layer specimens from the dental and biomechanics literature. Conclusions Failure modes can change over a lifetime, depending on restoration geometry, loading conditions and material properties. Modes that operate in single-cycle loading may be dominated by alternative modes in multi-cycle loading. While post-mortem examination of failed prostheses can determine the sources of certain fractures, the evolution of these fractures en route to failure remains poorly understood. Whereas it is commonly held that loss of load-bearing capacity of dental ceramics in repetitive loading is attributable to chemically-assisted 'slow crack growth' in the presence of water, we demonstrate the existence of more deleterious fatigue mechanisms, mechanical rather than chemical in nature. Neglecting to account for mechanical fatigue can lead to gross overestimates in predicted survival rates. Clinical significance Strategies for prolonging the clinical lifetimes of ceramic restorations are proposed based on a crack-containment philosophy. PMID:24135295

Fatigue of dental ceramics.

PubMed

Zhang, Yu; Sailer, Irena; Lawn, Brian R

2013-12-01

Clinical data on survival rates reveal that all-ceramic dental prostheses are susceptible to fracture from repetitive occlusal loading. The objective of this review is to examine the underlying mechanisms of fatigue in current and future dental ceramics. The nature of various fatigue modes is elucidated using fracture test data on ceramic layer specimens from the dental and biomechanics literature. Failure modes can change over a lifetime, depending on restoration geometry, loading conditions and material properties. Modes that operate in single-cycle loading may be dominated by alternative modes in multi-cycle loading. While post-mortem examination of failed prostheses can determine the sources of certain fractures, the evolution of these fractures en route to failure remains poorly understood. Whereas it is commonly held that loss of load-bearing capacity of dental ceramics in repetitive loading is attributable to chemically assisted 'slow crack growth' in the presence of water, we demonstrate the existence of more deleterious fatigue mechanisms, mechanical rather than chemical in nature. Neglecting to account for mechanical fatigue can lead to gross overestimates in predicted survival rates. Strategies for prolonging the clinical lifetimes of ceramic restorations are proposed based on a crack-containment philosophy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects on respiratory homeostasis of prolonged, continuous hyperoxia at 1.5 to 3.0 ATA in man in Predictive Studies V

NASA Technical Reports Server (NTRS)

Gelfand, R.; Clark, J. M.; Lambertsen, C. J.; Pisarello, J. B.

1987-01-01

Prolonged exposures of men to continuous hyperoxia at 3.0, 2.5, 2.0, and 1.5 ATA were conducted to define CNS oxygen tolerance and to investigate the effects of prolonged hyperoxia on CNS and other organ functions. Altered respiratory homeostasis was evident during exposures of men to 2.5 and 3.0 ATA O2 as nonprogressive increment in ventilation and reciprocal decrement in PET(CO2). These changes were progressive during exposure at 1.5 ATA O2. Mean values of respiratory reactivity at CO2 were somewhat increased following prolonged hyperoxia at 1.5 and 2.5 ATA, compared to preexposure mean values. Hypoxic ventilatory response was unchanged or enhanced after oxygen exposures at 1.5 and 2.5 ATA. Observed respiratory and body temperature changes were not of sufficient magnitude to impair function.

Optimal swim speeds for traversing velocity barriers: An analysis of volitional high-speed swimming behavior of migratory fishes

USGS Publications Warehouse

Castro-Santos, T.

2005-01-01

Migrating fish traversing velocity barriers are often forced to swim at speeds greater than their maximum sustained speed (Ums). Failure to select an appropriate swim speed under these conditions can prevent fish from successfully negotiating otherwise passable barriers. I propose a new model of a distance-maximizing strategy for fishes traversing velocity barriers, derived from the relationships between swim speed and fatigue time in both prolonged and sprint modes. The model predicts that fish will maximize traversed distance by swimming at a constant groundspeed against a range of flow velocities, and this groundspeed is equal to the negative inverse of the slope of the swim speed-fatigue time relationship for each mode. At a predictable flow velocity, they should switch from the optimal groundspeed for prolonged mode to that for sprint mode. Data from six migratory fish species (anadromous clupeids: American shad Alosa sapidissima, alewife A. pseudoharengus and blueback herring A. aestivalis; amphidromous: striped bass Morone saxatilis; and potomodromous species: walleye (previously known as Stizostedion vitrium) and white sucker Catostomus commersonii) were used to explore the ability of fish to approximate the predicted distance-maximizing behaviors, as well as the consequences of deviating from the optima. Fish volitionally sprinted up an open-channel flume against fixed flow velocities of 1.5-4.5 m s-1, providing data on swim speeds and fatigue times, as well as their groundspeeds. Only anadromous clupeids selected the appropriate distance-maximizing groundspeed at both prolonged and sprint modes. The other three species maintained groundspeeds appropriate to the prolonged mode, even when they should have switched to the sprint optima. Because of this, these species failed to maximize distance of ascent. The observed behavioral variability has important implications both for distributional limits and fishway design.

Immediate effect of exercise on achilles tendon properties: systematic review.

PubMed

Obst, Steven J; Barrett, Rod S; Newsham-West, Richard

2013-08-01

Understanding the mechanical and morphological adaptation of the Achilles tendon (AT) in response to acute exercise could have important implications for athletic performance, injury prevention, and rehabilitation. The purpose of this study was to conduct a systematic review and critical evaluation of the literature to determine the immediate effect of a single bout of exercise on the mechanical and morphological properties of the AT in vivo. Five electronic research databases were systematically searched for intervention-based studies reporting mechanical and morphological properties of the AT after a single bout of exercise. Searches revealed 3292 possible articles; 21 met the inclusion criteria. There is evidence that maximal isometric contractions and prolonged static stretching (>5 min) of the triceps surae complex cause an immediate decrease in AT stiffness, whereas prolonged running and hopping have minimal effect. Limited but consistent evidence exists, indicating that AT hysteresis is reduced after prolonged static stretching. Consistent evidence supports a reduction in free AT diameter (anterior-posterior) after dynamic ankle exercise, and this change appears most pronounced in the healthy tendon and after eccentric exercise. The mechanical and morphological properties of the AT in vivo are affected by acute exercise in a mode- and dose-dependent manner. Transient changes in AT stiffness, hysteresis, and diameter after unaccustomed exercise modes and doses may expose the tendon to increased risk of strain injury and impact on the mechanical function of the triceps surae muscle-tendon unit.

Index of prolonged air leak score validation in case of video-assisted thoracoscopic surgery anatomical lung resection: results of a nationwide study based on the French national thoracic database, EPITHOR.

PubMed

Orsini, Bastien; Baste, Jean Marc; Gossot, Dominique; Berthet, Jean Philippe; Assouad, Jalal; Dahan, Marcel; Bernard, Alain; Thomas, Pascal Alexandre

2015-10-01

The incidence rate of prolonged air leak (PAL) after lobectomy, defined as any air leak prolonged beyond 7 days, can be estimated to be in between 6 and 15%. In 2011, the Epithor group elaborated an accurate predictive score for PAL after open lung resections, so-called IPAL (index of prolonged air leak), from a nation-based surgical cohort constituted between 2004 and 2008. Since 2008, video-assisted thoracic surgery (VATS) has become popular in France among the thoracic surgical community, reaching almost 14% of lobectomies performed with this method in 2012. This minimally invasive approach was reported as a means to reduce the duration of chest tube drainage. The aim of our study was thus to validate the IPAL scoring system in patients having received VATS anatomical lung resections. We collected all anatomical VATS lung resections (lobectomy and segmentectomy) registered in the French national general thoracic surgery database (EPITHOR) between 2009 and 2012. The area under the receiver operating characteristic (ROC) curve estimated the discriminating value of the IPAL score. The slope value described the relation between the predicted and observed incidences of PALs. The Hosmer-Lemeshow test was also used to estimate the quality of adequacy between predicted and observed values. A total of 1233 patients were included: 1037 (84%) lobectomies and 196 (16%) segmentectomies. In 1099 cases (89.1%), the resection was performed for a malignant disease. Ninety-six patients (7.7%) presented with a PAL. The IPAL score provided a satisfactory predictive value with an area under the ROC curve of 0.72 (0.67-0.77). The value of the slope, 1.25 (0.9-1.58), and the Hosmer-Lemeshow test (χ(2) = 11, P = 0.35) showed that predicted and observed values were adequate. The IPAL score is valid for the estimation of the predictive risk of PAL after VATS lung resections. It may thus a priori be used to characterize any surgical population submitted to potential preventive measures. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics

PubMed Central

Bravo, Roberto; Gutierrez, Tomás; Paredes, Felipe; Gatica, Damián; Rodriguez, Andrea E.; Pedrozo, Zully; Chiong, Mario; Parra, Valentina; Quest, Andrew F.G.; Rothermel, Beverly A.; Lavandero, Sergio

2014-01-01

Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER–mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders. PMID:22064245

Superior diastolic function with KATP channel opener diazoxide in a novel mouse Langendorff model.

PubMed

Makepeace, Carol M; Suarez-Pierre, Alejandro; Kanter, Evelyn M; Schuessler, Richard B; Nichols, Colin G; Lawton, Jennifer S

2018-07-01

Adenosine triphosphate-sensitive potassium (K ATP ) channel openers have been found to be cardioprotective in multiple animal models via an unknown mechanism. Mouse models allow genetic manipulation of K ATP channel components for the investigation of this mechanism. Mouse Langendorff models using 30 min of global ischemia are known to induce measurable myocardial infarction and injury. Prolongation of global ischemia in a mouse Langendorff model could allow the determination of the mechanisms involved in K ATP channel opener cardioprotection. Mouse hearts (C57BL/6) underwent baseline perfusion with Krebs-Henseleit buffer (30 min), assessment of function using a left ventricular balloon, delivery of test solution, and prolonged global ischemia (90 min). Hearts underwent reperfusion (30 min) and functional assessment. Coronary flow was measured using an inline probe. Test solutions included were as follows: hyperkalemic cardioplegia alone (CPG, n = 11) or with diazoxide (CPG + DZX, n = 12). Although the CPG + DZX group had greater percent recovery of developed pressure and coronary flow, this was not statistically significant. Following a mean of 74 min (CPG) and 77 min (CPG + DZX), an additional increase in end-diastolic pressure was noted (plateau), which was significantly higher in the CPG group. Similarly, the end-diastolic pressure (at reperfusion and at the end of experiment) was significantly higher in the CPG group. Prolongation of global ischemia demonstrated added benefit when DZX was added to traditional hyperkalemic CPG. This model will allow the investigation of DZX mechanism of cardioprotection following manipulation of targeted K ATP channel components. This model will also allow translation to prolonged ischemic episodes associated with cardiac surgery. Copyright © 2018 Elsevier Inc. All rights reserved.

Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale?

PubMed Central

Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C.

2013-01-01

Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes. PMID:24653586

System identification of dynamic closed-loop control of total peripheral resistance by arterial and cardiopulmonary baroreceptors

NASA Technical Reports Server (NTRS)

Aljuri, A. N.; Bursac, N.; Marini, R.; Cohen, R. J.

2001-01-01

Prolonged exposure to microgravity in space flight missions (days) impairs the mechanisms responsible for defense of arterial blood pressure (ABP) and cardiac output (CO) against orthostatic stress in the post-flight period. The mechanisms responsible for the observed orthostatic intolerance are not yet completely understood. Additionally, effective counter measures to attenuate this pathophysiological response are not available. The aim of this study was to investigate the ability of our proposed system identification method to predict closed-loop dynamic changes in TPR induced by changes in mean arterial pressure (MAP) and right atrial pressure (RAP). For this purpose we designed and employed a novel experimental animal model for the examination of arterial and cardiopulmonary baroreceptors in the dynamic closed-loop control of total peripheral resistance (TPR), and applied system identification to the analysis of beat-to-beat fluctuations in the measured signals. Grant numbers: NAG5-4989. c 2001. Elsevier Science Ltd. All rights reserved.

Personalizing therapies for gastric cancer: Molecular mechanisms and novel targeted therapies

PubMed Central

Luis, Michael; Tavares, Ana; Carvalho, Liliana S; Lara-Santos, Lúcio; Araújo, António; de Mello, Ramon Andrade

2013-01-01

Globally, gastric cancer is the 4th most frequently diagnosed cancer and the 2nd leading cause of death from cancer, with an estimated 990000 new cases and 738000 deaths registered in 2008. In the advanced setting, standard chemotherapies protocols acquired an important role since last decades in prolong survival. Moreover, recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER2) therapies. Trastuzumab, an anti-HER2 monoclonal antibody, was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy. Further, HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field. Thus, we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer, providing a comprehensive overview of molecular mechanisms and novel trials involved. PMID:24151357

An algorithm for the beat-to-beat assessment of cardiac mechanics during sleep on Earth and in microgravity from the seismocardiogram.

PubMed

Di Rienzo, Marco; Vaini, Emanuele; Lombardi, Prospero

2017-11-15

Seismocardiogram, SCG, is the measure of precordial vibrations produced by the beating heart, from which cardiac mechanics may be explored on a beat-to-beat basis. We recently collected a large amount of SCG data (>69 recording hours) from an astronaut to investigate cardiac mechanics during sleep aboard the International Space Station and on Earth. SCG sleep recordings are characterized by a prolonged duration and wide heart rate swings, thus a specific algorithm was developed for their analysis. In this article we describe the new algorithm and its performance. The algorithm is composed of three parts: 1) artifacts removal, 2) identification in each SCG waveform of four fiducial points associated with the opening and closure of the aortic and mitral valves, 3) beat-to-beat computation of indexes of cardiac mechanics from the SCG fiducial points. The algorithm was tested on two sleep recordings and yielded the identification of the fiducial points in more than 36,000 beats with a precision, quantified by the Positive Predictive Value, ≥99.2%. These positive findings provide the first evidence that cardiac mechanics may be explored by the automatic analysis of SCG long-lasting recordings, taken out of the laboratory setting, and in presence of significant heart rate modulations.

Modelling the seasonality of Lyme disease risk and the potential impacts of a warming climate within the heterogeneous landscapes of Scotland.

PubMed

Li, Sen; Gilbert, Lucy; Harrison, Paula A; Rounsevell, Mark D A

2016-03-01

Lyme disease is the most prevalent vector-borne disease in the temperate Northern Hemisphere. The abundance of infected nymphal ticks is commonly used as a Lyme disease risk indicator. Temperature can influence the dynamics of disease by shaping the activity and development of ticks and, hence, altering the contact pattern and pathogen transmission between ticks and their host animals. A mechanistic, agent-based model was developed to study the temperature-driven seasonality of Ixodes ricinus ticks and transmission of Borrelia burgdorferi sensu lato across mainland Scotland. Based on 12-year averaged temperature surfaces, our model predicted that Lyme disease risk currently peaks in autumn, approximately six weeks after the temperature peak. The risk was predicted to decrease with increasing altitude. Increases in temperature were predicted to prolong the duration of the tick questing season and expand the risk area to higher altitudinal and latitudinal regions. These predicted impacts on tick population ecology may be expected to lead to greater tick-host contacts under climate warming and, hence, greater risks of pathogen transmission. The model is useful in improving understanding of the spatial determinants and system mechanisms of Lyme disease pathogen transmission and its sensitivity to temperature changes. © 2016 The Author(s).

Modelling the seasonality of Lyme disease risk and the potential impacts of a warming climate within the heterogeneous landscapes of Scotland

PubMed Central

Gilbert, Lucy; Harrison, Paula A.; Rounsevell, Mark D. A.

2016-01-01

Lyme disease is the most prevalent vector-borne disease in the temperate Northern Hemisphere. The abundance of infected nymphal ticks is commonly used as a Lyme disease risk indicator. Temperature can influence the dynamics of disease by shaping the activity and development of ticks and, hence, altering the contact pattern and pathogen transmission between ticks and their host animals. A mechanistic, agent-based model was developed to study the temperature-driven seasonality of Ixodes ricinus ticks and transmission of Borrelia burgdorferi sensu lato across mainland Scotland. Based on 12-year averaged temperature surfaces, our model predicted that Lyme disease risk currently peaks in autumn, approximately six weeks after the temperature peak. The risk was predicted to decrease with increasing altitude. Increases in temperature were predicted to prolong the duration of the tick questing season and expand the risk area to higher altitudinal and latitudinal regions. These predicted impacts on tick population ecology may be expected to lead to greater tick–host contacts under climate warming and, hence, greater risks of pathogen transmission. The model is useful in improving understanding of the spatial determinants and system mechanisms of Lyme disease pathogen transmission and its sensitivity to temperature changes. PMID:27030039

Effect of PR Interval on Outcomes Following Cardiac Resynchronization Therapy: A Secondary Analysis of the COMPANION Trial.

PubMed

Lin, Jeffrey; Buhr, Kevin A; Kipp, Ryan

2017-02-01

Prolonged PR intervals may impair atrioventricular mechanical coupling and adversely affect cardiac performance. We hypothesize that patients with advanced systolic heart failure, wide QRS complexes, and prolonged PR intervals will have improved survival from CRT-D regardless of whether left bundle branch block (LBBB) or non-LBBB is present. A total of 308 patients enrolled in the optimal pharmacologic therapy (OPT) and 595 patients in the cardiac resynchronization therapy with defibrillation (CRT-D) arms of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial were stratified according to normal (≤230 ms) or prolonged PR interval (>230 ms). The incidence of all-cause mortality (ACM) or hospitalization (primary endpoint) and ACM (secondary endpoint) was compared using Kaplan-Meier curves. Cox proportional hazards models for the primary and secondary endpoints were fit with LBBB status and baseline PR interval. CRT-D treatment reduced both hospitalization/ACM (P = 0.002) and ACM (P = 0.003) compared to OPT. However, CRT-D was increasingly more effective in reducing ACM hazard in patients with longer baseline PR intervals (P = 0.002) regardless of LBBB status. In particular, in the prolonged baseline PR interval subgroup, ACM was reduced with CRT-D compared to OPT (P = 0.001) with little evidence of ACM reduction in the normal PR subgroup (P = 0.07). In patients with advanced systolic heart failure, wide QRS complexes, and prolonged PR intervals, restoration of atrioventricular mechanical coupling with CRT-D may improve survival regardless of LBBB status. In patients with non-LBBB, a benefit from CRT-D may occur with prolonged PR intervals. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Physiological consequences of rapid or prolonged aircraft decompression: evaluation using a human respiratory model.

PubMed

Wolf, Matthew

2014-04-01

Aircraft passengers and crew may be subjected to rapid or prolonged decompression to high cabin altitude when an aircraft develops a hole in the fuselage. The accepted measure of neurological damage due to the hypobaric hypoxia produced is the subjective 'time of useful consciousness' (TUC) measure, which is appropriate for pilots and crew who perform their given tasks, however, TUC is measured under conditions different than the decompression scenarios that passengers undergo in today's aircraft. Ernsting proposed that prolonged exposure to alveolar O2 pressures less than 30 mmHg (P30) causes neurological damage. The current study proposes that a critical value of arterial O2 saturation of 70% (S70) can be used in place of P30 and that this physiological measure is more suited for determination of hypobaric hypoxia in passengers. The study shows the equivalence of model-predicted P30 and S70 values in the Ernsting-decompression scenarios. The model is also used to predict values of these physiological measures in actual aircraft-decompression scenarios. The model can be used by others to quantitatively predict the degree of hypobaric hypoxia for virtually any kind of decompression scenario, including those where supplemental O2 is used. Use of this tool avoids the prohibitive costs of human-subject testing for new aircraft and the potential danger inherent in such tests.

Waiting to see the doctor: understanding appraisal and utilization components of consultation delay for new breast symptoms in Chinese women.

PubMed

Li, Wylie W Y; Lam, Wendy W T; Wong, Jennifer H F; Chiu, April; Chan, Miranda; Or, Amy; Kwong, Ava; Suen, Dacita; Chan, Sharon W W; Fielding, Richard

2012-12-01

Delayed consultation for potential cancer symptoms influences treatment outcomes and remains problematic. Delay components (Appraisal versus Utilization) and respective associations are poorly understood. Eligible participants were Cantonese-speaking Chinese women, ≥21 years old, with self-discovered breast symptoms, recruited in surgical clinics before their first consultation, and naïve to their diagnosis. Overall 425/433 (98%) women completed a questionnaire on psychosocial, demographic and medical factors, how and when women discovered their breast symptom(s), and their subsequent decision making; 135/425 women (32%) were later diagnosed with breast cancer. Twenty-two per cent of women delayed >3 months before consultation. Women with breast cancer (28%) more often had prolonged delay than women with benign disease (19%). Attributing symptom to a non-cancerous condition, low fear on symptom discovery, not disclosing symptoms to others, and no prior breast symptom history predicted prolonged (>60 days) Appraisal Delay. Low fear on symptom discovery, seldom thinking about the symptom, and consultation for other reasons predicted prolonged (>14 days) Utilization Delay. Factors predicting Appraisal and Utilization Delays differentiated cancer from non-cancer groups. Indecision over symptom meaning comprised the main component of Appraisal and Total Delay, suggesting that educational strategies targeting atypical symptoms should reduce avoidable delays following self-discovered breast symptoms. Copyright © 2011 John Wiley & Sons, Ltd.

Diet-consumer nitrogen isotope fractionation for prolonged fasting arthropods.

PubMed

Mizota, Chitoshi; Yamanaka, Toshiro

2011-12-01

Nitrogen acquisition for cellular metabolism during diapause is a primary concern for herbivorous arthropods. Analyses of naturally occurring stable isotopes of nitrogen help elucidate the mechanism. Relevant articles have cited (58 times up to mid-June 2011) anomalously elevated δ(15)N (per mil deviation of (15)N/(14)N, relative to atmospheric nitrogen=0 ‰) values (diet-consumer nitrogen isotope fractionation; up to 12 ‰) for a prolonged fasting raspberry beetle (Byturus tomentosus Degeer (Coleoptera: Byturidae)), which feeds on red raspberries (Rubus idaeus: δ(15)N= ~ +2 ‰). Biologists have hypothesised that extensive recycling of amino acid nitrogen is responsible for the prolonged fasting. Since this hypothesis was proposed in 1995, scientists have integrated biochemical and molecular knowledge to support the mechanism of prolonged diapausing of animals. To test the validity of the recycling hypothesis, we analysed tissue nitrogen isotope ratios for four Japanese arthropods: the shield bug Parastrachia japonensis Scott (Hemiptera: Cydnidae), the burrower bug Canthophorus niveimarginatus Scott (Hemiptera: Cydnidae), leaf beetle Gastrophysa atrocyanea Motschulsky (Coleoptera: Chrysomelidae) and the Japanese oak silkworm Antheraea yamamai (Lepidoptera: Saturniidae), all of which fast for more than 6 months as part of their life-history strategy. Resulting diet-consumer nitrogen isotope discrimination during fasting ranged from 0 to 7‰, as in many commonly known terrestrial arthropods. We conclude that prolonged fasting of arthropods does not always result in anomalous diet-consumer nitrogen isotope fractionation, since the recycling process is closed or nearly closed with respect to nitrogen isotopes.

Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage

PubMed Central

Lehtinen, Sonja; Blanquart, François; Croucher, Nicholas J.; Turner, Paul; Lipsitch, Marc; Fraser, Christophe

2017-01-01

Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance. PMID:28096340

The influence of executive capacity on selective attention and subsequent processing

PubMed Central

Daffner, Kirk R.; Tarbi, Elise C.; Haring, Anna E.; Zhuravleva, Tatyana Y.; Sun, Xue; Rentz, Dorene M.; Holcomb, Phillip J.

2012-01-01

Recent investigations that suggest selective attention (SA) is dependent on top-down control mechanisms lead to the expectation that individuals with high executive capacity (EC) would exhibit more robust neural indices of SA. This prediction was tested by using event-related potentials (ERPs) to examine differences in markers of information processing across 25 subjects divided into two groups based on high vs. average EC, as defined by neuropsychological test scores. Subjects performed an experimental task requiring SA to a specified color. In contrast to expectation, individuals with high and average EC did not differ in the size of ERP indices of SA: the anterior Selection Positivity (SP) and posterior Selection Negativity (SN). However, there were substantial differences between groups in markers of subsequent processing, including the anterior N2 (a measure of attentional control) and the P3a (an index of the orienting of attention). EC predicted speed of processing at both early and late attentional stages. Individuals with lower EC exhibited prolonged SN, P3a, and P3b latencies. However, the delays in carrying out SA operations did not account for subsequent delays in decision making, or explain excessive orienting and reduced attentional control mechanisms in response to stimuli that should have been ignored. SN latency, P3 latency, and the size of the anterior N2 made independent contributions to the variance of EC. In summary, our findings suggest that current views regarding the relationship between top-down control mechanisms and SA may need refinement. PMID:22701415

Causes of prolonged hospitalization among general internal medicine patients of a tertiary care center.

PubMed

Ruangkriengsin, Darat; Phisalprapa, Pochamana

2014-03-01

Unnecessary days of prolonged hospitalization may lead to the increase in hospital-related complications and costs, especially in tertiary care center Currently, there have not been many studies about the causes of prolonged hospitalization. Some identified causes could, however, be prevented and improved. To identify the prevalence, causes, predictive factors, prognosis, and economic burden of prolonged hospitalization in patients who had been in general internal medicine wards of the tertiary care center for 7 days or more. Retrospective chart review study was conducted among all patients who were admitted for 7 days or more in general internal medicine wards of Siriraj Hospital, the largest tertiary care center in Thailand. The period of this study was from 1 August 2012 to 30 September 2012. Demographic data, principle diagnosis, comorbid diseases, complications, discharge status, total costs of admission and percentage of reimbursement were collected. The causes of prolonged hospitalization at day 7, 14, 30, and 90 were assessed. Five hundred and sixty-two charts were reviewed. The average length of stay was 25.9 days. The two most common causes of prolonged admission at day 7 were treatment of main diagnosed disease with stable condition (27.6%) and waiting for completion of intravenous antibiotics administration with stable condition (19.5%). The causes of prolonged hospitalization at day 14 were unstable condition from complications (22.6%) and those waiting for completion of intravenous antibiotics administration with stable condition (15.8%). The causes of prolonged admission at day 30 were unstable conditions from complications (25.6%), difficulty weaning or ventilator dependence (17.6%), and caregiver problems (15.2%). The causes of prolonged hospitalization at day 90 were unstable condition from complications (30.0%), caregiver problems (30.0%), and palliative care (25.0%). Poor outcomes were shown in the patients admitted more than 90 days. Percentage of death, being bedridden, and re-admission were 55, 40, and 22, respectively. The goal of treatment was only palliative care in 80 percent of this patient group. Respiratory failure among the hospitalized was the strongest predictive factors of death (Odds ratio = 7.5, p < 0.001). The average costs of admission per patient was 163,870 THB and the percentage of reimbursement was only 72%. For total costs of admission in these two months, Siriraj Hospital lost a large amount of money (about 26 million THB) for patients admitted for 7 days or more and almost 50% of this was spent on the patients admitted for 90 days or more. The average cost of admission per patient in the latter group was 1,073,004 THB. Prolonged hospitalization had adverse outcomes for the patients and the hospital, such as high complications, poor outcomes, high costs of treatment and low reimbursement ratio that created an enormous economic burden for the hospital. Therefore possible preventable causes of prolonged admission must be identified, prevented and managed by improving quality of multidisciplinary health care system and ancillary services.

High-Temperature Graphitization Failure of Primary Superheater Tube

NASA Astrophysics Data System (ADS)

Ghosh, D.; Ray, S.; Roy, H.; Mandal, N.; Shukla, A. K.

2015-12-01

Failure of boiler tubes is the main cause of unit outages of the plant, which further affects the reliability, availability and safety of the unit. So failure analysis of boiler tubes is absolutely essential to predict the root cause of the failure and the steps are taken for future remedial action to prevent the failure in near future. This paper investigates the probable cause/causes of failure of the primary superheater tube in a thermal power plant boiler. Visual inspection, dimensional measurement, chemical analysis, metallographic examination and hardness measurement are conducted as the part of the investigative studies. Apart from these tests, mechanical testing and fractographic analysis are also conducted as supplements. Finally, it is concluded that the superheater tube is failed due to graphitization for prolonged exposure of the tube at higher temperature.

Have We Entered a 21st Century Prolonged Minimum of Solar Activity? Updated Implications of a 1987 Prediction

NASA Astrophysics Data System (ADS)

Shirley, James H.

2009-05-01

Fairbridge and Shirley (1987) predicted that a new prolonged minimum of solar activity would be underway by the year 2013 (Solar Physics 110, 191). While it is much too early to tell if this prediction will be fully realized, recent observations document a striking reduction in the Sun's general level of activity. While other forecasts of reduced future activity levels on decadal time scales have appeared, the Fairbridge-Shirley (FS) prediction is unique in pinpointing the current epoch. We are unaware of any forecast method that shows a better correspondence with the actual behavior of the Sun to this point. The FS prediction was based on the present-day recurrence of two physical indicators that were correlated in time with the occurrence of the Wolf, Sporer, and Maunder Minima. The amplitude of the inertial revolution of the axis of symmetry of the Sun's orbital motion about the solar system barycenter, and the direction in space of that axis, each bear a relationship to the occurrence of the prolonged minima of the historic record. The FS prediction appeared before the importance of solar meridional flows was generally appreciated, and before the existence and role of the tachocline was suspected. We will update and restate some of the physical implications of the FS results, along with those of some more recent investigations, particularly with reference to orbit-spin coupling hypotheses (Shirley, 2006: M.N.R.A.S. 368, 280). New investigations combining and integrating modern dynamo models with physical solutions describing key aspects of the variability of the solar motion may lead to significant advances in our ability to forecast future changes in the Sun. Acknowledgement: This work was supported by the resources of the author. No part of this work was performed at the Jet Propulsion Laboratory under a contract from NASA.

The influence of surround suppression on adaptation effects in primary visual cortex

PubMed Central

Wissig, Stephanie C.

2012-01-01

Adaptation, the prolonged presentation of stimuli, has been used to probe mechanisms of visual processing in physiological, imaging, and perceptual studies. Previous neurophysiological studies have measured adaptation effects by using stimuli tailored to evoke robust responses in individual neurons. This approach provides an incomplete view of how an adapter alters the representation of sensory stimuli by a population of neurons with diverse functional properties. We implanted microelectrode arrays in primary visual cortex (V1) of macaque monkeys and measured orientation tuning and contrast sensitivity in populations of neurons before and after prolonged adaptation. Whereas previous studies in V1 have reported that adaptation causes stimulus-specific suppression of responsivity and repulsive shifts in tuning preference, we have found that adaptation can also lead to response facilitation and shifts in tuning toward the adapter. To explain this range of effects, we have proposed and tested a simple model that employs stimulus-specific suppression in both the receptive field and the spatial surround. The predicted effects on tuning depend on the relative drive provided by the adapter to these two receptive field components. Our data reveal that adaptation can have a much richer repertoire of effects on neuronal responsivity and tuning than previously considered and suggest an intimate mechanistic relationship between spatial and temporal contextual effects. PMID:22423001

Association between increased blood interleukin-6 levels on emergency department arrival and prolonged length of intensive care unit stay for blunt trauma.

PubMed

Taniguchi, Masashi; Nakada, Taka-Aki; Shinozaki, Koichiro; Mizushima, Yasuaki; Matsuoka, Tetsuya

2016-01-01

Systemic immune response to injury plays a key role in the pathophysiological mechanism of blunt trauma. We tested the hypothesis that increased blood interleukin-6 (IL-6) levels of blunt trauma patients on emergency department (ED) arrival are associated with poor clinical outcomes, and investigated the utility of rapid measurement of the blood IL-6 level. We enrolled 208 consecutive trauma patients who were transferred from the scene of an accident to a level I trauma centre in Japan and admitted to the intensive care unit (ICU). Blood IL-6 levels on ED arrival were measured by using a rapid measurement assay. The primary outcome variable was prolonged ICU stay (length of ICU stay > 7 days). The secondary outcomes were 28-day mortality, probability of survival and Abbreviated Injury Scale (AIS) scores. Patients with prolonged ICU stay had significantly higher blood IL-6 levels on ED arrival than the patients without prolonged ICU stay (P < 0.0001). The receiver-operating characteristic curves produced an area under the curve of 0.75 (95 % confidence interval [CI], 0.66-0.84; P < 0.0001) for prolonged ICU stay. The patients who had increased blood IL-6 levels on ED arrival had increased 28-day mortality (P = 0.021) and decreased probability of survival (P < 0.0001). The AIS scores for the thorax, abdomen, extremity, and external body regions independently correlated with blood IL-6 levels (unstandardized coefficients [95 % CI] for the thorax: 23.8 [12.6-35.1]; P < 0.0001; abdomen: 42.7 [23.8-61.7]; P < 0.0001; extremity: 19.0 [5.5-32.4]; P = 0.0060; external body regions: 62.9 [13.2-112.7]; P = 0.030); the standardized coefficients for the thorax (0.27) and abdomen (0.28) were larger than those for the extremity (0.18) and external body regions (0.15). Increased blood IL-6 level on ED arrival was significantly associated with prolonged length of ICU stay. Blood IL-6 level on ED arrival independently correlated with the AIS scores for the abdomen and thorax, and, to a lesser extent, those for the extremity and external body regions. The rapid measurement of blood IL-6 level on ED arrival can be utilized as a fast screening tool to improve assessment of injury severity and prediction of clinical outcomes in the initial phase of trauma care.

Prolonged corrected QT interval is predictive of future stroke events even in subjects without ECG-diagnosed left ventricular hypertrophy.

PubMed

Ishikawa, Joji; Ishikawa, Shizukiyo; Kario, Kazuomi

2015-03-01

We attempted to evaluate whether subjects who exhibit prolonged corrected QT (QTc) interval (≥440 ms in men and ≥460 ms in women) on ECG, with and without ECG-diagnosed left ventricular hypertrophy (ECG-LVH; Cornell product, ≥244 mV×ms), are at increased risk of stroke. Among the 10 643 subjects, there were a total of 375 stroke events during the follow-up period (128.7±28.1 months; 114 142 person-years). The subjects with prolonged QTc interval (hazard ratio, 2.13; 95% confidence interval, 1.22-3.73) had an increased risk of stroke even after adjustment for ECG-LVH (hazard ratio, 1.71; 95% confidence interval, 1.22-2.40). When we stratified the subjects into those with neither a prolonged QTc interval nor ECG-LVH, those with a prolonged QTc interval but without ECG-LVH, and those with ECG-LVH, multivariate-adjusted Cox proportional hazards analysis demonstrated that the subjects with prolonged QTc intervals but not ECG-LVH (1.2% of all subjects; incidence, 10.7%; hazard ratio, 2.70, 95% confidence interval, 1.48-4.94) and those with ECG-LVH (incidence, 7.9%; hazard ratio, 1.83; 95% confidence interval, 1.31-2.57) had an increased risk of stroke events, compared with those with neither a prolonged QTc interval nor ECG-LVH. In conclusion, prolonged QTc interval was associated with stroke risk even among patients without ECG-LVH in the general population. © 2014 American Heart Association, Inc.

Minocycline reduces mechanical allodynia and depressive-like behaviour in type-1 diabetes mellitus in the rat.

PubMed

Amorim, Diana; Puga, Sónia; Bragança, Rui; Braga, António; Pertovaara, Antti; Almeida, Armando; Pinto-Ribeiro, Filipa

2017-06-01

A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN. Copyright © 2017 Elsevier B.V. All rights reserved.

Setting the scene: definition of prolonged seizures, acute repetitive seizures, and status epilepticus. Do we know why seizures stop?

PubMed

Cross, J Helen

2014-10-01

Status epilepticus is recognised as an acute emergency requiring urgent intervention. The optimal timing of such an intervention during a prolonged seizure, and the reasons for such, have provided much discussion. For operational purposes, a definition of a prolonged seizure of ≥5 minutes requiring intervention appears justified. However, a definition of status epilepticus of ≥30 minutes should stand, with the proportion of seizures proceeding to this clinical state remaining small. The reasons for this may be inherent to an individual, but an understanding of the mechanisms underlying the predisposition may lead to improved management pathways in the future.

Effect of water on the triaxial response under monotonic loading of asphalt concrete used in dams

NASA Astrophysics Data System (ADS)

Gaxiola Hernández, Alberto; Ossa López, Alexandra

2018-01-01

Embankment dams with asphalt concrete cores have been constructed on practically all continents with satisfactory results. Nowadays many advantages, such as the mechanical strength, are known that makes asphalt concrete a competitive alternative for the construction of the impervious elements of dams. However, the current available information does not describe the effect of prolonged contact between asphalt concrete and water on the structure of an embankment dam. In this research cylindrical asphalt concrete specimens with a void content similar to that used in impervious barriers of dams were fabricated and submerged in water for a prolonged period to simulate the conditions experienced by asphalt concrete placed inside an embankment dam as its core material. Subsequently, triaxial compression tests were conducted on the specimens. The results indicated that the asphalt concrete exhibited a reduction in strength because of the saturation process to which the material was subjected. However, no changes were observed in the mechanical response to prolonged contact with water for periods of up to 12 months.

Update on the mechanism of action of antiepileptic drugs.

PubMed

Meldrum, B S

1996-01-01

Novel antiepileptic drugs (AEDs) are thought to act on voltage-sensitive ion channels, on inhibitory neurotransmission or on excitatory neurotransmission. Two successful examples of rational AED design that potentiate GABA-mediated inhibition are vigabatrin (VGB) by irreversible inhibition of GABA-transaminase, and tiagabine (TGB) by blocking GABA uptake. Lamotrigine (LTG) prolongs inactivation of voltage-dependent sodium channels. The anticonvulsant action of remacemide (RCM) is probably largely due to blockade of NMDA receptors and prolonged inactivation of sodium channels induced by its desglycinated metabolite. Felbamate (FBM) apparently blocks NMDA receptors, potentiates GABA-mediated responses, blocks L-type calcium channels, and possibly also prolongs sodium channel inactivation. Similarly, topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors. Gabapentin (GBP) apparently has a completely novel type of action, probably involving potentiation of GABA-mediated inhibition and possibly also inactivation of sodium channels. The therapeutic advantages of the novel AEDs are as yet only partially explained by our present understanding of their mechanisms of action.

Multiple nosocomial infections: a risk of modern intensive care.

PubMed

Leviten, D L; Shulman, S T

1980-03-01

Many components of modern medical care greatly predispose subjects to nosocomial infection. These include cancer chemotherapy, organ transplantation, immunosuppression, and intensive supportive care, particularly in conjunction with mechanical ventilatory support, invasive monitoring devices and prolonged central or peripheral intravenous therapy. The hazard of nosocomial infection associated with residence in a modern intensive care unit is dramatized by the case history of a near-drowning victim whose hospital course was complicated by an unusually large number and variety of nosocomial bacterial infections. Sixteen different bacterial organisms were isolated from cultures of blood, purulent thoracostomy tube drainage, or purulent tracheal secretions during the patient's prolonged hospital course. Factors which predisposed this patient to nosocomial infections included prolonged positive pressure mechanical ventilation, long-term broad spectrum antibiotics, indwelling arterial and central venous lines, violation of anatomic barriers by foreign bodies such as multiple thoracostomy tubes, and residence in an intensive care unit. This patient's case demonstrates that effective means to prevent nosocomial colonization and infection are urgently needed.

Choroidal Infiltration by Retinoblastoma: Predictive Clinical Features and Outcome.

PubMed

Kaliki, Swathi; Tahiliani, Prerana; Iram, Sadiya; Ali, Mohammed Hasnat; Mishra, Dilip K; Reddy, Vijay Anand P

2016-11-01

To identify the clinical features predictive of choroidal infiltration by retinoblastoma on histopathology and to report the outcome in these patients. Retrospective study. Of the 403 patients who underwent primary enucleation for retinoblastoma, 113 patients had choroidal tumor infiltration and 290 patients had no choroidal tumor infiltration. There was a higher incidence of metastasis and related death in the choroidal tumor infiltration group compared to the no choroidal tumor infiltration group (4% vs 1%; P = .02). On multivariate analysis, the clinical features predictive of histopathologic massive choroidal infiltration included prolonged duration of symptoms for more than 6 months (hazard ratio [HR] = 3.04; P = .001) and secondary glaucoma (HR = 2.24; P = .005). In this study, the patients with retinoblastoma with prolonged duration of symptoms (> 6 months) had a three-fold greater risk and those with secondary glaucoma at presentation had a two-fold greater risk of massive choroidal tumor infiltration. [J Pediatr Ophthalmol Strabismus. 2016;53(6):349-356.]. Copyright 2016, SLACK Incorporated.

Self-Identity After Bereavement: Reduced Self-Clarity and Loss-Centrality in Emotional Problems After the Death of a Loved One.

PubMed

Boelen, Paul A

2017-05-01

There is evidence that both the centrality of a loss-event as well as reduced self-concept clarity are involved in emotional problems after the death of a loved one. One issue that is still unexplored is the relative importance of these two concepts in predicting bereavement outcome. The current study examined the degree to which both concepts contribute to emotional distress after loss, both concurrently and longitudinally. Data were available from 124 individuals, all bereaved within the previous half year, who completed measures of prolonged grief, posttraumatic stress, and depression at inclusion into the study and again 6 months later. Loss-centrality and self-unclarity were associated with all three outcome measures, in cross-sectional analyses. Longitudinal analyses indicated that loss-centrality predicted symptom levels of prolonged grief, self-unclarity predicted symptom levels of depression, and both loss-centrality and self-unclarity were associated with posttraumatic stress 6 months after baseline. Implications of these findings are discussed.

Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example.

PubMed

Wiśniowska, Barbara; Polak, Sebastian

2016-11-01

A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher's human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded C max values below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro-in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Prolonged action potential duration in cardiac ablation of PDK1 mice.

PubMed

Han, Zhonglin; Jiang, Yu; Yang, Zhongzhou; Cao, Kejiang; Wang, Dao W

2015-01-01

The involvement of the AGC protein kinase family in regulating arrhythmia has drawn considerable attention, but the underlying mechanisms are still not clear. The aim of this study is to explore the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1), one of upstream protein kinases of the AGC protein kinase family, in the pathogenesis of dysregulated electrophysiological basis. PDK1(F/F) αMHC-Cre mice and PDK1(F/F) mice were divided into experiment group and control group. Using patch clamping technology, we explored action potential duration in both groups, and investigated the functions of transient outward potassium channel and L-type Ca(2+) channel to explain the abnormal action potential duration. Significant prolongation action potential duration was found in mice with PDK1 deletion. Further, the peak current of transient outward potassium current and L-type Ca(2+) current were decreased by 84% and 49% respectively. In addition, dysregulation of channel kinetics lead to action potential duration prolongation further. In conclusion, we have demonstrated that PDK1 participates in action potential prolongation in cardiac ablation of PDK1 mice. This effect is likely to be mediated largely through downregulation of transient outward potassium current. These findings indicate the modulation of the PDK1 pathway could provide a new mechanism for abnormal electrophysiological basis.

Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation

PubMed Central

Sobieski, Courtney; Shu, Hong-Jin

2018-01-01

Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations. PMID:29617444

Hippocampal activation of microglia may underlie the shared neurobiology of comorbid posttraumatic stress disorder and chronic pain.

PubMed

Sun, Rao; Zhang, Zuoxia; Lei, Yishan; Liu, Yue; Lu, Cui'e; Rong, Hui; Sun, Yu'e; Zhang, Wei; Ma, Zhengliang; Gu, Xiaoping

2016-01-01

The high comorbidity rates of posttraumatic stress disorder and chronic pain have been widely reported, but the underlying mechanisms remain unclear. Emerging evidence suggested that an excess of inflammatory immune activities in the hippocampus involved in the progression of both posttraumatic stress disorder and chronic pain. Considering that microglia are substrates underlying the initiation and propagation of the neuroimmune response, we hypothesized that stress-induced activation of hippocampal microglia may contribute to the pathogenesis of posttraumatic stress disorder-pain comorbidity. We showed that rats exposed to single prolonged stress, an established posttraumatic stress disorder model, exhibited persistent mechanical allodynia and anxiety-like behavior, which were accompanied by increased activation of microglia and secretion of pro-inflammatory cytokines in the hippocampus. Correlation analyses showed that hippocampal activation of microglia was significantly correlated with mechanical allodynia and anxiety-like behavior. Our data also showed that both intraperitoneal and intra-hippocampal injection of minocycline suppressed single prolonged stress-induced microglia activation and inflammatory cytokines accumulation in the hippocampus, and attenuated both single prolonged stress-induced mechanical allodynia and anxiety-like behavior. Taken together, the present study suggests that stress-induced microglia activation in the hippocampus may serve as a critical mechanistic link in the comorbid relationship between posttraumatic stress disorder and chronic pain. The novel concept introduces the possibility of cotreating chronic pain and posttraumatic stress disorder. © The Author(s) 2016.

Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

PubMed

Martin-Lorenzo, Marta; Martinez, Paula J; Baldan-Martin, Montserrat; Ruiz-Hurtado, Gema; Prado, Jose Carlos; Segura, Julian; de la Cuesta, Fernando; Barderas, Maria G; Vivanco, Fernando; Ruilope, Luis Miguel; Alvarez-Llamas, Gloria

2017-11-01

Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered ( P <0.0001). Metabolic concentrations were quantified and ranged from ng/mL malate to μg/mL citrate. Citrate and oxaloacetate increased in RH versus pseudoresistant. Together with α-ketoglutarate and malate, they were able to discriminate between responders and nonresponders, being the 4 metabolites increased in nonresponders. Combined as a prediction panel, they showed receiver operating characteristiccurve with area under the curve of 0.96. We show that citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone. © 2017 American Heart Association, Inc.

HIV-1-Tat excites cardiac parasympathetic neurons of nucleus ambiguus and triggers prolonged bradycardia in conscious rats

PubMed Central

Brailoiu, Eugen; Deliu, Elena; Sporici, Romeo A.; Benamar, Khalid

2014-01-01

The mechanisms of autonomic imbalance and subsequent cardiovascular manifestations in HIV-1-infected patients are poorly understood. We report here that HIV-1 transactivator of transcription (Tat, fragment 1–86) produced a concentration-dependent increase in cytosolic Ca2+ in cardiac-projecting parasympathetic neurons of nucleus ambiguus retrogradely labeled with rhodamine. Using store-specific pharmacological agents, we identified several mechanisms of the Tat-induced Ca2+ elevation: 1) lysosomal Ca2+ mobilization, 2) Ca2+ release via inositol 1,4,5-trisphosphate-sensitive endoplasmic reticulum pools, and 3) Ca2+ influx via transient receptor potential vanilloid type 2 (TRPV2) channels. Activation of TRPV2, nonselective cation channels, induced a robust and prolonged neuronal membrane depolarization, thus triggering an additional P/Q-mediated Ca2+ entry. In vivo microinjection studies indicate a dose-dependent, prolonged bradycardic effect of Tat administration into the nucleus ambiguus of conscious rats, in which neuronal TRPV2 played a major role. Our results support previous studies, indicating that Tat promotes bradycardia and, consequently, may be involved in the QT interval prolongation reported in HIV-infected patients. In the context of an overall HIV-dependent autonomic dysfunction, these Tat-mediated mechanisms may account for the higher prevalence of sudden cardiac death in HIV-1-infected patients compared with general population with similar risk factors. Our results may be particularly relevant in view of the recent findings that significant Tat levels can still be identified in the cerebrospinal fluid of HIV-infected patients with viral load suppression due to efficient antiretroviral therapy. PMID:24694382

Cytokines in chronically critically ill patients after activity and rest.

PubMed

Winkelman, Chris; Higgins, Patricia A; Chen, Yea Jyh Kathy; Levine, Alan D

2007-04-01

Inflammation, a common problem for patients in the intensive care unit (ICU), frequently is associated with serious and prolonged critical illnesses. To date, no study has examined whether physical activity influences inflammatory factors in critically ill adults. The objectives of this study were to (a) examine the relationships between type and duration of physical activity and serum levels of interleukin 6 (IL-6), a proinflammatory cytokine; IL-10, an anti-inflammatory cytokine; and their ratio and (b) determine if there are associations between cytokines or their ratio and activity or outcomes. This descriptive feasibility study investigated the approaches to measuring levels of physical activity and its relationship to serum levels of IL-6 and IL-10 and the ratio between them in patients with prolonged mechanical ventilation during periods of activity and rest. Measurements included serum IL-6 and IL-10 levels, direct observation and actigraphy, and prospective chart review. Ten critically ill patients who were mechanically ventilated for an average of 10 days in a large, urban, teaching hospital were enrolled. The average ratio of IL-6 to IL-10 improved after an average of 14.7 min of passive physical activity, typically multiple in-bed turns associated with hygiene. IL-6, IL-10, and their ratio were not associated with patient outcomes of weaning success or length of stay. High levels of IL-6 were associated with mortality. Cytokine balance may be improved by low levels of activity among patients with prolonged critical illness. The pattern of cytokines produced after activity may improve patients' recovery from prolonged critical illness and mechanical ventilation.

Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells.

PubMed Central

Connors, S. P.; Gill, E. W.; Terrar, D. A.

1992-01-01

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1393293

The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication.

PubMed

Basol, Nursah; Erbas, Oytun

2016-01-01

Amitriptyline, a frequently used tricyclic antidepressant agent, has powerful cardiotoxic effects especially in high doses. Serum and urine levels of amitriptyline dosages are not correlated with severity of toxicity; therefore, it increases the importance of electrocardiography (ECG) abnormalities. The prolongation of QTc can be a predictive marker for cardiotoxicity. Hence, in this study, it is aimed to evaluate possible effects of metoprolol and diltiazem in amitriptyline toxicity. The rats were separated into four groups. First one was control group, the second was the amitriptyline + saline group, third one was the amitriptyline + metoprolol group, and forth one was the amitriptyline + diltiazem group. ECG were recorded on rats under anesthesia. In amitriptyline group, QTc duration was prolonged compared with all other groups. The prolongation of QTc was shorter in amitriptyline + metoprolol group and amitriptyline + diltiazem group than amitriptyline group (p < 0.01 and p < 0.01, respectively). According to the results, it is possible to report ameliorating effects of both metoprolol and diltiazem on QTc prolongation related with amitriptyline intoxication. With further studies, these agents may be used for amitriptyline toxicity and besides, they may be used for patients in cardiovascular risk groups who take amitriptyline treatment regularly. © The Author(s) 2015.

Reactive Oxygen Species Function to Mediate the Fe Deficiency Response in an Fe-Efficient Apple Genotype: An Early Response Mechanism for Enhancing Reactive Oxygen Production.

PubMed

Sun, Chaohua; Wu, Ting; Zhai, Longmei; Li, Duyue; Zhang, Xinzhong; Xu, Xuefeng; Ma, Huiqin; Wang, Yi; Han, Zhenhai

2016-01-01

Reactive oxygen species (ROS) are important signaling molecules in plants that contribute to stress acclimation. This study demonstrated that ROS play a critical role in Fe deficiency-induced signaling at an early stage in Malus xiaojinensis . Once ROS production has been initiated, prolonged Fe starvation leads to activation of ROS scavenging mechanisms. Further, we demonstrated that ROS scavengers are involved in maintaining the cellular redox homeostasis during prolonged Fe deficiency treatment. Taken together, our results describe a feedback repression loop for ROS to preserve redox homeostasis and maintain a continuous Fe deficiency response in the Fe-efficient woody plant M. xiaojinensis . More broadly, this study reveals a new mechanism in which ROS mediate both positive and negative regulation of plant responses to Fe deficiency stress.

A study of the effects of long-term exposure to fuels and fluids on the behavior of advanced composite materials

NASA Technical Reports Server (NTRS)

Tanimoto, E. Y.

1981-01-01

The periodic testing and evaluation of graphite/epoxy and Kevlar/epoxy material systems after subjecting test specimens to prolonged exposure to several laboratory-controlled environments deemed typical of normal aircraft operations is discussed. It is noted that specimen immersion in water or water-based fluids resulted in the greatest effect on the mechanical properties tested. Also, the environmental fluids showed a tendency to affect Kevlar/epoxy systems at an earlier exposure period than the graphite/epoxy systems. Results also indicate mechanical property strength retention generally being lower for the Kevlar/epoxy systems when compared to the corresponding graphite/epoxy systems in similar environments, after prolonged exposure.

Prolonged physiological reactivity and loss: Association of pupillary reactivity with negative thinking and feelings.

PubMed

Siegle, Greg J; D'Andrea, Wendy; Jones, Neil; Hallquist, Michael N; Stepp, Stephanie D; Fortunato, Andrea; Morse, Jennifer Q; Pilkonis, Paul A

2015-11-01

Prolonged psychophysiological reactions to negative information have long been associated with negative thinking and feeling. This association is operationalized in the RDoC negative affect construct of loss, which is nominally indexed by prolonged physiological reactivity, cognitive loss-related constructs such as rumination and guilt, and more feeling-related constructs such as sadness, crying, and anhedonia. These associations have not been tested explicitly. If thinking and feeling aspects of loss reflect different physiological mechanisms, as might be suggested by their putative neurobiology, different intervention pathways might be suggested. Here we examined the extent to which self-reported negative thinking and feeling constructs were associated with prolonged pupillary reactivity following negative words and a subsequent cognitive distractor in a diverse heterogeneously diagnosed sample of N=84 participants. We also considered indices of abuse and variables associated with borderline personality disorder as possible moderators. Consistently, feeling-related negative affect constructs were related to prolonged pupillary reactivity during the distractor after a negative stimulus whereas thinking-related constructs were not. These data suggest that people who have sustained physiological reactions to emotional stimuli may be more strongly characterized by non-linguistic negative feelings than explicit cognitions related to loss. Sustained physiological reactions could reflect efforts to regulate feeling states. In contrast to cognitive and affective variables, abuse was associated with decreased physiological reactivity, consistent with decreased neural engagement. Interventions that target mechanisms underlying feelings and their regulation may be more mechanistically specific to sustained reactivity than those which directly address cognitions. Copyright © 2015. Published by Elsevier B.V.

The promoter of the cereal VERNALIZATION1 gene is sufficient for transcriptional induction by prolonged cold.

PubMed

Alonso-Peral, Maria M; Oliver, Sandra N; Casao, M Cristina; Greenup, Aaron A; Trevaskis, Ben

2011-01-01

The VERNALIZATION1 (VRN1) gene of temperate cereals is transcriptionally activated by prolonged cold during winter (vernalization) to promote flowering. To investigate the mechanisms controlling induction of VRN1 by prolonged cold, different regions of the VRN1 gene were fused to the GREEN FLUORESCENT PROTEIN (GFP) reporter and expression of the resulting gene constructs was assayed in transgenic barley (Hordeum vulgare). A 2 kb segment of the promoter of VRN1 was sufficient for GFP expression in the leaves and shoot apex of transgenic barley plants. Fluorescence increased at the shoot apex prior to inflorescence initiation and was subsequently maintained in the developing inflorescence. The promoter was also sufficient for low-temperature induction of GFP expression. A naturally occurring insertion in the proximal promoter, which is associated with elevated VRN1 expression and early flowering in some spring wheats, did not abolish induction of VRN1 transcription by prolonged cold, however. A translational fusion of the promoter and transcribed regions of VRN1 to GFP, VRN1::GFP, was localised to nuclei of cells at the shoot apex of transgenic barley plants. The distribution of VRN1::GFP at the shoot apex was similar to the expression pattern of the VRN1 promoter-GFP reporter gene. Fluorescence from the VRN1::GFP fusion protein increased in the developing leaves after prolonged cold treatment. These observations suggest that the promoter of VRN1 is targeted by mechanisms that trigger vernalization-induced flowering in economically important temperate cereal crops.

Post-traumatic stress disorder after weaning from prolonged mechanical ventilation.

PubMed

Jubran, Amal; Lawm, Gerald; Duffner, Lisa A; Collins, Eileen G; Lanuza, Dorothy M; Hoffman, Leslie A; Tobin, Martin J

2010-12-01

Weaning from prolonged mechanical ventilation may be associated with mental discomfort. It is not known whether such discomfort is linked with the development of post-traumatic stress disorder (PTSD). Accordingly, we investigated whether PTSD occurs in patients after weaning from prolonged ventilation. We also determined whether administering a questionnaire would identify patients at risk for developing PTSD. A prospective longitudinal study of patients transferred to a long-term acute-care hospital for weaning from prolonged ventilation was undertaken: 72 patients were studied 1 week after weaning, and 41 patients were studied again 3 months later. An experienced psychologist conducted a structured clinical interview 3 months after weaning to establish a diagnosis of PTSD. To assess for the presence of PTSD-related symptoms, the post-traumatic stress syndrome (PTSS-10) questionnaire was administered 1 week after weaning and 3 months later. The psychologist diagnosed PTSD in 12% of patients 3 months after ventilator weaning. Patients who developed PTSD were more likely to have a previous history of psychiatric disorders (P < 0.02). A PTSS-10 score >20 one week after weaning reliably identified patients who were diagnosed with PTSD 3 months later: sensitivity 1.0; specificity 0.76; area under the receiver-operating characteristic curve 0.91. PTSD was diagnosed in 12% of patients who were weaned from prolonged ventilation. A PTSS-10 score >20 one week after weaning identified patients diagnosed with PTSD 3 months later. This finding suggests that a simple questionnaire administered before hospital discharge can identify patients at risk for developing PTSD.

Impact of caloric intake in critically ill patients with, and without, refeeding syndrome: A retrospective study.

PubMed

Olthof, Laura E; Koekkoek, W A C Kristine; van Setten, Coralien; Kars, Johannes C N; van Blokland, Dick; van Zanten, Arthur R H

2017-08-10

Refeeding syndrome comprises metabolic disturbances that occur after the reintroduction of feeding after prolonged fasting. Standard care consists of correcting fluid and electrolytes imbalances. Energy intake during refeeding syndrome is heavily debated. This study addresses the effect of caloric intake on outcome during the management of refeeding syndrome. A retrospective study among critically ill invasive mechanically ventilated patients admitted for >7 days to a medical-surgical ICU. Refeeding syndrome was diagnosed by the occurrence of new onset hypophosphatemia (<0.65 mmol/l) within 72 h of the start of nutritional support. Primary outcome was 6-month mortality. Secondary outcomes were 3-month mortality, ICU and hospital length of stay and duration of mechanical ventilation. Outcomes of patients with and without refeeding syndrome were compared and subgroup analysis on energy intake within the refeeding population was performed for the duration of survival. Of 337 enrolled patients, 124 (36.8%) developed refeeding syndrome and 213 patients (63.2%) maintained normal serum phosphate levels. Between the two groups, no statistical significant differences in clinical outcomes were observed. Within the refeeding syndrome group, a reduced 6-month mortality risk for low caloric intake (<50% of target) was seen compared with normal intake, adjusted Hazard Ratio 0.39, (95% CI 0.16-0.95, p = 0.037). In this group, low caloric intake was associated with an increased overall survival time at day 180 (153.0 (SE 10.1) vs 119.1 (SE 8.0) days, log-rank p = 0.018). Refeeding syndrome is common among prolonged mechanically ventilated critically ill patients, however not predictable by baseline characteristics. Among patients that develop refeeding syndrome low caloric intake was associated with a reduction in 6-month mortality risk. This effect was not seen in patients without refeeding syndrome. Findings support caloric restriction in refeeding syndrome during critical illness. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Applicability of near-infrared spectroscopy in the monitoring of film coating and curing process of the prolonged release coated pellets.

PubMed

Korasa, Klemen; Hudovornik, Grega; Vrečer, Franc

2016-10-10

Although process analytical technology (PAT) guidance has been introduced to the pharmaceutical industry just a decade ago, this innovative approach has already become an important part of efficient pharmaceutical development, manufacturing, and quality assurance. PAT tools are especially important in technologically complex operations which require strict control of critical process parameters and have significant effect on final product quality. Manufacturing of prolonged release film coated pellets is definitely one of such processes. The aim of the present work was to study the applicability of the at-line near-infrared spectroscopy (NIR) approach in the monitoring of pellet film coating and curing steps. Film coated pellets were manufactured by coating the active ingredient containing pellets with film coating based on polymethacrylate polymers (Eudragit® RS/RL). The NIR proved as a useful tool for the monitoring of the curing process since it was able to determine the extent of the curing and hence predict drug release rate by using partial least square (PLS) model. However, such approach also showed a number of limitations, such as low reliability and high susceptibility to pellet moisture content, and was thus not able to predict drug release from pellets with high moisture content. On the other hand, the at-line NIR was capable to predict the thickness of Eudragit® RS/RL film coating in a wide range (up to 40μm) with good accuracy even in the pellets with high moisture content. To sum up, high applicability of the at-line NIR in the monitoring of the prolonged release pellets production was demonstrated in the present study. The present findings may contribute to more efficient and reliable PAT solutions in the manufacturing of prolonged release dosage forms. Copyright © 2016 Elsevier B.V. All rights reserved.

Prolonged grief: where to after Diagnostic and Statistical Manual of Mental Disorders, 5th Edition?

PubMed

Bryant, Richard A

2014-01-01

Although there is much evidence for the construct of prolonged grief, there was much controversy over the proposal to introduce a prolonged grief diagnosis into Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), and it was finally rejected as a diagnosis in DSM-5. This review outlines the evidence for and against the diagnosis, and highlights the implications of the DSM-5 decision. Convergent evidence indicates that prolonged grief characterized by persistently severe yearning for the deceased is a distinct construct from bereavement-related depression and anxiety, is associated with marked functional impairment, is responsive to targeted treatments for prolonged grief, and has been validated across different cultures, age groups, and types of bereavement. Although DSM-5 has rejected the construct as a formal diagnosis, evidence continues to emerge on related mechanisms, including maladaptive appraisals, memory and attentional processes, immunological and arousal responses, and neural circuitry. It is most likely that the International Classification of Diseases (ICD-11) will introduce a diagnosis to recognize prolonged grief, even though DSM-5 has decided against this option. It is probable that the DSM-5 decision may result in more prolonged grief patients being incorrectly diagnosed with depression after bereavement and possibly incorrectly treated. The DSM-5 decision is unlikely to impact on future research agendas.

Financial validation of the European Society of Thoracic Surgeons risk score predicting prolonged air leak after video-assisted thoracic surgery lobectomy.

PubMed

Brunelli, Alessandro; Pompili, Cecilia; Dinesh, Padma; Bassi, Vinod; Imperatori, Andrea

2018-04-27

The objective of this study was to verify whether the European Society of Thoracic Surgeons prolonged air leak risk score for video-assisted thoracoscopic lobectomy was associated with incremental postoperative costs. We retrospectively analyzed 353 patients subjected to video-assisted thoracoscopic lobectomy or segmentectomy (April 2014 to March 2016). Postoperative costs were obtained from the hospital Finance Department. Patients were grouped in different classes of risk according to their prolonged air leak risk score. To verify the independent association of the prolonged air leak risk score with postoperative costs, we performed a stepwise multivariable regression analysis in which the dependent variable was postoperative cost. Prolonged air leak developed in 56 patients (15.9%). Their length of stay was 3 days longer compared with those without prolonged air leak (8.3 vs 5.4, P < .0001). Their postoperative cost was higher than that of patients without prolonged air leak: $5939.8 versus $4381.7 (P = .001). After grouping the patients according to their prolonged air leak risk score, prolonged air leak incidence was 12.3% in class A, 13.7% in class B, 28.8% in class C, and 22.2% in class D (P = .020). The average postoperative cost was $4031.0 in class A, $4498.2 in class B, $6146.6 in class C, and $6809.3 in class D (analysis of variance test, P < .001). Multivariable regression analysis showed that being in classes C and D of PAL score (P = .001) and the presence of cardiopulmonary complications (P < .0001) were the only independent factors significantly associated with postoperative costs. We financially validated the European Society of Thoracic Surgeons prolonged air leak risk score for video-assisted thoracoscopic lobectomies, which appears useful in selecting those patients in whom the application of additional intraoperative interventions to avoid prolonged air leak may be more cost-effective. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Characteristics and outcomes of ventilated patients according to time to liberation from mechanical ventilation.

PubMed

Peñuelas, Oscar; Frutos-Vivar, Fernando; Fernández, Cristina; Anzueto, Antonio; Epstein, Scott K; Apezteguía, Carlos; González, Marco; Nin, Nicholas; Raymondos, Konstantinos; Tomicic, Vinko; Desmery, Pablo; Arabi, Yaseen; Pelosi, Paolo; Kuiper, Michael; Jibaja, Manuel; Matamis, Dimitros; Ferguson, Niall D; Esteban, Andrés

2011-08-15

A new classification of patients based on the duration of liberation of mechanical ventilation has been proposed. To analyze outcomes based on the new weaning classification in a cohort of mechanically ventilated patients. Secondary analysis included 2,714 patients who were weaned and underwent scheduled extubation from a cohort of 4,968 adult patients mechanically ventilated for more than 12 hours. Patients were classified according to a new weaning classification: 1,502 patients (55%) as simple weaning,1,058 patients (39%) as difficult weaning, and 154 (6%) as prolonged weaning.Variables associated with prolonged weaning(.7d)were: severity at admission (odds ratio [OR] per unit of Simplified Acute Physiology Score II, 1.01; 95% confidence interval [CI], 1.001–1.02), duration of mechanical ventilation before first attempt of weaning (OR per day, 1.10; 95% CI, 1.06–1.13), chronic pulmonary disease other than chronic obstructive pulmonary disease (OR,13.23; 95% CI, 3.44–51.05), pneumonia as the reason to start mechanical ventilation (OR, 1.82; 95% CI, 1.07–3.08), and level of positive end-expiratory pressure applied before weaning (OR per unit,1.09; 95% CI, 1.04–1.14). The prolonged weaning group had a nonsignificant trend toward a higher rate of reintubation (P ¼ 0.08),tracheostomy (P ¼ 0.15), and significantly longer length of stay and higher mortality in the intensive care unit (OR for death, 1.97;95%CI, 1.17–3.31). The adjusted probability of death remained constant until Day 7, at which point it increased to 12.1%.

Quantum mechanics in non-inertial reference frames: Time-dependent rotations and loop prolongations

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

Klink, W.H., E-mail: william-klink@uiowa.edu; Wickramasekara, S., E-mail: wickrama@grinnell.edu; Department of Physics, Grinnell College, Grinnell, IA 50112

2013-09-15

This is the fourth in a series of papers on developing a formulation of quantum mechanics in non-inertial reference frames. This formulation is grounded in a class of unitary cocycle representations of what we have called the Galilean line group, the generalization of the Galilei group to include transformations amongst non-inertial reference frames. These representations show that in quantum mechanics, just as the case in classical mechanics, the transformations to accelerating reference frames give rise to fictitious forces. In previous work, we have shown that there exist representations of the Galilean line group that uphold the non-relativistic equivalence principle asmore » well as representations that violate the equivalence principle. In these previous studies, the focus was on linear accelerations. In this paper, we undertake an extension of the formulation to include rotational accelerations. We show that the incorporation of rotational accelerations requires a class of loop prolongations of the Galilean line group and their unitary cocycle representations. We recover the centrifugal and Coriolis force effects from these loop representations. Loops are more general than groups in that their multiplication law need not be associative. Hence, our broad theoretical claim is that a Galilean quantum theory that holds in arbitrary non-inertial reference frames requires going beyond groups and group representations, the well-established framework for implementing symmetry transformations in quantum mechanics. -- Highlights: •A formulation of Galilean quantum mechanics in non-inertial reference frames is presented. •The Galilei group is generalized to infinite dimensional Galilean line group. •Loop prolongations of Galilean line group contain central extensions of Galilei group. •Unitary representations of the loops are constructed. •These representations lead to terms in the Hamiltonian corresponding to fictitious forces, including centrifugal and Coriolis forces.« less

Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies

PubMed Central

Meng, Ian D; Dodick, David; Ossipov, Michael H; Porreca, Frank

2017-01-01

Introduction Medication overuse headache (MOH) is a clinical concern in the management of migraine headache. MOH arises from the frequent use of medications used for the treatment of a primary headache. Medications that can cause MOH include opioid analgesics as well as formulations designed for the treatment of migraine, such as triptans, ergot alkaloids, or drug combinations that include caffeine and barbiturates. Literature review Gathering evidence indicates that migraine patients are more susceptible to development of MOH, and that prolonged use of these medications increases the prognosis for development of chronic migraine, leading to the suggestion that similar underlying mechanisms may drive both migraine headache and MOH. In this review, we examine the link between several mechanisms that have been linked to migraine headache and a potential role in MOH. For example, cortical spreading depression (CSD), associated with migraine development, is increased in frequency with prolonged use of topiramate or paracetamol. Conclusions Increased CGRP levels in the blood have been linked to migraine and elevated CGRP can be casued by prolonged sumatriptan exposure. Possible mechanisms that may be common to both migraine and MOH include increased endogenous facilitation of pain and/or diminished diminished endogenous pain inhibition. Neuroanatomical pathways mediating these effects are examined. PMID:21444643

Prolonged mechanical ventilation in Canadian intensive care units: a national survey.

PubMed

Rose, Louise; Fowler, Robert A; Fan, Eddy; Fraser, Ian; Leasa, David; Mawdsley, Cathy; Pedersen, Cheryl; Rubenfeld, Gordon

2015-02-01

We sought to describe prevalence and care practices for patients experiencing prolonged mechanical ventilation (PMV), defined as ventilation for 21 or more consecutive days and medical stability. We provided the survey to eligible units via secure Web link to a nominated unit champion from April to November 2012. Weekly telephone and e-mail reminders were sent for 6 weeks. Response rate was 215 (90%) of 238 units identifying 308 patients requiring PMV on the survey day occupying 11% of all Canadian ventilator-capable beds. Most units (81%) used individualized plans for both weaning and mobilization. Weaning and mobilization protocols were available in 48% and 38% of units, respectively. Of those units with protocols, only 25% reported weaning guidance specific to PMV, and 11% reported mobilization content for PMV. Only 30% of units used specialized mobility equipment. Most units referred to speech language pathologists (88%); use of communication technology was infrequent (11%). Only 29% routinely referred to psychiatry/psychology, and 17% had formal discharge follow-up services. Prolonged mechanical ventilation patients occupied 11% of Canadian acute care ventilator bed capacity. Most units preferred an individualized approach to weaning and mobilization with considerable variation in weaning methods, protocol availability, access to specialized rehabilitation equipment, communication technology, psychiatry, and discharge follow-up. Copyright © 2014 Elsevier Inc. All rights reserved.

O-GlcNAc-mediated interaction between VER2 and TaGRP2 elicits TaVRN1 mRNA accumulation during vernalization in winter wheat

PubMed Central

Xiao, Jun; Xu, Shujuan; Li, Chunhua; Xu, Yunyuan; Xing, Lijing; Niu, Yuda; Huan, Qing; Tang, Yimiao; Zhao, Changping; Wagner, Doris; Gao, Caixia; Chong, Kang

2014-01-01

Vernalization, sensing of prolonged cold, is important for seasonal flowering in eudicots and monocots. While vernalization silences a repressor (FLC, MADS-box transcription factor) in eudicots, it induces an activator (TaVRN1, an AP1 clade MADS-box transcription factor) in monocots. The mechanism for TaVRN1 induction during vernalization is not well understood. Here we reveal a novel mechanism for controlling TaVRN1 mRNA accumulation in response to prolonged cold sensing in wheat. The carbohydrate-binding protein VER2, a jacalin lectin, promotes TaVRN1 upregulation by physically interacting with the RNA-binding protein TaGRP2. TaGRP2 binds to TaVRN1 pre-mRNA and inhibits TaVRN1 mRNA accumulation. The physical interaction between VER2 and TaGRP2 is controlled by TaGRP2 O-GlcNAc modification, which gradually increases during vernalization. The interaction between VER2 and O-GlcNAc-TaGRP2 reduces TaGRP2 protein accumulation in the nucleus and/or promotes TaGRP2 dissociation from TaVRN1, leading to TaVRN1 mRNA accumulation. Our data reveal a new mechanism for sensing prolonged cold in temperate cereals. PMID:25091017

Adaptation and acclimation of traits associated with swimming capacity in Lake Whitefish (coregonus clupeaformis) ecotypes.

PubMed

Laporte, Martin; Dalziel, Anne C; Martin, Nicolas; Bernatchez, Louis

2016-08-11

Improved performance in a given ecological niche can occur through local adaptation, phenotypic plasticity, or a combination of these mechanisms. Evaluating the relative importance of these two mechanisms is needed to better understand the cause of intra specific polymorphism. In this study, we reared populations of Lake Whitefish (Coregonus clupeaformis) representing the'normal' (benthic form) and the 'dwarf' (derived limnetic form) ecotypes in two different conditions (control and swim-training) to test the relative importance of adaptation and acclimation in the differentiation of traits related to swimming capacity. The dwarf whitefish is a more active swimmer than the normal ecotype, and also has a higher capacity for aerobic energy production in the swimming musculature. We hypothesized that dwarf fish would show changes in morphological and physiological traits consistent with reductions in the energetic costs of swimming and maintenance metabolism. We found differences in traits predicted to decrease the costs of prolonged swimming and standard metabolic rate and allow for a more active lifestyle in dwarf whitefish. Dwarf whitefish evolved a more streamlined body shape, predicted to lead to a decreased drag, and a smaller brain, which may decrease their standard metabolic rate. Contrary to predictions, we also found evidence of acclimation in liver size and metabolic enzyme activities. Results support the view that local adaptation has contributed to the genetically-based divergence of traits associated with swimming activity. Presence of post-zygotic barriers limiting gene flow between these ecotype pairs may have favoured repeated local adaptation to the limnetic niches.

Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity

PubMed Central

Kooijman, Sander; van den Berg, Rosa; Ramkisoensing, Ashna; Boon, Mariëtte R.; Kuipers, Eline N.; Loef, Marieke; Zonneveld, Tom C. M.; Lucassen, Eliane A.; Sips, Hetty C. M.; Chatzispyrou, Iliana A.; Houtkooper, Riekelt H.; Meijer, Johanna H.; Coomans, Claudia P.; Biermasz, Nienke R.; Rensen, Patrick C. N.

2015-01-01

Disruption of circadian rhythmicity is associated with obesity and related disorders, including type 2 diabetes and cardiovascular disease. Specifically, prolonged artificial light exposure associates with obesity in humans, although the underlying mechanism is unclear. Here, we report that increasing the daily hours of light exposure increases body adiposity through attenuation of brown adipose tissue (BAT) activity, a major contributor of energy expenditure. Mice exposed to a prolonged day length of 16- and 24-h light, compared with regular 12-h light, showed increased adiposity without affecting food intake or locomotor activity. Mechanistically, we demonstrated that prolonged day length decreases sympathetic input into BAT and reduces β3-adrenergic intracellular signaling. Concomitantly, prolonging day length decreased the uptake of fatty acids from triglyceride-rich lipoproteins, as well as of glucose from plasma selectively by BAT. We conclude that impaired BAT activity is an important mediator in the association between disturbed circadian rhythm and adiposity, and anticipate that activation of BAT may overcome the adverse metabolic consequences of disturbed circadian rhythmicity. PMID:25964318

What factors are associated with increased risk for prolonged postoperative opioid usage after colorectal surgery?

PubMed

Stafford, Caitlin; Francone, Todd; Roberts, Patricia L; Ricciardi, Rocco

2018-02-06

Opioid-related deaths have increased substantially over the last 10 years placing clinician's prescription practices under intense scrutiny. Given the substantial risk of opioid dependency after colorectal surgery, we sought to analyze risk of postoperative prolonged opioid use after colorectal resections. Between 2008 and 2014, patients undergoing abdominopelvic procedure with intestinal resection at a tertiary care facility were retrospectively identified. Patient's postoperative narcotic usage including their prescriptions on discharge and their total opioid medication use was recorded. Patient variables such as demographics, surgical characteristics, and prescription use were evaluated. Finally, we developed multivariate models to identify risk factors for prolonged opioid use (> 30 days after incident surgical procedure). We identified 9423 recorded procedures of which 2173 consisted of abdominopelvic procedures with intestinal resection and survived > 1 year. Of these, 91% (n = 1981) were discharged on opioids, and 98% (n = 1955) of those patients filled only one prescription. A total of 92 (4%) patients remained on opioids beyond 30 days, and from this group, 25% (n = 23 patients) remained at 90 days. We found no association between postoperative complications, stoma formation, and patient's sex with risk of prolonged opioid use. However, younger age and history of chronic pain were associated with an increased risk of prolonged opioid use. The use of minimally invasive techniques also attenuated the risk of prolonged opioid use (Table 2). A small but considerable proportion of patients remain on opioids beyond 30 days. Predictors of opioid use for greater than 30 days include a history of chronic pain and younger age. The use of minimally invasive techniques reduced the risk of prolonged opioid use. We identified several immutable risk factors that predicted prolonged postoperative opioid use; however, surgeons may be able to attenuate prolonged opioid use through the use of minimally invasive techniques.

Mechanisms Mediating Vibration-induced Chronic Musculoskeletal Pain Analyzed in the Rat

PubMed Central

Dina, Olayinka A.; Joseph, Elizabeth K.; Levine, Jon D.; Green, Paul G.

2009-01-01

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and re-exposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60–80 Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a pro-inflammatory cytokine or re-exposure to vibration. Exposure of a hind limb to vibration produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for ~2 weeks. When nociceptive thresholds had returned to baseline, exposure to a pro-inflammatory cytokine or re-exposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia induced by vibration was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cε, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-α (TNFα) receptor. Finally, in TNFα-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged. Perspective These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFα and the second messenger PKCε as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome. PMID:19962353

Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat.

PubMed

Dina, Olayinka A; Joseph, Elizabeth K; Levine, Jon D; Green, Paul G

2010-04-01

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and reexposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60-80Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a proinflammatory cytokine or reexposure to vibration. Exposure of a hind limb to vibration-produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for approximately 2 weeks. When nociceptive thresholds had returned to baseline, exposure to a proinflammatory cytokine or reexposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cepsilon, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-alpha (TNFalpha) receptor. Finally, in TNFalpha-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged. These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFalpha and the second messenger protein kinase Cepsilon as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome. Copyright 2010 American Pain Society. All rights reserved.

Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice.

PubMed

Ratner, Veniamin; Sosunov, Sergey A; Niatsetskaya, Zoya V; Utkina-Sosunova, Irina V; Ten, Vadim S

2013-12-01

Hyperoxia inhibits pulmonary bioenergetics, causing delayed alveolarization in mice. We hypothesized that mechanical ventilation (MV) also causes a failure of bioenergetics to support alveolarization. To test this hypothesis, neonatal mice were ventilated with room air for 8 hours (prolonged) or for 2 hours (brief) with 15 μl/g (aggressive) tidal volume (Tv), or for 8 hours with 8 μl/g (gentle) Tv. After 24 hours or 10 days of recovery, lung mitochondria were examined for adenosine diphosphate (ADP)-phosphorylating respiration, using complex I (C-I)-dependent, complex II (C-II)-dependent, or cytochrome C oxidase (C-IV)-dependent substrates, ATP production rate, and the activity of C-I and C-II. A separate cohort of mice was exposed to 2,4-dinitrophenol (DNP), a known uncoupler of oxidative phosphorylation. At 10 days of recovery, pulmonary alveolarization and the expression of vascular endothelial growth factor (VEGF) were assessed. Sham-operated littermates were used as control mice. At 24 hours after aggressive MV, mitochondrial ATP production rates and the activity of C-I and C-II were significantly decreased compared with control mice. However, at 10 days of recovery, only mice exposed to prolonged-aggressive MV continued to exhibit significantly depressed mitochondrial respiration. This was associated with significantly poorer alveolarization and VEGF expression. In contrast, mice exposed to brief-aggressive or prolonged-gentle MV exhibited restored mitochondrial ADP-phosphorylation, normal alveolarization and pulmonary VEGF content. Exposure to DNP fully replicated the phenotype consistent with alveolar developmental arrest. Our data suggest that the failure of bioenergetics to support normal lung development caused by aggressive and prolonged ventilation should be considered a fundamental mechanism for the development of bronchopulmonary dysplasia in premature neonates.

Plasma FGF21 concentrations, adipose fibroblast growth factor receptor-1 and β-klotho expression decrease with fasting in northern elephant seals.

PubMed

Suzuki, Miwa; Lee, Andrew Y; Vázquez-Medina, José Pablo; Viscarra, Jose A; Crocker, Daniel E; Ortiz, Rudy M

2015-05-15

Fibroblast growth factor (FGF)-21 is secreted from the liver, pancreas, and adipose in response to prolonged fasting/starvation to facilitate lipid and glucose metabolism. Northern elephant seals naturally fast for several months, maintaining a relatively elevated metabolic rate to satisfy their energetic requirements. Thus, to better understand the impact of prolonged food deprivation on FGF21-associated changes, we analyzed the expression of FGF21, FGF receptor-1 (FGFR1), β-klotho (KLB; a co-activator of FGFR) in adipose, and plasma FGF21, glucose and 3-hydroxybutyrate in fasted elephant seal pups. Expression of FGFR1 and KLB mRNA decreased 98% and 43%, respectively, with fasting duration. While the 80% decrease in mean adipose FGF21 mRNA expression with fasting did not reach statistical significance, it paralleled the 39% decrease in plasma FGF21 concentrations suggesting that FGF21 is suppressed with fasting in elephant seals. Data demonstrate an atypical response of FGF21 to prolonged fasting in a mammal suggesting that FGF21-mediated mechanisms have evolved differentially in elephant seals. Furthermore, the typical fasting-induced, FGF21-mediated actions such as the inhibition of lipolysis in adipose may not be required in elephant seals as part of a naturally adapted mechanism to support their unique metabolic demands during prolonged fasting. Copyright © 2015 Elsevier Inc. All rights reserved.

Thalidomide prolongs survival after experimental musculoskeletal injury, through an effect on mononuclear apoptosis.

PubMed

Panousis, Konstantinos; Nikolaou, Vassilios S; Tsaganos, Thomas; Lallos, Stergios; Giamarellos-Bourboulis, Evangelos J; Efstathopoulos, Nicolas

2014-05-01

This study was conducted to investigate the effects of intravenous thalidomide administration in an experimental model of musculoskeletal trauma. We hypothesized that because thalidomide inhibits secretion of tumor necrosis factor alpha (TNF-α), survival of animals that received thalidomide would be significantly prolonged. After an open fracture of the right femur, 24 rabbits were randomly assigned to control and thalidomide groups. Intravenous therapy with thalidomide was started 30 min after fracture. Hemodynamic monitoring of all animals was performed for 4 h. Survival was recorded and bacterial growth in blood and organs was measured after animal death or sacrifice. Blood was sampled for TNF-α measurement and for isolation of peripheral blood mononuclear cells (PBMCs). Apoptosis of PBMCs was measured by flow cytometry. Survival was significantly prolonged in the thalidomide group. Apoptosis of PBMCs was increased in the control group compared with the thalidomide group at 24 h. There were no differences in vital signs, blood and tissue cultures, and serum TNF-α concentration between the two groups. Intravenous thalidomide prolonged survival in an experimental model of severe musculoskeletal injury in rabbits. Its mechanism of action did not involve TNF-α suppression but prevention of mononuclear apoptosis. In view of these promising results, further research is needed to clarify the immunomodulatory mechanism of action of thalidomide and its potential use for the management of severe trauma. Copyright © 2014 Elsevier Inc. All rights reserved.

Plasma FGF21 Concentrations, Adipose Fibroblast Growth Factor Receptor-1 and β-Klotho Expression Decrease with Fasting in Northern Elephant Seals

PubMed Central

Suzuki, Miwa; Lee, Andrew; Vázquez-Medina, Jose Pablo; Viscarra, Jose A.; Crocker, Daniel E.; Ortiz, Rudy M.

2015-01-01

Fibroblast growth factor (FGF)-21 is secreted from the liver, pancreas, and adipose in response to prolonged fasting/starvation to facilitate lipid and glucose metabolism. Northern elephant seals naturally fast for several months, maintaining a relatively elevated metabolic rate to satisfy their energetic requirements. Thus, to better understand the impact of prolonged food deprivation on FGF21-associated changes, we analyzed the expression of FGF21, FGF receptor-1 (FGFR1), β-klotho (KLB; a co-activator of FGFR) in adipose, and plasma FGF21, glucose and 3-hydroxybutyrate in fasted elephant seal pups. Expression of FGFR1 and KLB mRNA decreased 98% and 43%, respectively, with fasting duration. While the 80% decrease in mean adipose FGF21 mRNA expression with fasting did not reach statistical significance, it paralleled the 39% decrease in plasma FGF21 concentrations suggesting that FGF21 is suppressed with fasting in elephant seals. Data demonstrate an atypical response of FGF21 to prolonged fasting in a mammal suggesting that FGF21-mediated mechanisms have evolved differentially in elephant seals. Furthermore, the typical fasting-induced, FGF21-mediated actions such as the inhibition of lipolysis in adipose may not be required in elephant seals as part of a naturally adapted mechanism to support their unique metabolic demands during prolonged fasting. PMID:25857751

Predictive value of ultrasound assessed fetal head position in primiparous women with prolonged first stage of labor.

PubMed

Torkildsen, Erik A; Salvesen, Kjell Å; VON Brandis, Philip; Eggebø, Torbjørn M

2012-11-01

To examine how well ultrasound-assessed occipitoposterior (OP) position or high sagittal (HS) position in primiparous women with a prolonged first stage of labor predicts a vaginal delivery and the duration of labor. Prospective observational study. Stavanger University Hospital, a secondary referral center in Norway. 105 primiparous women with prolonged first stage of labor. Ultrasound assessment of fetal head position. Main outcome measures. Vaginal delivery vs. cesarean section and duration of labor. Twenty-five fetuses (24%) were delivered with cesarean section (CS), 45 (43%) had an operative vaginal delivery and 35 (33%) delivered spontaneously. Eleven (27%) of 41 fetuses in OP position at the time of inclusion were born in OP position. Ten (24%) of the 41 fetuses in OP position at inclusion were delivered with CS compared with 15/64 (23%) fetuses in other positions (p= 0.91). Twenty-eight fetuses were in sagittal position and 12 in HS position, assessed with ultrasound at the time of diagnosed prolonged labor. Seven (58%) of 12 in HS position delivered vaginally and five (42%) had a CS (p= 0.89). Time from inclusion to labor was not significant longer either for fetuses in OP compared with non-OP positions or for fetuses in HS compared with non-HS positions. Most fetuses in OP or HS positions in the first stage of labor will rotate spontaneously and have a high probability of being delivered vaginally. © 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.

Reactive Oxygen Species Function to Mediate the Fe Deficiency Response in an Fe-Efficient Apple Genotype: An Early Response Mechanism for Enhancing Reactive Oxygen Production

PubMed Central

Sun, Chaohua; Wu, Ting; Zhai, Longmei; Li, Duyue; Zhang, Xinzhong; Xu, Xuefeng; Ma, Huiqin; Wang, Yi; Han, Zhenhai

2016-01-01

Reactive oxygen species (ROS) are important signaling molecules in plants that contribute to stress acclimation. This study demonstrated that ROS play a critical role in Fe deficiency-induced signaling at an early stage in Malus xiaojinensis. Once ROS production has been initiated, prolonged Fe starvation leads to activation of ROS scavenging mechanisms. Further, we demonstrated that ROS scavengers are involved in maintaining the cellular redox homeostasis during prolonged Fe deficiency treatment. Taken together, our results describe a feedback repression loop for ROS to preserve redox homeostasis and maintain a continuous Fe deficiency response in the Fe-efficient woody plant M. xiaojinensis. More broadly, this study reveals a new mechanism in which ROS mediate both positive and negative regulation of plant responses to Fe deficiency stress. PMID:27899933

Impact of acute atrial fibrillation termination and prolongation of atrial fibrillation cycle length on the outcome of ablation of persistent atrial fibrillation: A substudy of the STAR AF II trial.

PubMed

Kochhäuser, Simon; Jiang, Chen-Yang; Betts, Timothy R; Chen, Jian; Deisenhofer, Isabel; Mantovan, Roberto; Macle, Laurent; Morillo, Carlos A; Haverkamp, Wilhelm; Weerasooriya, Rukshen; Albenque, Jean-Paul; Nardi, Stefano; Menardi, Endrj; Novak, Paul; Sanders, Prashanthan; Verma, Atul

2017-04-01

Controversy exists about the impact of acute atrial fibrillation (AF) termination and prolongation of atrial fibrillation cycle length (AFCL) during ablation on long-term procedural outcome. The purpose of this study was to analyze the influence of AF termination and AFCL prolongation on freedom from AF in patients from the STAR AF II (Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial-Part II) trial. Acute changes in AFCL and AF termination were collected during the index procedure of the STAR AF II trial and compared to recurrence of AF at 18 months. Recurrence was assessed by ECG, Holter (3, 6, 9, 12, 18 months), and weekly transtelephonic ECG monitoring for 18 months. AF terminated in 8% of the pulmonary vein isolation (PVI) arm, 45% in the PVI+complex electrogram arm, and 22% of the PVI+linear ablation arm (P <.001), but freedom from AF did not differ among the 3 groups (P = .15). Freedom from AF was significantly higher in patients who presented to the laboratory in sinus rhythm (SR) compared to those without AF termination (63% vs 44%, P = .007). Patients with AF termination had an intermediate outcome (53%) that was not significantly different from those in SR (P = .84) or those who did not terminate (P = .08). AF termination was a univariable predictor of success (P = .007), but by multivariable analysis, presence of early SR was the strongest predictor of success (hazard ratio 0.67, P = .004). Prolongation of AFCL was not predictive of 18-month freedom from AF. Acute AF termination and prolongation in AFCL did not consistently predict 18-month freedom from AF. Presence of SR before or early during the ablation was the strongest predictor of better outcome. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Utilizing the Deep Space Gateway to Characterize DNA Damage Due to Space Radiation and Repair Mechanisms

NASA Astrophysics Data System (ADS)

Zea, L.; Niederwieser, T.; Anthony, J.; Stodieck, L.

2018-02-01

The radiation environment experienced in the Deep Space Gateway enables the interrogation of DNA damage and repair mechanisms, which may serve to determine the likelihood and consequence of the high radiation risk to prolonged human presence beyond LEO.

Microenvironment temperature prediction between body and seat interface using autoregressive data-driven model.

PubMed

Liu, Zhuofu; Wang, Lin; Luo, Zhongming; Heusch, Andrew I; Cascioli, Vincenzo; McCarthy, Peter W

2015-11-01

There is a need to develop a greater understanding of temperature at the skin-seat interface during prolonged seating from the perspectives of both industrial design (comfort/discomfort) and medical care (skin ulcer formation). Here we test the concept of predicting temperature at the seat surface and skin interface during prolonged sitting (such as required from wheelchair users). As caregivers are usually busy, such a method would give them warning ahead of a problem. This paper describes a data-driven model capable of predicting thermal changes and thus having the potential to provide an early warning (15- to 25-min ahead prediction) of an impending temperature that may increase the risk for potential skin damages for those subject to enforced sitting and who have little or no sensory feedback from this area. Initially, the oscillations of the original signal are suppressed using the reconstruction strategy of empirical mode decomposition (EMD). Consequentially, the autoregressive data-driven model can be used to predict future thermal trends based on a shorter period of acquisition, which reduces the possibility of introducing human errors and artefacts associated with longer duration "enforced" sitting by volunteers. In this study, the method had a maximum predictive error of <0.4 °C when used to predict the temperature at the seat and skin interface 15 min ahead, but required 45 min data prior to give this accuracy. Although the 45 min front loading of data appears large (in proportion to the 15 min prediction), a relative strength derives from the fact that the same algorithm could be used on the other 4 sitting datasets created by the same individual, suggesting that the period of 45 min required to train the algorithm is transferable to other data from the same individual. This approach might be developed (along with incorporation of other measures such as movement and humidity) into a system that can give caregivers prior warning to help avoid exacerbating the skin disorders of patients who suffer from low body insensitivity and disability requiring them to be immobile in seats for prolonged periods. Copyright © 2015 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

Deciphering landslide behavior using large-scale flume experiments

USGS Publications Warehouse

Reid, Mark E.; Iverson, Richard M.; Iverson, Neal R.; LaHusen, Richard G.; Brien, Dianne L.; Logan, Matthew

2008-01-01

Landslides can be triggered by a variety of hydrologic events and they can exhibit a wide range of movement dynamics. Effective prediction requires understanding these diverse behaviors. Precise evaluation in the field is difficult; as an alternative we performed a series of landslide initiation experiments in the large-scale, USGS debris-flow flume. We systematically investigated the effects of three different hydrologic triggering mechanisms, including groundwater exfiltration from bedrock, prolonged rainfall infiltration, and intense bursts of rain. We also examined the effects of initial soil porosity (loose or dense) relative to the soil’s critical-state porosity. Results show that all three hydrologic mechanisms can instigate landsliding, but water pathways, sensor response patterns, and times to failure differ. Initial soil porosity has a profound influence on landslide movement behavior. Experiments using loose soil show rapid soil contraction during failure, with elevated pore pressures liquefying the sediment and creating fast-moving debris flows. In contrast, dense soil dilated upon shearing, resulting in slow, gradual, and episodic motion. These results have fundamental implications for forecasting landslide behavior and developing effective warning systems.

Radionuclide gastric emptying studies in patients with anorexia nervosa

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

Domstad, P.A.; Shih, W.J.; Humphries, L.

1987-05-01

To evaluate gastric emptying in anorexia nervosa patients, 26 patients (17 females, two males, ranging in age from 13 to 40 yr) with upper GI symptoms ingested 150-200 microCi (/sup 99m/Tc)triethelenetetraamine polysterene resin in cereal and were imaged in the supine position. Data were accumulated at 5 min intervals to obtain the gastric emptying time (GET). The results of the studies were divided into three categories: prolonged, 13 patients; rapid, 11; and normal 3. Twelve of 13 patients with prolonged GET were given 10 mg metoclopramide i.v. injections; nine of the 12 patients had a good response and three hadmore » no response. Five of the nine patients underwent metoclopramide therapy and four of the patients showed benefit from the therapy. One patient discontinued metoclopramide therapy because of somnolence. Although all patients had subjective symptoms of gastric dysfunction, our results indicated only 50% had objectively prolonged GET, and another 50% showed normal or even rapid GET. Therefore, this radionuclide study enables quantitatively objective documentation of gastric emptying, separation of those patients with rapid or normal GET from those with prolonged GET, thereby avoiding the possible side effects from metoclopramide medication, and prediction of effectiveness of metoclopramide therapy in patients with prolonged GET.« less

HIF-2α Expression Regulates Sprout Formation into 3D Fibrin Matrices in Prolonged Hypoxia in Human Microvascular Endothelial Cells.

PubMed

Nauta, Tessa D; Duyndam, Monique C A; Weijers, Ester M; van Hinsbergh, Victor M W; Koolwijk, Pieter

2016-01-01

During short-term hypoxia, Hypoxia Inducible Factors (particular their subunits HIF-1α and HIF-2α) regulate the expression of many genes including the potent angiogenesis stimulator VEGF. However, in some pathological conditions chronic hypoxia occurs and is accompanied by reduced angiogenesis. We investigated the effect of prolonged hypoxia on the proliferation and sprouting ability of human microvascular endothelial cells and the involvement of the HIFs and Dll4/Notch signaling. Human microvascular endothelial cells (hMVECs), cultured at 20% oxygen for 14 days and seeded on top of 3D fibrin matrices, formed sprouts when stimulated with VEGF-A/TNFα. In contrast, hMVECs precultured at 1% oxygen for 14 days were viable and proliferative, but did not form sprouts into fibrin upon VEGF-A/TNFα stimulation at 1% oxygen. Silencing of HIF-2α with si-RNA partially restored the inhibition of endothelial sprouting, whereas HIF-1α or HIF-3α by si-RNA had no effect. No involvement of Dll4/Notch pathway in the inhibitory effect on endothelial sprouting by prolonged hypoxia was found. In addition, hypoxia decreased the production of urokinase-type plasminogen activator (uPA), needed for migration and invasion, without a significant effect on its inhibitor PAI-1. This was independent of HIF-2α, as si-HIF-2α did not counteract uPA reduction. Prolonged culturing of hMVECs at 1% oxygen inhibited endothelial sprouting into fibrin. Two independent mechanisms contribute. Silencing of HIF-2α with si-RNA partially restored the inhibition of endothelial sprouting pointing to a HIF-2α-dependent mechanism. In addition, reduction of uPA contributed to reduced endothelial tube formation in a fibrin matrix during prolonged hypoxia.

Prolonged release matrix tablet of pyridostigmine bromide: formulation and optimization using statistical methods.

PubMed

Bolourchian, Noushin; Rangchian, Maryam; Foroutan, Seyed Mohsen

2012-07-01

The aim of this study was to design and optimize a prolonged release matrix formulation of pyridostigmine bromide, an effective drug in myasthenia gravis and poisoning with nerve gas, using hydrophilic - hydrophobic polymers via D-optimal experimental design. HPMC and carnauba wax as retarding agents as well as tricalcium phosphate were used in matrix formulation and considered as independent variables. Tablets were prepared by wet granulation technique and the percentage of drug released at 1 (Y(1)), 4 (Y(2)) and 8 (Y(3)) hours were considered as dependent variables (responses) in this investigation. These experimental responses were best fitted for the cubic, cubic and linear models, respectively. The optimal formulation obtained in this study, consisted of 12.8 % HPMC, 24.4 % carnauba wax and 26.7 % tricalcium phosphate, had a suitable prolonged release behavior followed by Higuchi model in which observed and predicted values were very close. The study revealed that D-optimal design could facilitate the optimization of prolonged release matrix tablet containing pyridostigmine bromide. Accelerated stability studies confirmed that the optimized formulation remains unchanged after exposing in stability conditions for six months.

Incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities - a nationwide population-based study.

PubMed

Lehtonen, Arttu O; Langén, Ville L; Puukka, Pauli J; Kähönen, Mika; Nieminen, Markku S; Jula, Antti M; Niiranen, Teemu J

Scant data exist on incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities in the general population. We recorded ECG and measured conventional cardiovascular risk factors in 5667 Finns who were followed up for incident atrial fibrillation (AF). We obtained repeat ECGs from 3089 individuals 11years later. The incidence rates of prolonged P-wave duration, abnormal P terminal force (PTF), left P-wave axis deviation, and right P-wave axis deviation were 16.0%, 7.4%, 3.4%, and 2.2%, respectively. Older age and higher BMI were associated with incident prolonged P-wave duration and abnormal PTF (P≤0.01). Higher blood pressure was associated with incident prolonged P-wave duration and right P-wave axis deviation (P≤0.01). During follow-up, only prolonged P-wave duration predicted AF (multivariable-adjusted hazard ratio, 1.38; P=0.001). Modifiable risk factors associate with P-wave abnormalities that are common and may represent intermediate steps of atrial cardiomyopathy on a pathway leading to AF. Copyright © 2017 Elsevier Inc. All rights reserved.

Intrarectal pressures and balloon expulsion related to evacuation proctography.

PubMed Central

Halligan, S; Thomas, J; Bartram, C

1995-01-01

Seventy four patients with constipation were examined by standard evacuation proctography and then attempted to expel a small, non-deformable rectal balloon, connected to a pressure transducer to measure intrarectal pressure. Simultaneous imaging related the intrarectal position of the balloon to rectal deformity. Inability to expel the balloon was associated proctographically with prolonged evacuation, incomplete evacuation, reduced anal canal diameter, and acute anorectal angulation during evacuation. The presence and size of rectocoele or intussusception was unrelated to voiding of paste or balloon. An independent linear combination of pelvic floor descent and evacuation time on proctography correctly predicted maximum intrarectal pressure in 74% of cases. No patient with both prolonged evacuation and reduced pelvic floor descent on proctography could void the balloon, as maximum intrarectal pressure was reduced in this group. A prolonged evacuation time on proctography, in combination with reduced pelvic floor descent, suggests defecatory disorder may be caused by inability to raise intrarectal pressure. A diagnosis of anismus should not be made on proctography solely on the basis of incomplete/prolonged evacuation, as this may simply reflect inadequate straining. PMID:7672656

Sleep, Torpor and Memory Impairment

NASA Astrophysics Data System (ADS)

Palchykova, S.; Tobler, I.

It is now well known that daily torpor induces a sleep deficit. Djungarian hamsters emerging from this hypometabolic state spend most of the time in sleep. This sleep is characterized by high initial values of EEG slow-wave activity (SWA) that monotonically decline during recovery sleep. These features resemble the changes seen in numerous species during recovery after prolonged wakefulness or sleep deprivation (SD). When hamsters are totally or partially sleep deprived immediately after emerging from torpor, an additional increase in SWA can be induced. It has been therefore postulated, that these slow- waves are homeostatically regulated, as predicted by the two-process model of sleep regulation, and that during daily torpor a sleep deficit is accumulated as it is during prolonged waking. The predominance of SWA in the frontal EEG observed both after SD and daily torpor provides further evidence for the similarity of these conditions. It has been shown in several animal and human studies that sleep can enhance memory consolidation, and that SD leads to memory impairment. Preliminary data obtained in the Djungarian hamster showed that both SD and daily torpor result in object recognition deficits. Thus, animals subjected to SD immediately after learning, or if they underwent an episode of daily torpor between learning and retention, displayed impaired recognition memory for complex object scenes. The investigation of daily torpor can reveal mechanisms that could have important implications for hypometabolic state induction in other mammalian species, including humans.

Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI)

NASA Technical Reports Server (NTRS)

Gelfand, R.; Lambertsen, C. J.; Clark, J. M.; Hopkin, E.

1998-01-01

Potential adverse effects on the O2-sensing function of the carotid body when its cells are exposed to toxic O2 pressures were assessed during investigations of human organ tolerance to prolonged continuous and intermittent hyperoxia (Predictive Studies V and VI). Isocapnic hypoxic ventilatory responses (HVR) were determined at 1.0 ATA before and after severe hyperoxic exposures: 1) continuous O2 breathing at 1.5, 2.0, and 2.5 ATA for 17.7, 9.0, and 5.7 h and 2) intermittent O2 breathing at 2.0 ATA (30 min O2-30 min normoxia) for 14.3 O2 h within 30-h total time. Postexposure curvature of HVR hyperbolas was not reduced compared with preexposure controls. The hyperbolas were temporarily elevated to higher ventilations than controls due to increments in respiratory frequency that were proportional to O2 exposure time, not O2 pressure. In humans, prolonged hyperoxia does not attenuate the hypoxia-sensing function of the peripheral chemoreceptors, even after exposures that approach limits of human pulmonary and central nervous system O2 tolerance. Current applications of hyperoxia in hyperbaric O2 therapy and in subsea- and aerospace-related operations are guided by and are well within these exposure limits.

Survival of Listeria monocytogenes and Staphylococcus aureus in Synthetic Brines. Studying the Effects of Salt, Temperature and Sugar through the Approach of the Design of Experiments.

PubMed

Bevilacqua, Antonio; Campaniello, Daniela; Speranza, Barbara; Sinigaglia, Milena; Corbo, Maria R

2018-01-01

The fermentation of table olives relies on a complex microbiota of lactic acid bacteria (LAB), yeasts, and enterobacteria. Producers often add sugar to increase the growth rate of LAB, "but this practice could also increase the survival rate of some pathogens. Therefore, the main topic of this paper was to study the effect of sugar, salt and temperature on the survival of Staphylococcus aureus and Listeria monocytogenes in a synthetic brine through the theory of the Design of Experiments (simplex centroid). The addition of sugar could prolong the survival time of L. monocytogenes by 40 days, whereas an increase of the temperature caused a decrease of survival from 18 to 3 days. The survival time of S. aureus was prolonged by 50 days by combining sugar (2-4 g/l) and low temperatures (5-15°C). The use of desirability approach and prediction profiles suggests that the prolongation of the survival time of L. monocytogenes could be related to a shift in the geometrical shape of the death kinetic. This paper offers a structured statistical approach on the variables acting on the survival of two pathogens in brines and represents the first step to set up and design a predictive approach for olive producers.

Reduced transpiration response to precipitation pulses precedes mortality in a piñon-juniper woodland subject to prolonged drought.

PubMed

Plaut, Jennifer A; Wadsworth, W Duncan; Pangle, Robert; Yepez, Enrico A; McDowell, Nate G; Pockman, William T

2013-10-01

Global climate change is predicted to alter the intensity and duration of droughts, but the effects of changing precipitation patterns on vegetation mortality are difficult to predict. Our objective was to determine whether prolonged drought or above-average precipitation altered the capacity to respond to the individual precipitation pulses that drive productivity and survival. We analyzed 5 yr of data from a rainfall manipulation experiment in piñon-juniper (Pinus edulis-Juniperus monosperma) woodland using mixed effects models of transpiration response to event size, antecedent soil moisture, and post-event vapor pressure deficit. Replicated treatments included irrigation, drought, ambient control and infrastructure control. Mortality was highest under drought, and the reduced post-pulse transpiration in the droughted trees that died was attributable to treatment effects beyond drier antecedent conditions and reduced event size. In particular, trees that died were nearly unresponsive to antecedent shallow soil moisture, suggesting reduced shallow absorbing root area. Irrigated trees showed an enhanced response to precipitation pulses. Prolonged drought initiates a downward spiral whereby trees are increasingly unable to utilize pulsed soil moisture. Thus, the additive effects of future, more frequent droughts may increase drought-related mortality. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Prolonged grief and post-traumatic growth after loss: Latent class analysis.

PubMed

Zhou, Ningning; Yu, Wei; Tang, Suqin; Wang, Jianping; Killikelly, Clare

2018-06-06

Bereavement may trigger different psychological outcomes, such as prolonged grief disorder or post-traumatic growth. The relationship between these two outcomes and potential precipitators remain unknown. The current study aimed to identify classes of Chinese bereaved individuals based on prolonged grief symptoms and post-traumatic growth and to examine predictors for these classes. We used data from 273 Chinese individuals who lost a relative due to disease (92.3%), accident (4.4%) and other reasons (1.8%). Latent class analysis revealed three classes: a resilient class, a growth class, and a combined grief/growth class. A higher level of functional impairment was found for the combined grief/growth class than for the other two classes. Membership in the combined grief/growth class was significantly predicted by the younger age of the deceased and the death of a parent, child or spouse. Subjective closeness with the deceased and gender were marginally significant predictors. When the four variables were included in the multinomial regression analysis, death of a parent, child or spouse significantly predicted the membership to the combined grief/growth class. These findings provide valuable information for the development of tailored interventions that may build on the bereaved individuals' personal strengths. Copyright © 2018. Published by Elsevier B.V.

Prolonged bradycardia, asystole and outcome of high spinal cord injury patients: Risk factors and management

PubMed Central

Shaikh, Nissar; Rhaman, M. A.; Raza, Ali; Shabana, Adel; Malstrom, Mahommad Faisal; Al-Sulaiti, Ghanem

2016-01-01

Background: High spinal cord injury (HSCI) is one of the devastating traumatic injuries. 80% of these patients are young male, and 93% will have major neurological disabilities. There is a paucity of literature about prolonged bradycardia in HSCI patients. The aim of this study was to know the prevalence, risk factors, precipitating factors for prolonged bradycardia in the HSCI patients. Materials and Methods: All patients who were admitted to the Intensive Care Unit (ICU) of a tertiary hospital, with spinal cord injury above level of dorsal (D4) were enrolled in this study prospectively. Patient's demographic data, mechanism, level and type of spinal injury, associated injuries, injury severity score (ISS), spinal shock, vasopressors used, time of occurrence of bradycardia, treatment for bradycardia, precipitating as well as risk factors and outcome were recorded. Results: During the study period, a total of 138 patients were admitted to the ICU with HSCI. Majority of patients were male. The most frequently associated injury in these patients was skeletal fractures (38.4%). Most common complication was pneumonia 56 (41%). Forty-five (33%) of the total patients had prolonged bradycardia; 87% of these patients had pneumonia when bradycardia occurred. 53.4% had cardiac asystole. 29 (21%) patients had bradycardia at the time of endotracheal suctioning, whereas 27 (20%) patients developed bradycardia at the time of positioning. Majority of the patients were managed conservatively. Those HSCI patients who developed prolonged bradycardia, their ISS score was statistically higher, ICU and hospital stay was significantly higher compared with those HSCI patient who did not have prolonged bradycardia. Multivariate analysis revealed that hypotension on admission; pneumonia, and tracheostomy were risk factors for the development of prolonged bradycardia in HSCI patients. Conclusion: Prolonged bradycardia was associated with significantly higher incidence of asystole. Endotracheal suctioning and positioning of HSCI patients were significant provocative factors for prolonged bradycardia; hypotension on admission, pneumonia and tracheostomy were the risk factors for the development of prolonged bradycardia in these patients. PMID:27695550

Prolonged jaundice in newborns is associated with low antioxidant capacity in breast milk.

PubMed

Uras, Nurdan; Tonbul, Alpaslan; Karadag, Ahmet; Dogan, Derya G; Erel, Ozcan; Tatli, Mustafa M

2010-10-01

In breastfeeding newborns who are otherwise healthy, the mechanism of prolonged jaundice remains unclear. The aim of this study was to investigate relations between prolonged jaundice and oxidative parameters in breast milk. Full-term, otherwise healthy newborns with jaundice lasting more than 2 weeks were enrolled prospectively in the study. As a control group, newborns in the same age group but without prolonged jaundice were selected. All newborns in the study were exclusively breastfed. In the newborns with prolonged jaundice, investigations of the etiology of the jaundice included complete blood count, peripheral blood smear, blood typing, direct Coombs test, measurement of serum levels of total and direct bilirubin, tests for liver and thyroid function (TSH, free T4, total T4), urine culture and measurement of urine reducing substances, and determination of glucose 6 phosphate dehydrogenase enzyme levels. Breast milk was collected from the mothers of the newborns in both groups. The antioxidant status of the breast milk was assessed via determination of total antioxidant capacity (TAC). Oxidative stress was also assessed in breast milk by measurement of total oxidation status (TOS) and calculation of the oxidative stress index (OSI). The prolonged jaundice group differed significantly from the control group in terms of mean TAC and OSI (p < 0.001), but not in terms of TOS. In conclusion, in the breast milk of mothers of newborns with prolonged jaundice, oxidative stress was found to be increased, and protective antioxidant capacity was found to be decreased.

MECHANISMS OF MANGANESE-INDUCED RAT PHEOCHROMOCYTOMA (PC12) CELL DEATH AND CELL DIFFERENTIATION. (R826248)

EPA Science Inventory

Mn is a neurotoxin that leads to a syndrome resembling Parkinson's disease after prolonged exposure to high concentrations. Our laboratory has been investigating the mechanism by which Mn induces neuronal cell death. To accomplish this, we have utilized rat pheochromocytom...

Adaptation to prolonged bedrest in man: A compendium of research. [bibliographies on clinical medicine and human pathology

NASA Technical Reports Server (NTRS)

Greenleaf, J. E.; Greenleaf, C. J.; Vanderveer, D.; Dorchak, K. J.

1976-01-01

A compilation of major studies that describe the clinical observations and elucidate the physiological mechanisms of the adaptive process of man undergoing prolonged bed rest is presented. Additional studies are included that provide background information in the form of reviews or summaries of the process. Wherever possible a detailed annotation is provided under the subheadings: (1) purpose, (2) procedure and methods, (3) results, and (4) conclusions. Additional references are provided in a selected bibliography.

Role of Endoplasmic Reticulum Stress in Metabolic Disease and Other Disorders

PubMed Central

Ozcan, Lale; Tabas, Ira

2012-01-01

Perturbations in the normal functions of the endoplasmic reticulum (ER) trigger a signaling network that coordinates adaptive and apoptotic responses. There is accumulating evidence implicating prolonged ER stress in the development and progression of many diseases, including neurodegeneration, atherosclerosis, type 2 diabetes, liver disease, and cancer. With the improved understanding of the underlying molecular mechanisms, therapeutic interventions that target the ER stress response would be potential strategies to treat various diseases driven by prolonged ER stress. PMID:22248326

Intractable Polyuria Mimicking Diabetes Insipidus-Source Traced to Vecuronium Infusion.

PubMed

Haldar, Rudrashish; Samanta, Sukhen; Singla, Ankush

2016-01-01

Continuous infusion of vecuronium is a commonly used technique for patients requiring prolonged neuromuscular blockade for mechanical ventilation. As compared with older neuromuscular blocking agents, it confers the advantages of rapid excretion and intermediate duration of action. Prolongation of neuromuscular blockade and muscle weakness are the known complications of continuous vecuronium infusion. This report attempts to describe polyuria, as a hitherto unknown complication of vecuronium infusion, which can occur due to the mannitol present in commercially available preparation of vecuronium bromide.

Predicting time on prolonged benefits for injured workers with acute back pain.

PubMed

Steenstra, Ivan A; Busse, Jason W; Tolusso, David; Davilmar, Arold; Lee, Hyunmi; Furlan, Andrea D; Amick, Ben; Hogg-Johnson, Sheilah

2015-06-01

Some workers with work-related compensated back pain (BP) experience a troubling course of disability. Factors associated with delayed recovery among workers with work-related compensated BP were explored. This is a cohort study of workers with compensated BP in 2005 in Ontario, Canada. Follow up was 2 years. Data was collected from employers, employees and health-care providers by the Workplace Safety and Insurance Board (WSIB). Exclusion criteria were: (1) no-lost-time claims, (2) >30 days between injury and claim filing, (3) <4 weeks benefits duration, and (4) age >65 years. Using proportional hazard models, we examined the prognostic value of information collected in the first 4 weeks after injury. Outcome measures were time on benefits during the first episode and time until recurrence after the first episode. Of 6,657 workers, 1,442 were still on full benefits after 4 weeks. Our final model containing age, physical demands, opioid prescription, union membership, availability of a return-to-work program, employer doubt about work-relatedness of injury, worker's recovery expectations, participation in a rehabilitation program and communication of functional ability was able to identify prolonged claims to a fair degree [area under the curve (AUC) = .79, 95% confidence interval (CI) .74-.84]. A model containing age, sex, physical demands, opioid prescription and communication of functional ability was less successful at predicting time until recurrence (AUC = .61, 95% CI .57, .65). Factors contained in information currently collected by the WSIB during the first 4 weeks on benefits can predict prolonged claims, but not recurrent claims.

Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

PubMed Central

Dutta, Sara; Mincholé, Ana; Zacur, Ernesto; Quinn, T. Alexander; Taggart, Peter; Rodriguez, Blanca

2016-01-01

Aims Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia. Methods and results A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase. Conclusions Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve. PMID:26850675

Preoperative prediction of intensive care unit stay following cardiac surgery.

PubMed

De Cocker, Jeroen; Messaoudi, Nouredin; Stockman, Bernard A; Bossaert, Leo L; Rodrigus, Inez E R

2011-01-01

Following cardiac surgery, a great variety in intensive care unit (ICU) stay is observed, making it often difficult to adequately predict ICU stay preoperatively. Therefore, a study was conducted to investigate, which preoperative variables are independent risk factors for a prolonged ICU stay and whether a patient's risk of experiencing an extended ICU stay can be estimated from these predictors. The records of 1566 consecutive adult patients who underwent cardiac surgery at our institution were analysed retrospectively over a 2-year period. Procedures included in the analyses were coronary artery bypass grafting, valve replacement or repair, ascending and aortic arch surgery, ventricular rupture and aneurysm repair, septal myectomy and cardiac tumour surgery. For this patient group, ICU stay was registered and 57 preoperative variables were collected for analysis. Descriptives and log-rank tests were calculated and Kaplan-Meier curves drawn for all variables. Significant predictors in the univariate analyses were included in a Cox proportional hazards model. The definitive model was validated on an independent sample of 395 consecutive adult patients who underwent cardiac surgery at our institution over an additional 6-month period. In this patient group, the accuracy and discriminative abilities of the model were evaluated. Twelve independent preoperative predictors of prolonged ICU stay were identified: age at surgery>75 years, female gender, dyspnoea status>New York Heart Association class II (NYHA II), unstable symptoms, impaired kidney function (estimated glomerular filtration rate (eGFR)<60 ml min(-1)), extracardiac arterial disease, presence of arrhythmias, mitral insufficiency>colour flow mapping (CFM) grade II, inotropic support, intra-aortic balloon pumping (IABP), non-elective procedures and aortic surgery. The individual effect of every predictor on ICU stay was quantified and inserted into a mathematical algorithm (called the Morbidity Defining Cardiosurgical (MDC) index), making it possible to calculate a patient's risk of having an extended ICU stay. The model showed very good calibration and very good to excellent discriminative ability in predicting ICU stay >2, >5 and >7 days (C-statistic of 0.78; 0.82 and 0.85, respectively). Twelve independent preoperative risk factors for a prolonged ICU stay following cardiac surgery were identified and constructed into a proportional hazards model. Using this risk model, one can predict whether a patient will have a prolonged ICU stay or not. Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

PubMed Central

Chain, Anne SY; Dubois, Vincent FS; Danhof, Meindert; Sturkenboom, Miriam CJM; Della Pasqua, Oscar

2013-01-01

Aims Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule. PMID:23351036

An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells

NASA Technical Reports Server (NTRS)

Wang, Xiang; Khadpe, Jay; Hu, Baocheng; Iliakis, George; Wang, Ya

2003-01-01

Induction of checkpoint responses in G1, S, and G2 phases of the cell cycle after exposure of cells to ionizing radiation (IR) is essential for maintaining genomic integrity. Ataxia telangiectasia mutated (ATM) plays a key role in initiating this response in all three phases of the cell cycle. However, cells lacking functional ATM exhibit a prolonged G2 arrest after IR, suggesting regulation by an ATM-independent checkpoint response. The mechanism for this ataxia telangiectasia (AT)-independent G2-checkpoint response remains unknown. We report here that the G2 checkpoint in irradiated human AT cells derives from an overactivation of the ATR/CHK1 pathway. Chk1 small interfering RNA abolishes the IR-induced prolonged G2 checkpoint and radiosensitizes AT cells to killing. These results link the activation of ATR/CHK1 with the prolonged G2 arrest in AT cells and show that activation of this G2 checkpoint contributes to the survival of AT cells.

Prolonged spontaneous emission and dephasing of localized excitons in air-bridged carbon nanotubes

NASA Astrophysics Data System (ADS)

Sarpkaya, Ibrahim; Zhang, Zhengyi; Walden-Newman, William; Wang, Xuesi; Hone, James; Wong, Chee W.; Strauf, Stefan

2013-07-01

The bright exciton emission of carbon nanotubes is appealing for optoelectronic devices and fundamental studies of light-matter interaction in one-dimensional nanostructures. However, to date, the photophysics of excitons in carbon nanotubes is largely affected by extrinsic effects. Here we perform time-resolved photoluminescence measurements over 14 orders of magnitude for ultra-clean carbon nanotubes bridging an air gap over pillar posts. Our measurements demonstrate a new regime of intrinsic exciton photophysics with prolonged spontaneous emission times up to T1=18 ns, about two orders of magnitude better than prior measurements and in agreement with values hypothesized by theorists about a decade ago. Furthermore, we establish for the first time exciton decoherence times of individual nanotubes in the time domain and find fourfold prolonged values up to T2=2.1 ps compared with ensemble measurements. These first observations motivate new discussions about the magnitude of the intrinsic dephasing mechanism while the prolonged exciton dynamics is promising for applications.

Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

PubMed Central

Anand, Kanwaljeet J. S.; Willson, Douglas F.; Berger, John; Harrison, Rick; Meert, Kathleen L.; Zimmerman, Jerry; Carcillo, Joseph; Newth, Christopher J. L.; Prodhan, Parthak; Dean, J. Michael; Nicholson, Carol

2012-01-01

OBJECTIVE After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS Relevant manuscripts published in the English language were searched in Medline by using search terms “opioid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “tolerance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and “individual opioid drugs.” Clinical and preclinical studies were reviewed for data synthesis. RESULTS Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal. PMID:20403936

Wash and Wean: Bathing Patients Undergoing Weaning Trials During Prolonged Mechanical Ventilation

PubMed Central

Happ, Mary Beth; Tate, Judith A.; Swigart, Valerie A.; DiVirgilio-Thomas, Dana; Hoffman, Leslie A.

2010-01-01

BACKGROUND Bathing is a fundamental nursing care activity performed for or with the self-assistance of critically ill patients. Few studies address caregiver and/or patient-family perspectives about bathing activity during weaning from prolonged mechanical ventilation. OBJECTIVE To describe practices and beliefs about bathing patients during weaning from prolonged mechanical ventilation (PMV). METHODS Secondary analysis of qualitative data (observational field notes, interviews, and clinical record review) from a larger ethnographic study involving 30 patients weaning from PMV and the clinicians who cared for them using basic qualitative description. RESULTS Bathing, hygiene, and personal care were highly valued and equated with “good” nursing care by families and nurses. Nurses and respiratory therapists reported “working around” bath time and promoted conducting weaning trials before or after bathing. Patients were nevertheless bathed during weaning trials despite clinicians expressed concerns for energy conservation. Clinicians’ recognized individual patient response to bathing during PMV weaning trials. CONCLUSION Bathing is a central care activity for PMV patients and a component of daily work processes in the ICU. Bathing requires assessment of patient condition and activity tolerance and nurse-respiratory therapist negotiation and accommodation with respect to the initiation and/or continuation of PMV weaning trials during bathing. Further study is needed to validate the impact (or lack of impact) of various timing strategies for bathing PMV patients. PMID:20561877

MRI patterns in prolonged low response states following traumatic brain injury in children and adolescents.

PubMed

Patrick, Peter D; Mabry, Jennifer L; Gurka, Matthew J; Buck, Marcia L; Boatwright, Evelyn; Blackman, James A

2007-01-01

To explore the relationship between location and pattern of brain injury identified on MRI and prolonged low response state in children post-traumatic brain injury (TBI). This observational study compared 15 children who spontaneously recovered within 30 days post-TBI to 17 who remained in a prolonged low response state. 92.9% of children with brain stem injury were in the low response group. The predicted probability was 0.81 for brain stem injury alone, increasing to 0.95 with a regional pattern of injury to the brain stem, basal ganglia, and thalamus. Low response state in children post-TBI is strongly correlated with two distinctive regions of injury: the brain stem alone, and an injury pattern to the brain stem, basal ganglia, and thalamus. This study demonstrates the need for large-scale clinical studies using MRI as a tool for outcome assessment in children and adolescents following severe TBI.

Not All Prehospital Time is Equal: Influence of Scene Time on Mortality

PubMed Central

Brown, Joshua B.; Rosengart, Matthew R.; Forsythe, Raquel M.; Reynolds, Benjamin R.; Gestring, Mark L.; Hallinan, William M.; Peitzman, Andrew B.; Billiar, Timothy R.; Sperry, Jason L.

2016-01-01

Background Trauma is time-sensitive and minimizing prehospital (PH) time is appealing. However, most studies have not linked increasing PH time with worse outcomes, as raw PH times are highly variable. It is unclear whether specific PH time patterns affect outcomes. Our objective was to evaluate the association of PH time interval distribution with mortality. Methods Patients transported by EMS in the Pennsylvania trauma registry 2000-2013 with total prehospital time (TPT)≥20min were included. TPT was divided into three PH time intervals: response, scene, and transport time. The number of minutes in each PH time interval was divided by TPT to determine the relative proportion each interval contributed to TPT. A prolonged interval was defined as any one PH interval contributing ≥50% of TPT. Patients were classified by prolonged PH interval or no prolonged PH interval (all intervals<50% of TPT). Patients were matched for TPT and conditional logistic regression determined the association of mortality with PH time pattern, controlling for confounders. PH interventions were explored as potential mediators, and prehospital triage criteria used identify patients with time-sensitive injuries. Results There were 164,471 patients included. Patients with prolonged scene time had increased odds of mortality (OR 1.21; 95%CI 1.02–1.44, p=0.03). Prolonged response, transport, and no prolonged interval were not associated with mortality. When adjusting for mediators including extrication and PH intubation, prolonged scene time was no longer associated with mortality (OR 1.06; 0.90–1.25, p=0.50). Together these factors mediated 61% of the effect between prolonged scene time and mortality. Mortality remained associated with prolonged scene time in patients with hypotension, penetrating injury, and flail chest. Conclusions Prolonged scene time is associated with increased mortality. PH interventions partially mediate this association. Further study should evaluate whether these interventions drive increased mortality because they prolong scene time or by another mechanism, as reducing scene time may be a target for intervention. Level of Evidence IV, prognostic study PMID:26886000

Hyperglycemia and subsequent torsades de pointes with marked QT prolongation during refeeding.

PubMed

Nakashima, Takashi; Kubota, Tomoki; Takasugi, Nobuhiro; Kitagawa, Yuichiro; Yoshida, Takahiro; Ushikoshi, Hiroaki; Kawasaki, Masanori; Nishigaki, Kazuhiko; Ogura, Shinji; Minatoguchi, Shinya

2017-01-01

A fatal cardiac complication can occasionally present in malnourished patients during refeeding; this is known as refeeding syndrome. However, to our knowledge, hyperglycemia preceding torsades de pointes with QT prolongation during refeeding has not been reported. In the present study, we present a case in which hyperglycemia preceded torsades de pointes with QT prolongation during refeeding. The aim of this study was to determine the possible mechanism underlying QT prolongation during refeeding and indicate how to prevent it. A 32-y-old severely malnourished woman (body mass index 14.57 kg/m 2 ) was admitted to the intensive care unit of our institution after resuscitation from cardiopulmonary arrest due to ventricular fibrillation. She was diagnosed with anorexia nervosa. Although no obvious electrolyte abnormalities were observed, her blood glucose level was 11 mg/dL. A 12-lead electrocardiogram at admission showed sinus rhythm with normal QT interval (QTc 0.448). Forty mL of 50% glucose (containing 20 g of glucose) was intravenously injected, followed by a drip infusion of glucose to maintain blood glucose level within normal range. After 9 h, the patient's blood glucose level increased to 569 mg/dL. However, after 38 h, an episode of marked QT prolongation (QTc 0.931) followed by torsades de pointes developed. Hyperglycemia during refeeding can present with QT prolongation; consequently, monitoring blood glucose levels may be useful in avoiding hyperglycemia, which can result in QT prolongation. Furthermore, additional monitoring of QT intervals using a 12-lead electrocardiogram should allow the early detection of QT prolongation when glucose solution is administered to a malnourished patient with (severe) hypoglycemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Postural strategy and trunk muscle activation during prolonged standing in chronic low back pain patients.

PubMed

Ringheim, Inge; Austein, Helene; Indahl, Aage; Roeleveld, Karin

2015-10-01

Prolonged standing has been associated with development and aggravation of low back pain (LBP). However, the underlying mechanisms are not well known. The aim of the present study was to investigate postural control and muscle activation during and as a result of prolonged standing in chronic LBP (cLBP) patients compared to healthy controls (HCs). Body weight shifts and trunk and hip muscle activity was measured during 15 min standing. Prior and after the standing trial, strength, postural sway, reposition error (RE), flexion relaxation ratio (FRR), and pain were assessed and after the prolonged standing, ratings of perceived exertion. During prolonged standing, the cLBP patients performed significantly more body weight shifts (p<.01) with more activated back and abdominal muscles (p=.01) and similar temporal variability in muscle activation compared to HCs, while the cLBP patients reported more pain and perceived exertion at the end of prolonged standing. Moreover, both groups had a similar change in strength, postural sway, RE and FRR from before to after prolonged standing, where changes in HC were towards pre-standing values of cLBP patients. Thus, despite a more variable postural strategy, the cLBP patients did not have higher muscle activation variability, but a general increased muscle activation level. This may indicate a reduced ability to individually deactivate trunk muscles. Plausibly, due to the increased variable postural strategy, the cLBP patients could compensate for the relatively high muscle activation level, resulting in normal variation in muscle activation and normal reduction in strength, RE and FRR after prolonged standing. Copyright © 2015 Elsevier B.V. All rights reserved.

Inhibition of spontaneous recovery of fear by mGluR5 after prolonged extinction training.

PubMed

Mao, Sheng-Chun; Chang, Chih-Hua; Wu, Chia-Chen; Orejarena, M Juliana; Orejanera, Maria Juliana; Manzoni, Olivier J; Gean, Po-Wu

2013-01-01

Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1-/- mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR2(3Y), a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.

Identifying Patients at Higher Risk of Prolonged Air Leak After Lung Resection.

PubMed

Gilbert, Sebastien; Maghera, Sonam; Seely, Andrew J; Maziak, Donna E; Shamji, Farid M; Sundaresan, Sudhir R; Villeneuve, Patrick J

2016-11-01

Predictive models of prolonged air leak have relied on information not always available preoperatively (eg, extent of resection, pleural adhesions). Our objective was to construct a model to identify patients at increased risk of prolonged air leak using preoperative factors exclusively. From 2012 to 2014, data on consecutive patients undergoing pulmonary resection were collected prospectively. Prolonged air leak was defined as lasting longer than 7 days and requiring hospitalization. Factors associated with the primary outcome (p < 0.2) were included in a multivariate model. Regression coefficients were used to develop a weighted risk score for prolonged air leak. Of 225 patients, 8% (18/225) experienced a prolonged air leak. Male gender (p = 0.08), smoking history (p = 0.03), body mass index (BMI) 25 or below (p < 0.01), Medical Research Council (MRC) dyspnea score above 1 (p = 0.06), and diffusion capacity for carbon monoxide below 80% (Dlco) (p = 0.01) were selected for inclusion in the final model. Weighted scores were male gender (1 point), BMI 25 or below (0.5 point), smoker (2 points), Dlco% below 80% (2 points), and MRC dyspnea score above 1 (1 point). The area under the receiver operating characteristic curve was 0.8 (95% confidence interval [CI] = 0.7 to 0.9]. An air leak score above 4 points offered the best combination of sensitivity (83% [95% CI = 58 to 96]) and specificity (65% [95% CI = 58 to 71]). A subgroup of lung resection patients at higher risk for a prolonged air leak can be effectively identified with the use of widely available, preoperative factors. The proposed scoring system is simple, is clinically relevant to the informed consent, and allows preoperative patient selection for interventions to reduce the risk of prolonged air leak. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Therapeutic neuroprotective agents for amyotrophic lateral sclerosis

PubMed Central

Pandya, Rachna S.; Zhu, Haining; Li, Wei; Bowser, Robert; Friedlander, Robert M.

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient’s life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression. PMID:23864030

Chronic exposure to chlorpyrifos reveals two modes of action in the springtail Folsomia candida.

PubMed

Jager, Tjalling; Crommentuijn, Trudie; van Gestel, Cornelis A M; Kooijman, Sebastiaan A L M

2007-01-01

Organophosphates are popular insecticides, but relatively little is known about their chronic effects on ecologically relevant endpoints. In this paper, we examine a life-cycle experiment with the springtail Folsomia candida, exposed via food to chlorpyrifos (CPF). The results for all endpoints (survival, growth and reproduction) were analyzed using the DEBtox model. Growth was unaffected by CPF, even at concentrations causing severe effects on survival and reproduction. Model analysis suggests that CPF directly affects the process of egg production. For the short-term response (45 days), this single mode of action accurately agreed with the data. However, the full data set (120 days) revealed a dose-related decrease in reproduction at low concentrations after prolonged exposure, not covered by the same mechanism. It appears that CPF interacts with senescence by increasing oxidative damage. This assumption fits the data well, but has little consequences for the predicted response at the population level.

Recent Advancements in the Global Understanding of what Drives Heatwaves

NASA Astrophysics Data System (ADS)

Perkins-Kirkpatrick, S.

2016-12-01

Heatwaves, defined as prolonged periods of extreme heat, are disastrous events that impact human, natural and industrial systems all over the world. In recent years, the global research effort has greatly increased our understanding on quantifying heatwaves and how they have changed, what drives them, and their future projections. This talk will summarize critical developments made in this field, with particular emphasis on the physical driving mechanisms and the role of internal climate variability. Case studies from various global regions will illustrate both similarities and differences in the physical set-ups of these fascinating events. Future projections of heatwaves and the human contribution behind specific observed heatwave events will be briefly discussed. The talk will conclude by highlighting research priorities such that future investigation is targeted, and closes existing knowledge gaps on what drives heatwaves as effectively as possible. Such developments will ultimately aid in the predictability of heatwaves, thus aiding in reducing their devastating impacts.

Chronic cocaine disrupts mesocortical learning mechanisms

PubMed Central

Buchta, William C.; Riegel, Arthur C.

2016-01-01

The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID:25704202

[Research Progress on the Interaction Effects and Its Neural Mechanisms between Physical Fatigue and Mental Fatigue].

PubMed

Zhang, Lixin; Zhang, Chuncui; He, Feng; Zhao, Xin; Qi, Hongzhi; Wan, Baikun; Ming, Dong

2015-10-01

Fatigue is an exhaustion state caused by prolonged physical work and mental work, which can reduce working efficiency and even cause industrial accidents. Fatigue is a complex concept involving both physiological and psychological factors. Fatigue can cause a decline of concentration and work performance and induce chronic diseases. Prolonged fatigue may endanger life safety. In most of the scenarios, physical and mental workloads co-lead operator into fatigue state. Thus, it is very important to study the interaction influence and its neural mechanisms between physical and mental fatigues. This paper introduces recent progresses on the interaction effects and discusses some research challenges and future development directions. It is believed that mutual influence between physical fatigue and mental fatigue may occur in the central nervous system. Revealing the basal ganglia function and dopamine release may be important to explore the neural mechanisms between physical fatigue and mental fatigue. Future effort is to optimize fatigue models, to evaluate parameters and to explore the neural mechanisms so as to provide scientific basis and theoretical guidance for complex task designs and fatigue monitoring.

Effects of specific and prolonged expression of zebrafish growth factors, Fgf2 and Lif in primordial germ cells in vivo

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

Wong, Ten-Tsao, E-mail: wong20@purdue.edu; Collodi, Paul

2013-01-04

Highlights: Black-Right-Pointing-Pointer We discovered that nanos3 3 Prime UTR prolonged PGC-specific protein expression up to 26 days. Black-Right-Pointing-Pointer Expression of Fgf2 in PGCs significantly increased PGC number at later developmental stages. Black-Right-Pointing-Pointer Expression of Lif in PGCs resulted in a significant disruption of PGC migration. Black-Right-Pointing-Pointer Lif illicited its effect on PGC migration through Lif receptor a. Black-Right-Pointing-Pointer Our approach could be used to achieve prolonged PGC-specific expression of other proteins. -- Abstract: Primordial germ cells (PGCs), specified early in development, proliferate and migrate to the developing gonad before sexual differentiation occurs in the embryo and eventually give rise tomore » spermatogonia or oogonia. In this study, we discovered that nanos3 3 Prime UTR, a common method used to label PGCs, not only directed PGC-specific expression of DsRed but also prolonged this expression up to 26 days post fertilization (dpf) when DsRed-nanos3 3 Prime UTR hybrid mRNAs were introduced into 1- to 2-cell-stage embryos. As such, we employed this knowledge to express zebrafish leukemia inhibitory factor (Lif), basic fibroblast growth factor (Fgf2) and bone morphogenetic protein 4 (Bmp4) in the PGCs and evaluate their effects on PGC development in vivo for over a period of 3 weeks. The results show that expression of Fgf2 significantly increased PGC number at 14- and 21-dpf while Bmp4 resulted in severe ventralization and death of the embryos by 3 days. Expression of Lif resulted in a significant disruption of PGC migration. Mopholino knockdown experiments indicated that Lif illicited its effect on PGC migration through Lif receptor a (Lifra) but not Lifrb. The general approach described in this study could be used to achieve prolonged PGC-specific expression of other proteins to investigate their roles in germ cell and gonad development. The results also indicate that zebrafish PGCs have a mechanism to stabilize and prolong the expression of mRNA that carries nanos3 3 Prime UTR. Understanding this mechanism may make it possible to achieve prolonged RNA expression in other cell types.« less

Choline-modulated arsenic trioxide-induced prolongation of cardiac repolarization in Guinea pig.

PubMed

Sun, Hong-Li; Chu, Wen-Feng; Dong, De-Li; Liu, Yan; Bai, Yun-Long; Wang, Xiao-Hui; Zhou, Jin; Yang, Bao-Feng

2006-04-01

Arsenic trioxide (As(2)O(3)) has been found to be effective for relapsed or refractory acute promyelocytic leukaemia, but its clinical use is burdened by QT prolongation, Torsade de pointes tachycardias, and sudden cardiac death. The aim of the present study was to elucidate the ionic mechanisms of As(2)O(3)-induced abnormalities of cardiac electrophysiology and the therapeutic action of choline on As(2)O(3)-caused QT prolongation in guinea pig. Intravenous administration of As(2)O(3) prolonged the QT interval in a dose- and time-dependent manner in guinea pig hearts, and the QT prolongation could be modulated by choline. By using whole-cell patch clamp technique and confocal laser scanning microscopy, we found that As(2)O(3) significantly lengthened action potential duration measured at 50 and 90% of repolarization, enhanced L-type calcium currents (I(Ca-L)), inhibited delayed rectifier potassium currents (I(K)), and increased intracellular calcium concentration ([Ca(2+)](i)) in guinea pig ventricular myocytes. Choline corrected As(2)O(3)-mediated alterations of action potential duration, I(Ca-L) and [Ca(2+)](i), but had no effect on the I(K) inhibition. As(2)O(3) markedly disturbed the normal equilibrium of transmembrane currents (increasing I(Ca-L) and suppressing I(K)) in guinea pig cardiomyocyte, and induced prolongation of action potential duration, further degenerated into QT prolongation. Choline normalized QT interval abnormality and corrected lengthened action potential duration by inhibiting the elevated I(Ca-L) and [Ca(2+)](i) in ventricular myocytes during As(2)O(3) application.

Prolonged fasting activates Nrf2 in post-weaned elephant seals

PubMed Central

Vázquez-Medina, José Pablo; Soñanez-Organis, José G.; Rodriguez, Ruben; Viscarra, Jose A.; Nishiyama, Akira; Crocker, Daniel E.; Ortiz, Rudy M.

2013-01-01

SUMMARY Elephant seals naturally experience prolonged periods of absolute food and water deprivation (fasting). In humans, rats and mice, prolonged food deprivation activates the renin–angiotensin system (RAS) and increases oxidative damage. In elephant seals, prolonged fasting activates RAS without increasing oxidative damage likely due to an increase in antioxidant defenses. The mechanism leading to the upregulation of antioxidant defenses during prolonged fasting remains elusive. Therefore, we investigated whether prolonged fasting activates the redox-sensitive transcription factor Nrf2, which controls the expression of antioxidant genes, and if such activation is potentially mediated by systemic increases in RAS. Blood and skeletal muscle samples were collected from seals fasting for 1, 3, 5 and 7 weeks. Nrf2 activity and nuclear content increased by 76% and 167% at week 7. Plasma angiotensin II (Ang II) and transforming growth factor β (TGF-β) were 5000% and 250% higher at week 7 than at week 1. Phosphorylation of Smad2, an effector of Ang II and TGF signaling, increased by 120% at week 7 and by 84% in response to intravenously infused Ang II. NADPH oxidase 4 (Nox4) mRNA expression, which is controlled by smad proteins, increased 430% at week 7, while Nox4 protein expression, which can activate Nrf2, was 170% higher at week 7 than at week 1. These results demonstrate that prolonged fasting activates Nrf2 in elephant seals and that RAS stimulation can potentially result in increased Nox4 through Smad phosphorylation. The results also suggest that Nox4 is essential to sustain the hormetic adaptive response to oxidative stress in fasting seals. PMID:23619404

Prolonged fasting activates Nrf2 in post-weaned elephant seals.

PubMed

Vázquez-Medina, José Pablo; Soñanez-Organis, José G; Rodriguez, Ruben; Viscarra, Jose A; Nishiyama, Akira; Crocker, Daniel E; Ortiz, Rudy M

2013-08-01

Elephant seals naturally experience prolonged periods of absolute food and water deprivation (fasting). In humans, rats and mice, prolonged food deprivation activates the renin-angiotensin system (RAS) and increases oxidative damage. In elephant seals, prolonged fasting activates RAS without increasing oxidative damage likely due to an increase in antioxidant defenses. The mechanism leading to the upregulation of antioxidant defenses during prolonged fasting remains elusive. Therefore, we investigated whether prolonged fasting activates the redox-sensitive transcription factor Nrf2, which controls the expression of antioxidant genes, and if such activation is potentially mediated by systemic increases in RAS. Blood and skeletal muscle samples were collected from seals fasting for 1, 3, 5 and 7 weeks. Nrf2 activity and nuclear content increased by 76% and 167% at week 7. Plasma angiotensin II (Ang II) and transforming growth factor β (TGF-β) were 5000% and 250% higher at week 7 than at week 1. Phosphorylation of Smad2, an effector of Ang II and TGF signaling, increased by 120% at week 7 and by 84% in response to intravenously infused Ang II. NADPH oxidase 4 (Nox4) mRNA expression, which is controlled by smad proteins, increased 430% at week 7, while Nox4 protein expression, which can activate Nrf2, was 170% higher at week 7 than at week 1. These results demonstrate that prolonged fasting activates Nrf2 in elephant seals and that RAS stimulation can potentially result in increased Nox4 through Smad phosphorylation. The results also suggest that Nox4 is essential to sustain the hormetic adaptive response to oxidative stress in fasting seals.

Development of a vancomycin dosing approach for critically ill patients receiving hybrid hemodialysis using Monte Carlo simulation.

PubMed

Lewis, Susan J; Mueller, Bruce A

2018-01-01

Prolonged intermittent renal replacement therapy is an increasingly popular treatment for acute kidney injury in critically ill patients that runs at different flow rates and durations than conventional hemodialysis or continuous renal replacement therapies. Pharmacokinetic studies conducted in patients receiving prolonged intermittent renal replacement therapy are scarce; consequently, clinicians are challenged to dose antibiotics effectively. The purpose of this study was to develop vancomycin dosing recommendations for patients receiving prolonged intermittent renal replacement therapy. Monte Carlo simulations were performed in thousands of virtual patients derived from previously published demographic, pharmacokinetic, and dialytic information derived from critically ill patients receiving vancomycin and other forms of renal replacement therapy. We conducted "in silico" vancomycin pharmacokinetic/pharmacodynamics analyses in these patients receiving prolonged intermittent renal replacement therapy to determine what vancomycin dose would achieve vancomycin 24-h area under the curve (AUC 24h ) of 400-700 mg·h/L, a target associated with positive clinical outcomes. Nine different vancomycin dosing regimens were tested using four different, commonly used prolonged intermittent renal replacement therapy modalities. A dosing nomogram based on serum concentration data achieved after the third dose was developed to individualize vancomycin therapy. An initial vancomycin dose of 15 or 20 mg/kg immediately followed by 15 mg/kg after subsequent prolonged intermittent renal replacement therapy treatments achieved AUC 24h of ≥400 mg·h/L for ≥90% of patients regardless of prolonged intermittent renal replacement therapy duration, modality, or time of vancomycin dose relative to prolonged intermittent renal replacement therapy. Many patients experienced AUC 24h of ≥700 mg·h/L, but once the dosing nomogram was applied to serum concentrations obtained after the third vancomycin dose, 67%-88% of patients achieved AUC 24h of 400-700 mg·h/L. An initial loading dose of 15-20 mg/kg followed by a maintenance regimen of 15 mg/kg after every prolonged intermittent renal replacement therapy session coupled with serum concentration monitoring should be used to individualize vancomycin dosing. These predictions need clinical verification.

Developmental Modulation of the Temporal Relationship Between Brain and Behavior

PubMed Central

Crandall, Shane R.; Aoki, Naoya; Nick, Teresa A.

2008-01-01

Humans and songbirds shape learned vocalizations during a sensorimotor sensitive period or “babbling” phase. The brain mechanisms that underlie the shaping of vocalizations by sensory feedback are not known. We examined song behavior and brain activity in zebra finches during singing as they actively shaped their song toward a tutor model. We now show that the temporal relationship of behavior and activity in the premotor area HVC changes with the development of song behavior. During sensorimotor learning, HVC bursting activity both preceded and followed learned vocalizations by hundreds of milliseconds. Correspondingly, the duration of bursts that occurred during ongoing song motif behavior was prolonged in juveniles, as compared with adults, and was inversely correlated with song maturation. Multielectrode single-unit recording in juveniles revealed that single fast-spiking neurons were active both before and after vocalization. These same neurons responded to auditory stimuli. Collectively, these data indicate that a key aspect of sensory critical periods—prolonged bursting—also applies to sensorimotor development. In addition, prolonged motor discharge and sensory input coincide in single neurons of the developing song system, providing the necessary cellular elements for sensorimotor shaping through activity-dependent mechanisms. PMID:17079340

Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study.

PubMed

Liu, Xinyang; Qin, Shukui; Wang, Zhichao; Xu, Jianming; Xiong, Jianping; Bai, Yuxian; Wang, Zhehai; Yang, Yan; Sun, Guoping; Wang, Liwei; Zheng, Leizhen; Xu, Nong; Cheng, Ying; Guo, Weijian; Yu, Hao; Liu, Tianshu; Lagiou, Pagona; Li, Jin

2017-09-05

Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan-Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64-0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53-0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival. Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.

Recurrence of CMV Infection and the Effect of Prolonged Antivirals in Organ Transplant Recipients.

PubMed

Natori, Yoichiro; Humar, Atul; Husain, Shahid; Rotstein, Coleman; Renner, Eberhard; Singer, Lianne; Kim, S Joseph; Kumar, Deepali

2017-06-01

Although initial therapy for cytomegalovirus (CMV) is usually successful, a significant subset of patients may have recurrent viremia. However, the epidemiology and risk factors for recurrence have not been fully defined, as well as the utility of prolonged antivirals after initial clearance. Solid organ transplant patients with first episode of CMV disease or asymptomatic viremia (≥1000 IU/mL) requiring treatment were identified by chart review. Clinical and virologic data were collected. The primary outcome was recurrence of CMV viremia or disease within 6 months of treatment discontinuation. The first episode of CMV viremia requiring antiviral therapy was assessed in 282 patients (147 CMV disease and 135 asymptomatic viremia). Cytomegalovirus occurred at 5.6 (0.63-27.7) months posttransplant. Recurrent CMV occurred in 30.5% patients at a median of 51 (0-160) days after discontinuation of therapy. Factors predictive of recurrence were treatment phase viral kinetics (P = 0.005), lung transplant (P = 0.002), CMV donor (D)+/recipient (R)- serostatus(P = 0.04) and recent acute rejection(P = 0.02). Prolonged antiviral therapy was given to 226 (80.1%) of 282 patients. Recurrence occurred in 73 (32.3%) of 226 patients that received prolonged antivirals versus 13 (23.2%) of 56 in those with no prolonged antivirals (P = 0.19). Recurrent CMV occurs in a significant percentage of patients after treatment of the first episode of CMV viremia/disease. CMV D+/R- serostatus, lung transplant, and treatment phase viral kinetics were significant predictors of recurrence. Continuation of prolonged antivirals beyond initial clearance was not associated with a reduced risk of recurrence.

Current health and preferences for life-prolonging treatments: an application of prospect theory to end-of-life decision making.

PubMed

Winter, Laraine; Parker, Barbara

2007-10-01

As a substantial body of research attests, the acceptability of life-prolonging treatment (e.g., tube feeding) tends to be greater among people in worse health than among healthier ones. Because a decision for or against a life-prolonging treatment represents a choice between two prospects-life (usually in poor health) and death-we propose a decision model, Prospect Theory, as a theoretical account of this phenomenon. Prospect Theory postulates that pairs of distant prospects are less distinguishable than pairs of closer ones. Thus, to healthy individuals, the prospects of death and life in poor health would both be remote, and therefore, the distinction between them, small. To less healthy individuals, however, the difference between the same pairs of prospects would appear greater, and therefore, life-prolonging treatment may be more acceptable. In a cross-sectional study of 304 community-dwelling people, aged 60 years and over in the Philadelphia area, USA, preferences for 4 life-prolonging treatments in 9 health scenarios were examined in relation to participants' current health, operationalized as number of deficits in physical functioning. As predicted, less healthy people expressed stronger preferences for all life-prolonging treatments compared with healthier ones, with differences greatest in the worse-health scenarios. Preferences also varied by health scenario, with any treatment preferred in the better health scenarios. Treatment preferences did not differ by type of treatment, depressed mood or any demographic characteristic except race, with African-Americans expressing stronger treatment preferences. Implications for advance care planning are discussed.

Association between QRS duration and obstructive sleep apnea.

PubMed

Gupta, Shuchita; Cepeda-Valery, Beatriz; Romero-Corral, Abel; Shamsuzzaman, Abu; Somers, Virend K; Pressman, Gregg S

2012-12-15

Both obstructive sleep apnea (OSA) and prolonged QRS duration are associated with hypertension, heart failure, and sudden cardiac death. However, possible links between QRS duration and OSA have not been explored. Cross-sectional study of 221 patients who underwent polysomnography at our center. Demographics, cardiovascular risk factors and ECG were collected to explore a relationship between OSA and QRS duration. The apnea-hypopnea index (AHI) was positively correlated with QRS duration (r = 0.141, p = 0.03). Patients were divided into 3 groups: AHI < 5 (61), AHI 5-29 (104), and AHI > 30 (55). The mean QRS duration prolonged significantly as OSA worsened (AHI < 5, 85 ± 9.5; AHI 5-29, 89 ± 11.9; and AHI > 30, 95 ± 19.9 ms, p = 0.001). QRS ≥ 100 ms was present in 12.7% of patients with severe OSA compared with 0% in the rest of the sample (p < 0.0001). After adjustment for age, race, and cardiovascular risk factors, this association remained significant in women but not in men. QRS duration and OSA were significantly associated. Severity of OSA independently predicted prolonged QRS in women but not men. Nevertheless, prolongation of QRS duration in either sex may potentiate arrhythmic risks associated with OSA.

Resilience and vulnerability: prolonged grief in the bereaved spouses of marital partners who died of AIDS.

PubMed

Yu, Nancy Xiaonan; Chan, Cecilia L W; Zhang, Jianxin; Stewart, Sunita M

2016-01-01

Spousal bereavement is closely linked to prolonged grief, that is, significant adjustment symptoms that last for more than six months after the loss. This article focused on potential risk and protective factors that may influence bereavement outcomes. Participants in this study were surviving spouses of individuals who died of acquired immune deficiency syndrome (AIDS). These participants were themselves living with human immunodeficiency syndrome. In this cross-sectional study, 120 bereaved participants completed measures of grief, quality of dying and death of the deceased, negative conceptions of death resulting from AIDS, death attitudes, and personal resilience. The results showed that one-third (35.0%) of the bereaved participants reported grief levels above the prolonged grief cut-off scores, and can be categorized as the "prolonged grief" group. Although quality of dying and death was not associated with the intensity of grief, negative conceptions of death from AIDS, fear of death and resilience independently predicted grief symptoms in the regression models. Our findings provide insight into the grief process for the surviving spouse of AIDS victims in rural China. Since resilience is malleable, developing resilience interventions to enhance adjustment to bereavement may be a promising direction in grief counselling and therapies.

Accelerated Degradation Test and Predictive Failure Analysis of B10 Copper-Nickel Alloy under Marine Environmental Conditions

PubMed Central

Sun, Bo; Ye, Tianyuan; Feng, Qiang; Yao, Jinghua; Wei, Mumeng

2015-01-01

This paper studies the corrosion behavior of B10 copper-nickel alloy in marine environment. Accelerated degradation test under marine environmental conditions was designed and performed based on the accelerated testing principle and the corrosion degradation mechanism. With the prolongation of marine corrosion time, the thickness of Cu2O film increased gradually. Its corrosion product was Cu2(OH)3Cl, which increased in quantity over time. Cl− was the major factor responsible for the marine corrosion of copper and copper alloy. Through the nonlinear fitting of corrosion rate and corrosion quantity (corrosion weight loss), degradation data of different corrosion cycles, the quantitative effects of two major factors, i.e., dissolved oxygen (DO) and corrosion medium temperature, on corrosion behavior of copper alloy were analyzed. The corrosion failure prediction models under different ambient conditions were built. One-day corrosion weight loss under oxygenated stirring conditions was equivalent to 1.31-day weight loss under stationary conditions, and the corrosion rate under oxygenated conditions was 1.31 times higher than that under stationary conditions. In addition, corrosion medium temperature had a significant effect on the corrosion of B10 copper sheet. PMID:28793549

Accelerated Degradation Test and Predictive Failure Analysis of B10 Copper-Nickel Alloy under Marine Environmental Conditions.

PubMed

Sun, Bo; Ye, Tianyuan; Feng, Qiang; Yao, Jinghua; Wei, Mumeng

2015-09-10

This paper studies the corrosion behavior of B10 copper-nickel alloy in marine environment. Accelerated degradation test under marine environmental conditions was designed and performed based on the accelerated testing principle and the corrosion degradation mechanism. With the prolongation of marine corrosion time, the thickness of Cu₂O film increased gradually. Its corrosion product was Cu₂(OH)₃Cl, which increased in quantity over time. Cl - was the major factor responsible for the marine corrosion of copper and copper alloy. Through the nonlinear fitting of corrosion rate and corrosion quantity (corrosion weight loss), degradation data of different corrosion cycles, the quantitative effects of two major factors, i.e. , dissolved oxygen (DO) and corrosion medium temperature, on corrosion behavior of copper alloy were analyzed. The corrosion failure prediction models under different ambient conditions were built. One-day corrosion weight loss under oxygenated stirring conditions was equivalent to 1.31-day weight loss under stationary conditions, and the corrosion rate under oxygenated conditions was 1.31 times higher than that under stationary conditions. In addition, corrosion medium temperature had a significant effect on the corrosion of B10 copper sheet.

Predictors of Intra-Aortic Balloon Pump Insertion in Coronary Surgery and Mid-Term Results

PubMed Central

Yurekli, Ismail; Celik, Ersin; Yetkin, Ufuk; Yilik, Levent; Gurbuz, Ali

2013-01-01

Background We aimed to investigate the preoperative, operative, and postoperative factors affecting intra-aortic balloon pump (IABP) insertion in patients undergoing isolated on-pump coronary artery bypass grafting (CABG). We also investigated factors affecting morbidity, mortality, and survival in patients with IABP support. Methods Between January 2002 and December 2009, 1,657 patients underwent isolated CABG in İzmir Katip Celebi University Atatürk Training and Research Hospital. The number of patients requiring support with IABP was 134 (8.1%). Results In a multivariate logistic regression analysis, prolonged cardiopulmonary bypass time and prolonged operation time were independent predictive factors of IABP insertion. The postoperative mortality rate was 35.8% and 1% in patients with and without IABP support, respectively (p=0.000). Postoperative renal insufficiency, prolonged ventilatory support, and postoperative atrial fibrillation were independent predictive factors of postoperative mortality in patients with IABP support. The mean follow-up time was 38.55±22.70 months and 48.78±25.20 months in patients with and without IABP support, respectively. The follow-up mortality rate was 3% (n=4) and 5.3% (n=78) in patients with and without IABP support, respectively. Conclusion The patients with IABP support had a higher postoperative mortality rate and a longer length of intensive care unit and hospital stay. The mid-term survival was good for patients surviving the early postoperative period. PMID:24368971

Survival of Listeria monocytogenes and Staphylococcus aureus in Synthetic Brines. Studying the Effects of Salt, Temperature and Sugar through the Approach of the Design of Experiments

PubMed Central

Bevilacqua, Antonio; Campaniello, Daniela; Speranza, Barbara; Sinigaglia, Milena; Corbo, Maria R.

2018-01-01

The fermentation of table olives relies on a complex microbiota of lactic acid bacteria (LAB), yeasts, and enterobacteria. Producers often add sugar to increase the growth rate of LAB, “but this practice could also increase the survival rate of some pathogens. Therefore, the main topic of this paper was to study the effect of sugar, salt and temperature on the survival of Staphylococcus aureus and Listeria monocytogenes in a synthetic brine through the theory of the Design of Experiments (simplex centroid). The addition of sugar could prolong the survival time of L. monocytogenes by 40 days, whereas an increase of the temperature caused a decrease of survival from 18 to 3 days. The survival time of S. aureus was prolonged by 50 days by combining sugar (2–4 g/l) and low temperatures (5–15°C). The use of desirability approach and prediction profiles suggests that the prolongation of the survival time of L. monocytogenes could be related to a shift in the geometrical shape of the death kinetic. This paper offers a structured statistical approach on the variables acting on the survival of two pathogens in brines and represents the first step to set up and design a predictive approach for olive producers. PMID:29497414

Restitution slope is principally determined by steady-state action potential duration.

PubMed

Shattock, Michael J; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela W C; Niederer, Steven; MacLeod, Kenneth T; Winter, James

2017-06-01

The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM - to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology

Restitution slope is principally determined by steady-state action potential duration

PubMed Central

Shattock, Michael J.; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela W. C.; Niederer, Steven; MacLeod, Kenneth T.

2017-01-01

Aims The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Methods and results Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Conclusion(s) Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death. PMID:28371805

Prophylactic tracheotomy and lung cancer resection in patient with low predictive pulmonary function: a randomized clinical trials.

PubMed

Filaire, Marc; Tardy, Marie M; Richard, Ruddy; Naamee, Adel; Chadeyras, Jean Baptiste; Da Costa, Valence; Bailly, Patrick; Eisenmann, Nathanaël; Pereira, Bruno; Merle, Patrick; Galvaing, Géraud

2015-12-01

Whether prophylactic tracheotomy can shorten the duration of mechanical ventilation (MV) in high risk patients eligible for lung cancer resection. The objective was to compare duration of MV and outcome in 39 patients randomly assigned to prophylactic tracheotomy or control. Prospective randomized controlled, single-center trial (ClinicalTrials.gov Identifier: NCT01053624). The primary outcome measure was the cumulative number of MV days after operation until discharge. The secondary outcome measures were the 60 days mortality rate, the ICU and the hospital length of stay, the incidence of postoperative respiratory, cardiac and general complications, the reventilation rate, the need of noninvasive ventilation (NIV), the need of a tracheotomy in control group and the tracheal complications. The duration of MV was not significantly different between the tracheotomy group (3.5±6 days) and the control group (4.7±9.3 days) (P=0.54). Among patients needing prolonged MV >4 days, tracheotomy patients had a shortened duration of MV than control patients (respectively 11.4±7.1 and 20.4±9.6 days, P=0.04). The rate of respiratory complications were significantly lower in the tracheotomy group than in the control group (28% vs. 51%, P=0.03). Six patients (15%) needed a postoperative tracheotomy in the control group because of a prolonged MV >7 days. Tracheotomy was associated with a reduced need of NIV (P=0.04). There was no difference in 60-day mortality rate, cardiac complications, intensive care unit and hospital length of stay. No death was related with the tracheotomy. Prophylactic tracheotomy in patients with ppo FEV1 <50% who underwent thoracotomy for lung cancer resection provided benefits in terms of duration of prolonged MV and respiratory complications but was not associated with a decreased mortality rate, ICU and hospital length of stay and non-respiratory complications.

MRI-Based Computational Fluid Dynamics in Experimental Vascular Models: Toward the Development of an Approach for Prediction of Cardiovascular Changes During Prolonged Space Missions

NASA Technical Reports Server (NTRS)

Spirka, T. A.; Myers, J. G.; Setser, R. M.; Halliburton, S. S.; White, R. D.; Chatzimavroudis, G. P.

2005-01-01

A priority of NASA is to identify and study possible risks to astronauts health during prolonged space missions [l]. The goal is to develop a procedure for a preflight evaluation of the cardiovascular system of an astronaut and to forecast how it will be affected during the mission. To predict these changes, a computational cardiovascular model must be constructed. Although physiology data can be used to make a general model, a more desirable subject-specific model requires anatomical, functional, and flow data from the specific astronaut. MRI has the unique advantage of providing images with all of the above information, including three-directional velocity data which can be used as boundary conditions in a computational fluid dynamics (CFD) program [2,3]. MRI-based CFD is very promising for reproduction of the flow patterns of a specific subject and prediction of changes in the absence of gravity. The aim of this study was to test the feasibility of this approach by reconstructing the geometry of MRI-scanned arterial models and reproducing the MRI-measured velocities using CFD simulations on these geometries.

Lifetime Prediction of Nano-Silica based Glass Fibre/Epoxy composite by Time Temperature Superposition Principle

NASA Astrophysics Data System (ADS)

Anand, Abhijeet; Banerjee, Poulami; Prusty, Rajesh Kumar; Ray, Bankin Chandra

2018-03-01

The incorporation of nano fillers in Fibre reinforced polymer (FRP) composites has been a source of experimentation for researchers. Addition of nano fillers has been found to improve mechanical, thermal as well as electrical properties of Glass fibre reinforced polymer (GFRP) composites. The in-plane mechanical properties of GFRP composite are mainly controlled by fibers and therefore exhibit good values. However, composite exhibits poor through-thickness properties, in which the matrix and interface are the dominant factors. Therefore, it is conducive to modify the matrix through dispersion of nano fillers. Creep is defined as the plastic deformation experienced by a material for a temperature at constant stress over a prolonged period of time. Determination of Master Curve using time-temperature superposition principle is conducive for predicting the lifetime of materials involved in naval and structural applications. This is because such materials remain in service for a prolonged time period before failure which is difficult to be kept marked. However, the failure analysis can be extrapolated from its behaviour in a shorter time at an elevated temperature as is done in master creep analysis. The present research work dealt with time-temperature analysis of 0.1% SiO2-based GFRP composites fabricated through hand-layup method. Composition of 0.1% for SiO2nano fillers with respect to the weight of the fibers was observed to provide optimized flexural properties. Time and temperature dependence of flexural properties of GFRP composites with and without nano SiO2 was determined by conducting 3-point bend flexural creep tests over a range of temperature. Stepwise isothermal creep tests from room temperature (30°C) to the glass transition temperature Tg (120°C) were performed with an alternative creep/relaxation period of 1 hour at each temperature. A constant stress of 40MPa was applied during the creep tests. The time-temperature superposition principle was followed while determining the Master Curve and cumulative damage law. The purpose of a Master Curve was to determine the variation of compliance with respect to increase in time and temperature of the specimen. The shift factors at any reference temperature were determined by Arrhenius activation energy method at a far lower temperature than Tg (Glass transition temperature) and by manual shift method at a temperature near Tg (Glass transition temperature).

Mechanism-related circulating proteins as biomarkers for clinical outcome in patients with unresectable hepatocellular carcinoma receiving sunitinib

PubMed Central

2011-01-01

Background Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -β, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome. Methods Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT). Results At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS. Conclusions Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib. Trial registration ClinicalTrials.gov: NCT00247676 PMID:21787417

Effects of prolonged vibration to vastus intermedius muscle on force steadiness of knee extensor muscles during isometric force-matching task.

PubMed

Saito, Akira; Ando, Ryosuke; Akima, Hiroshi

2016-12-01

Afferent inputs from Ia fibers in muscle spindles are essential for the control of force and prolonged vibration has been applied to muscle-tendon units to manipulate the synaptic input from Ia afferents onto α-motor neurons. The vastus intermedius (VI) reportedly provides the highest contribution to the low-level knee extension torque among the individual synergists of quadriceps femoris (QF). The purpose of the present study was to examine the effect of prolonged vibration to the VI on force steadiness of the QF. Nine healthy men (25.1±4.3years) performed submaximal force-matching task of isometric knee extension for 15s before and after mechanical vibration to the superficial region of VI for 30min. Target forces were 2.5%, 10%, and 30% of maximal voluntary contraction (MVC), and force steadiness was determined by the coefficient of variation (CV) of force. After the prolonged VI vibration, the CV of force at 2.5%MVC was significantly increased, but CVs at 10% and 30%MVCs were not significantly changed. The present study concluded that application of prolonged vibration to the VI increased force fluctuations of the QF during a very low-level force-matching task. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multigrid methods in structural mechanics

NASA Technical Reports Server (NTRS)

Raju, I. S.; Bigelow, C. A.; Taasan, S.; Hussaini, M. Y.

1986-01-01

Although the application of multigrid methods to the equations of elasticity has been suggested, few such applications have been reported in the literature. In the present work, multigrid techniques are applied to the finite element analysis of a simply supported Bernoulli-Euler beam, and various aspects of the multigrid algorithm are studied and explained in detail. In this study, six grid levels were used to model half the beam. With linear prolongation and sequential ordering, the multigrid algorithm yielded results which were of machine accuracy with work equivalent to 200 standard Gauss-Seidel iterations on the fine grid. Also with linear prolongation and sequential ordering, the V(1,n) cycle with n greater than 2 yielded better convergence rates than the V(n,1) cycle. The restriction and prolongation operators were derived based on energy principles. Conserving energy during the inter-grid transfers required that the prolongation operator be the transpose of the restriction operator, and led to improved convergence rates. With energy-conserving prolongation and sequential ordering, the multigrid algorithm yielded results of machine accuracy with a work equivalent to 45 Gauss-Seidel iterations on the fine grid. The red-black ordering of relaxations yielded solutions of machine accuracy in a single V(1,1) cycle, which required work equivalent to about 4 iterations on the finest grid level.

The Second Century: Our Vision for the Future.

ERIC Educational Resources Information Center

Dickman, Donna M.; Levinson, Ken

1990-01-01

This paper speculates on the coming century's opportunities and challenges for the Alexander Graham Bell Association. Medical advancements prolonging life and the subsequent increase in the elderly population are discussed, as are computer and telecommunications advances. Futurists' predictions of increasing disposable income and social conscience…

Biology and the Future of Man.

ERIC Educational Resources Information Center

Canipe, Stephen L.

The purpose of this unit is to provoke discussion and thought by the reader. Topics considered include cloning; amniocentesis and sex determination; predicting abnormalities and abortion; transplants; life prolonging machines; cryogenics; prenatal surgery; sperm and egg banks; radiation; psychobehavior, ESB (electrical stimulation of the brain),…

Munc13 controls the location and efficiency of dense-core vesicle release in neurons.

PubMed

van de Bospoort, Rhea; Farina, Margherita; Schmitz, Sabine K; de Jong, Arthur; de Wit, Heidi; Verhage, Matthijs; Toonen, Ruud F

2012-12-10

Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2-null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.

Prolonged environment-induced hyperthermia alters autophagy in oxidative skeletal muscle in Sus scrofa.

PubMed

Ganesan, Shanthi; Brownstein, Alexandra J; Pearce, Sarah C; Hudson, Matthew B; Gabler, Nicolas K; Baumgard, Lance H; Rhoads, Robert P; Selsby, Joshua T

2018-05-01

Prolonged heat stress represents a continuing threat to human health and agricultural production. Despite the broad, negative impact of prolonged hyperthermia little is known about underlying pathological mechanisms leading to negative health outcomes, which has limited the development of etiological interventions and left clinicians and producers with only cooling and rehydration strategies. The purpose of this investigation was to determine the extent to which prolonged environment-induced hyperthermia altered autophagy in oxidative skeletal muscle in a large animal model, serving the dual purpose of accurately modeling human physiology as well as agricultural production. We hypothesized that prolonged hyperthermia would induce autophagy in skeletal muscle, independent of the accompanying caloric restriction. To test this hypothesis pigs were treated as follows: thermoneutral (20 °C), heat stress (35 °C), or were held under thermoneutral conditions but pair-fed to the heat stress group for seven days. Upon euthanasia the red portion of the semitendinosus was collected. We found that prolonged hyperthermic exposure increased oxidative stress without a corresponding change in antioxidant enzyme activities. Hyperthermia prevented initiation of autophagy despite increased markers of nucleation, elongation and autophagosome formation. However, p62 relative protein abundance, which is inversely correlated with autophagic degradation, was strongly increased suggesting suppressed degradation of autophagosomes. Markers of mitophagy and mitochondrial abundance were largely similar between groups. These data indicate that faulty autophagy plays a key role in hyperthermic muscle dysfunction. Copyright © 2018 Elsevier Ltd. All rights reserved.

Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials

PubMed Central

2011-01-01

Background The emergence of multi-drug resistant Gram-negatives (MDRGNs) coupled with an alarming scarcity of new antibiotics has forced the optimization of the therapeutic potential of available antibiotics. To exploit the time above the minimum inhibitory concentration mechanism of β-lactams, prolonging their infusion may improve outcomes. The primary objective of this meta-analysis was to determine if prolonged β-lactam infusion resulted in decreased mortality and improved clinical cure compared to intermittent β-lactam infusion. Methods Relevant studies were identified from searches of MEDLINE, EMBASE, and CENTRAL. Heterogeneity was assessed qualitatively, in addition to I2 and Chi-square statistics. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel random-effects models. Results Fourteen randomized controlled trials (RCTs) were included. Prolonged infusion β-lactams were not associated with decreased mortality (n= 982; RR 0.92; 95% CI:0.61-1.37) or clinical cure (n = 1380; RR 1.00 95% CI:0.94-1.06) compared to intermittent infusions. Subgroup analysis for β-lactam subclasses and equivalent total daily β-lactam doses yielded similar results. Most studies had notable methodological flaws. Conclusions No clinical advantage was observed for prolonged infusion β-lactams. The limited number of studies with MDRGNs precluded evaluation of prolonged infusion of β-lactams for this subgroup. A large, multicenter RCT with critically ill patients infected with MDRGNs is needed. PMID:21696619

A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake

PubMed Central

Fulcher, Ben D.; Phillips, Andrew J. K.; Postnova, Svetlana; Robinson, Peter A.

2014-01-01

The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia. PMID:24651580

Hydraulic limits preceding mortality in a piñon-juniper woodland under experimental drought.

PubMed

Plaut, Jennifer A; Yepez, Enrico A; Hill, Judson; Pangle, Robert; Sperry, John S; Pockman, William T; McDowell, Nate G

2012-09-01

Drought-related tree mortality occurs globally and may increase in the future, but we lack sufficient mechanistic understanding to accurately predict it. Here we present the first field assessment of the physiological mechanisms leading to mortality in an ecosystem-scale rainfall manipulation of a piñon-juniper (Pinus edulis-Juniperus monosperma) woodland. We measured transpiration (E) and modelled the transpiration rate initiating hydraulic failure (E(crit) ). We predicted that isohydric piñon would experience mortality after prolonged periods of severely limited gas exchange as required to avoid hydraulic failure; anisohydric juniper would also avoid hydraulic failure, but sustain gas exchange due to its greater cavitation resistance. After 1 year of treatment, 67% of droughted mature piñon died with concomitant infestation by bark beetles (Ips confusus) and bluestain fungus (Ophiostoma spp.); no mortality occurred in juniper or in control piñon. As predicted, both species avoided hydraulic failure, but safety margins from E(crit) were much smaller in piñon, especially droughted piñon, which also experienced chronically low hydraulic conductance. The defining characteristic of trees that died was a 7 month period of near-zero gas exchange, versus 2 months for surviving piñon. Hydraulic limits to gas exchange, not hydraulic failure per se, promoted drought-related mortality in piñon pine. © 2012 Blackwell Publishing Ltd.

Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation.

PubMed

Dolinay, Tamas; Himes, Blanca E; Shumyatcher, Maya; Lawrence, Gladys Gray; Margulies, Susan S

2017-08-01

Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI.

Branched-Chain Amino Acid Supplementation Reduces Oxidative Stress and Prolongs Survival in Rats with Advanced Liver Cirrhosis

PubMed Central

Mifuji-Moroka, Rumi; Hara, Nagisa; Miyachi, Hirohide; Sugimoto, Ryosuke; Tanaka, Hideaki; Fujita, Naoki; Gabazza, Esteban C.; Takei, Yoshiyuki

2013-01-01

Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver. PMID:23936183

Acute first-time hamstring strains during slow-speed stretching: clinical, magnetic resonance imaging, and recovery characteristics.

PubMed

Askling, Carl M; Tengvar, Magnus; Saartok, Tönu; Thorstensson, Alf

2007-10-01

Hamstring strains can be of 2 types with different injury mechanisms, 1 occurring during high-speed running and the other during stretching exercises. A stretching type of injury to the proximal rear thigh may involve specific muscle-tendon structures that could affect recovery time. Case series (prognosis); Level of evidence, 2. Fifteen professional dancers with acute first-time hamstring strains were prospectively included in the study. All subjects were examined, clinically and with magnetic resonance imaging, on 4 occasions after injury: at day 2 to 4, 10, 21, and 42. The clinical follow-up period was 2 years. All dancers were injured during slow hip-flexion movements with extended knee and experienced relatively mild acute symptoms. All injuries were located proximally in the posterior thigh close to the ischial tuberosity. The injury involved the semimembranosus (87%), quadratus femoris (87%), and adductor magnus (33%). All injuries to the semimembranosus involved its proximal free tendon. There were no significant correlations between clinical or magnetic resonance imaging parameters and the time to return to preinjury level (median, 50 weeks; range, 30-76 weeks). Stretching exercises can give rise to a specific type of strain injury to the posterior thigh. A precise history and careful palpation provide the clinician enough information to predict a prolonged time until return to preinjury level. One factor underlying prolonged recovery time could be the involvement of the free tendon of the semimembranosus muscle.

Fetal stomach position predicts neonatal outcomes in isolated left-sided congenital diaphragmatic hernia

PubMed Central

Basta, Amaya M; Lusk, Leslie A; Keller, Roberta L; Filly, Roy A

2015-01-01

Introduction We sought to determine the relationship between degree of stomach herniation by antenatal sonography and neonatal outcomes in fetuses with isolated left-sided congenital diaphragmatic hernia (CDH). Materials and Methods We retrospectively reviewed neonatal medical records and antenatal sonography of fetuses with isolated left CDH cared for at a single institution (2000–2012). Fetal stomach position was classified on sonography as follows: intra-abdominal, anterior left chest, mid-to-posterior left chest, or retrocardiac (right chest). Results Ninety fetuses were included with 70% surviving to neonatal discharge. Stomach position was intra-abdominal in 14% (n=13), anterior left chest in 19% (n=17), mid-to-posterior left chest in 41% (n=37), and retrocardiac in 26% (n=23). Increasingly abnormal stomach position was linearly associated with an increased odds of death (OR 4.8, 95%CI 2.1–10.9), extracorporeal membrane oxygenation (ECMO) (OR 5.6, 95%CI 1.9–16.7), nonprimary diaphragmatic repair (OR 2.7, 95%CI 1.4–5.5), prolonged mechanical ventilation (OR 5.9, 95%CI 2.3–15.6), and prolonged respiratory support (OR 4.0, 95%CI 1.6–9.9). All fetuses with intra-abdominal stomach position survived without substantial respiratory morbidity or need for ECMO. Discussion Fetal stomach position is strongly associated with neonatal outcomes in isolated left CDH. This objective tool may allow for accurate prognostication in a variety of clinical settings. PMID:26562540

Fetal Stomach Position Predicts Neonatal Outcomes in Isolated Left-Sided Congenital Diaphragmatic Hernia.

PubMed

Basta, Amaya M; Lusk, Leslie A; Keller, Roberta L; Filly, Roy A

2016-01-01

We sought to determine the relationship between the degree of stomach herniation by antenatal sonography and neonatal outcomes in fetuses with isolated left-sided congenital diaphragmatic hernia (CDH). We retrospectively reviewed neonatal medical records and antenatal sonography of fetuses with isolated left CDH cared for at a single institution (2000-2012). Fetal stomach position was classified on sonography as follows: intra-abdominal, anterior left chest, mid-to-posterior left chest, or retrocardiac (right chest). Ninety fetuses were included with 70% surviving to neonatal discharge. Stomach position was intra-abdominal in 14% (n = 13), anterior left chest in 19% (n = 17), mid-to-posterior left chest in 41% (n = 37), and retrocardiac in 26% (n = 23). Increasingly abnormal stomach position was linearly associated with an increased odds of death (OR 4.8, 95% CI 2.1-10.9), extracorporeal membrane oxygenation (ECMO; OR 5.6, 95% CI 1.9-16.7), nonprimary diaphragmatic repair (OR 2.7, 95% CI 1.4-5.5), prolonged mechanical ventilation (OR 5.9, 95% CI 2.3-15.6), and prolonged respiratory support (OR 4.0, 95% CI 1.6-9.9). All fetuses with intra-abdominal stomach position survived without substantial respiratory morbidity or need for ECMO. Fetal stomach position is strongly associated with neonatal outcomes in isolated left CDH. This objective tool may allow for accurate prognostication in a variety of clinical settings. © 2015 S. Karger AG, Basel.

Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain.

PubMed

Nokia, Miriam S; Anderson, Megan L; Shors, Tracey J

2012-12-01

Chemotherapy, especially if prolonged, disrupts attention, working memory and speed of processing in humans. Most cancer drugs that cross the blood-brain barrier also decrease adult neurogenesis. Because new neurons are generated in the hippocampus, this decrease may contribute to the deficits in working memory and related thought processes. The neurophysiological mechanisms that underlie these deficits are generally unknown. A possible mediator is hippocampal oscillatory activity within the theta range (3-12 Hz). Theta activity predicts and promotes efficient learning in healthy animals and humans. Here, we hypothesised that chemotherapy disrupts learning via decreases in hippocampal adult neurogenesis and theta activity. Temozolomide was administered to adult male Sprague-Dawley rats in a cyclic manner for several weeks. Treatment was followed by training with different types of eyeblink classical conditioning, a form of associative learning. Chemotherapy reduced both neurogenesis and endogenous theta activity, as well as disrupted learning and related theta-band responses to the conditioned stimulus. The detrimental effects of temozolomide only occurred after several weeks of treatment, and only on a task that requires the association of events across a temporal gap and not during training with temporally overlapping stimuli. Chemotherapy did not disrupt the memory for previously learned associations, a memory independent of (new neurons in) the hippocampus. In conclusion, prolonged systemic chemotherapy is associated with a decrease in hippocampal adult neurogenesis and theta activity that may explain the selective deficits in processes of learning that describe the 'chemobrain'. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Inhibition of the ubiquitin-proteasome pathway does not protect against ventilator-induced accelerated proteolysis or atrophy in the diaphragm.

PubMed

Smuder, Ashley J; Nelson, W Bradley; Hudson, Matthew B; Kavazis, Andreas N; Powers, Scott K

2014-07-01

Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown that calpain, caspase-3, and the ubiquitin-proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, although it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in the development of VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD. The authors tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8 per group). The results of this study reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 h of MV. Also, inhibition of the UPP does not affect MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, muscle ring finger-1 (MuRF1), and atrogin-1/MaFbx. Collectively, these results indicate that proteasome activation does not play a required role in VIDD development during the first 12 h of MV.

Postoperative air leak grading is useful to predict prolonged air leak after pulmonary lobectomy.

PubMed

Oh, Sang Gi; Jung, Yochun; Jheon, Sanghoon; Choi, Yunhee; Yun, Ju Sik; Na, Kook Joo; Ahn, Byoung Hee

2017-01-23

Results of studies to predict prolonged air leak (PAL; air leak longer than 5 days) after pulmonary lobectomy have been inconsistent and are of limited use. We developed a new scale representing the amount of early postoperative air leak and determined its correlation with air leak duration and its potential as a predictor of PAL. We grade postoperative air leak using a 5-grade scale. All 779 lobectomies from January 2005 to December 2009 with available medical records were reviewed retrospectively. We devised six 'SUM' variables using air leak grades in the initial 72 h postoperatively. Excluding unrecorded cases and postoperative broncho-pleural fistulas, there were 720 lobectomies. PAL occurred in 135 cases (18.8%). Correlation analyses showed each SUM variable highly correlated with air leak duration, and the SUM 4to9 , which was the sum of six consecutive values of air leak grades for every 8 h record on postoperative days 2 and 3, was proved to be the most powerful predictor of PAL; PAL could be predicted with 75.7% and 77.7% positive and negative predictive value, respectively, when SUM 4to9  ≥ 16. When 4 predictors derived from multivariable logistic regression of perioperative variables were combined with SUM 4to9 , there was no significant increase in predictability compared with SUM 4to9 alone. This simple new method to predict PAL using SUM 4to9 showed that the amount of early postoperative air leak is the most powerful predictor of PAL, therefore, grading air leak after pulmonary lobectomy is a useful method to predict PAL.

Excitation-transcription coupling via calcium/calmodulin-dependent protein kinase/ERK1/2 signaling mediates the coordinate induction of VGLUT2 and Narp triggered by a prolonged increase in glutamatergic synaptic activity.

PubMed

Doyle, Sukhjeevan; Pyndiah, Slovénie; De Gois, Stéphanie; Erickson, Jeffrey D

2010-05-07

Homeostatic scaling of glutamatergic and GABAergic transmission is triggered by prolonged alterations in synaptic neuronal activity. We have previously described a presynaptic mechanism for synaptic homeostasis and plasticity that involves scaling the level of vesicular glutamate (VGLUT1) and gamma-aminobutyric acid (GABA) (VGAT) transporter biosynthesis. These molecular determinants of vesicle filling and quantal size are regulated by neuronal activity in an opposite manner and bi-directionally. Here, we report that a striking induction of VGLUT2 mRNA and synaptic protein is triggered by a prolonged increase in glutamatergic synaptic activity in mature neocortical neuronal networks in vitro together with two determinants of inhibitory synaptic strength, the neuronal activity-regulated pentraxin (Narp), and glutamate decarboxylase (GAD65). Activity-dependent induction of VGLUT2 and Narp exhibits a similar intermediate-early gene response that is blocked by actinomycin D and tetrodotoxin, by inhibitors of ionotropic glutamate receptors and L-type voltage-gated calcium channels, and is dependent on downstream signaling via calmodulin, calcium/calmodulin-dependent protein kinase (CaMK) and extracellular signal-regulated kinase 1/2 (ERK1/2). The co-induction of VGLUT2 and Narp triggered by prolonged gamma-aminobutyric acid type A receptor blockade is independent of brain-derived nerve growth factor and TrkB receptor signaling. VGLUT2 protein induction occurs on a subset of cortically derived synaptic vesicles in excitatory synapses on somata and dendritic processes of multipolar GABAergic interneurons, recognized sites for the clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptors by Narp. We propose that VGLUT2 and Narp induction by excitation-transcription coupling leads to increased glutamatergic transmission at synapses on GABAergic inhibitory feedback neurons as part of a coordinated program of Ca(2+)-signal transcription involved in mechanisms of homeostatic plasticity after prolonged hyperactivity.

The mechanisms of delayed onset type adverse reactions to oseltamivir

PubMed Central

Hama, Rokuro

2016-01-01

Abstract Oseltamivir is recommended for the treatment and prophylaxis of influenza in persons at higher risk for influenza complications such as individuals with diabetes, neuropsychiatric illnesses, and respiratory, cardiac, renal, hepatic or haematological diseases. However, a recent Cochrane review reported that reduction of antibody production, renal disorders, hyperglycaemia, psychiatric disorders, and QT prolongation may be related to oseltamivir use. The underlying mechanisms are reviewed. There is decisive evidence that administration of a clinically compatible dose of oseltamivir in mice challenged by a respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed symptom-relieving effects and inhibition of viral clearance. These effects were accompanied by decreased level of T cell surface sialoglycosphingolipid (ganglioside) GM1 that is regulated by the endogenous neuraminidase in response to viral challenge. Clinical and non-clinical evidence supports the view that the usual dose of oseltamivir suppresses pro-inflammatory cytokines such as interferon-gamma, interleukin-6, and tumour necrosis factor-alpha almost completely with partial suppression of viral shedding in human influenza virus infection experiment. Animal toxicity tests support the clinical evidence with regard to renal and cardiac disorders (bradycardia and QT prolongation) and do not disprove the metabolic effect. Reduction of antibody production and cytokine induction and renal, metabolic, cardiac, and prolonged psychiatric disorders after oseltamivir use may be related to inhibition of the host’s endogenous neuraminidase. While the usual clinical dose of zanamivir may not have this effect, a higher dose or prolonged administration of zanamivir and other neuraminidase inhibitors may induce similar delayed reactions, including reduction of the antibody and/or cytokine production. PMID:27251370

Organ toxicity and mortality in propofol-sedated rabbits under prolonged mechanical ventilation.

PubMed

Ypsilantis, Petros; Politou, Maria; Mikroulis, Dimitrios; Pitiakoudis, Michail; Lambropoulou, Maria; Tsigalou, Christina; Didilis, Vasilios; Bougioukas, Georgios; Papadopoulos, Nikolaos; Manolas, Constantinos; Simopoulos, Constantinos

2007-07-01

Prolonged administration of propofol at large doses has been implicated in propofol infusion syndrome in intensive care unit patients. In this study we investigated organ toxicity and mortality of propofol sedation at large doses in prolonged mechanically ventilated rabbits and determined the role of propofol's lipid vehicle. Eighteen healthy male rabbits were endotracheally intubated and sedated with propofol 2% (Group P), sevoflurane (Group S) or sevoflurane while receiving Intralipid 10% (Group SI). Sedation lasted 48 h or until death (Group P) or the maximum surviving period of Group P (Groups S and SI). The initial propofol infusion rate (20 mg x kg(-1) x h(-1)) or sevoflurane concentration (1.5%) was adjusted, if needed, to maintain a standard level of sedation. Blood biochemical analysis was performed in serial blood samples and histologic examination in the heart, lungs, liver, gallbladder, kidneys, urinary bladder, and quadriceps femoris muscle at autopsy. The mortality rate was 100% (surviving period, 26-38 h) for Group P, whereas 0% for Groups S and SI. The initial propofol infusion rate had to be increased up to 65.7 +/- 4.6 mg x kg(-1) x h(-1) and sevoflurane concentration up to 4%. Serum liver function indices, lipids and creatine kinase were significantly increased (P < 0.05) in Groups P and SI and lactate was increased only in Group P, whereas amylase was increased in all groups. In Group P, histologic examination revealed myocarditis, pulmonary edema with interstitial pneumonia, hepatitis, steatosis, and focal liver necrosis, cholangitis, gallbladder necrosis, acute tubular necrosis of the kidneys, focal loss of the urinary bladder epithelium, and rhabdomyolysis of skeletal muscles; in Group S, low-grade bronchitis and incipient inflammation of the liver and the kidneys; and in Group SI, low-grade bronchitis, liver steatosis and hepatitis, and incipient inflammation of the gallbladder, kidneys, and urinary bladder. Continuous infusion of 2% propofol at large doses for the sedation of rabbits undergoing prolonged mechanical ventilation induced fatal multiorgan dysfunction syndrome similar to the propofol infusion syndrome seen in humans. Our novel findings including lung, liver, gallbladder, and urinary bladder injury were also noted. The role of propofol's lipid vehicle in the manifestation of the syndrome was minor. Sevoflurane proved to be a safe alternative medication for prolonged sedation.

Expanded Prediction Equations of Human Sweat Loss and Water Needs

DTIC Science & Technology

2009-01-01

Evaluation of the limits to accurate sweat loss prediction during prolonged exercise. Eur J Appl Physiol 101: 215–224, 2007. 4. Chinevere TD ...113–117, 2001. 17. Miller RG. Simultaneous Statistical Interference (2nd ed.). New York: Springer, 1981. 18. Mitchell JW, Nadel ER, Stolwijk JAJ ...modeling of physiological responses and human performance in the heat. Comput Biol Med 16: 319–329, 1986. 20. Saltin B, Gagge AP, Stolwijk JAJ . Body

Interactive influence of the Atlantic and Pacific climates and their contribution to the multidecadal variations of global temperature and precipitation.

NASA Astrophysics Data System (ADS)

Barcikowska, M. J.; Knutson, T. R.; Zhang, R.

2016-12-01

This study investigates mechanisms and global-scale climate impacts of multidecadal climate variability. Here we show, using observations and CSIRO-Mk3.6.0 model control run, that multidecadal variability of the Atlantic Meridional Overturning Circulation (AMOC) may have a profound impact on the thermal- and hydro-climatic changes over the Pacific region. In our model-based analysis we propose a mechanism, which comprises a coupled ocean-atmosphere teleconnection, established through the atmospheric overturning circulation cell between the tropical North Atlantic and tropical Pacific. For example, warming SSTs over the tropical North Atlantic intensify local convection and reinforce subsidence, low-level divergence in the eastern tropical Pacific. This is also accompanied with an intensification of trade winds, cooling and drying anomalies in the tropical central-east Pacific. The derived multidecadal changes, associated with the AMOC, contribute remarkably to the global temperature and precipitation variations. This highlights its potential predictive value. Shown here results suggest a possibility that: 1) recently observed slowdown in global warming may partly originate from internal variability, 2) climate system may be undergoing a transition to a cold AMO phase which could prolong the global slowdown.

Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants Ventilated With Continuous Positive Airway Pressure vs. Mechanical Ventilation

PubMed Central

Thomas, Cameron W.; Meinzen-Derr, Jareen; Hoath, Steven B.; Narendran, Vivek

2012-01-01

OBJECTIVE To compare continuous positive airway pressure (CPAP) vs. traditional mechanical ventilation (MV) at 24 h of age as predictors of neurodevelopmental (ND) outcomes in extremely low birth weight (ELBW) infants at 18-22 mo corrected gestational age (CGA). METHODS Infants ≤ 1000g birth weight born from January 2000 through December 2006 at two hospitals at the Cincinnati site of the National Institute of Child Health and Human Development Neonatal Research Network were evaluated comparing CPAP (N = 198) vs. MV (N = 109). Primary outcomes included the Bayley Score of Infant Development Version II (BSID-II), presence of deafness, blindness, cerebral palsy, bronchopulmonary dysplasia and death. RESULTS Ventilatory groups were similar in gender, rates of preterm prolonged rupture of membranes, antepartum hemorrhage, use of antenatal antibiotics, steroids, and tocolytics. Infants receiving CPAP weighed more, were older, were more likely to be non-Caucasian and from a singleton pregnancy. Infants receiving CPAP had better BSID-II scores, and lower rates of BPD and death. CONCLUSIONS After adjusting for acuity differences, ventilatory strategy at 24 h of age independently predicts long-term neurodevelopmental outcome in ELBW infants. PMID:21853318

Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig.

PubMed

Guns, P-J; Johnson, D M; Weltens, E; Lissens, J

2012-09-01

Assessment of the propensity of novel drugs to cause proarrhythmia is essential in the drug development process. It is increasingly recognized, however, that QT prolongation alone is an imperfect surrogate marker for Torsades de Pointes (TdP) arrhythmia prediction. In the present study we investigated the behavior of a novel surrogate marker for TdP, the electro-mechanical (E-M) window, prior to triggering of TdP episodes with sympathetic stimulation after administration of a number of reference compounds. Experiments were carried out in closed chest pentobarbital anesthetized guinea pigs. Test compounds were administered intravenously together with a specific I(Ks) blocker (JNJ303; 0.2 mgkg(-1)min(-1) for 3 min) and adrenaline (0.06 mgkg(-1)min(-1) for 2 min) was applied to trigger TdP. ECG, blood- and left ventricular pressure signals were measured continuously throughout the experiments. The E-M window i.e. the duration of the mechanical systole (QLVP(end) interval) minus the duration of the electrical activity (QT interval) was assessed for individual beats. Drugs with documented TdP liability (quinidine, haloperidol, domperidone, terfenadine, moxifloxacin, ciprofloxacin and dofetilide) produced TdP in the protocol after adrenaline infusion, whereas negative control compounds (verapamil, ranolazine, amiodarone and saline) did not cause TdP arrhythmia, even though increases in repolarization times were observed. TdP were typically preceded by large (greater than -50 ms) negative electro-mechanical windows and were accompanied by aftercontractions. The present study in anesthetized guinea pigs indicates that negative E-M windows are a prerequisite for sympathetically-driven TdP induction after the administration of various agents with known proarrhythmic potential. These data are a first step in the validation of this novel protocol; however we believe that this proarrhythmia model in small animals might be a valuable additional tool in the prediction of TdP risk of new chemical entities at the early stages of drug discovery. Copyright © 2012 Elsevier Inc. All rights reserved.

A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers.

PubMed

Kim, Anhye; Lim, Kyoung Soo; Lee, Howard; Chung, Hyewon; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Jang, In-Jin; Chung, Jae-Yong

2016-07-01

Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4×4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for ΔΔQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the ΔΔQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on ΔΔQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-ΔΔQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose-response manner.

Risk Factors for Severe Infection, Hospitalization, and Prolonged Antimicrobial Therapy in Patients with Babesiosis.

PubMed

Mareedu, Neeharik; Schotthoefer, Anna M; Tompkins, Jason; Hall, Matthew C; Fritsche, Thomas R; Frost, Holly M

2017-10-01

Babesiosis is an emerging tick-borne disease transmitted by the hard tick Ixodes scapularis , which also transmits Lyme disease. Better gradation of prognostic indicators are needed to determine which patients may develop serious complications requiring hospitalization, and to provide early guidance on appropriate therapy. In this study, we evaluated 128 patients with smear or real time polymerase chain reaction-confirmed Babesia microti infections over a period of 16 years. Patients with asplenia or immunocompromising conditions were more likely to have severe infection ( P < 0.01), require hospitalization ( P < 0.01), or receive prolonged courses of antimicrobials ( P < 0.01). Nausea or vomiting ( P < 0.01) and diarrhea ( P < 0.01) along with hyperbilirubinemia ( P < 0.01) were predictive of severe infection, hospitalization, and prolonged antimicrobial therapy. Patients with concurrent Lyme disease were less likely to require hospitalization and had similar severity of disease and length of antibiotic treatment compared with those without Lyme disease.

[Factors related to the QT prolongation in chronic renal failure].

PubMed

Kurosu, M; Ando, Y; Akimoto, T; Ono, S; Kusano, E; Asano, Y

1999-04-01

QT prolongation, a risk factor for arrhythmia and cardiac death, is observed in uremic patients. Though hypocalcemia, autonomic nerve dysfunction and cardiac hypertrophy are assumed to cause the uremic QT prolongation, the exact mechanism remains unspecified. We therefore examined factors related to the QT interval in chronic renal failure (CRF). Corrected QT interval (QTc) was significantly prolonged in CRF just before the induction of dialysis therapy (group A) compared with nephrotic syndrome with the intact or mildly impaired renal function (group B). QTc was also prolonged in acute renal failure (group C). Cardio-thoracic ratio, serum albumin and Ca correlated with QTc in group A, but not in B or C. A single HD session in group A failed to shorten QTc, despite a significant increase in serum Ca++. Autonomic dysfunction did not appear to be a major determinant of QT prolongation, since QTc was not different between diabetics and non-diabetics in group A and in chronic HD patients (group D). In group D, QTc did not correlate with SV1 + RV5 on ECG or left ventricular wall thickness (LVWT) on echocardiography. In another group of chronic HD patients (group E), there was no significant correlation between QTc and the parameters of left ventricular mass, plasma brain natriuretic peptide (BNP). However, in the patients subjected to repeated echocardiography in group D, QTc and LVWT changed in parallel. In a retrospective analysis of QTc in group D, QTc was maximally prolonged at the time of starting HD therapy, and gradually improved in the following 1-5 years in both diabetics and non-diabetics. In contrast, chronic CAPD patients (group F) revealed no improvement of QTc. Thus, uremic QT prolongation cannot be explained simply by any of the previously assumed factors, but appears to be affected by multiple factors, which are partially correctable by chronic HD therapy.

Sidestep and crossover lower limb kinematics during a prolonged sport-like agility test.

PubMed

Potter, Danielle; Reidinger, Kellie; Szymialowicz, Rebecca; Martin, Thomas; Dione, Donald; Feinn, Richard; Wallace, David; Garbalosa, Juan C

2014-10-01

Non-contact anterior cruciate ligament (ACL) injuries in athletes occur more often towards the end of athletic competitions. However, the exact mechanisms of how prolonged activity increases the risk for ACL injuries are not clear. To determine the effect of prolonged activity on the hip and knee kinematics observed during self-selected cutting maneuvers performed in a timed agility test. Nineteen female Division I collegiate soccer players completed a self-selected cutting agility test until they were unable to meet a set performance time (one standard deviation of the average baseline trial). Using the 3D dimensional coordinate data the cut type was identified by the principle investigators. The 3D hip and knee angles at 32ms post heel strike were analyzed using a two-factor, linear mixed model to assess the effect of prolonged activity and cut type on the recorded mean hip and knee angles. Athletes performed either sidestep or crossover cuts. An effect of cut type and prolonged activity was seen at the hip and knee. During the prolonged activity trials, the knee was relatively more adducted and both the hip and knee were less flexed than during the baseline trials regardless of cut type. Regardless of activity status, during sidestep cuts, the hip was more internally rotated and abducted, and less flexed than during crossover cuts while the knee was more abducted and less flexed during the sidestep than crossover cuts. During a sport-like agility test, prolonged activity appears to predispose the athlete to position their knee in a more extended and abducted posture and their hip in a more extended posture. This position has been suggested to place stress on the ACL and potentially increase the risk for injury. Clinicians may want to consider the effects of prolonged activity on biomechanical risk factors for sustaining ACL injuries in the design of intervention strategies to prevent ACL injuries. Level 4.

Making Better Scar: Emerging Approaches for Modifying Mechanical and Electrical Properties Following Infarction and Ablation

PubMed Central

Holmes, Jeffrey W.; Laksman, Zachary; Gepstein, Lior

2015-01-01

Following myocardial infarction (MI), damaged myocytes are replaced by collagenous scar tissue, which serves an important mechanical function – maintaining integrity of the heart wall against enormous mechanical forces – but also disrupts electrical function as structural and electrical remodeling in the infarct and borderzone predispose to re-entry and ventricular tachycardia. Novel emerging regenerative approaches aim to replace this scar tissue with viable myocytes. Yet an alternative strategy of therapeutically modifying selected scar properties may also prove important, and in some cases may offer similar benefits with lower risk or regulatory complexity. Here, we review potential goals for such modifications as well as recent proof-of-concept studies employing specific modifications, including gene therapy to locally increase conduction velocity or prolong the refractory period in and around the infarct scar, and modification of scar anisotropy to improve regional mechanics and pump function. Another advantage of scar modification techniques is that they have applications well beyond MI. In particular, ablation treats electrical abnormalities of the heart by intentionally generating scar to block aberrant conduction pathways. Yet in diseases such as atrial fibrillation (AF) where ablation can be extensive, treating the electrical disorder can significantly impair mechanical function. Creating smaller, denser scars that more effectively block conduction, and choosing the location of those lesions by balancing their electrical and mechanical impacts, could significantly improve outcomes for AF patients. We review some recent advances in this area, including the use of computational models to predict the mechanical effects of specific lesion sets and gene therapy for functional ablation. Overall, emerging techniques for modifying scar properties represents a potentially important important set of tools for improving patient outcomes across a range of heart diseases, whether used in place of or as an adjunct to regenerative approaches. PMID:26615948

Evaluating the utility of two gestural discomfort evaluation methods

PubMed Central

Son, Minseok; Jung, Jaemoon; Park, Woojin

2017-01-01

Evaluating physical discomfort of designed gestures is important for creating safe and usable gesture-based interaction systems; yet, gestural discomfort evaluation has not been extensively studied in HCI, and few evaluation methods seem currently available whose utility has been experimentally confirmed. To address this, this study empirically demonstrated the utility of the subjective rating method after a small number of gesture repetitions (a maximum of four repetitions) in evaluating designed gestures in terms of physical discomfort resulting from prolonged, repetitive gesture use. The subjective rating method has been widely used in previous gesture studies but without empirical evidence on its utility. This study also proposed a gesture discomfort evaluation method based on an existing ergonomics posture evaluation tool (Rapid Upper Limb Assessment) and demonstrated its utility in evaluating designed gestures in terms of physical discomfort resulting from prolonged, repetitive gesture use. Rapid Upper Limb Assessment is an ergonomics postural analysis tool that quantifies the work-related musculoskeletal disorders risks for manual tasks, and has been hypothesized to be capable of correctly determining discomfort resulting from prolonged, repetitive gesture use. The two methods were evaluated through comparisons against a baseline method involving discomfort rating after actual prolonged, repetitive gesture use. Correlation analyses indicated that both methods were in good agreement with the baseline. The methods proposed in this study seem useful for predicting discomfort resulting from prolonged, repetitive gesture use, and are expected to help interaction designers create safe and usable gesture-based interaction systems. PMID:28423016

Prediction of L70 lumen maintenance and chromaticity for LEDs using extended Kalman filter models

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

Lall, Pradeep; Wei, Junchao; Davis, Lynn

2013-09-30

Solid-state lighting (SSL) luminaires containing light emitting diodes (LEDs) have the potential of seeing excessive temperatures when being transported across country or being stored in non-climate controlled warehouses. They are also being used in outdoor applications in desert environments that see little or no humidity but will experience extremely high temperatures during the day. This makes it important to increase our understanding of what effects high temperature exposure for a prolonged period of time will have on the usability and survivability of these devices. Traditional light sources “burn out” at end-of-life. For an incandescent bulb, the lamp life is definedmore » by B50 life. However, the LEDs have no filament to “burn”. The LEDs continually degrade and the light output decreases eventually below useful levels causing failure. Presently, the TM-21 test standard is used to predict the L70 life of LEDs from LM-80 test data. Several failure mechanisms may be active in a LED at a single time causing lumen depreciation. The underlying TM-21 Model may not capture the failure physics in presence of multiple failure mechanisms. Correlation of lumen maintenance with underlying physics of degradation at system-level is needed. In this paper, Kalman Filter (KF) and Extended Kalman Filters (EKF) have been used to develop a 70-percent Lumen Maintenance Life Prediction Model for LEDs used in SSL luminaires. Ten-thousand hour LM-80 test data for various LEDs have been used for model development. System state at each future time has been computed based on the state space at preceding time step, system dynamics matrix, control vector, control matrix, measurement matrix, measured vector, process noise and measurement noise. The future state of the lumen depreciation has been estimated based on a second order Kalman Filter model and a Bayesian Framework. The measured state variable has been related to the underlying damage using physics-based models. Life prediction of L70 life for the LEDs used in SSL luminaires from KF and EKF based models have been compared with the TM-21 model predictions and experimental data.« less

L70 life prediction for solid state lighting using Kalman Filter and Extended Kalman Filter based models

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

Lall, Pradeep; Wei, Junchao; Davis, Lynn

2013-08-08

Solid-state lighting (SSL) luminaires containing light emitting diodes (LEDs) have the potential of seeing excessive temperatures when being transported across country or being stored in non-climate controlled warehouses. They are also being used in outdoor applications in desert environments that see little or no humidity but will experience extremely high temperatures during the day. This makes it important to increase our understanding of what effects high temperature exposure for a prolonged period of time will have on the usability and survivability of these devices. Traditional light sources “burn out” at end-of-life. For an incandescent bulb, the lamp life is definedmore » by B50 life. However, the LEDs have no filament to “burn”. The LEDs continually degrade and the light output decreases eventually below useful levels causing failure. Presently, the TM-21 test standard is used to predict the L70 life of LEDs from LM-80 test data. Several failure mechanisms may be active in a LED at a single time causing lumen depreciation. The underlying TM-21 Model may not capture the failure physics in presence of multiple failure mechanisms. Correlation of lumen maintenance with underlying physics of degradation at system-level is needed. In this paper, Kalman Filter (KF) and Extended Kalman Filters (EKF) have been used to develop a 70-percent Lumen Maintenance Life Prediction Model for LEDs used in SSL luminaires. Ten-thousand hour LM-80 test data for various LEDs have been used for model development. System state at each future time has been computed based on the state space at preceding time step, system dynamics matrix, control vector, control matrix, measurement matrix, measured vector, process noise and measurement noise. The future state of the lumen depreciation has been estimated based on a second order Kalman Filter model and a Bayesian Framework. The measured state variable has been related to the underlying damage using physics-based models. Life prediction of L70 life for the LEDs used in SSL luminaires from KF and EKF based models have been compared with the TM-21 model predictions and experimental data.« less

Prediction of Lumen Output and Chromaticity Shift in LEDs Using Kalman Filter and Extended Kalman Filter Based Models

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

Lall, Pradeep; Wei, Junchao; Davis, J Lynn

2014-06-24

Abstract— Solid-state lighting (SSL) luminaires containing light emitting diodes (LEDs) have the potential of seeing excessive temperatures when being transported across country or being stored in non-climate controlled warehouses. They are also being used in outdoor applications in desert environments that see little or no humidity but will experience extremely high temperatures during the day. This makes it important to increase our understanding of what effects high temperature exposure for a prolonged period of time will have on the usability and survivability of these devices. Traditional light sources “burn out” at end-of-life. For an incandescent bulb, the lamp life ismore » defined by B50 life. However, the LEDs have no filament to “burn”. The LEDs continually degrade and the light output decreases eventually below useful levels causing failure. Presently, the TM-21 test standard is used to predict the L70 life of LEDs from LM-80 test data. Several failure mechanisms may be active in a LED at a single time causing lumen depreciation. The underlying TM-21 Model may not capture the failure physics in presence of multiple failure mechanisms. Correlation of lumen maintenance with underlying physics of degradation at system-level is needed. In this paper, Kalman Filter (KF) and Extended Kalman Filters (EKF) have been used to develop a 70-percent Lumen Maintenance Life Prediction Model for LEDs used in SSL luminaires. Ten-thousand hour LM-80 test data for various LEDs have been used for model development. System state at each future time has been computed based on the state space at preceding time step, system dynamics matrix, control vector, control matrix, measurement matrix, measured vector, process noise and measurement noise. The future state of the lumen depreciation has been estimated based on a second order Kalman Filter model and a Bayesian Framework. Life prediction of L70 life for the LEDs used in SSL luminaires from KF and EKF based models have been compared with the TM-21 model predictions and experimental data.« less

Influence of LVAD function on mechanical unloading and electromechanical delay: a simulation study.

PubMed

Heikhmakhtiar, Aulia Khamas; Ryu, Ah Jin; Shim, Eun Bo; Song, Kwang-Soup; Trayanova, Natalia A; Lim, Ki Moo

2018-05-01

This study hypothesized that a left ventricular assist device (LVAD) shortens the electromechanical delay (EMD) by mechanical unloading. The goal of this study is to examine, by computational modeling, the influence of LVAD on EMD for four heart failure (HF) cases ranging from mild HF to severe HF. We constructed an integrated model of an LVAD-implanted cardiovascular system, then we altered the Ca 2+ transient magnitude, with scaling factors 1, 0.9, 0.8, and 0.7 representing HF1, HF2, HF3, and HF4, respectively, in order of increasing HF severity. The four HF conditions are classified into two groups. Group one is the four HF conditions without LVAD, and group two is the conditions treated with continuous LVAD pump. The single-cell mechanical responses showed that EMD was prolonged with the higher load. The findings indicated that in group one, the HF-induced Ca2 + transient remodeling prolonged the mechanical activation time (MAT) and decreased the contractile tension, which reduced the left ventricle (LV) pressure, and increased the end-diastolic strain. In group two, LVAD shortened MAT of the ventricles. Furthermore, LVAD reduced the contractile tension, and end-diastolic strain, but increased the aortic pressure. The computational study demonstrated that LVAD shortens EMD by mechanical unloading of the ventricle.

Gravitational force modulates G2/M phase exit in mechanically unloaded myoblasts

PubMed Central

Benavides Damm, Tatiana; Franco-Obregón, Alfredo; Egli, Marcel

2013-01-01

Prolonged spaceflight gives rise to muscle loss and reduced strength, a condition commonly referred to as space atrophy. During exposure to microgravity, skeletal muscle myoblasts are mechanically unloaded and respond with attenuated cell proliferation, slowed cell cycle progression, and modified protein expression. To elucidate the underlying mechanisms by which muscle mass declines in response to prolonged microgravity exposure, we grew C2C12 mouse muscle cells under conditions of simulated microgravity (SM) and analyzed their proliferative capacity, cell cycle progression, and cyclin B and D expression. We demonstrated that the retarded cell growth observed in SM was correlated with an approximate 16 h delay in G2/M phase progression, where cells accumulated specifically between the G2 checkpoint and the onset of anaphase, concomitantly with a positive expression for cyclin B. The effect was specific for gravitational mechanical unloading as cells grown under conditions of hypergravity (HG, 4 g) for similar durations of time exhibited normal proliferation and normal cell cycle progression. Our results show that SM and HG exert phenomenological distinct responses over cell cycle progression. The deficits of SM can be restored by terrestrial gravitational force, whereas the effects of HG are indistinguishable from the 1 g control. This suggests that the mechanotransduction apparatus of cells responds differently to mechanical unloading and loading. PMID:23974110

Disambiguating Dependency and Attachment Among Conjugally Bereaved Adults

PubMed Central

DENCKLA, CHRISTY A.; BORNSTEIN, ROBERT F.; MANCINI, ANTHONY D.; BONANNO, GEORGE A.

2017-01-01

This study aims to investigate the effects of dependency and attachment in adjusting to the loss of a loved one by directly comparing the relative contribution of each to bereavement outcomes among midlife adults. Comparisons among attachment and dependency are made using models that control for attachment among three groups of bereaved adults (N=102): prolonged grievers (n=25), resolved grievers (n=41), and a married comparison group (n=36). Prolonged grievers displayed higher marginal means of dysfunctional detachment dependency and lower marginal means of healthy dependency compared to resolved grievers and married adults, even when controlling for attachment style. Findings suggest that attachment and dependency predict unique domains of grief outcome. PMID:28855854

Disambiguating Dependency and Attachment Among Conjugally Bereaved Adults.

PubMed

Denckla, Christy A; Bornstein, Robert F; Mancini, Anthony D; Bonanno, George A

2015-01-01

This study aims to investigate the effects of dependency and attachment in adjusting to the loss of a loved one by directly comparing the relative contribution of each to bereavement outcomes among midlife adults. Comparisons among attachment and dependency are made using models that control for attachment among three groups of bereaved adults ( N =102): prolonged grievers ( n =25), resolved grievers ( n =41), and a married comparison group ( n =36). Prolonged grievers displayed higher marginal means of dysfunctional detachment dependency and lower marginal means of healthy dependency compared to resolved grievers and married adults, even when controlling for attachment style. Findings suggest that attachment and dependency predict unique domains of grief outcome.

Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residue in the Voltage Sensor

PubMed Central

McBride, Christie M.; Smith, Ashley M.; Smith, Jennifer L.; Reloj, Allison R.; Velasco, Ellyn J.; Powell, Jonathan; Elayi, Claude S.; Bartos, Daniel C.; Burgess, Don E.

2013-01-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing IKr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (IKv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients’ genotypes) mostly corrected the changes in IKv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing IKr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease IKr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient. PMID:23546015

Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.

PubMed

McBride, Christie M; Smith, Ashley M; Smith, Jennifer L; Reloj, Allison R; Velasco, Ellyn J; Powell, Jonathan; Elayi, Claude S; Bartos, Daniel C; Burgess, Don E; Delisle, Brian P

2013-05-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

Reliability of solid-state lighting electrical drivers subjected to WHTOL accelerated aging

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

Lall, Pradeep; Sakalauku, Peter; Davis, Lynn

An investigation of a solid-state lighting (SSL) luminaire with the focus on the electronic driver which has been exposed to a standard wet hot temperature operating life (WHTOL) of 85% RH and 85°C in order to assess reliability of prolonged exposer to a harsh environment has been conducted. SSL luminaires are beginning introduced as head lamps in some of today's luxury automobiles and may also be fulfilling a variety of important outdoor applications such as overhead street lamps, traffic signals and landscape lighting. SSL luminaires in these environments are almost certain to encounter excessive moisture from humidity and high temperaturesmore » for a persistent period of time. The lack of accelerated test methods for LEDs to assess long-term reliability prior to introduction into the marketplace, a need for SSL physics based PHM modeling indicators for assessment and prediction of LED life, as well as the U.S. Department of Energy's R&D roadmap to replace todays lighting with SSL luminaires makes it important to increase the understanding of the reliability of SSL devices, specifically, in harsh environment applications. In this work, a set of SSL electrical drivers were investigated to determine failure mechanisms that occur during prolonged harsh environment applications. Each driver consists of four aluminum electrolytic capacitors (AECs) of three different types and was considered the weakest component inside the SSL electrical driver. The reliability of the electrical driver was assessed by monitoring the change in capacitance and the change in equivalent series resistance for each AEC, as well as monitoring the luminous flux of the SSL luminaire or the output of the electrical driver. The luminous flux of a pristine SSL electrical driver was also monitored in order to detect minute changes in the electrical drivers output and to aid in the investigation of the SSL luminaires reliability. The failure mechanisms of the electrical drivers have been determined and are presented in this paper.« less

Infant Growth in Length Follows Prolonged Sleep and Increased Naps

PubMed Central

Lampl, Michelle; Johnson, Michael L.

2011-01-01

Study Objectives: The mechanisms underlying infant sleep irregularity are unknown. This study tests the hypothesis that sleep and episodic (saltatory) growth in infant length are temporally coupled processes. Study design: Daily parental diaries continuously recorded sleep onset and awakening for 23 infants (14 females) over 4-17 months (n = 5798 daily records). Multiple model-independent methods compared day-to-day sleep patterns and saltatory length growth. Measurements and Results: Approximate entropy (ApEn) quantified temporal irregularity in infant sleep patterns; breastfeeding and infant sex explained 44% of inter-individual variance (P = 0.001). Random effects mixed-model regression identified that saltatory length growth was associated with increased total daily sleep hours (P < 0.001) and number of sleep bouts (P = 0.001), with breastfeeding, infant sex, and age as covariates. Infant size and illness onset were non-contributory. CLUSTER analysis identified peaks in individual sleep of 4.5 more h and/or 3 more naps per day, compared to intervening intervals, that were non-randomly concordant with saltatory length growth for all individuals (P < 0.05), with a time lag of 0-4 days. Subject-specific probabilities of a growth saltation associated with sleep included a median odds ratio of 1.20 for each additional hour (n = 8, 95% CI 1.15 to 1.29) and 1.43 for each additional sleep bout (n = 12, 95% CI 1.21-2.03). Increased sleep bout duration predicted weight (P < 0.001) and abdominal skinfold accrual (P = 0.05) contingent on length growth, and truncal adiposity independent of growth (P < 0.001). Conclusions: Sleeping and length growth are temporally related biological processes, suggesting an integrated anabolic system. Infant behavioral state changes may reflect biological mechanisms underlying the timing and control of human growth. Citation: Lampl M; Johnson ML. Infant growth in length follows prolonged sleep and increased naps. SLEEP 2011;34(5):641-650. PMID:21532958

Glucocorticoid receptors and extinction retention deficits in the single prolonged stress model.

PubMed

Knox, D; Nault, T; Henderson, C; Liberzon, I

2012-10-25

Single prolonged stress (SPS) is a rodent model of post traumatic stress disorder that is comprised of serial application of restraint (r), forced swim (fs), and ether (eth) followed by a 7-day quiescent period. SPS induces extinction retention deficits and it is believed that these deficits are caused by the combined stressful effect of serial exposure to r, fs, and eth. However, this hypothesis remains untested. Neurobiological mechanisms by which SPS induces extinction retention deficits are unknown, but SPS enhances glucocorticoid receptor (GR) expression in the hippocampus, which is critical for contextual modulation of extinction retrieval. Upregulation of GRs in extinction circuits may be a mechanism by which SPS induces extinction retention deficits, but this hypothesis has not been examined. In this study, we systematically altered the stressors that constitute SPS (i.e. r, fs, eth), generating a number of partial SPS (p-SPS) groups, and observed the effects SPS and p-SPSs had on extinction retention and GR levels in the hippocampus and prefrontal cortex (PFC). PFC GRs were assayed, because regions of the PFC are critical for maintaining extinction. We predicted that only exposure to full SPS would result in extinction retention deficits and enhance hippocampal and PFC GR levels. Only exposure to full SPS induced extinction retention deficits. Hippocampal and PFC GR expression was enhanced by SPS and most p-SPSs, however hippocampal GR expression was significantly larger following the full SPS exposure than all other conditions. Our findings suggest that the combined stressful effect of serial exposure to r, fs, and eth results in extinction retention deficits. The results also suggest that simple enhancements in GR expression in the hippocampus and PFC are insufficient to result in extinction retention deficits, but raise the possibility that a threshold-enhancement in hippocampal GR expression contributes to SPS-induced extinction retention deficits. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

The role of HIV integration in viral persistence: no more whistling past the proviral graveyard

PubMed Central

Maldarelli, Frank

2016-01-01

A substantial research effort has been directed to identifying strategies to eradicate or control HIV infection without a requirement for combination antiretroviral therapy (cART). A number of obstacles prevent HIV eradication, including low-level viral persistence during cART, long-term persistence of HIV-infected cells, and latent infection of resting CD4+ T cells. Mechanisms of persistence remain uncertain, but integration of the provirus into the host genome represents a central event in replication and pathogenesis of all retroviruses, including HIV. Analysis of HIV proviruses in CD4+ lymphocytes from individuals after prolonged cART revealed that a substantial proportion of the infected cells that persist have undergone clonal expansion and frequently have proviruses integrated in genes associated with regulation of cell growth. These data suggest that integration may influence persistence and clonal expansion of HIV-infected cells after cART is introduced, and these processes may represent key mechanisms for HIV persistence. Determining the diversity of host genes with integrants in HIV-infected cells that persist for prolonged periods may yield useful information regarding pathways by which infected cells persist for prolonged periods. Moreover, many integrants are defective, and new studies are required to characterize the role of clonal expansion in the persistence of replication-competent HIV. PMID:26829624

The Upregulation of α2δ-1 Subunit Modulates Activity-Dependent Ca2+ Signals in Sensory Neurons

PubMed Central

Margas, Wojciech; Cassidy, John S.

2015-01-01

As auxiliary subunits of voltage-gated Ca2+ channels, the α2δ proteins modulate membrane trafficking of the channels and their localization to specific presynaptic sites. Following nerve injury, upregulation of the α2δ-1 subunit in sensory dorsal root ganglion neurons contributes to the generation of chronic pain states; however, very little is known about the underlying molecular mechanisms. Here we show that the increased expression of α2δ-1 in rat sensory neurons leads to prolonged Ca2+ responses evoked by membrane depolarization. This mechanism is coupled to CaV2.2 channel-mediated responses, as it is blocked by a ω-conotoxin GVIA application. Once initiated, the prolonged Ca2+ transients are not dependent on extracellular Ca2+ and do not require Ca2+ release from the endoplasmic reticulum. The selective inhibition of mitochondrial Ca2+ uptake demonstrates that α2δ-1-mediated prolonged Ca2+ signals are buffered by mitochondria, preferentially activated by Ca2+ influx through CaV2.2 channels. Thus, by controlling channel abundance at the plasma membrane, the α2δ-1 subunit has a major impact on the organization of depolarization-induced intracellular Ca2+ signaling in dorsal root ganglion neurons. PMID:25878262

[Lung abscess: changes in treatment?].

PubMed

Clottu, E; Nicod, L P

2015-11-18

Lung abscess occurs in very pleomorphic according to germs initially involved. The mechanism commonly found is an aspiration of the oropharyngeal flora in patients with disorders of consciousness or swallowing. The infection is polymicrobial, with presence of anaerobic germs in 2/3 of the cases. The support consists of a prolonged antibiotic treatment, as well as anaerobic until resolution or stability of the radiological image. In case of prolonged toxic state, drainage of the abscess is to be discussed especially if there is no airways drainage. Surgical sanctions is rarely needed regardless of the size of the abscess, unless underlying carcinoma is present.

Vegetation productivity responds to sub-annual climate conditions across semiarid biomes

USDA-ARS?s Scientific Manuscript database

In the Southwestern United States (SW), the current prolonged warm drought is similar to the predicted future climate change scenarios for the region. This study aimed to determine patterns in vegetation response to the early 21st century drought across multiple biomes. We hypothesized that differen...

Exercise and reproductive dysfunction.

PubMed

Chen, E C; Brzyski, R G

1999-01-01

To provide an overview of our current understanding of exercise-induced reproductive dysfunction and an approach to its evaluation and management. A MEDLINE search was performed to review all articles with title words related to menstrual dysfunction, amenorrhea, oligomenorrhea, exercise, and athletic activities from 1966 to 1998. The pathophysiology, proposed mechanisms, clinical manifestations, evaluation, and management of exercise-associated reproductive dysfunction were compiled. Exercise-induced menstrual irregularity appears to be multifactorial in origin and remains a diagnosis of exclusion. The underlying mechanisms are mainly speculative. Clinical manifestations range from luteal phase deficiency to anovulation, amenorrhea, and even delayed menarche. Evaluation should include a thorough history and a complete physical plus pelvic examination. Most cases are reversible with dietary and exercise modifications. Hormonal replacement in cases of a prolonged hypoestrogenic state with evidence of increased bone loss is recommended, although the long-term consequences of prolonged hormonal deficiency are ill-defined.

Brachial Plexus Injury from CT-Guided RF Ablation Under General Anesthesia

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

Shankar, Sridhar, E-mail: shankars@ummhc.org; Sonnenberg, Eric van; Silverman, Stuart G.

2005-06-15

Brachial plexus injury in a patient under general anesthesia (GA) is not uncommon, despite careful positioning and, particularly, awareness of the possibility. The mechanism of injury is stretching and compression of the brachial plexus over a prolonged period. Positioning the patient within the computed tomography (CT) gantry for abdominal or chest procedures can simulate a surgical procedure, particularly when GA is used. The potential for brachial plexus injury is increased if the case is prolonged and the patient's arms are raised above the head to avoid CT image degradation from streak artifacts. We report a case of profound brachial plexusmore » palsy following a CT-guided radiofrequency ablation procedure under GA. Fortunately, the patient recovered completely. We emphasize the mechanism of injury and detail measures to combat this problem, such that radiologists are aware of this potentially serious complication.« less

Gluteus medius coactivation response in field hockey players with and without low back pain.

PubMed

Bussey, Melanie D; Kennedy, James E; Kennedy, Gavin

2016-01-01

To examine the effect of prolonged standing on gluteus medius coactivation and to observe whether the changes in gluteus medius coactivation over time were related to the development of low back pain in elite female field hockey players. Prospective cohort design. Participants were 39 elite female field hockey players (14 with a history of low back pain). Before the prolonged stand, maximal hip abduction strength, side bridge hold endurance and hip abduction range of motion were measured bilaterally. Surface electromyography was collected from the gluteus medius for coactivation analysis during a prolonged stand for 70 min. Low back pain was rated every 10 min on a visual analogue scale. Fourteen of 39 participants developed low back pain. The Time effect was significant for gluteus medius coactivation response (p = 0.003) and visual analogue scale score (p < 0.001). There were no significant group × time interactions. Yet athletes who developed pain had higher coactivation for the majority of the stand task. While female field hockey players have high agonist-antagonist coactivation patterns during prolonged standing, stand task is a useful tool to predict low back pain occurrence in players with and without history of pain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prolonged financial stress predicts subsequent obesity: results from a prospective study of an Australian national sample.

PubMed

Siahpush, Mohammad; Huang, Terry T-K; Sikora, Asia; Tibbits, Melissa; Shaikh, Raees A; Singh, Gopal K

2014-02-01

The aim of this research was to assess the association of prolonged financial stress (FS) with subsequent obesity. Data were from Waves 8 (2008), 9 (2009), and 10 (2010) of Household Income and Labor Dynamics in Australia (HILDA) survey. The outcome was obesity measured in 2010. Prolonged FS was defined as having experienced FS in both 2008 and 2009. FS was measured in each year using seven questionnaire items. Analyses adjusted for health, physical activity, income, education, baseline obesity, and other covariates. Prolonged FS was a strong predictor of subsequent obesity. The adjusted risk of being obese in 2010 were 20% higher (RR: 1.20; 95% CI: 1.10-1.30) among individuals who experienced FS in both 2008 and 2009 than those who did not experience FS in either year. The association of FS with obesity was independent of income and constant across income categories. Obesity prevention research should pay more attention to FS as an important dimension of economic deprivation, a concept that is distinct from common indicators of socioeconomic status such as income. Future research can examine the effect of financial education and counseling programs that help individuals with such skills as money management, budgeting, and saving on a reduction in FS and obesity. Copyright © 2013 The Obesity Society.

Does unconscious stress play a role in prolonged cardiovascular stress recovery?

PubMed

Brosschot, J F; Geurts, S A E; Kruizinga, I; Radstaak, M; Verkuil, B; Quirin, M; Kompier, M A J

2014-08-01

According to recent insights, humans might not be aware of a substantial part of their cognitive stress representations while these still have prolonged physiological effects. 'Unconscious stress' can be measured by implicit affect (IA) tests. It was shown that IA predicts physiological stress responses, in fact better than explicit ('conscious') affect. It is not known yet whether IA is associated with concurrent prolonged stress responses. In two studies (n = 62 and 123), anger harassment was used to induce stress. Blood pressure (BP) and heart rate (HR) were measured continuously. During BP and HR recovery, IA was measured by an 'anger' version of the implicit association test (IAT) or the implicit positive and negative affect test (IPANAT). Blood pressure and HR increased during anger harassment and recovery afterwards. When using the IPANAT BP recovery levels were lower when positive IA was high and higher when negative IA was high, independent of explicit affect and rumination. These results were not found using the IAT. These results provide preliminary evidence that physiological stress recovery is associated with IA. This is in line with the theory that unconscious stress is responsible for a-possibly considerable-part of unhealthy prolonged stress-related physiological activity. Copyright © 2014 John Wiley & Sons, Ltd.

Strategies to improve plasma half life time of peptide and protein drugs.

PubMed

Werle, M; Bernkop-Schnürch, A

2006-06-01

Due to the obvious advantages of long-acting peptide and protein drugs, strategies to prolong plasma half life time of such compounds are highly on demand. Short plasma half life times are commonly due to fast renal clearance as well as to enzymatic degradation occurring during systemic circulation. Modifications of the peptide/protein can lead to prolonged plasma half life times. By shortening the overall amino acid amount of somatostatin and replacing L: -analogue amino acids with D: -amino acids, plasma half life time of the derivate octreotide was 1.5 hours in comparison to only few minutes of somatostatin. A PEG(2,40 K) conjugate of INF-alpha-2b exhibited a 330-fold prolonged plasma half life time compared to the native protein. It was the aim of this review to provide an overview of possible strategies to prolong plasma half life time such as modification of N- and C-terminus or PEGylation as well as methods to evaluate the effectiveness of drug modifications. Furthermore, fundamental data about most important proteolytic enzymes of human blood, liver and kidney as well as their cleavage specificity and inhibitors for them are provided in order to predict enzymatic cleavage of peptide and protein drugs during systemic circulation.

Experimental evidence for chick discrimination without recognition in a brood parasite host.

PubMed

Grim, Tomás

2007-02-07

Recognition is considered a critical basis for discriminatory behaviours in animals. Theoretically, recognition and discrimination of parasitic chicks are not predicted to evolve in hosts of brood parasitic birds that evict nest-mates. Yet, an earlier study showed that host reed warblers (Acrocephalus scirpaceus) of an evicting parasite, the common cuckoo (Cuculus canorus), can avoid the costs of prolonged care for unrelated young by deserting the cuckoo chick before it fledges. Desertion was not based on specific recognition of the parasite because hosts accept any chick cross-fostered into their nests. Thus, the mechanism of this adaptive host response remains enigmatic. Here, I show experimentally that the cue triggering this 'discrimination without recognition' behaviour is the duration of parental care. Neither the intensity of brood care nor the presence of a single-chick in the nest could explain desertions. Hosts responded similarly to foreign chicks, whether heterospecific or experimental conspecifics. The proposed mechanism of discrimination strikingly differs from those found in other parasite-host systems because hosts do not need an internal recognition template of the parasite's appearance to effectively discriminate. Thus, host defences against parasitic chicks may be based upon mechanisms qualitatively different from those operating against parasitic eggs. I also demonstrate that this discriminatory mechanism is non-costly in terms of recognition errors. Comparative data strongly suggest that parasites cannot counter-evolve any adaptation to mitigate effects of this host defence. These findings have crucial implications for the process and end-result of host-parasite arms races and our understanding of the cognitive basis of discriminatory mechanisms in general.

Experimental evidence for chick discrimination without recognition in a brood parasite host

PubMed Central

Grim, Tomáš

2006-01-01

Recognition is considered a critical basis for discriminatory behaviours in animals. Theoretically, recognition and discrimination of parasitic chicks are not predicted to evolve in hosts of brood parasitic birds that evict nest-mates. Yet, an earlier study showed that host reed warblers (Acrocephalus scirpaceus) of an evicting parasite, the common cuckoo (Cuculus canorus), can avoid the costs of prolonged care for unrelated young by deserting the cuckoo chick before it fledges. Desertion was not based on specific recognition of the parasite because hosts accept any chick cross-fostered into their nests. Thus, the mechanism of this adaptive host response remains enigmatic. Here, I show experimentally that the cue triggering this ‘discrimination without recognition’ behaviour is the duration of parental care. Neither the intensity of brood care nor the presence of a single-chick in the nest could explain desertions. Hosts responded similarly to foreign chicks, whether heterospecific or experimental conspecifics. The proposed mechanism of discrimination strikingly differs from those found in other parasite–host systems because hosts do not need an internal recognition template of the parasite's appearance to effectively discriminate. Thus, host defences against parasitic chicks may be based upon mechanisms qualitatively different from those operating against parasitic eggs. I also demonstrate that this discriminatory mechanism is non-costly in terms of recognition errors. Comparative data strongly suggest that parasites cannot counter-evolve any adaptation to mitigate effects of this host defence. These findings have crucial implications for the process and end-result of host–parasite arms races and our understanding of the cognitive basis of discriminatory mechanisms in general. PMID:17164201

The QT Interval and Risk of Incident Atrial Fibrillation

PubMed Central

Mandyam, Mala C.; Soliman, Elsayed Z.; Alonso, Alvaro; Dewland, Thomas A.; Heckbert, Susan R.; Vittinghoff, Eric; Cummings, Steven R.; Ellinor, Patrick T.; Chaitman, Bernard R.; Stocke, Karen; Applegate, William B.; Arking, Dan E.; Butler, Javed; Loehr, Laura R.; Magnani, Jared W.; Murphy, Rachel A.; Satterfield, Suzanne; Newman, Anne B.; Marcus, Gregory M.

2013-01-01

BACKGROUND Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. OBJECTIVE To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. METHODS We examined a prolonged QT corrected by the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (Health ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by other formulae. RESULTS Among 14,538 ARIC participants, a prolonged QTFram predicted a roughly two-fold increased risk of AF (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.42–2.96, p<0.001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in CHS and Health ABC and were similar across various QT correction methods. Also in ARIC, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14, 95%CI 1.10–1.17, p<0.001) and adjusted (HR 1.11, 95%CI 1.07–1.14, p<0.001) risk of AF. Findings regarding a short QT were inconsistent across cohorts. CONCLUSIONS A prolonged QT interval is associated with an increased risk of incident AF. PMID:23872693

Climate Patterns and Trends of Tree-Mortality in the Southwestern United States

NASA Astrophysics Data System (ADS)

Yi, C.; Mu, G.; Hendrey, G. R.; Vicente-Serrano, S.

2016-12-01

Evidence suggests a world-wide increase in tree mortality associated with climate change in regions subjected to prolonged drought. This is particularly evident in the Southwestern USA (SWUSA) where trees are dying at an accelerating and alarming rate where we investigated climate patterns and trends over the past century in combination with abundant tree-ring data, and thresholds of tree-mortality. In this drought-prone region we found a strong correlation between annual tree-ring width and the corresponding annual average temperature and amount of precipitation. A standardized precipitation-evapotranspiration index (SPEI) was a robust predictor of annual tree growth. At a SPEI of -1.6, tree-ring width was found to be zero. We hypothesize that this is a tipping point for tree-ring mortality. This is confirmed in that approximately 225 million trees died in SWUSA in 2002 when SPEI fell below this tipping point. An analysis of future trends in SPEI based on four GHG concentration scenarios of the IPCC predicts that in coming decades, the conifer forest in SWUSA is expected to be lost entirely due to the prolonged drought there, as the SPEI is predicted to pass the tipping point. It can be anticipated that as the area impacted by prolonged drought increases with SPEI falling below -1.6 tree mortality will become a regional or semi-continental phenomenon. Acknowledgement:This research was supported by PSC-CUNY award (PSC-CUNY-ENHC-68849-0046) and the CUNY Collaborative Incentive Research Grant (CUNY-CIRG-80209-08 22).

Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas

PubMed Central

Peyre, Matthieu; Cartalat-Carel, Stéphanie; Meyronet, David; Ricard, Damien; Jouvet, Anne; Pallud, Johan; Mokhtari, Karima; Guyotat, Jacques; Jouanneau, Emmanuel; Sunyach, Marie-Pierre; Frappaz, Didier; Honnorat, Jérôme; Ducray, François

2010-01-01

Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). PCV (procarbazine, CCNU, vincristine) chemotherapy has demonstrated efficacy in treating LGGs, but this therapy cannot be used for a prolonged period because of the cumulative toxicity. The aim of the present study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth kinetics. The mean tumor diameter (MTD) of 21 LGGs was measured on serial magnetic resonance images before (n=13), during, and after PCV onset (n=21). During PCV treatment, a decrease in the MTD was observed in all patients. After PCV discontinuation, an ongoing decrease in MTD was observed in 20 of the 21 patients. Median duration of the MTD decrease was 3.4 years (range, 0.8–7.7) after PCV onset and 2.7 years (range, 0–7) after the end of PCV treatment with 60% of LGGs, demonstrating an ongoing and prolonged (>2 years) response despite chemotherapy no longer being administered. According to McDonald's criteria, the rates of partial and minor responses were 5% and 38% at the end of PCV but 38% and 42% at the time of maximal MTD decrease, which occurred after a median period of 3.4 years after PCV onset. These results challenge the idea that a prolonged duration of chemotherapy is necessary for treating LGGs and raise the issue of understanding the mechanisms involved in the persistent tumor volume decrease once chemotherapy is terminated. PMID:20488959

Prolonged particulate chromate exposure does not inhibit homologous recombination repair in North Atlantic right whale (Eubalaena glacialis) lung cells.

PubMed

Browning, Cynthia L; Wise, Catherine F; Wise, John Pierce

2017-09-15

Chromosome instability is a common feature of cancers that forms due to the misrepair of DNA double strand breaks. Homologous recombination (HR) repair is a high fidelity DNA repair pathway that utilizes a homologous DNA sequence to accurately repair such damage and protect the genome. Prolonged exposure (>72h) to the human lung carcinogen, particulate hexavalent chromium (Cr(VI)), inhibits HR repair, resulting in increased chromosome instability in human cells. Comparative studies have shown acute Cr(VI) exposure induces less chromosome damage in whale cells than human cells, suggesting investigating the effect of this carcinogen in other species may inform efforts to prevent Cr(VI)-induced chromosome instability. Thus, the goal of this study was to determine the effect of prolonged Cr(VI) exposure on HR repair and clastogenesis in North Atlantic right whale (Eubalaena glacialis) lung cells. We show particulate Cr(VI) induces HR repair activity after both acute (24h) and prolonged (120h) exposure in North Atlantic right whale cells. Although the RAD51 response was lower following prolonged Cr(VI) exposure compared to acute exposure, the response was sufficient for HR repair to occur. In accordance with active HR repair, no increase in Cr(VI)-induced clastogenesis was observed with increased exposure time. These results suggest prolonged Cr(VI) exposure affects HR repair and genomic stability differently in whale and human lung cells. Future investigation of the differences in how human and whale cells respond to chemical carcinogens may provide valuable insight into mechanisms of preventing chemical carcinogenesis. Copyright © 2017. Published by Elsevier Inc.

Prolonged restricted sitting effects in UH-60 helicopters.

PubMed

Games, Kenneth E; Lakin, Joni M; Quindry, John C; Weimar, Wendi H; Sefton, JoEllen M

2015-01-01

Advances in flight technologies and the demand for long-range flight have increased mission lengths for U.S. Army Black Hawk UH-60 crewmembers. Prolonged mission times have increased reports of pilot discomfort and symptoms of paresthesia thought to be due to UH-60 seat design and areas of locally high pressure. Discomfort created by the seat-system decreases situational awareness, putting aviators and support crew at risk of injury. Therefore, the purpose of this study was to examine the effects of prolonged restricted sitting in a UH-60 on discomfort, sensory function, and vascular measures in the lower extremities. There were 15 healthy men (age = 23.4 ± 3.1 yr) meeting physical flight status requirements who sat in an unpadded, UH-60 pilot's seat for 4 h while completing a common cognitive task. During the session, subjective discomfort, sensory function, and vascular function were measured. Across 4 h of restricted sitting, subjective discomfort increased using the Category Partitioning Scale (30.27 point increase) and McGill Pain Questionnaire (8.53 point increase); lower extremity sensory function was diminished along the S1 dermatome; and skin temperature decreased on both the lateral (2.85°C decrease) and anterior (2.78°C decrease) aspects of the ankle. The results suggest that prolonged sitting in a UH-60 seat increases discomfort, potentially through a peripheral nervous or vascular system mechanism. Further research is needed to understand the etiology and onset of pain and paresthesia during prolonged sitting in UH-60 pilot seats. Games KE, Lakin JM, Quindry JC, Weimar WH, Sefton JM. Prolonged restricted sitting effects in UH-60 helicopters.

Dofetilide promotes repolarization abnormalities in perfused Guinea-pig heart.

PubMed

Osadchii, Oleg E

2012-12-01

Dofetilide is class III antiarrhythmic agent which prolongs cardiac action potential duration because of selective inhibition of I (Kr), the rapid component of the delayed rectifier K(+) current. Although clinical studies reported on proarrhythmic risk associated with dofetilide treatment, the contributing electrophysiological mechanisms remain poorly understood. This study was designed to determine if dofetilide-induced proarrhythmia may be attributed to abnormalities in ventricular repolarization and refractoriness. The monophasic action potential duration and effective refractory periods (ERP) were assessed at distinct epicardial and endocardial sites along with volume-conducted ECG recordings in isolated, perfused guinea-pig heart preparations. Dofetilide was found to produce the reverse rate-dependent prolongation of ventricular repolarization, increased the steepness of action potential duration rate adaptation, and amplified transepicardial variability in electrical restitution kinetics. Dofetilide also prolonged the T peak-to-end interval on ECG, and elicited a greater prolongation of endocardial than epicardial ERP, thereby increasing transmural dispersion of refractoriness. At epicardium, dofetilide prolonged action potential duration to a greater extent than ERP, thus extending the critical interval for ventricular re-excitation. This change was associated with triangulation of epicardial action potential because of greater dofetilide-induced prolonging effect at 90 % than 30 % repolarization. Premature ectopic beats and spontaneous short-lasting episodes of monomorphic ventricular tachycardia were observed in 44 % of dofetilide-treated heart preparations. Proarrhythmic potential of dofetilide in guinea-pig heart is attributed to steepened electrical restitution, increased transepicardial variability in electrical restitution kinetics, amplified transmural dispersion of refractoriness, increased critical interval for ventricular re-excitation, and triangulation of epicardial action potential.

Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8+ T cells

PubMed Central

Wang, Zhongfang; Wan, Yanmin; Qiu, Chenli; Quiñones-Parra, Sergio; Zhu, Zhaoqin; Loh, Liyen; Tian, Di; Ren, Yanqin; Hu, Yunwen; Zhang, Xiaoyan; Thomas, Paul G.; Inouye, Michael; Doherty, Peter C.; Kedzierska, Katherine; Xu, Jianqing

2015-01-01

The avian origin A/H7N9 influenza virus causes high admission rates (>99%) and mortality (>30%), with ultimately favourable outcomes ranging from rapid recovery to prolonged hospitalization. Using a multicolour assay for monitoring adaptive and innate immunity, here we dissect the kinetic emergence of different effector mechanisms across the spectrum of H7N9 disease and recovery. We find that a diversity of response mechanisms contribute to resolution and survival. Patients discharged within 2–3 weeks have early prominent H7N9-specific CD8+ T-cell responses, while individuals with prolonged hospital stays have late recruitment of CD8+/CD4+ T cells and antibodies simultaneously (recovery by week 4), augmented even later by prominent NK cell responses (recovery >30 days). In contrast, those who succumbed have minimal influenza-specific immunity and little evidence of T-cell activation. Our study illustrates the importance of robust CD8+ T-cell memory for protection against severe influenza disease caused by newly emerging influenza A viruses. PMID:25967273

Modeling somatic and dendritic spike mediated plasticity at the single neuron and network level.

PubMed

Bono, Jacopo; Clopath, Claudia

2017-09-26

Synaptic plasticity is thought to be the principal neuronal mechanism underlying learning. Models of plastic networks typically combine point neurons with spike-timing-dependent plasticity (STDP) as the learning rule. However, a point neuron does not capture the local non-linear processing of synaptic inputs allowed for by dendrites. Furthermore, experimental evidence suggests that STDP is not the only learning rule available to neurons. By implementing biophysically realistic neuron models, we study how dendrites enable multiple synaptic plasticity mechanisms to coexist in a single cell. In these models, we compare the conditions for STDP and for synaptic strengthening by local dendritic spikes. We also explore how the connectivity between two cells is affected by these plasticity rules and by different synaptic distributions. Finally, we show that how memory retention during associative learning can be prolonged in networks of neurons by including dendrites.Synaptic plasticity is the neuronal mechanism underlying learning. Here the authors construct biophysical models of pyramidal neurons that reproduce observed plasticity gradients along the dendrite and show that dendritic spike dependent LTP which is predominant in distal sections can prolong memory retention.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism.

PubMed

Hameed, Shihab; Mendoza-Cruz, Abel C; Neville, Kristen A; Woodhead, Helen J; Walker, Jan L; Verge, Charles F

2012-06-09

Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120-156 on the old regimen. She was discharged home. This practical regimen improved sodium control, parental independence, and allowed discharge home.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism

PubMed Central

2012-01-01

Background/Aims Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. Methods A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. Results After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120–156 on the old regimen. She was discharged home. Conclusion This practical regimen improved sodium control, parental independence, and allowed discharge home. PMID:22682315

Understanding the relationship between the Centers for Medicare and Medicaid Services' Hospital Compare star rating, surgical case volume, and short-term outcomes after major cancer surgery.

PubMed

Kaye, Deborah R; Norton, Edward C; Ellimoottil, Chad; Ye, Zaojun; Dupree, James M; Herrel, Lindsey A; Miller, David C

2017-11-01

Both the Centers for Medicare and Medicaid Services' (CMS) Hospital Compare star rating and surgical case volume have been publicized as metrics that can help patients to identify high-quality hospitals for complex care such as cancer surgery. The current study evaluates the relationship between the CMS' star rating, surgical volume, and short-term outcomes after major cancer surgery. National Medicare data were used to evaluate the relationship between hospital star ratings and cancer surgery volume quintiles. Then, multilevel logistic regression models were fit to examine the association between cancer surgery outcomes and both star rankings and surgical volumes. Lastly, a graphical approach was used to compare how well star ratings and surgical volume predicted cancer surgery outcomes. This study identified 365,752 patients undergoing major cancer surgery for 1 of 9 cancer types at 2,550 hospitals. Star rating was not associated with surgical volume (P < .001). However, both the star rating and surgical volume were correlated with 4 short-term cancer surgery outcomes (mortality, complication rate, readmissions, and prolonged length of stay). The adjusted predicted probabilities for 5- and 1-star hospitals were 2.3% and 4.5% for mortality, 39% and 48% for complications, 10% and 15% for readmissions, and 8% and 16% for a prolonged length of stay, respectively. The adjusted predicted probabilities for hospitals with the highest and lowest quintile cancer surgery volumes were 2.7% and 5.8% for mortality, 41% and 55% for complications, 12.2% and 11.6% for readmissions, and 9.4% and 13% for a prolonged length of stay, respectively. Furthermore, surgical volume and the star rating were similarly associated with mortality and complications, whereas the star rating was more highly associated with readmissions and prolonged length of stay. In the absence of other information, these findings suggest that the star rating may be useful to patients when they are selecting a hospital for major cancer surgery. However, more research is needed before these ratings can supplant surgical volume as a measure of surgical quality. Cancer 2017;123:4259-4267. © 2017 American Cancer Society. © 2017 American Cancer Society.

Prolonged exposure to particulate chromate inhibits RAD51 nuclear import mediator proteins.

PubMed

Browning, Cynthia L; Wise, John Pierce

2017-09-15

Particulate hexavalent chromium (Cr(VI)) is a human lung carcinogen and a human health concern. The induction of structural chromosome instability is considered to be a driving mechanism of Cr(VI)-induced carcinogenesis. Homologous recombination repair protects against Cr(VI)-induced chromosome damage, due to its highly accurate repair of Cr(VI)-induced DNA double strand breaks. However, recent studies demonstrate Cr(VI) inhibits homologous recombination repair through the misregulation of RAD51. RAD51 is an essential protein in HR repair that facilitates the search for a homologous sequence. Recent studies show prolonged Cr(VI) exposure prevents proper RAD51 subcellular localization, causing it to accumulate in the cytoplasm. Since nuclear import of RAD51 is crucial to its function, this study investigated the effect of Cr(VI) on the RAD51 nuclear import mediators, RAD51C and BRCA2. We show acute (24h) Cr(VI) exposure induces the proper localization of RAD51C and BRCA2. In contrast, prolonged (120h) exposure increased the cytoplasmic localization of both proteins, although RAD51C localization was more severely impaired. These results correlate temporally with the previously reported Cr(VI)-induced RAD51 cytoplasmic accumulation. In addition, we found Cr(VI) does not inhibit interaction between RAD51 and its nuclear import mediators. Altogether, our results suggest prolonged Cr(VI) exposure inhibits the nuclear import of RAD51C, and to a lesser extent, BRCA2, which results in the cytoplasmic accumulation of RAD51. Cr(VI)-induced inhibition of nuclear import may play a key role in its carcinogenic mechanism since the nuclear import of many tumor suppressor proteins and DNA repair proteins is crucial to their function. Copyright © 2017 Elsevier Inc. All rights reserved.

Prolonged food deprivation increases mRNA expression of deiodinase 1 and 2, and thyroid hormone receptor β-1 in a fasting-adapted mammal

PubMed Central

Martinez, Bridget; Soñanez-Organis, José G.; Vázquez-Medina, José Pablo; Viscarra, Jose A.; MacKenzie, Duncan S.; Crocker, Daniel E.; Ortiz, Rudy M.

2013-01-01

SUMMARY Food deprivation in mammals is typically associated with reduced thyroid hormone (TH) concentrations and deiodinase content and activity to suppress metabolism. However, in prolonged-fasted, metabolically active elephant seal pups, TH levels are maintained, if not elevated. The functional relevance of this apparent paradox is unknown and demonstrates variability in the regulation of TH levels, metabolism and function in food-deprived mammals. To address our hypothesis that cellular TH-mediated activity is upregulated with fasting duration, we quantified the mRNA expression and protein content of adipose and muscle deiodinase type I (DI1) and type II (DI2), and TH receptor beta-1 (THrβ-1) after 1, 3 and 7 weeks of fasting in northern elephant seal pups (N=5–7 per week). Fasting did not decrease the concentrations of plasma thyroid stimulating hormone, total triiodothyronine (tT3), free T3, total thyroxine (tT4) or free T4, suggesting that the hypothalamic–pituitary–thyroid axis is not suppressed, but rather maintained during fasting. Mean mRNA expression of adipose DI1 and DI2 increased threefold and fourfold, respectively, and 20- and 30-fold, respectively, in muscle. With the exception of adipose DI1, protein expression of adipose DI2 and muscle DI1 and DI2 increased twofold to fourfold. Fasting also increased adipose (fivefold) and muscle (fourfold) THrβ-1 mRNA expression, suggesting that the mechanisms mediating cellular TH activity are upregulated with prolonged fasting. The data demonstrate a unique, atypical mechanism of TH activity and regulation in mammals adapted to prolonged food deprivation in which the potential responsiveness of peripheral tissues and cellular TH activity are increased, which may contribute to their lipid-based metabolism. PMID:24307712

Inhibition of forkhead boxO-specific transcription prevents mechanical ventilation-induced diaphragm dysfunction.

PubMed

Smuder, Ashley J; Sollanek, Kurt J; Min, Kisuk; Nelson, W Bradley; Powers, Scott K

2015-05-01

Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation-induced diaphragm weakness remains unknown. This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness. University research laboratory. Young adult female Sprague-Dawley rats. Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm. Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3. Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that targeting forkhead boxO transcription could be a key therapeutic target to combat ventilator-induced diaphragm dysfunction.

The effect of shorter exposure versus prolonged exposure on treatment outcome in Tourette syndrome and chronic tic disorders - an open trial.

PubMed

van de Griendt, Jolande M T M; van Dijk, Maarten K; Verdellen, Cara W J; Verbraak, Marc J P M

2018-01-11

Exposure and response prevention has shown to be an effective strategy and is considered a first-line intervention in the behavioural treatment of tic disorders. Prior research demonstrated significant tic reduction after 12 two hour sessions. In this open trial, the question is addressed whether, relative to these prolonged sessions, exposure sessions of shorter duration yield differential outcome for patients with tic disorders. A total of 29 patients diagnosed with Tourette syndrome (TS) or chronic tic disorder were treated with shorter exposure sessions (1 h), and these data were compared to the data from a study about prolonged exposure (2 h, n = 21). Outcome was measured by the Yale Global Tic Severity Scale (YGTSS). Results suggest that after taking the difference in illness duration between the two groups into account, the effectiveness of shorter exposure sessions is not inferior to that of prolonged exposure. Results suggest that treatment with shorter exposure might be more efficient and more patients can be reached. Future research is needed to gain more insight into the mechanisms underlying the efficacy of behavioural treatments for tics.

Associations between change in sedentary behavior and outcome in standard behavioral weight loss treatment.

PubMed

Kerrigan, Stephanie G; Call, Christine; Schaumberg, Katherine; Forman, Evan; Butryn, Meghan L

2018-03-01

Sedentary behavior, particularly in prolonged periods, is an important determinant of health. Little research exploring changes in sedentary behavior during behavioral weight loss programs exists. This study evaluated the magnitude of changes in total and prolonged sedentary behavior and how these changes related to changes in weight and cardiovascular outcomes during a behavioral weight loss program. Participants (n = 450) in two lifestyle modification programs underwent assessments of sedentary behavior (by accelerometry), weight, waist circumference, blood pressure, and resting heart rate at baseline and after 6 months of treatment. Sedentary behavior was defined as both total and prolonged (≥30 continuous minutes) sedentary minutes/day. Reductions in total and prolonged sedentary time were significant and were accounted for by increases in moderate-to-vigorous physical activity (MVPA). Only changes in MVPA significantly predicted change in weight when entered into a model simultaneously with changes in sedentary behavior. Changes in total and prolonged sedentary time were not associated with changes in waist circumference, heart rate, or blood pressure. Change in sedentary time was not independently associated with change in health outcomes during a behavioral weight loss treatment. High variability in changes in sedentary time indicate that individual differences may be important to examine. Reducing sedentary time may not be powerful enough to impact these health outcomes above the effects of other changes made during these programs; alternatively, it may be that increasing focus in treatment on reducing sedentary time may engender greater decreases in sedentariness, which could lead to better health outcomes.

Understanding the science of climate change: Talking points - Impacts to the Gulf Coast

Treesearch

Rachel Loehman; Greer Anderson

2010-01-01

Predicted climate changes in the Gulf Coast bioregion include increased air and sea surface temperatures, altered fire regimes and rainfall patterns, increased frequency of extreme weather events, rising sea levels, increased hurricane intensity, and potential destruction of coastal wetlands and the species that reside within them. Prolonged drought conditions, storm...

Prediction-based Dynamic Energy Management in Wireless Sensor Networks

PubMed Central

Wang, Xue; Ma, Jun-Jie; Wang, Sheng; Bi, Dao-Wei

2007-01-01

Energy consumption is a critical constraint in wireless sensor networks. Focusing on the energy efficiency problem of wireless sensor networks, this paper proposes a method of prediction-based dynamic energy management. A particle filter was introduced to predict a target state, which was adopted to awaken wireless sensor nodes so that their sleep time was prolonged. With the distributed computing capability of nodes, an optimization approach of distributed genetic algorithm and simulated annealing was proposed to minimize the energy consumption of measurement. Considering the application of target tracking, we implemented target position prediction, node sleep scheduling and optimal sensing node selection. Moreover, a routing scheme of forwarding nodes was presented to achieve extra energy conservation. Experimental results of target tracking verified that energy-efficiency is enhanced by prediction-based dynamic energy management.

Definition of tolerance to continuous hyperoxia in man - An abstract report of Predictive Studies V

NASA Technical Reports Server (NTRS)

Lambertsen, C. J.; Clark, J. M.; Gelfand, R.; Pisarello, J. B.; Cobbs, W. H.

1987-01-01

The overall goals, design, and procedures of Predictive Studies V are discussed as well as the specific elements of neural effects produced by prolonged hyperoxia. It is noted that Predictive Studies V study of oxygen poisoning in normal men during uninterrupted exposures to oxygen over the range of hyperbaric oxygen exposure most useful in diving, the treatment of gas lesion diseases, and general hyperbaric medicine. It is found that, throughout the study, the most striking observations were related to effects on visual function, on the lung, and the probable interactions of preconvulsive neural activity with effects on cardiovascular and respiratory-pulmonary functions.

Pseudoprogression and hyperprogression after checkpoint blockade.

PubMed

Wang, Qiaohong; Gao, Jingze; Wu, Xia

2018-05-01

Immune checkpoint inhibitors appear to be one of the most promising immunotherapies with significant clinical benefits and durable responses in multiple tumor types. A heterogeneity of responses appears in patients receiving checkpoint blockade, including pseudoprogression where the tumor burden or number of tumor lesions increases initially before decreasing. Another special response observed after checkpoint blockade is hyperprogression, a phenomenon reflecting a very rapid tumor progression following immunotherapy, suggesting that checkpoint blockade could impact detrimentally on a small subset of patients. As immunotherapeutics, especially anti-PD-1/PD-L1 agents, become more widely available, evaluating the efficacy of these novel drugs poses a major challenge to clinicians, who aim to avoid either premature withdrawal of the treatment or prolonging ineffective treatment. Although the mechanism and recognition of pseudoprogression have gradually come to light, the incidence, basis, identification and predictive biomarkers of hyperprogression have been largely unknown, and this review documents the existing research findings and points out the areas where further studies are badly needed. Copyright © 2018 Elsevier B.V. All rights reserved.

Interactions of Gut Microbiota, Endotoxemia, Immune Function, and Diet in Exertional Heatstroke

PubMed Central

Lee, Elaine C.; Armstrong, Elizabeth M.

2018-01-01

Exertional heatstroke (EHS) is a medical emergency that cannot be predicted, requires immediate whole-body cooling to reduce elevated internal body temperature, and is influenced by numerous host and environmental factors. Widely accepted predisposing factors (PDF) include prolonged or intense exercise, lack of heat acclimatization, sleep deprivation, dehydration, diet, alcohol abuse, drug use, chronic inflammation, febrile illness, older age, and nonsteroidal anti-inflammatory drug use. The present review links these factors to the human intestinal microbiota (IM) and diet, which previously have not been appreciated as PDF. This review also describes plausible mechanisms by which these PDF lead to EHS: endotoxemia resulting from elevated plasma lipopolysaccharide (i.e., a structural component of the outer membrane of Gram-negative bacteria) and tissue injury from oxygen free radicals. We propose that recognizing the lifestyle and host factors which are influenced by intestine-microbial interactions, and modifying habitual dietary patterns to alter the IM ecosystem, will encourage efficient immune function, optimize the intestinal epithelial barrier, and reduce EHS morbidity and mortality. PMID:29850597

Themes in fibrosis and gastrointestinal inflammation

PubMed Central

Lund, P. Kay

2011-01-01

Wound healing is an appropriate response to inflammation and tissue injury in the gastrointestinal tract. If wound healing responses are excessive, perpetuated, or prolonged, they lead to fibrosis, distortion of tissue architecture, and loss of function. This introductory editorial and the minireviews or reviews in this themes series highlight the diversity in severity and location of fibrosis in response to gastrointestinal inflammation. The multiplicity of cellular and molecular mediators and new players, including stem cells or extracellular matrix-producing cells derived from nonmesenchymal cell types, is reviewed. Comparisons of inflammation-induced fibrosis across organ systems and the need for integrated and systems-based molecular approaches, new imaging modalities, well-characterized animal models, cell culture models, and improved diagnostic or predictive markers are reviewed. To date, intestinal fibrosis has received much less attention than inflammation in terms of defining mechanisms and underlying causes. This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease. PMID:21415411

Ground Motion Prediction for M7+ scenarios on the San Andreas Fault using the Virtual Earthquake Approach

NASA Astrophysics Data System (ADS)

Denolle, M.; Dunham, E. M.; Prieto, G.; Beroza, G. C.

2013-05-01

There is no clearer example of the increase in hazard due to prolonged and amplified shaking in sedimentary, than the case of Mexico City in the 1985 Michoacan earthquake. It is critically important to identify what other cities might be susceptible to similar basin amplification effects. Physics-based simulations in 3D crustal structure can be used to model and anticipate those effects, but they rely on our knowledge of the complexity of the medium. We propose a parallel approach to validate ground motion simulations using the ambient seismic field. We compute the Earth's impulse response combining the ambient seismic field and coda-wave enforcing causality and symmetry constraints. We correct the surface impulse responses to account for the source depth, mechanism and duration using a 1D approximation of the local surface-wave excitation. We call the new responses virtual earthquakes. We validate the ground motion predicted from the virtual earthquakes against moderate earthquakes in southern California. We then combine temporary seismic stations on the southern San Andreas Fault and extend the point source approximation of the Virtual Earthquake Approach to model finite kinematic ruptures. We confirm the coupling between source directivity and amplification in downtown Los Angeles seen in simulations.

Support for viral persistence in bats from age-specific serology and models of maternal immunity.

PubMed

Peel, Alison J; Baker, Kate S; Hayman, David T S; Broder, Christopher C; Cunningham, Andrew A; Fooks, Anthony R; Garnier, Romain; Wood, James L N; Restif, Olivier

2018-03-01

Spatiotemporally-localised prediction of virus emergence from wildlife requires focused studies on the ecology and immunology of reservoir hosts in their native habitat. Reliable predictions from mathematical models remain difficult in most systems due to a dearth of appropriate empirical data. Our goal was to study the circulation and immune dynamics of zoonotic viruses in bat populations and investigate the effects of maternally-derived and acquired immunity on viral persistence. Using rare age-specific serological data from wild-caught Eidolon helvum fruit bats as a case study, we estimated viral transmission parameters for a stochastic infection model. We estimated mean durations of around 6 months for maternally-derived immunity to Lagos bat virus and African henipavirus, whereas acquired immunity was long-lasting (Lagos bat virus: mean 12 years, henipavirus: mean 4 years). In the presence of a seasonal birth pulse, the effect of maternally-derived immunity on virus persistence within modelled bat populations was highly dependent on transmission characteristics. To explain previous reports of viral persistence within small natural and captive E. helvum populations, we hypothesise that some bats must experience prolonged infectious periods or within-host latency. By further elucidating plausible mechanisms of virus persistence in bat populations, we contribute to guidance of future field studies.

Combined expectancies: electrophysiological evidence for the adjustment of expectancy effects

PubMed Central

Mattler, Uwe; van der Lugt, Arie; Münte, Thomas F

2006-01-01

Background When subjects use cues to prepare for a likely stimulus or a likely response, reaction times are facilitated by valid cues but prolonged by invalid cues. In studies on combined expectancy effects, two cues can independently give information regarding two dimensions of the forthcoming task. In certain situations, cueing effects on one dimension are reduced when the cue on the other dimension is invalid. According to the Adjusted Expectancy Model, cues affect different processing levels and a mechanism is presumed which is sensitive to the validity of early level cues and leads to online adjustment of expectancy effects at later levels. To examine the predictions of this model cueing of stimulus modality was combined with response cueing. Results Behavioral measures showed the interaction of cueing effects. Electrophysiological measures of the lateralized readiness potential (LRP) and the N200 amplitude confirmed the predictions of the model. The LRP showed larger effects of response cues on response activation when modality cues were valid rather than invalid. N200 amplitude was largest with valid modality cues and invalid response cues, medium with invalid modality cues, and smallest with two valid cues. Conclusion Findings support the view that the validity of early level expectancies modulates the effects of late level expectancies, which included response activation and response conflict in the present study. PMID:16674805

Progesterone-induced Neuroprotection: Factors that may predict therapeutic efficacy

PubMed Central

Singh, Meharvan; Su, Chang

2013-01-01

Both progesterone and estradiol have well-described neuroprotective effects against numerous insults in a variety of cell culture models, animal models and in humans. However, the efficacy of these hormones may depend on a variety of factors, including the type of hormone used (ex. progesterone versus medroxyprogesterone acetate), the duration of the postmenopausal period prior to initiating the hormone intervention, and potentially, the age of the subject. The latter two factors relate to the proposed existence of a “window of therapeutic opportunity” for steroid hormones in the brain. While such a window of opportunity has been described for estrogen, there is a paucity of information to address whether such a window of opportunity exists for progesterone and its related progestins. Here, we review known cellular mechanisms likely to underlie the protective effects of progesterone and furthermore, describe key differences in the neurobiology of progesterone and the synthetic progestin, medroxyprogesterone acetate (MPA). Based on the latter, we offer a model that defines some of the key cellular and molecular players that predict the neuroprotective efficacy of progesterone. Accordingly, we suggest how changes in the expression or function of these cellular and molecular targets of progesterone with age or prolonged duration of hormone withdrawal (such as following surgical or natural menopause) may impact the efficacy of progesterone. PMID:23340161

Human circulatory responses to prolonged hyperbaric hyperoxia in Predictive Studies V

NASA Technical Reports Server (NTRS)

Pisarello, J. B.; Clark, J. M.; Lambertsen, C. J.; Gelfand, R.

1987-01-01

Selected results of cardiocirculatory measurements in healthy volunteers who breathed 100 percent O2 continuously at 3.0 ATA for up to 3.5 hr, at 2.5 ATA for up to 6.0 hr, at 2.0 ATA for up to 11.9 hr, and at 1.5 ATA for up to 19.0 hr are reported. The results indicate that resting hemodynamic responses to prolonged hyperbaric oxygen breathing in man usually consist of small deviations from normal sea-level responses. Rapid onset of bradycardia occurred at all four oxygen pressures investigated. This effect was accompanied by a rate-dependent reduction in cardiac output and a degree of systematic vasoconstriction which were small in magnitude and appeared to be functionally unimportant.

Physiological and pharmacologic aspects of peripheral nerve blocks

PubMed Central

Vadhanan, Prasanna; Tripaty, Debendra Kumar; Adinarayanan, S.

2015-01-01

A successful peripheral nerve block not only involves a proper technique, but also a thorough knowledge and understanding of the physiology of nerve conduction and pharmacology of local anesthetics (LAs). This article focuses on what happens after the block. Pharmacodynamics of LAs, underlying mechanisms of clinically observable phenomena such as differential blockade, tachyphylaxis, C fiber resistance, tonic and phasic blockade and effect of volume and concentration of LAs. Judicious use of additives along with LAs in peripheral nerve blocks can prolong analgesia. An entirely new group of drugs-neurotoxins has shown potential as local anesthetics. Various methods are available now to prolong the duration of peripheral nerve blocks. PMID:26330722

Prolonged Delirium Secondary to Hypoxic-ischemic Encephalopathy Following Cardiac Arrest

PubMed Central

Yogaratnam, Jegan; Jacob, Rajesh; Naik, Sandeep; Magadi, Harish

2013-01-01

Hypoxic-ischemic brain injury encompasses a complex constellation of pathophysiological and cellular brain injury induced by hypoxia, ischemia, cytotoxicity, or combinations of these mechanisms and can result in poor outcomes including significant changes in personality and cognitive impairments in memory, cognition, and attention. We report a case of a male patient with normal premorbid functioning who developed prolonged delirium following hypoxic-ischemic brain insults subsequent to cardiac arrest. The case highlights the importance of adopting a multidisciplinary treatment approach involving the coordinated care of medical and nursing teams to optimise management of patients suffering from such a debilitating organic brain syndrome. PMID:23678354

[Complete atrioventricular block in Duchenne muscular dystrophy].

PubMed

Kuru, Satoshi; Tanahashi, Tamotsu; Matsumoto, Shinjirou; Kitamura, Tetsuya; Konagaya, Masaaki

2012-01-01

We report a case of complete atrioventricular (AV) block in a 40-year-old patient with Duchenne muscular dystrophy (DMD). While he was bed-ridden and required mechanical ventilation, his cardiac involvement was mild. He had the deletion of exon 45-52 in the dystrophin gene. He underwent transient complete AV block and came to require pacemaker implantation due to recurrence of complete AV block ten days after the first attack. Electrophysiological study revealed mild prolonged AH and HV interval. Although DMD patients with AV block have been rarely reported so far, attention should be paid to AV block for patients who prolonged their lives.

[Basic results of an experiment with mammals on the Kosmos-782 biosatellite].

PubMed

Gazenko, O G; Genin, A M; Il'in, E A; Portugalov, V V; Serova, L V

1978-01-01

The rat experiments carried out onboard the biosatellite Cosmos-782 contributed to our understanding of mechanisms of animal adaption to prolonged weightlessness. Postflight analysis helped to study nonspecific changes related to the stress-reaction accompanying space flight and return to the Earth gravity as well as specific changes associated with functional unloading of the musculoskeletal system in weightlessness. The flight results confirmed the previously made conclusions concerning possible adaptation of mammals to prolonged weightlessness and lack of pathological changes in vital weightlessness. They included: metabolic and hormonal changes, muscle atrophy, osteoporosis and delayed bone growth, decrease of ATPase activity of myocardial myosin, inhibition of erythropoiesis.

The role of mitochondria in protection of the heart by preconditioning

PubMed Central

Halestrap, Andrew P.; Clarke, Samantha J.; Khaliulin, Igor

2007-01-01

A prolonged period of ischaemia followed by reperfusion irreversibly damages the heart. Such reperfusion injury (RI) involves opening of the mitochondrial permeability transition pore (MPTP) under the conditions of calcium overload and oxidative stress that accompany reperfusion. Protection from MPTP opening and hence RI can be mediated by ischaemic preconditioning (IP) where the prolonged ischaemic period is preceded by one or more brief (2–5 min) cycles of ischaemia and reperfusion. Following a brief overview of the molecular characterisation and regulation of the MPTP, the proposed mechanisms by which IP reduces pore opening are reviewed including the potential roles for reactive oxygen species (ROS), protein kinase cascades, and mitochondrial potassium channels. It is proposed that IP-mediated inhibition of MPTP opening at reperfusion does not involve direct phosphorylation of mitochondrial proteins, but rather reflects diminished oxidative stress during prolonged ischaemia and reperfusion. This causes less oxidation of critical thiol groups on the MPTP that are known to sensitise pore opening to calcium. The mechanisms by which ROS levels are decreased in the IP hearts during prolonged ischaemia and reperfusion are not known, but appear to require activation of protein kinase Cε, either by receptor-mediated events or through transient increases in ROS during the IP protocol. Other signalling pathways may show cross-talk with this primary mechanism, but we suggest that a role for mitochondrial potassium channels is unlikely. The evidence for their activity in isolated mitochondria and cardiac myocytes is reviewed and the lack of specificity of the pharmacological agents used to implicate them in IP is noted. Some K+ channel openers uncouple mitochondria and others inhibit respiratory chain complexes, and their ability to produce ROS and precondition hearts is mimicked by bona fide uncouplers and respiratory chain inhibitors. IP may also provide continuing protection during reperfusion by preventing a cascade of MPTP-induced ROS production followed by further MPTP opening. This phase of protection may involve survival kinase pathways such as Akt and glycogen synthase kinase 3 (GSK3) either increasing ROS removal or reducing mitochondrial ROS production. PMID:17631856

Obesity/Type II diabetes alters macrophage polarization resulting in a fibrotic tendon healing response

PubMed Central

Ackerman, Jessica E.; Geary, Michael B.; Orner, Caitlin A.; Bawany, Fatima

2017-01-01

Type II Diabetes (T2DM) dramatically impairs the tendon healing response, resulting in decreased collagen organization and mechanics relative to non-diabetic tendons. Despite this burden, there remains a paucity of information regarding the mechanisms that govern impaired healing of diabetic tendons. Mice were placed on either a high fat diet (T2DM) or low fat diet (lean) and underwent flexor tendon transection and repair surgery. Healing was assessed via mechanical testing, histology and changes in gene expression associated with collagen synthesis, matrix remodeling, and macrophage polarization. Obese/diabetic tendons healed with increased scar formation and impaired mechanical properties. Consistent with this, prolonged and excess expression of extracellular matrix (ECM) components were observed in obese/T2DM tendons. Macrophages are involved in both inflammatory and matrix deposition processes during healing. Obese/T2DM tendons healed with increased expression of markers of pro-inflammatory M1 macrophages, and elevated and prolonged expression of M2 macrophages markers that are involved in ECM deposition. Here we demonstrate that tendons from obese/diabetic mice heal with increased scar formation and increased M2 polarization, identifying excess M2 macrophage activity and matrix synthesis as a potential mechanism of the fibrotic healing phenotype observed in T2DM tendons, and as such a potential target to improve tendon healing in T2DM. PMID:28686669

Effects of prolonged exposure and virtual reality exposure on suicidal ideation in active duty soldiers: An examination of potential mechanisms.

PubMed

Norr, Aaron M; Smolenski, Derek J; Reger, Greg M

2018-05-12

The current study sought to investigate the effects of exposure therapy on suicidal ideation (SI), as well as potential mechanistic pathways of SI reduction among active duty military personnel. Active duty army soldiers (N = 162) were recruited from a military base in the U.S. and were enrolled in a randomized clinical trial comparing Prolonged Exposure (PE), Virtual Reality Exposure (VRE), and a wait-list control for the treatment of posttraumatic stress disorder (PTSD) stemming from deployments to Iraq or Afghanistan. PTSD diagnosis followed DSM-IV-TR criteria. Outcome measures were assessed via self-report and clinician interview. PTSD symptoms, depressive symptoms, and SI were included in an autoregressive cross-lagged panel model to examine mechanistic pathways. Analyses revealed that PE/VRE had a lower probability of post-treatment suicidal ideation (OR = 0.23, 95% CI [0.06, 0.86]) compared to the waitlist control. Mediation analyses revealed a significant indirect effect from treatment condition to post-treatment PTSD symptoms through mid-treatment SI (Estimate = -1.420, 95% CI -3.559, -0.223]). Baseline suicidal ideation did not interact with treatment condition to predict PTSD symptom change at mid-treatment (p = .231) or post-treatment (p = .672). PE/VRE successfully reduced SI, and the presence of SI at baseline did not affect PTSD symptom reduction, promoting the utility of using PE/VRE to address suicidality among individuals with PTSD. Mediation analyses suggest that reductions in SI were achieved early in treatment. Published by Elsevier Ltd.

Tonic pain and continuous EEG: prediction of subjective pain perception by alpha-1 power during stimulation and at rest.

PubMed

Nir, Rony-Reuven; Sinai, Alon; Moont, Ruth; Harari, Eyal; Yarnitsky, David

2012-03-01

Pain neurophysiology has been chiefly characterized via event-related potentials (ERPs), which are exerted using brief, phase-locked noxious stimuli. Striving for objectively characterizing clinical pain states using more natural, prolonged stimuli, tonic pain has been recently associated with the individual peak frequency of alpha oscillations. This finding encouraged us to explore whether alpha power, reflecting the magnitude of the synchronized activity within this frequency range, will demonstrate a corresponding relationship with subjective perception of tonic pain. Five-minute-long continuous EEG was recorded in 18 healthy volunteers under: (i) resting-state; (ii) innocuous temperature; and (iii) psychophysically-anchored noxious temperature. Numerical pain scores (NPSs) collected during the application of tonic noxious stimuli were tested for correlation with alpha-1 and alpha-2 power. NPSs and alpha power remained stable throughout the recording conditions (Ps⩾0.381). In the noxious condition, alpha-1 power obtained at the bilateral temporal scalp was negatively correlated with NPSs (Ps⩽0.04). Additionally, resting-state alpha-1 power recorded at the bilateral temporal scalp was negatively correlated with NPSs reported during the noxious condition (Ps⩽0.038). Current findings suggest alpha-1 power may serve as a direct, objective and experimentally stable measure of subjective perception of tonic pain. Furthermore, resting-state alpha-1 power might reflect individuals' inherent tonic pain responsiveness. The relevance of alpha-1 power to tonic pain perception may deepen the understanding of the mechanisms underlying the processing of prolonged noxious stimulation. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Nonlinear analysis of gait kinematics to track changes in oxygen consumption in prolonged load carriage walking: a pilot study.

PubMed

Schiffman, Jeffrey M; Chelidze, David; Adams, Albert; Segala, David B; Hasselquist, Leif

2009-09-18

Linking human mechanical work to physiological work for the purpose of developing a model of physical fatigue is a complex problem that cannot be solved easily by conventional biomechanical analysis. The purpose of the study was to determine if two nonlinear analysis methods can address the fundamental issue of utilizing kinematic data to track oxygen consumption from a prolonged walking trial: we evaluated the effectiveness of dynamical systems and fractal analysis in this study. Further, we selected, oxygen consumption as a measure to represent the underlying physiological measure of fatigue. Three male US Army Soldier volunteers (means: 23.3 yr; 1.80 m; 77.3 kg) walked for 120 min at 1.34 m/s with a 40-kg load on a level treadmill. Gait kinematic data and oxygen consumption (VO(2)) data were collected over the 120-min period. For the fractal analysis, utilizing stride interval data, we calculated fractal dimension. For the dynamical systems analysis, kinematic angle time series were used to estimate phase space warping based features at uniform time intervals: smooth orthogonal decomposition (SOD) was used to extract slowly time-varying trends from these features. Estimated fractal dimensions showed no apparent trend or correlation with independently measured VO(2). While inter-individual difference did exist in the VO(2) data, dominant SOD time trends tracked and correlated with the VO(2) for all volunteers. Thus, dynamical systems analysis using gait kinematics may be suitable to develop a model to predict physiologic fatigue based on biomechanical work.

Effect Of Pressure Support Versus Unassisted Breathing Through A Tracheostomy Collar On Weaning Duration In Patients Requiring Prolonged Mechanical Ventilation: A Randomized Trial

PubMed Central

Jubran, Amal; Grant, Brydon J.B.; Duffner, Lisa A.; Collins, Eileen G.; Lanuza, Dorothy M.; Hoffman, Leslie A.; Tobin, Martin J.

2013-01-01

Context Patients requiring prolonged mechanical ventilation (more than 21 days) are commonly weaned at long-term acute care hospitals (LTACHs). The most effective method of weaning such patients has not been investigated. Objective To compare weaning duration with pressure support versus unassisted breathing through a tracheostomy (trach collar) in patients transferred to a LTACH for weaning from prolonged ventilation. Design, Settings, and Participants Between 2000 and 2010, a randomized study was conducted in tracheotomized patients transferred to a single LTACH for weaning from prolonged ventilation. Of 500 patients who underwent a five-day screening procedure, 316 failed and were randomly assigned to wean with pressure support (n=155) or a trach collar (n=161). Six- and twelve-month survival was also determined. Main outcome measure Primary outcome was weaning duration. Secondary outcome was survival at six and twelve months after enrollment. Results Of 316 patients, four were withdrawn and not included in analysis. Of 152 patients in the pressure-support arm, 68 (44.7%) were weaned; 22 (14.5%) died. Of 160 patients in the trach-collar arm, 85 (53.1%) were weaned; 16 (10.0%) died. Median weaning time was shorter with trach collar than with pressure support: 15 [interquartile range, 8–25] versus 19 [12–31] days, p=0.004. The hazard ratio (HR) for successful weaning rate was higher with trach collar than with pressure support (HR, 1.43; 95% confidence interval [CI], 1.03–1.98, p<0.03) after adjusting for baseline clinical covariates. Trach collar achieved faster weaning than did pressure support among subjects who failed the screening procedure at 12–120 hours (HR, 3.33; 95% CI, 1.44–7.70, p<0.01), whereas weaning time was equivalent with the two methods in patients who failed the screening procedure within 0–12 hours. Mortality was equivalent in the pressure-support and trach-collar arms at six months (55.9% versus 51.3%; 4.7 difference, 95% CI −6.4 to 15.7%) and twelve months (66.4% versus 60.0%; 6.5 difference, 95% CI −4.2 to 17.1 %). Conclusion Among patients requiring prolonged mechanical ventilation and treated at a single long-term care facility, unassisted breathing through a tracheostomy, compared with pressure support, resulted in shorter median weaning time, although weaning mode had no effect on survival at 6 and 12 months. PMID:23340588

Effect of pressure support vs unassisted breathing through a tracheostomy collar on weaning duration in patients requiring prolonged mechanical ventilation: a randomized trial.

PubMed

Jubran, Amal; Grant, Brydon J B; Duffner, Lisa A; Collins, Eileen G; Lanuza, Dorothy M; Hoffman, Leslie A; Tobin, Martin J

2013-02-20

Patients requiring prolonged mechanical ventilation (>21 days) are commonly weaned at long-term acute care hospitals (LTACHs). The most effective method of weaning such patients has not been investigated. To compare weaning duration with pressure support vs unassisted breathing through a tracheostomy collar in patients transferred to an LTACH for weaning from prolonged ventilation. Between 2000 and 2010, a randomized study was conducted in tracheotomized patients transferred to a single LTACH for weaning from prolonged ventilation. Of 500 patients who underwent a 5-day screening procedure, 316 did not tolerate the procedure and were randomly assigned to receive weaning with pressure support (n = 155) or a tracheostomy collar (n = 161). Survival at 6- and 12-month time points was also determined. Primary outcome was weaning duration. Secondary outcome was survival at 6 and 12 months after enrollment. Of 316 patients, 4 were withdrawn and not included in analysis. Of 152 patients in the pressure-support group, 68 (44.7%) were weaned; 22 (14.5%) died. Of 160 patients in the tracheostomy collar group, 85 (53.1%) were weaned; 16 (10.0%) died. Median weaning time was shorter with tracheostomy collar use (15 days; interquartile range [IQR], 8-25) than with pressure support (19 days; IQR, 12-31), P = .004. The hazard ratio (HR) for successful weaning rate was higher with tracheostomy collar use than with pressure support (HR, 1.43; 95% CI, 1.03-1.98; P = .033) after adjusting for baseline clinical covariates. Use of the tracheostomy collar achieved faster weaning than did pressure support among patients who did not tolerate the screening procedure between 12 and 120 hours (HR, 3.33; 95% CI, 1.44-7.70; P = .005), whereas weaning time was equivalent with the 2 methods in patients who did not tolerate the screening procedure within 0 to 12 hours. Mortality was equivalent in the pressure-support and tracheostomy collar groups at 6 months (55.92% vs 51.25%; 4.67% difference, 95% CI, -6.4% to 15.7%) and at 12 months (66.45% vs 60.00%; 6.45% difference, 95% CI, -4.2% to 17.1%). Among patients requiring prolonged mechanical ventilation and treated at a single long-term care facility, unassisted breathing through a tracheostomy, compared with pressure support, resulted in shorter median weaning time, although weaning mode had no effect on survival at 6 and 12 months. clinicaltrials.gov Identifier: NCT01541462.

The sFlt-1/PlGF ratio associates with prolongation and adverse outcome of pregnancy in women with (suspected) preeclampsia: analysis of a high-risk cohort.

PubMed

Saleh, Langeza; Verdonk, Koen; Jan Danser, A H; Steegers, Eric A P; Russcher, Henk; van den Meiracker, Anton H; Visser, Willy

2016-04-01

To evaluate the additive value of the sFlt-1/PlGF ratio for diagnosing preeclampsia (PE) and predicting prolongation of pregnancy and adverse outcome in a cohort of women with PE or at high risk of PE. Patients with suspected or confirmed clinical PE were recruited. At time of inclusion blood for measurement of sFlt-1and PlGF was taken. Values were determined after delivery. A cut-off ratio of ≥85 was defined as a positive test. A total of 107 patients were included. Of the patients, 62 (58%) met the clinical criteria of PE at time of blood sampling. In 10% of these patients (n=6) the ratio was <85 (false negative), whereas in 7% (n=3) of patients without clinical PE the ratio was ≥85 (false positive), resulting in positive and negative predictive values of 95% and 88% respectively. One patient with false positive ratio developed superimposed PE and 2 developed gestational hypertension, and adverse outcome occurred in all three. An adverse pregnancy outcome was only encountered in 1 of the 6 patients with a false negative ratio. Using a binary regression model with adjustment for gestational age <34 weeks, the adverse outcome risk was 11 times increased on the basis of clinical PE, and 30 times on the basis of an elevated ratio (P=0.036). The additive value of an increased ratio for diagnosing PE is limited since most patients with clinical PE also have a positive ratio. However, an elevated ratio is superior to the clinical diagnosis of PE for predicting an adverse pregnancy outcome. Furthermore, irrespective of clinical PE, a low ratio is inversely correlated with prolongation of pregnancy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The impact of prolonged violent video-gaming on adolescent sleep: an experimental study.

PubMed

King, Daniel L; Gradisar, Michael; Drummond, Aaron; Lovato, Nicole; Wessel, Jason; Micic, Gorica; Douglas, Paul; Delfabbro, Paul

2013-04-01

Video-gaming is an increasingly prevalent activity among children and adolescents that is known to influence several areas of emotional, cognitive and behavioural functioning. Currently there is insufficient experimental evidence about how extended video-game play may affect adolescents' sleep. The aim of this study was to investigate the short-term impact of adolescents' prolonged exposure to violent video-gaming on sleep. Seventeen male adolescents (mean age = 16 ± 1 years) with no current sleep difficulties played a novel, fast-paced, violent video-game (50 or 150 min) before their usual bedtime on two different testing nights in a sleep laboratory. Objective (polysomnography-measured sleep and heart rate) and subjective (single-night sleep diary) measures were obtained to assess the arousing effects of prolonged gaming. Compared with regular gaming, prolonged gaming produced decreases in objective sleep efficiency (by 7 ± 2%, falling below 85%) and total sleep time (by 27 ± 12 min) that was contributed by a near-moderate reduction in rapid eye movement sleep (Cohen's d = 0.48). Subjective sleep-onset latency significantly increased by 17 ± 8 min, and there was a moderate reduction in self-reported sleep quality after prolonged gaming (Cohen's d = 0.53). Heart rate did not differ significantly between video-gaming conditions during pre-sleep game-play or the sleep-onset phase. Results provide evidence that prolonged video-gaming may cause clinically significant disruption to adolescent sleep, even when sleep after video-gaming is initiated at normal bedtime. However, physiological arousal may not necessarily be the mechanism by which technology use affects sleep. © 2012 European Sleep Research Society.

Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model.

PubMed

Toib, Amir; Zhang, Chen; Borghetti, Giulia; Zhang, Xiaoxiao; Wallner, Markus; Yang, Yijun; Troupes, Constantine D; Kubo, Hajime; Sharp, Thomas E; Feldsott, Eric; Berretta, Remus M; Zalavadia, Neil; Trappanese, Danielle M; Harper, Shavonn; Gross, Polina; Chen, Xiongwen; Mohsin, Sadia; Houser, Steven R

2017-09-01

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na + and Ca 2+ in the development of HCM, but the role of repolarizing K + currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K + currents causes APD prolongation in MyBPC KO myocytes. We demonstrated that MyBPC KO mice developed severe hypertrophy and cardiac dysfunction compared with wild-type (WT) control mice. Telemetric electrocardiographic recordings of awake mice revealed prolongation of the corrected QT interval in the KO compared with WT control mice, with overt ventricular arrhythmias. Whole cell current- and voltage-clamp experiments comparing KO with WT mice demonstrated ventricular myocyte hypertrophy, AP prolongation, and decreased repolarizing K + currents. Quantitative RT-PCR analysis revealed decreased mRNA levels of several key K + channel subunits. In conclusion, decrease in repolarizing K + currents in MyBPC KO ventricular myocytes contributes to AP and corrected QT interval prolongation and could account for the arrhythmia susceptibility. NEW & NOTEWORTHY Ventricular myocytes isolated from the myosin-binding protein C knockout hypertrophic cardiomyopathy mouse model demonstrate decreased repolarizing K + currents and action potential and QT interval prolongation, linking cellular repolarization abnormalities with arrhythmia susceptibility and the risk for sudden cardiac death in hypertrophic cardiomyopathy. Copyright © 2017 the American Physiological Society.

Mechanical property loss and the occurrence of wood decay during experimental outdoor aging of wood based panels

Treesearch

Charles G. Carll; Alex C. Wiedenhoeft

2007-01-01

Small specimens of sheathing-grade oriented strandboard (OSB) and sheathing-grade plywood were evaluated for retention of mechanical properties in exterior exposure over a series of exposure times. In contrast to previous studies of this nature, specimens at prolonged exposure times were also evaluated (in something more than a cursory manner) for presence of decay....

Sound stress-induced long-term enhancement of mechanical hyperalgesia in rats is maintained by sympathoadrenal catecholamines.

PubMed

Khasar, Sachia G; Dina, Olayinka A; Green, Paul G; Levine, Jon D

2009-10-01

Although stress plays an important role in chronic widespread pain syndromes, such as fibromyalgia, the underlying mechanism has remained elusive. We have recently demonstrated, in a model of chronic widespread pain, that prolonged enhancement of immune mediator hyperalgesia, induced by unpredictable sound stress, requires a contribution of both the sympathoadrenal (epinephrine) and the hypothalamic-pituitary adrenal (corticosterone) neuroendocrine stress axes. Because this stress protocol produced sustained elevation of plasma epinephrine, in the current study we tested the hypothesis that the sympathoadrenal axis also plays a role in maintenance of symptoms in this model of chronic widespread pain. After establishment, adrenal medullectomy abolished the enhancement of epinephrine-induced cutaneous and muscle hyperalgesia. Administration of stress levels of epinephrine to adrenal medullectomized rats reconstituted the pain phenotype. These observations suggest that the sympathoadrenal stress axis plays a major role in the induction as well as maintenance of stress-induced enhancement of mechanical hyperalgesia, mediated by prolonged elevation of circulating epinephrine. We present data showing mechanical hyperalgesia persisting for up to 28 days after exposure to sound stress, with evidence that the sympathoadrenal axis mediator epinephrine plays a major role. These findings could have clinical implications with regard to novel potential treatments for chronic widespread pain syndromes, such as fibromyalgia.

Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus.

PubMed

Behl, Tapan; Kotwani, Anita; Kaur, Ishneet; Goel, Heena

2015-05-15

Nephrogenic diabetes insipidus is a clinical sub-type of a diversely expounded disorder, named diabetes insipidus. It is characterized by inability of the renal cells to sense and respond to the stimulus of vasopressin. Amongst its various etiologies, one of the most inevitable causes includes lithium-induced instigation. Numerous studies reported marked histological damage to the kidneys upon long-term treatment with lithium. The recent researches have hypothesized many lithium-mediated mechanisms to explain the damage and dysfunction caused in the kidneys following lithium exposure. These mechanisms, widely, intend to justify the lithium-induced electrolyte imbalance, its interference with some vital proteins and a specific steroidal hormone, obstruction caused to a certain imperative transducer pathway and the renal tubular acidification defect produced on its prolonged therapy. Thorough study of such mechanisms aids in better understanding of the role of lithium in the pathophysiology of this disorder. Hence, the ameliorated knowledge regarding disease-pathology might prove beneficial in developing therapies that aim on disrupting the various lithium-mediated pathways. Hence, this may effectively lead to the demonstration of a novel treatment for nephrogenic diabetes insipidus, which is, at present, limited to the use of diuretics which block lithium reuptake into the body. Copyright © 2015 Elsevier B.V. All rights reserved.

Bishop score and ultrasound assessment of the cervix for prediction of time to onset of labor and time to delivery in prolonged pregnancy.

PubMed

Strobel, E; Sladkevicius, P; Rovas, L; De Smet, F; Karlsson, E Dejin; Valentin, L

2006-09-01

To determine the ability of Bishop score and sonographic cervical length to predict time to spontaneous onset of labor and time to delivery in prolonged pregnancy. Ninety-seven women underwent transvaginal ultrasound examination and palpation of the cervix at 291-296 days' gestation according to ultrasound fetometry at 12-20 weeks' gestation. Sonographic cervical length and Bishop score were recorded. Multivariate logistic regression analysis was used to determine which variables were independent predictors of the onset of labor/delivery < or = 24 h, < or = 48 h, and < or = 96 h. Receiver-operating characteristics (ROC) curves were drawn to assess diagnostic performance. In nulliparous women (n = 45), both Bishop score and sonographic cervical length predicted the onset of labor/delivery < or = 24 h and < or = 48 h (area under ROC curve for the onset of labor < or = 24 h 0.79 vs. 0.80, P = 0.94; for delivery < or = 24 h 0.81 vs. 0.85, P = 0.64; for the onset of labor < or = 48 h 0.73 vs. 0.74, P = 0.90; for delivery < or = 48 h 0.77 vs. 0.71, P = 0.50). Only Bishop score discriminated between nulliparous women who went into labor/delivered < or = 96 h or > 96 h. A logistic regression model including Bishop score and cervical length was superior to Bishop score alone in predicting delivery < or = 24 h (area under ROC curve 0.93 vs. 0.81, P = 0.03) and superior to Bishop score alone and cervical length alone in predicting the onset of labor < or = 24 h (area under ROC curve 0.90 vs. 0.79, P = 0.06; and 0.90 vs. 0.80, P = 0.06). In parous women (n = 52), Bishop score and sonographic cervical length predicted the onset of labor/delivery < or = 24 h (area under ROC curve for the onset of labor 0.75 vs. 0.69, P = 0.49; for delivery 0.74 vs. 0.70, P = 0.62), but only Bishop score discriminated between women who went into labor/delivered < or = 48 h and > 48 h. Three parous women had not gone into labor and six had not given birth at 96 h. In parous women logistic regression models including both Bishop score and cervical length did not substantially improve prediction of the time to onset of labor/delivery. In prolonged pregnancy Bishop score and sonographic cervical length have a similar ability to predict the time to the onset of labor and delivery. In nulliparous women the use of logistic regression models including Bishop score and cervical length is likely to offer better prediction of the onset of labor/delivery < or = 24 h than the use of the Bishop score alone. Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd.

Ventricular dysfunction in type 1 myotonic dystrophy: electrical, mechanical, or both?

PubMed

Lindqvist, P; Mörner, S; Olofsson, B O; Backman, C; Lundblad, D; Forsberg, H; Henein, M Y

2010-09-03

Myotonic dystrophy type 1 (DM1) is a systemic disease which affects the heart and may be a cause of sudden death. Conduction disturbances are the major cardiac abnormalities seen in this condition. We sought to assess electrical and mechanical cardiac functions to identify abnormalities that might explain sudden cardiac death in DM1. Thirty six patients with DM1 and 16 controls were studied using echocardiography including myocardial Doppler. ECG recordings were also obtained. Left ventricular (LV) dimensions were maintained but systolic function was reduced (p<0.001), including stroke volume (p<0.05). LV segmental myocardial isovolumic contraction time was prolonged (p<0.001) and correlated with PR interval (p<0.001). Isovolumic relaxation time was prolonged (p<0.05) and filling time was reduced (p<0.001). LV cavity was significantly asynchronous demonstrated by prolonged total isovolumic time (t-IVT) (p<0.001), high Tei index (p<0.001) and low ejection index (p<0.001). Right ventricular (RV) strain was reduced (p<0.001) as were its systolic and diastolic velocities (p<0.05 for both). 22/36 patients had prolonged LV t-IVT>12.3 s/min (upper 95% normal CI), 13 of whom had PR≥200 ms, 11 had QRS duration>120 ms (5 had combined abnormality) and the remaining 5 had neither. Over the 3 years follow up 10 patients had events, 6 of them cardiac. t-IVT was prolonged in 5/6 patients, PR interval in 4 and QRS duration in one. In DM1 patients, LV conventional measurements are modestly impaired but cardiac time relations suggest marked asynchronous cavity function. Although our findings were primarily explained on the basis of long PR interval or broad QRS duration a minority presented an evidence for myocardial cause of asynchrony rather than electrical. Early identification of such abnormalities may guide towards a need for additional electrical resynchronization therapy which may improve survival in a way similar to what has been shown in heart failure trials. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Training shortens search times in children with visual impairment accompanied by nystagmus.

PubMed

Huurneman, Bianca; Boonstra, F Nienke

2014-01-01

Perceptual learning (PL) can improve near visual acuity (NVA) in 4-9 year old children with visual impairment (VI). However, the mechanisms underlying improved NVA are unknown. The present study compares feature search and oculomotor measures in 4-9 year old children with VI accompanied by nystagmus (VI+nys [n = 33]) and children with normal vision (NV [n = 29]). Children in the VI+nys group were divided into three training groups: an experimental PL group, a control PL group, and a magnifier group. They were seen before (baseline) and after 6 weeks of training. Children with NV were only seen at baseline. The feature search task entailed finding a target E among distractor E's (pointing right) with element spacing varied in four steps: 0.04°, 0.5°, 1°, and 2°. At baseline, children with VI+nys showed longer search times, shorter fixation durations, and larger saccade amplitudes than children with NV. After training, all training groups showed shorter search times. Only the experimental PL group showed prolonged fixation duration after training at 0.5° and 2° spacing, p's respectively 0.033 and 0.021. Prolonged fixation duration was associated with reduced crowding and improved crowded NVA. One of the mechanisms underlying improved crowded NVA after PL in children with VI+nys seems to be prolonged fixation duration.

Effect of local cooling on excitation-contraction coupling in myasthenic muscle: Another mechanism of ice-pack test in myasthenia gravis.

PubMed

Yamamoto, Daisuke; Imai, Tomihiro; Tsuda, Emiko; Hozuki, Takayoshi; Yamauchi, Rika; Hisahara, Shin; Kawamata, Jun; Shimohama, Shun

2017-11-01

The ice-pack test is a convenient diagnostic testing procedure for myasthenia gravis (MG). We investigated the underlying mechanism of the ice-pack test performed on bilateral masseters. We performed trigeminal repetitive nerve stimulation (RNS), excitation-contraction (E-C) coupling assessment (Imai's method) and bite force measurement before and after cooling of the masseters in MG patients and normal controls. After placing the ice-pack on the masseters for 3min, serial recordings of the three tests were performed at various time intervals during 10min after cooling. The bite force increased significantly after cooling in ice-pack-positive MG patients. The acceleration and acceleration ratio (acceleration at a given time to baseline acceleration) of jaw movement increased significantly after cooling of the masseters in ice-pack-positive MG patients compared to ice-pack-negative patients and normal controls. The prolonged effect of cooling continued until the end of recording even though decremental response to RNS had returned to baseline value. Cooling of myasthenic muscle may induce two effects. One is relatively short effect on electrical synaptic transmission at the endplate, and another is prolonged effect on E-C coupling in the muscle. The ice-pack test induces a prolonged effect of ameliorating impaired E-C coupling in MG. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

The role of immunoglobulin A in prolonged and relapsing hepatitis A virus infections.

PubMed

Dotzauer, Andreas; Heitmann, Alke; Laue, Thomas; Kraemer, Leena; Schwabe, Kerstin; Paulmann, Dajana; Flehmig, Bertram; Vallbracht, Angelika

2012-04-01

Hepatitis A virus (HAV) infections result in different courses of the disease, varying between normal, prolonged and relapsing. However, the reason for these heterogeneous clinical appearances is not understood. As HAV-anti-HAV IgA immunocomplexes (HAV-IgA) infect hepatocytes, IgA was postulated as a carrier supporting hepatotropic transport of HAV, and it was speculated that this carrier mechanism contributes to the various clinical outcomes. In this study, the IgA-carrier mechanism was investigated in a mouse model. We show that HAV-IgA immunocomplexes efficiently reached the liver not only in HAV-seronegative mice, but also, and this is in contrast to free-HAV particles, in immunized HAV-seropositive animals. This IgA-mediated transport of HAV to the liver in the presence of immunity depended on the stage of development of the immune response. We conclude that over a period of several weeks after infection, anti-HAV IgA is able to promote an enterohepatic cycling of HAV, resulting in continuous endogenous reinfections of the liver. Our experiments indicate that highly avid IgG antibodies, which are present at later times of the infection, can terminate the reinfections. However, the endogenous reinfections in the presence of a developing neutralizing immunity might contribute to prolonged as well as to relapsing courses of HAV infections. Furthermore, the results show that serum IgA may act as an infection protracting factor.

Prolonged lateral steep position impairs respiratory mechanics during continuous lateral rotation therapy in respiratory failure.

PubMed

Schellongowski, Peter; Losert, Heidrun; Locker, Gottfried J; Laczika, Klaus; Frass, Michael; Holzinger, Ulrike; Bojic, Andja; Staudinger, Thomas

2007-04-01

To establish whether prolonged lateral steep position during continuous rotation therapy leads to improvement on pulmonary gas exchange, respiratory mechanics and hemodynamics. Prospective observational study. Intensive care unit of a university hospital. Twelve consecutive patients suffering from acute lung injury or adult respiratory distress syndrome undergoing continuous rotation therapy. Blood gas analysis, static lung compliance, blood pressure, cardiac index and pulmonary shunt fraction were measured in supine as well as in left and right lateral steep position at 62 degrees during continuous rotation therapy (phase I). Rotation was then stopped for 30 min with the patients in supine position, left and right lateral steep position, and the same measurements were performed every 10 min (phase II). Phase I and II revealed no significant changes in PaO(2)/FiO(2) ratio, mean arterial blood pressure, pulmonary shunt fraction, or cardiac index. Significantly lower static compliance was observed in lateral steep position than in supine position (p<0.001). Concomitantly, PaCO(2) was significantly lower in supine position than in left and right lateral steep position (p<0.01). Lateral steep positioning impairs the compliance of the respiratory system. Prolonged lateral steep position does not lead to benefits with respect to oxygenation or hemodynamics. Individual response to the different positions is unpredictable. The pauses in "extreme" positions should be as short as possible.

Clinical dysphagia risk predictors after prolonged orotracheal intubation

PubMed Central

de Medeiros, Gisele Chagas; Sassi, Fernanda Chiarion; Mangilli, Laura Davison; Zilberstein, Bruno; de Andrade, Claudia Regina Furquim

2014-01-01

OBJECTIVES: To elucidate independent risk factors for dysphagia after prolonged orotracheal intubation. METHODS: The participants were 148 consecutive patients who underwent clinical bedside swallowing assessments from September 2009 to September 2011. All patients had received prolonged orotracheal intubations and were admitted to one of several intensive care units of a large Brazilian school hospital. The correlations between the conducted water swallow test results and dysphagia risk levels were analyzed for statistical significance. RESULTS: Of the 148 patients included in the study, 91 were male and 57 were female (mean age, 53.64 years). The univariate analysis results indicated that specific variables, including extraoral loss, multiple swallows, cervical auscultation, vocal quality, cough, choking, and other signs, were possible significant high-risk indicators of dysphagia onset. The multivariate analysis results indicated that cervical auscultation and coughing were independent predictive variables for high dysphagia risk. CONCLUSIONS: Patients displaying extraoral loss, multiple swallows, cervical auscultation, vocal quality, cough, choking and other signs should benefit from early swallowing evaluations. Additionally, early post-extubation dysfunction recognition is paramount in reducing the morbidity rate in this high-risk population. PMID:24473554

Acute toxicity of diphacinone in Northern bobwhite: Effects on survival and blood clotting

USGS Publications Warehouse

Rattner, Barnett A.; Horak, Katherine E.; Warner, Sarah E.; Johnston, John J.

2010-01-01

The anticoagulant rodenticide diphacinone was slightly toxic (acute oral LD50 2014 mg/kg) to Northern bobwhite (Colinus virginianus) in a 14-day acute toxicity trial. Precise and sensitive assays of blood clotting (prothrombin time, Russell?s Viper venom time, and thrombin clotting time) were adapted for use in quail, and this combination of assays is recommended to measure the effects of anticoagulant rodenticides. A single oral sublethal dose of diphacinone (434 mg/kg body weight) prolonged clotting time at 48 h post-dose compared to controls. At 783 mg/kg (approximate LD02), clotting time was prolonged at both 24 and 48 h post-dose. Prolongation of in vitro clotting time reflects impaired coagulation complex activity, and was detected before overt signs of toxicity were apparent at the greatest dosages (2868 and 3666 mg/kg) in the acute toxicity trial. These clotting time assays and toxicity data will assist in the development of a pharmacodynamic model to predict toxicity, and also facilitate rodenticide hazard and risk assessments in avian species.

Clinical dysphagia risk predictors after prolonged orotracheal intubation.

PubMed

Medeiros, Gisele Chagas de; Sassi, Fernanda Chiarion; Mangilli, Laura Davison; Zilberstein, Bruno; Andrade, Claudia Regina Furquim de

2014-01-01

To elucidate independent risk factors for dysphagia after prolonged orotracheal intubation. The participants were 148 consecutive patients who underwent clinical bedside swallowing assessments from September 2009 to September 2011. All patients had received prolonged orotracheal intubations and were admitted to one of several intensive care units of a large Brazilian school hospital. The correlations between the conducted water swallow test results and dysphagia risk levels were analyzed for statistical significance. Of the 148 patients included in the study, 91 were male and 57 were female (mean age, 53.64 years). The univariate analysis results indicated that specific variables, including extraoral loss, multiple swallows, cervical auscultation, vocal quality, cough, choking, and other signs, were possible significant high-risk indicators of dysphagia onset. The multivariate analysis results indicated that cervical auscultation and coughing were independent predictive variables for high dysphagia risk. Patients displaying extraoral loss, multiple swallows, cervical auscultation, vocal quality, cough, choking and other signs should benefit from early swallowing evaluations. Additionally, early post-extubation dysfunction recognition is paramount in reducing the morbidity rate in this high-risk population.

New developments in functional medical textiles and their mechanism of action

USDA-ARS?s Scientific Manuscript database

Functional medical textiles are undergoing a revolution in structural design. Medical textiles as non-implantables, implantables, and extracorporeals, are playing central roles in healthcare improvements enhancing and prolonging the quality of life. Developments in the design of materials that funct...

Sodium channel blockade with QRS widening after an escitalopram overdose.

PubMed

Schreffler, Susan M; Marraffa, Jeanna M; Stork, Christine M; Mackey, Jennifer

2013-09-01

Escitalopram is rarely associated with prolongation of the QTc interval; however, there are no reported cases of QRS complex widening associated with escitalopram overdose. We report a case of a patient who presented with both QRS complex widening and QTc interval prolongation after an escitalopram overdose. A 16-year-old girl presented to the emergency department after ingestion of escitalopram, tramadol/acetaminophen, and hydrocodone/acetaminophen. Laboratory results were significant for 4-hour acetaminophen 21.1 μg/mL. Serum electrolytes including potassium, magnesium, and calcium were all normal. Initial electrocardiogram (ECG) revealed a widened QRS with an incomplete right bundle branch pattern. After administration of 100-mEq sodium bicarbonate, a repeat ECG revealed narrowing of the QRS complex and a prolonged QTc interval. Magnesium sulfate 2 g intravenous and sodium bicarbonate drip were initiated. A repeat ECG, 1 hour after the second, revealed normalization of the QRS complex and QTc interval. Prolongation of the QTc interval is an expected effect of escitalopram. Both escitalopram and citalopram are metabolized to the cardiotoxic metabolite S-didesmethylcitalopram and didesmethylcitalopram, respectively, which have been implicated in numerous cardiac abnormalities including widening of the QRS complex. Although never previously described with escitalopram, this mechanism provides a reasonable explanation for the QRS complex widening and incomplete right bundle branch block that occurred in our patient. Both QRS complex widening and QTc interval prolongation should be monitored in cases of escitalopram and citalopram overdoses.

Crataegus extract prolongs action potential duration in guinea-pig papillary muscle.

PubMed

Müller, A; Linke, W; Zhao, Y; Klaus, W

1996-11-01

Crataegus extract is used in cardiology for the treatment of moderate heart failure (NYHA II). Recently it was shown that Crataegus extract prolongs the refractory period in isolated perfused guinea pig hearts. In order to find out what mechanism is responsible for this prolongation of refractory period, we investigated the effects of Crataegus extract (LI 132) on the action potential of guinea pig papillary muscle with the help of conventional microelectrode techniques. Crataegus extract, when put in a concentration (10 mg/l) capable of inducing an inotropic effect of about 20%, significantly increased action potential duration at all investigated levels of repolarisation. Maximum prolongation was 8.5±2.3 ms, 12.5±2.6 ms and 11.7±2.9 ms at 20%, 50% and 90% repolarisation, respectively (control APD(90): 172±4 ms). Experiments on the time course of recovery of the maximum upstroke velocity (V(max)) of the action potential revealed that Crataegus extract increased the time constant of recovery of V(max) from 8.80±2.33 ms to 22.60±5.77 ms, indicating a weak Class I-like antiarrhythmic action. In addition, we observed a small reduction in V(max). In summary, our results show that Crataegus extract prolongs action potential duration and delays recovery of V(max). We, therefore, suggest that Crataegus extract possesses certain antiarrhythmic properties. Copyright © 1996 Gustav Fischer Verlag · Stuttgart · Jena · New York. Published by Elsevier GmbH.. All rights reserved.

Evaluation and prediction of long term space environmental effects on non-metallic materials

NASA Technical Reports Server (NTRS)

Shepic, J. A.

1980-01-01

The effects of prolonged spacecraft materials were determined and the results compared with predicted behavior. The adhesion and dielectric properties of poly-thermaleze and therm-amid magnet wire insulation were studied. The tensile properties of Lexan, polyurethane, polyethelyne, lucite, and nylon were studied well as the flexure and tensile characteristic of Adlock 851, a phenolic laminate. The volume resistivity of Cho-seal, a conductive elastomer was also a examined. Tables show the time exposed at thermal vacuum, and the high, low, and average MPA and KSI.

The Nutritional Risk Screening 2002 tool for detecting malnutrition risk in hospitalised patients: perspective from a developing country.

PubMed

Gökcan, Hale; Selçuk, Haldun; Töre, Emine; Gülseren, Pınar; Cambaz, Hatice; Sarıtaş, Şeniz; Öcal, Ruhsen; Başaran, Özgür; Yılmaz, Uğur; Akın, Ebru

2014-12-01

To verify the validity of the Nutritional Risk Screening (NRS) 2002 test in a Turkish population. We prospectively investigated 2566 patients at a tertiary referral hospital. Nutritional status was screened using NRS 2002, and the length of the stay (LOS) was the main outcome measure. Hospital stays >10 days were accepted as prolonged LOS. NRS scores ≥3 were accepted as indicating risk for malnutrition. Statistical analyses were performed to determine the independent risk factors for malnutrition risk and prolonged LOS. The mean age of patients was 56.6±16.9 years. According to the NRS 2002, 964 patients (37.6%) were without risk, 1320 (51.4%) warranted surveillance and 282 (11%) were at high risk for malnutrition. Malnutrition rate was the highest in the intensive care unit (22.01%). Prolonged LOS was seen in 24.4% of patients. Intensive care unit stay [odds ratio (OR): 0.585; confidence interval (CI): 1.45-2.22; p<0.001] and an NRS score ≥3 (OR: 0.88; CI: 1.87-3.13; p<0.001) were independent risk factors for prolonged LOS. Improving healthcare outcomes while avoiding preventable healthcare costs is an important goal of healthcare provision in developing countries. NRS 2002 was predictive of LOS, and thus, of patient prognosis. Further community-based studies are warranted to assess the impact of NRS 2002 on reducing healthcare costs.

Heat shock and prolonged heat stress attenuate neurotoxin and sporulation gene expression in group I Clostridium botulinum strain ATCC 3502

PubMed Central

Selby, Katja; Mascher, Gerald; Somervuo, Panu; Korkeala, Hannu

2017-01-01

Foodborne pathogenic bacteria are exposed to a number of environmental stresses during food processing, storage, and preparation, and in the human body. In order to improve the safety of food, the understanding of molecular stress response mechanisms foodborne pathogens employ is essential. Many response mechanisms that are activated during heat shock may cross-protect bacteria against other environmental stresses. To better understand the molecular mechanisms Clostridium botulinum, the causative agent of botulism, utilizes during acute heat stress and during adaptation to stressfully high temperature, the C. botulinum Group I strain ATCC 3502 was grown in continuous culture at 39°C and exposed to heat shock at 45°C, followed by prolonged heat stress at 45°C to allow adaptation of the culture to the high temperature. Growth in continuous culture was performed to exclude secondary growth phase effects or other environmental impacts on bacterial gene transcription. Changes in global gene expression profiles were studied using DNA microarray hybridization. During acute heat stress, Class I and III heat shock genes as well as members of the SOS regulon were activated. The neurotoxin gene botA and genes encoding the neurotoxin-associated proteins were suppressed throughout the study. Prolonged heat stress led to suppression of the sporulation machinery whereas genes related to chemotaxis and motility were activated. Induced expression of a large proportion of prophage genes was detected, suggesting an important role of acquired genes in the stress resistance of C. botulinum. Finally, changes in the expression of a large number of genes related to carbohydrate and amino acid metabolism indicated remodeling of the cellular metabolism. PMID:28464023

Heat shock and prolonged heat stress attenuate neurotoxin and sporulation gene expression in group I Clostridium botulinum strain ATCC 3502.

PubMed

Selby, Katja; Mascher, Gerald; Somervuo, Panu; Lindström, Miia; Korkeala, Hannu

2017-01-01

Foodborne pathogenic bacteria are exposed to a number of environmental stresses during food processing, storage, and preparation, and in the human body. In order to improve the safety of food, the understanding of molecular stress response mechanisms foodborne pathogens employ is essential. Many response mechanisms that are activated during heat shock may cross-protect bacteria against other environmental stresses. To better understand the molecular mechanisms Clostridium botulinum, the causative agent of botulism, utilizes during acute heat stress and during adaptation to stressfully high temperature, the C. botulinum Group I strain ATCC 3502 was grown in continuous culture at 39°C and exposed to heat shock at 45°C, followed by prolonged heat stress at 45°C to allow adaptation of the culture to the high temperature. Growth in continuous culture was performed to exclude secondary growth phase effects or other environmental impacts on bacterial gene transcription. Changes in global gene expression profiles were studied using DNA microarray hybridization. During acute heat stress, Class I and III heat shock genes as well as members of the SOS regulon were activated. The neurotoxin gene botA and genes encoding the neurotoxin-associated proteins were suppressed throughout the study. Prolonged heat stress led to suppression of the sporulation machinery whereas genes related to chemotaxis and motility were activated. Induced expression of a large proportion of prophage genes was detected, suggesting an important role of acquired genes in the stress resistance of C. botulinum. Finally, changes in the expression of a large number of genes related to carbohydrate and amino acid metabolism indicated remodeling of the cellular metabolism.

Determining delayed admission to intensive care unit for mechanically ventilated patients in the emergency department.

PubMed

Hung, Shih-Chiang; Kung, Chia-Te; Hung, Chih-Wei; Liu, Ber-Ming; Liu, Jien-Wei; Chew, Ghee; Chuang, Hung-Yi; Lee, Wen-Huei; Lee, Tzu-Chi

2014-08-23

The adverse effects of delayed admission to the intensive care unit (ICU) have been recognized in previous studies. However, the definitions of delayed admission varies across studies. This study proposed a model to define "delayed admission", and explored the effect of ICU-waiting time on patients' outcome. This retrospective cohort study included non-traumatic adult patients on mechanical ventilation in the emergency department (ED), from July 2009 to June 2010. The primary outcomes measures were 21-ventilator-day mortality and prolonged hospital stays (over 30 days). Models of Cox regression and logistic regression were used for multivariate analysis. The non-delayed ICU-waiting was defined as a period in which the time effect on mortality was not statistically significant in a Cox regression model. To identify a suitable cut-off point between "delayed" and "non-delayed", subsets from the overall data were made based on ICU-waiting time and the hazard ratio of ICU-waiting hour in each subset was iteratively calculated. The cut-off time was then used to evaluate the impact of delayed ICU admission on mortality and prolonged length of hospital stay. The final analysis included 1,242 patients. The time effect on mortality emerged after 4 hours, thus we deduced ICU-waiting time in ED > 4 hours as delayed. By logistic regression analysis, delayed ICU admission affected the outcomes of 21 ventilator-days mortality and prolonged hospital stay, with odds ratio of 1.41 (95% confidence interval, 1.05 to 1.89) and 1.56 (95% confidence interval, 1.07 to 2.27) respectively. For patients on mechanical ventilation at the ED, delayed ICU admission is associated with higher probability of mortality and additional resource expenditure. A benchmark waiting time of no more than 4 hours for ICU admission is recommended.

Development and pilot testing of a decision aid for surrogates of patients with prolonged mechanical ventilation

PubMed Central

Cox, Christopher E.; Lewis, Carmen L.; Hanson, Laura C.; Hough, Catherine L.; Kahn, Jeremy M.; White, Douglas B.; Song, Mi-Kyung; Tulsky, James A.; Carson, Shannon S.

2013-01-01

Objective Shared decision making is inadequate in intensive care units (ICUs). Decision aids can improve decision making quality, though their role in an ICU setting is unclear. We aimed to develop and pilot test a decision aid for shared decision makers of patients undergoing prolonged mechanical ventilation. Setting ICUs at three medical centers. Subjects 53 surrogate decision makers and 58 physicians. Design and interventions We developed the decision aid using defined methodological guidelines. After an iterative revision process, formative cognitive testing was performed among surrogate-physician dyads. Next, we compared the decision aid to usual care control in a prospective, before/after design study. Measurements and main results Primary outcomes were physician-surrogate discordance for expected patient survival, comprehension of relevant medical information, and the quality of communication. Compared to control, the intervention group had lower surrogate-physician discordance (7 [10] vs 43 [21]), greater comprehension (11.4 [0.7] vs 6.1 [3.7]), and improved quality of communication (8.7 [1.3] vs 8.4 [1.3]) (all p<0.05) post-intervention. Hospital costs were lower in the intervention group ($110,609 vs $178,618; p=0.044); mortality did not differ by group (38% vs 50%, p=0.95). 94% of surrogates and 100% of physicians reported that the decision aid was useful in decision making. Conclusion We developed a prolonged mechanical ventilation decision aid that is feasible, acceptable, and associated with both improved decision making quality and less resource utilization. Further evaluation using a randomized controlled trial design is needed to evaluate the decision aid's effect on long-term patient and surrogate outcomes. PMID:22635048

Akt2 Knockout Alleviates Prolonged Caloric Restriction-Induced Change in Cardiac Contractile Function through Regulation of Autophagy

PubMed Central

Zhang, Yingmei; Han, Xuefeng; Hu, Nan; Huff, Anna F.; Gao, Feng; Ren, Jun

2014-01-01

Caloric restriction leads to changes in heart geometry and function although the underlying mechanism remains elusive. Autophagy, a conserved pathway for degradation of intracellular proteins and organelles, preserves energy and nutrient in the face of caloric insufficiency. This study was designed to examine the role of Akt2 in prolonged caloric restriction-induced change in cardiac homeostasis and the underlying mechanism(s) involved. Wild-type (WT) and Akt2 knockout mice were caloric restricted (by 40%) for 30 weeks. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties, autophagy and its regulatory proteins were evaluated. Caloric restriction compromised echocardiographic indices (decreased left ventricular mass, left ventricular diameters and cardiac output), cardiomyocyte contractile and intracellular Ca2+ properties associated with dampened SERCA2a phosphorylation, upregulated phospholamban and autophagy (Beclin-1, Atg7, LC3BII-to-LC3BI ratio), increased autophagy adaptor protein p62, elevated phosphorylation of AMPK, Akt2 and the Akt downstream signal molecule TSC2, the effects of which with the exception of autophagy protein markers (Beclin-1, Atg7, LC3B) and AMPK were mitigated or significantly alleviated by Akt2 knockout. Lysosomal inhibition using bafilomycin A1 negated Akt2 knockout-induced protective effect on p62. Evaluation of downstream signaling molecules of Akt and AMPK including mTOR and ULK1 revealed that caloric restriction suppressed and promoted phosphorylation of mTOR and ULK1, respectively, without affecting total mTOR and ULK1 expression. Akt2 knockout significantly augmented caloric restriction-induced responses on mTOR and ULK1. Taken together, these data suggest a beneficial role of Akt2 knockout in preservation of cardiac homeostasis against prolonged caloric restriction-induced pathological changes possibly through facilitating autophagy. PMID:24368095

Mechanism of As2O3-Induced Action Potential Prolongation and Using hiPS-CMs to Evaluate the Rescue Efficacy of Drugs With Different Rescue Mechanism.

PubMed

Yan, Meng; Feng, Lifang; Shi, Yanhui; Wang, Junnan; Liu, Yan; Li, Fengmei; Li, Baoxin

2017-08-01

Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking. Then we explored pharmacological rescue strategies on As2O3-induced LQTS, and found that 4 therapeutic agents exert rescue efficacy via 3 different pathways: fexofenadine and astemizole facilitate hERG trafficking via promotion of channel-chaperone formation after As2O3 incubation; ranolazine slows hERG degradation in the presence of As2O3; and resveratrol shows significant attenuation on calcium current increase triggered by As2O3. Moreover, we used human-induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) to evaluate the rescue effects of the above agents on As2O3-induced prolongation of action potential duration (APD) and demonstrated that fexofenadine and resveratrol significantly ameliorate the prolonged APD. These observations suggested that pharmacological chaperone like fexofenadine and resveratrol might have the potential to protect against the cardiotoxicity of As2O3. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk

PubMed Central

Guns, P-J; Johnson, DM; Van Op den bosch, J; Weltens, E; Lissens, J

2012-01-01

BACKGROUND AND PURPOSE QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A negative electro-mechanical (E-M) window has recently been proposed as an alternative risk marker for TdP in a canine LQT1 model. Here, we evaluated the E-M window in anaesthetized guinea pigs as a screening marker for TdP in humans. EXPERIMENTAL APPROACH The effects of various reference drugs and changes in body temperature on the E-M window were assessed in instrumented guinea pigs. The E-M window was defined as the delay between the duration of the electrical (QT interval) and mechanical (QLVPend) systole. KEY RESULTS Drugs with known TdP liability (quinidine, haloperidol, domperidone, terfenadine, thioridazine and dofetilide), but not those with no TdP risk in humans (salbutamol and diltiazem) consistently decreased the E-M window. Interestingly, drugs with known clinical QT prolongation, but with low risk for TdP (amiodarone, moxifloxacin and ciprofloxacin) did not decrease the E-M window. Furthermore, the E-M window was minimally affected by changes in heart rate or body temperature. CONCLUSIONS AND IMPLICATIONS A decreased E-M window was consistently observed with drugs already known to have high TdP risk, but not with drugs with low or no TdP risk. These results suggest that the E-M window in anaesthetized guinea pigs is a risk marker for TdP in humans. PMID:22122450

Coping with Physiological Oxidative Stress: A Review of Antioxidant Strategies in Seals

PubMed Central

Vázquez-Medina, José Pablo; Zenteno-Savín, Tania; Elsner, Robert; Ortiz, Rudy M.

2012-01-01

While diving, seals are exposed to apnea-induced hypoxemia and repetitive cycles of ischemia/reperfusion. While on land, seals experience sleep apnea, as well as prolonged periods of food and water deprivation. Prolonged fasting, sleep apnea, hypoxemia and ischemia/reperfusion increase oxidant production and oxidative stress in terrestrial mammals. In seals, however, neither prolonged fasting nor apnea-induced hypoxemia or ischemia/reperfusion increase systemic or local oxidative damage. The strategies seals evolved to cope with increased oxidant production are reviewed in the present manuscript. Among these strategies, high antioxidant capacity and the oxidant-mediated activation of hormetic responses against hypoxia and oxidative stress are discussed. In addition to expanding our knowledge of the evolution of antioxidant defenses and adaptive responses to oxidative stress, understanding the mechanisms that allow adapted mammals to avoid oxidative damage has the potential to advance our knowledge of oxidative stress-induced pathologies and to enhance the translative value of biomedical therapies in the long term. PMID:22327141

A randomized controlled trial of intranasal ketamine in migraine with prolonged aura.

PubMed

Afridi, Shazia K; Giffin, Nicola J; Kaube, Holger; Goadsby, Peter J

2013-02-12

The aim of our study was to test the hypothesis that ketamine would affect aura in a randomized controlled double-blind trial, and thus to provide direct evidence for the role of glutamatergic transmission in human aura. We performed a double-blinded, randomized parallel-group controlled study investigating the effect of 25 mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active control. Each subject recorded data from 3 episodes of migraine. Eighteen subjects completed the study. Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect. These data provide translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem. This study provides class III evidence that intranasal ketamine is effective in reducing aura severity in patients with migraine with prolonged aura.

Aggravation of laser-treated diabetic cystoid macular edema after prolonged flight: a case report.

PubMed

Daniele, S; Daniele, C

1995-05-01

A 62-year-old diabetic woman with pan-retinal laser treatment for non-proliferative, bilateral diabetic retinopathy and cystoid macular edema (CME) demonstrated an acute exacerbation of CME after 42 h of prolonged flight in commercial pressurized aircraft. When travelling by air, vital sensory functions of the human body are affected by a variety of disturbing factors. The most important of these--altitude-related oxygen deficiency--is compensated for by homeostatic mechanisms in healthy subjects. However, even with normal oxygen tension, the diabetic retina is hypoxic because the vascular response to oxygen variation is altered. Increased tissue demand for oxygen, owing to decreased ability of the circulating blood to release oxygen, cannot be met. In our patient, the aggravated CME appeared to result from hemodynamic changes induced by flight. In particular, the prolonged environmental oxygen deficiency may have exacerbated the retinal hypoxia leading to acute, vascular decompensation and dramatic plasma leakage with visual loss.

Evolution of perceived footwear comfort over a prolonged running session.

PubMed

Hintzy, F; Cavagna, J; Horvais, N

2015-12-01

The purpose of this study was to investigate the subjective perception of overall footwear comfort over a prolonged running session. Ten runners performed two similar sessions consisting of a 13-km trail run (5 laps of 2.6 km) as fast as possible. The overall footwear comfort was evaluated before running and at the end of each lap with a 150-mm visual analogic scale, as well as speed, heart rate and rate of perceived exertion. The results showed that both overall footwear comfort and speed decreased consistently during the run session, and significantly after 44 min of running (i.e. the 3rd lap). It could be hypothesized that the deterioration of overall footwear comfort was explained by mechanical and energetical parameter changes with time and/or fatigue occurring at the whole body, foot and footwear levels. These results justify the use of a prolonged running test for running footwear comfort evaluation. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Achilles' heel of left ventricular assist device therapy: right ventricle.

PubMed

Ranganath, Neel K; Smith, Deane E; Moazami, Nader

2018-06-01

Many patients suffer from either persistent right ventricular failure (RVF) at the time of left ventricular assist device (LVAD) or have ongoing symptoms consistent with RVF during chronic mechanical circulatory support. The lack of long-term right ventricular assist devices (RVADs) has limited the impact that mechanical circulatory support can provide to patients with biventricular failure. We aim to review the entire spectrum of RVF in patients receiving LVADs and reflect on why this entity remains the Achilles' heel of LVAD therapy. In the early postoperative period, LVAD implantation reduces right ventricle (RV) afterload, but RV dysfunction may be exacerbated secondary to increased venous return. With prolonged therapy, the decreased RV afterload leads to improved RV contractile function. Bayesian statistical models outperform previously published preoperative risk scores by considering inter-relationships and conditional probabilities amongst independent variables. Various echocardiographic parameters and the pulmonary artery pulsatility index have shown promise in predicting post-LVAD RVF. Recent publications have delineated the emergence of 'delayed' RVF. Several devices are currently being investigated for use as RVADs. Post-LVAD RVF depends on the RV's ability to adapt to acute hemodynamic changes imposed by the LVAD. Management options are limited due to the lack of an easily implantable, chronic-use RVAD.

The parathyroid hormone, its fragments and analogues--potent bone-builders for treating osteoporosis.

PubMed

Whitfield, J; Morley, P; Willick, G

2000-06-01

As populations age a rising number of men and women, but especially women during the first decade after menopause, become victims of a severe, accelerated loss of bone with crippling fractures known as osteoporosis. This often results in costly, prolonged hospitalisation and perhaps indirectly, death. Osteoporosis in women is caused by the menopausal oestrogen decline, which removes several key restraints on the generation, longevity and activity of bone-resorbing osteoclasts. Although there are many antiresorptive drugs on or coming onto the market (calcitonin, bisphosphonates, oestrogen and SERMS) that can slow or stop further bone loss, there are none that can restore lost bone mechanical strength by directly stimulating osteoblast activity and bone growth. However, there is a family of potent bone-building peptides, namely the 84 amino acid parathyroid hormone (PTH). Its 31 to 38 amino acid N-terminal fragments are currently in or about to enter clinical trials. We can predict that these peptides will be effective therapeutics for osteoporosis especially when supplemented with bisphosphonates or SERMs to protect the new bone from osteoclasts. These peptides should also accelerate the healing of fractures in persons of all ages and restore lost bone mass and mechanical strength to astronauts following their return to earth after long voyages in space.

Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors.

PubMed

Sahni, Jennifer M; Gayle, Sylvia S; Webb, Bryan M; Weber-Bonk, Kristen L; Seachrist, Darcie D; Singh, Salendra; Sizemore, Steven T; Restrepo, Nicole A; Bebek, Gurkan; Scacheri, Peter C; Varadan, Vinay; Summers, Matthew K; Keri, Ruth A

2017-10-01

Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. Although BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks an SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi. Cancer Res; 77(19); 5395-408. ©2017 AACR . ©2017 American Association for Cancer Research.

Abiraterone acetate in the treatment of prostate cancer.

PubMed

Thakur, Abhimanyu; Roy, Aishwarya; Ghosh, Arijit; Chhabra, Mohit; Banerjee, Sugato

2018-05-01

Among all cancer-related death, prostate cancer accounts for the second prominent reason for cancer-associated death in men. Despite the castration mediated reduction in testosterone synthesis, adrenal glands, as well as tissues of prostate cancer, continue to produce androgens, which ultimately lead to the growth of prostate cancer. This phase is referred as metastatic castration-resistant prostate cancer, which throws an obstacle to treatment. Androgen antagonists, in addition to deprivation of hormone, is being used for reducing the level of prostate-specific antigen but has not successfully come in front as a choice for prolonging the life of patients suffering from prostate cancer. In this prevailing scenario, abiraterone acetate (AA) has proved to be a boon for patients suffering from prostate cancer. AA selectively inhibits the actions of enzymes C17, 20-lyase and 17α-hydroxylase on cytochrome P450 (CYP) 17 when administered orally. The signaling of androgen receptor, being important for primary to metastatic phases of prostate cancer, CYP17 is essential for the synthesis of androgen. Herein, the in-detail pharmacological profile of AA, including androgen signaling, mechanism of action of AA, mechanism of AA resistance, pharmacokinetics, latest clinical findings, predictive markers, optimal treatment sequence, toxicity, and food interaction profiles have been reviewed. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Cortisol Reactivity and Regulation Associated with Shame Responding in Early Childhood

ERIC Educational Resources Information Center

Mills, Rosemary S. L.; Imm, Gorette P.; Walling, Bobbi R.; Weiler, Hope A.

2008-01-01

The purpose of this study was to characterize cortisol response and regulation associated with shame responding in early childhood and to examine how general the relation between shame and cortisol is. It was predicted that children responding to task failure with shame would show a larger and more prolonged cortisol response than other children.…

Investigation of the medical applications of the unique biocarbons developed by NASA

NASA Technical Reports Server (NTRS)

Mooney, V.

1976-01-01

Experience with 127 percutaneous implants in 43 patients and volunteers is discussed. Pure carbon has demonstrated the highest level of success. It is indicated that prolonged success of these implants can be expected if mechanical factors are reduced to a minimum.

Membrane module assembly

DOEpatents

Kaschemekat, Jurgen

1994-01-01

A membrane module assembly adapted to provide a flow path for the incoming feed stream that forces it into prolonged heat-exchanging contact with a heating or cooling mechanism. Membrane separation processes employing the module assembly are also disclosed. The assembly is particularly useful for gas separation or pervaporation.

Sleep apnoea during upper respiratory infection and metabolic alkalosis in infancy.

PubMed Central

Abreu e Silva, F A; MacFadyen, U M; Williams, A; Simpson, H

1986-01-01

Three to four hour polygraphic sleep studies were carried out in 10 infants, five with upper respiratory infection and five with metabolic alkalosis secondary to vomiting during and after recovery from illness. During upper respiratory infection, the main abnormality detected was brief (greater than 3 less than 6 seconds) or prolonged (greater than 6 seconds) attacks of obstructive apnoea. Other indices of apnoea were similar to recovery data. Gross body movements were also increased. In infants with metabolic alkalosis indices of central apnoea were significantly increased when compared with recovery or case control data. Prolonged (greater than 15 seconds) attacks of central apnoea and obstructive apnoea (greater than 6 seconds) were only observed during illness. Gross body movements and periodic breathing were also increased. These findings suggest that the functional consequences of apparently 'mild' illnesses in young infants may be greater than is generally suspected and perhaps relevant to mechanism(s) of death in sudden infant death syndrome. PMID:3789786

[The incidence and risk factors of ventilator-associated pneumonia in patients with severe traumatic brain injury].

PubMed

Marjanović, Vesna; Novak, Vesna; Velicković, Ljubinka; Marjanović, Goran

2011-01-01

Patients with severe traumatic brain injury are at a risk of developing ventilator-associated pneumonia. The aim of this study was to describe the incidence, etiology, risk factors for development of ventilator-associated pneumonia and outcome in patients with severe traumatic brain injury. A retrospective study was done in 72 patients with severe traumatic brain injury, who required mechanical ventilation for more than 48 hours. Ventilator-associated pneumonia was found in 31 of 72 (43.06%) patients with severe traumatic brain injury. The risk factors for ventilator-associated pneumonia were: prolonged mechanical ventilation (12.42 vs 4.34 days, p < 0.001), longer stay at intensive care unit (17 vs 5 days, p < 0.001) and chest injury (51.61 vs 19.51%, p < 0.009) compared to patients without ventilator-associated pneumonia. The mortality rate in the patients with ventilator-associated pneumonia was higher (38.71 vs 21.95%, p = 0.12). The development of ventilator-associated pneumonia in patients with severe traumatic brain injury led to the increased morbidity due to the prolonged mechanical ventilation, longer stay at intensive care unit and chest injury, but had no effect on mortality.

How do dispersal costs and habitat selection influence realized population connectivity?

PubMed

Burgess, Scott C; Treml, Eric A; Marshall, Dustin J

2012-06-01

Despite the importance of dispersal for population connectivity, dispersal is often costly to the individual. A major impediment to understanding connectivity has been a lack of data combining the movement of individuals and their survival to reproduction in the new habitat (realized connectivity). Although mortality often occurs during dispersal (an immediate cost), in many organisms costs are paid after dispersal (deferred costs). It is unclear how such deferred costs influence the mismatch between dispersal and realized connectivity. Through a series of experiments in the field and laboratory, we estimated both direct and indirect deferred costs in a marine bryozoan (Bugula neritina). We then used the empirical data to parameterize a theoretical model in order to formalize predictions about how dispersal costs influence realized connectivity. Individuals were more likely to colonize poor-quality habitat after prolonged dispersal durations. Individuals that colonized poor-quality habitat performed poorly after colonization because of some property of the habitat (an indirect deferred cost) rather than from prolonged dispersal per se (a direct deferred cost). Our theoretical model predicted that indirect deferred costs could result in nonlinear mismatches between spatial patterns of potential and realized connectivity. The deferred costs of dispersal are likely to be crucial for determining how well patterns of dispersal reflect realized connectivity. Ignoring these deferred costs could lead to inaccurate predictions of spatial population dynamics.

Study on the behavior and mechanism of polycarbonate with hot-water aging

NASA Astrophysics Data System (ADS)

Kong, L. P.; Zhao, Y. X.; Zhou, C. H.; Huang, Y. H.; Tang, M.; Gao, J. G.

2016-07-01

The present work was concerned with hot-water aging behavior and mechanism of Bisphenol A polycarbonate (PC) used as food and packaging materials. It indicated that with the aging time prolonged, PC sample had internal defects and the mechanical properties of PC materials changed not too much, molecular weight decreased, thermal stability declined. Phenolic hydroxyl absorption intensity enhanced in IR spectra and the maximum absorption wavelength red shift of benzene in UV-Vis spectra, the level of BPA increased. The color change of PC sample was not apparent.

Differential Changes in QTc Duration during In-Hospital Haloperidol Use

PubMed Central

Blom, Marieke T.; Bardai, Abdennasser; van Munster, Barbara C.; Nieuwland, Mei-Ing; de Jong, Hendrik; van Hoeijen, Daniel A.; Spanjaart, Anne M.; de Boer, Anthonius; de Rooij, Sophia E.; Tan, Hanno L.

2011-01-01

Aims To evaluate changes in QT duration during low-dose haloperidol use, and determine associations between clinical variables and potentially dangerous QT prolongation. Methods In a retrospective cohort study in a tertiary university teaching hospital in The Netherlands, all 1788 patients receiving haloperidol between 2005 and 2007 were studied; ninety-seven were suitable for final analysis. Rate-corrected QT duration (QTc) was measured before, during and after haloperidol use. Clinical variables before haloperidol use and at the time of each ECG recording were retrieved from hospital charts. Mixed model analysis was used to estimate changes in QT duration. Risk factors for potentially dangerous QT prolongation were estimated by logistic regression analysis. Results Patients with normal before-haloperidol QTc duration (male ≤430 ms, female ≤450 ms) had a significant increase in QTc duration of 23 ms during haloperidol use; twenty-three percent of patients rose to abnormal levels (male ≥450 ms, female ≥470 ms). In contrast, a significant decrease occurred in patients with borderline (male 430–450 ms, female 450–470 ms) or abnormal before-haloperidol QTc duration (15 ms and 46 ms, respectively); twenty-three percent of patients in the borderline group, and only 9% of patients in the abnormal group obtained abnormal levels. Potentially dangerous QTc prolongation was independently associated with surgery before haloperidol use (ORadj 34.9, p = 0.009) and before-haloperidol QTc duration (ORadj 0.94, p = 0.004). Conclusion QTc duration during haloperidol use changes differentially, increasing in patients with normal before-haloperidol QTc duration, but decreasing in patients with prolonged before-haloperidol QTc duration. Shorter before-haloperidol QTc duration and surgery before haloperidol use predict potentially dangerous QTc prolongation. PMID:21961030

Isosteviol prevents the prolongation of action potential in hypertrophied cardiomyoctyes by regulating transient outward potassium and L-type calcium channels.

PubMed

Fan, Zhuo; Lv, Nanying; Luo, Xiao; Tan, Wen

2017-10-01

Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of I to is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases. Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells. The decrease and increase of current densities for I to and I CaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of I to and I CaL are correlated to the alterations of the mRNA transcription level. Copyright © 2017. Published by Elsevier B.V.

A characterization of factors determining postoperative ileus after laparoscopic colectomy enables the generation of a novel predictive score.

PubMed

Kronberg, Udo; Kiran, Ravi P; Soliman, Mohamed S M; Hammel, Jeff P; Galway, Ursula; Coffey, John Calvin; Fazio, Victor W

2011-01-01

Postoperative ileus (POI) after colorectal surgery is associated with prolonged hospital stay and increased costs. The aim of this study is to investigate pre-, intra-, and postoperative risk factors associated with the development of POI in patients undergoing laparoscopic partial colectomy. Patients operated between 2004 and 2008 were retrospectively identified from a prospectively maintained database, and clinical, metabolic, and pharmacologic data were obtained. Postoperative ileus was defined as the absence of bowel function for 5 or more days or the need for reinsertion of a nasogastric tube after starting oral diet in the absence of mechanical obstruction. Associations between likelihood of POI and study variables were assessed univariably by using χ tests, Fisher exact tests, and logistic regression models. A scoring system for prediction of POI was constructed by using a multivariable logistic regression model based on forward stepwise selection of preoperative factors. A total of 413 patients (mean age, 58 years; 53.5% women) were included, and 42 (10.2%) of them developed POI. Preoperative albumin, postoperative deep-vein thrombosis, and electrolyte levels were associated with POI. Age, previous abdominal surgery, and chronic preoperative use of narcotics were independently correlated with POI on multivariate analysis, which allowed the creation of a predictive score. Patients with a score of 2 or higher had an 18.3% risk of POI (P < 0.001). Postoperative ileus after laparoscopic partial colectomy is associated with specific preoperative and postoperative factors. The likelihood of POI can be predicted by using a preoperative scoring system. Addressing the postoperative factors may be expected to reduce the incidence of this common complication in high-risk patients.

Sudden cardiac death secondary to antidepressant and antipsychotic drugs

PubMed Central

Sicouri, Serge; Antzelevitch, Charles

2008-01-01

A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use. PMID:18324881

Intracellular Signaling by Hydrolysis of Phospholipids and Activation of Protein Kinase C

NASA Astrophysics Data System (ADS)

Nishizuka, Yasutomi

1992-10-01

Hydrolysis of inositol phospholipids by phospholipase C is initiated by either receptor stimulation or opening of Ca2+ channels. This was once thought to be the sole mechanism to produce the diacylglycerol that links extracellular signals to intracellular events through activation of protein kinase C. It is becoming clear that agonist-induced hydrolysis of other membrane phospholipids, particularly choline phospholipids, by phospholipase D and phospholipase A_2 may also take part in cell signaling. The products of hydrolysis of these phospholipids may enhance and prolong the activation of protein kinase C. Such prolonged activation of protein kinase C is essential for long-term cellular responses such as cell proliferation and differentiation.

Bicarbonate refractory QRS prolongation and left bundle-branch block following escitalopram and lamotrigine overdose: A case report and literature review of toxic left bundle-branch block.

PubMed

Farkas, A N; Marcott, M; Yanta, J H; Pizon, A F

2018-05-02

Toxic prolongation of the QRS interval most often results from blockade of cardiac voltage-gated sodium channels and manifests on electrocardiogram with a right bundle-branch block-like morphology. Rarely, a left bundle-branch block (LBBB) morphology has been reported. We report a case of transient LBBB resultant from ingestion of lamotrigine and citalopram which was refractory to sodium bicarbonate therapy and eventually resolved spontaneously. Cases of toxic LBBB are less likely to respond to bicarbonate therapy, suggesting that this finding is due to a mechanism other than sodium channel blockade. © 2018 John Wiley & Sons Ltd.

Decreasing the infusion rate reduces the proarrhythmic risk of NS-7: confirming the relevance of short-term variability of repolarisation in predicting drug-induced torsades de pointes

PubMed Central

Detre, Elke; Thomsen, Morten B; Beekman, Jet D; Petersen, Karl-Uwe; Vos, Marc A

2005-01-01

The rate of infusion has been suggested to be important for drug-induced torsades de pointes (TdP) arrhythmias. We investigated the repolarisation-prolonging effects and proarrhythmic properties of NS-7, a neuroprotective drug in development, using two different infusion rates. A fast (5 min intravenously (i.v.)) escalating dosing regimen (0.3 and 3.0 mg kg−1, n=4) of NS-7 was investigated in anaesthetised control dogs in sinus rhythm (SR). This was compared to a slow infusion (60 min i.v.) of one dose (3.0 mg kg−1, n=4) NS-7. The similar dosing regimens were investigated in anaesthetised dogs with chronic, complete AV block (CAVB), an animal model of TdP (n=6). No electrophysiological effects were seen after 0.3 mg kg−1 NS-7. Fast infusion of 3.0 mg kg−1 caused prolongation of repolarisation, for example, heart rate corrected QT interval (QTc): in SR: 6±1%; in CAVB: 10±7%, which was accompanied by TdP in three of six CAVB dogs. No TdP were seen in SR dogs. Slow infusion did not cause TdP in the same CAVB dogs, although NS-7 caused repolarisation to prolong with a similar magnitude (QTc: 12±7%) as in the fast-infusion experiment. Short-term variability (STV) is a novel parameter for the prediction of drug-induced TdP analysing the beat-to-beat variability of repolarisation. STV was only increased after the fast infusion in CAVB dogs (2.6±0.3 versus 6.0±1.4 ms, P<0.05), while there was no increase (2.1±0.2 versus 2.5±1.0 ms) after the slow infusion of NS-7. Peak plasma concentrations attained were lower in slow (0.5±0.1 μg ml−1 after 50 min) than in fast-infusion regimen (2.1±0.4 μg ml−1 after 5 min; P<0.05). The results support the conclusion that limiting peak plasma concentration by decreasing the rate of infusion of NS-7 reduces the proarrhythmic risk despite comparable prolongation in repolarisation parameters. The relevance of STV in predicting drug-induced TdP was confirmed. PMID:15778734

Experimental Evidence for Weathering and Martian Sulfate Formation Under Extremely Cold Weather-Limited Environments

NASA Technical Reports Server (NTRS)

Niles, Paul B.; Golden, D. C.; Michalski, J.

2013-01-01

High resolution photography and spectroscopy of the martian surface (MOC, HiRISE) from orbit has revolutionized our view of Mars with one of the most important discoveries being wide-spread layered sedimentary deposits associated with sulfate minerals across the low to mid latitude regions of Mars [1, 2]. The mechanism for sulfate formation on Mars has been frequently attributed to playa-like evaporative environments under prolonged warm conditions [3]. However, there are several problems with the presence of prolonged surface temperatures on Mars above 273 K during the Noachian including the faint young Sun [4] and the presence of suitable greenhouse gases [5]. The geomorphic evidence for early warm conditions may instead be explained by periodic episodes of warming rather than long term prolonged warm temperatures [6]. An alternate view of the ancient martian climate contends that prolonged warm temperatures were never present and that the atmosphere and climate has been similar to modern conditions throughout most of its history [6]. This view is more consistent with the climate models, but has had a difficult time explaining the sedimentary history of Mars and in particular the presence of sulfate minerals. We suggest here that mixtures of atmospheric aerosols, ice, and dust have the potential for creating small films of cryo-concentrated acidic solutions that may represent an important unexamined environment for understanding weathering processes on Mars [7, 8]. This study seeks to test whether sulfate formation may be possible at temperatures well below 0 C in water limited environments removing the need for prolonged warm periods to form sulfates on early Mars.

Prolonged Particulate Hexavalent Chromium Exposure Suppresses Homologous Recombination Repair in Human Lung Cells

PubMed Central

Browning, Cynthia L.; Qin, Qin; Kelly, Deborah F.; Prakash, Rohit; Vanoli, Fabio; Jasin, Maria

2016-01-01

Abstract Genomic instability is one of the primary models of carcinogenesis and a feature of almost all cancers. Homologous recombination (HR) repair protects against genomic instability by maintaining high genomic fidelity during the repair of DNA double strand breaks. The defining step of HR repair is the formation of the Rad51 nucleofilament, which facilitates the search for a homologous sequence and invasion of the template DNA strand. Particulate hexavalent chromium (Cr(VI)), a human lung carcinogen, induces DNA double strand breaks and chromosome instability. Since the loss of HR repair increases Cr(VI)-induced chromosome instability, we investigated the effect of extended Cr(VI) exposure on HR repair. We show acute (24 h) Cr(VI) exposure induces a normal HR repair response. In contrast, prolonged (120 h) exposure to particulate Cr(VI) inhibited HR repair and Rad51 nucleofilament formation. Prolonged Cr(VI) exposure had a profound effect on Rad51, evidenced by reduced protein levels and Rad51 mislocalization to the cytoplasm. The response of proteins involved in Rad51 nuclear import and nucleofilament formation displayed varying responses to prolonged Cr(VI) exposure. BRCA2 formed nuclear foci after prolonged Cr(VI) exposure, while Rad51C foci formation was suppressed. These results suggest that particulate Cr(VI), a major chemical carcinogen, inhibits HR repair by targeting Rad51, causing DNA double strand breaks to be repaired by a low fidelity, Rad51-independent repair pathway. These results further enhance our understanding of the underlying mechanism of Cr(VI)-induced chromosome instability and thus, carcinogenesis. PMID:27449664

Functional response of U.S. grasslands to the early 21st-century drought

Treesearch

M. Susan Moran; Guillermo E. Ponce-Campos; Alfredo Huete; Mitchel P. McClaran; Yongguang Zhang; Erik P. Hamerlynck; David J. Augustine; Stacey A. Gunter; Stanley G. Kitchen; Debra P. C. Peters; Patrick J. Starks; Mariano Hernandez

2014-01-01

Grasslands across the United States play a key role in regional livelihood and national food security. Yet, it is still unclear how this important resource will respond to the prolonged warm droughts and more intense rainfall events predicted with climate change. The early 21st-century drought in the southwestern United States resulted in hydroclimatic conditions that...

Effect of vitro preservation on mechanical properties of brain tissue

NASA Astrophysics Data System (ADS)

Zhang, Wei; Liu, Yi-fan; Liu, Li-fu; Niu, Ying; Ma, Jian-li; Wu, Cheng-wei

2017-05-01

To develop the protective devices for preventing traumatic brain injuries, it requires the accurate characterization of the mechanical properties of brain tissue. For this, it necessary to elucidate the effect of vitro preservation on the mechanical performance of brain tissue as usually the measurements are carried out in vitro. In this paper, the thermal behavior of brain tissue preserved for various period of time was first investigated and the mechanical properties were also measured. Both reveals the deterioration with prolonged preservation duration. The observations of brain tissue slices indicates the brain tissue experiences karyorrhexis and karyorrhexis in sequence, which accounts for the deterioration phenomena.

A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients.

PubMed

Florian, J; Garnett, C E; Nallani, S C; Rappaport, B A; Throckmorton, D C

2012-04-01

Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.

Scheduling Chemotherapy: Catch 22 between Cell Kill and Resistance Evolution

DOE PAGES

Gardner, Shea N.

2000-01-01

Dose response curves show that prolonged drug exposure at a low concentration may kill more cells than short exposures at higher drug concentrations, particularly for cell cycle phase specific drugs. Applying drugs at low concentrations for prolonged periods, however, allows cells with partial resistance to evolve higher levels of resistance through stepwise processes such as gene amplification. Models are developed for cell cycle specific (CS) and cell cycle nonspecific (CNS) drugs to identify the schedule of drug application that balances this tradeoff. The models predict that a CS drug may be applied most effectively by splitting the cumulative dose intomore » many (>40) fractions applied by long-term chemotherapy, while CNS drugs may be better applied in fewer than 10 fractions applied over a shorter term. The model suggests that administering each fraction by continuous infusion may be more effective than giving the drug as a bolus, whether the drug is CS or CNS. In addition, tumors with a low growth fraction or slow rate of cell division are predicted to be controlled more easily with CNS drugs, while those with a high proliferative fraction or fast cell division rate may respond better to CS drugs.« less

Preferences for prolonging life: a prospect theory approach.

PubMed

Winter, Laraine; Lawton, M Powell; Ruckdeschel, Katy

2003-01-01

Kahneman and Tversky's (1979) Prospect theory was tested as a model of preferences for prolonging life under various hypothetical health statuses. A sample of 384 elderly people living in congregate housing (263 healthy, 131 frail) indicated how long (if at all) they would want to live under each of nine hypothetical health conditions (e.g., limited to bed or chair in a nursing home). Prospect theory, a decision model which takes into account the individual's point of reference, would predict that frail people would view prospective poorer health conditions as more tolerable and express preferences to live longer in worse health than would currently healthy people. In separate analyses of covariance, we evaluated preferences for continued life under four conditions of functional ability, four conditions of cognitive impairment, and three pain conditions--each as a function of participant's current health status (frail vs. healthy). The predicted interaction between frailty and declining prospective health status was obtained. Frail participants expressed preferences for longer life under more compromised health conditions than did healthy participants. The results imply that such preferences are malleable, changing as health deteriorates. They also help explain disparities between proxy decision-makers' and patients' own preferences as expressed in advance directives.

Pre-treatment Predictors of Dropout from Prolonged Exposure Therapy in Patients with Chronic Posttraumatic Stress Disorder and Comorbid Substance Use Disorders

PubMed Central

Belleau, Emily L.; Chin, Eu Gene; Wanklyn, Sonya G.; Zambrano-Vazquez, Laura; Schumacher, Julie A.; Coffey, Scott F.

2017-01-01

Posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) are commonly co-occurring disorders associated with more adverse consequences than PTSD alone. Prolonged exposure therapy (PE) is one of the most efficacious treatments for PTSD. However, among individuals with PTSD-SUD, 35–62% of individuals drop out of trauma-focused exposure treatments. Thus, it is important to identify predictors of PTSD treatment dropout among substance abusers with PTSD in order to gain information about adapting treatment strategies to enhance retention and outcomes. The current study explored pre-treatment predictors of early termination from PE treatment in a sample of 85 individuals receiving concurrent treatment for PTSD and a SUD in a residential treatment facility as part of a randomized controlled trial. The results indicated that less education and more anxiety sensitivity uniquely predicted PE treatment dropout. Demographic variables, PTSD severity, SUD severity, mental health comorbidities, and emotion regulation difficulties did not predict treatment dropout. These results suggest that adding pre-treatment interventions that address anxiety sensitivity, and promote social adjustment and cognitive flexibility, could possibly improve PE retention rates in clients with high anxiety or low education. PMID:28147254

Scheduling Chemotherapy: Catch 22 between Cell Kill and Resistance Evolution

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

Gardner, Shea N.

Dose response curves show that prolonged drug exposure at a low concentration may kill more cells than short exposures at higher drug concentrations, particularly for cell cycle phase specific drugs. Applying drugs at low concentrations for prolonged periods, however, allows cells with partial resistance to evolve higher levels of resistance through stepwise processes such as gene amplification. Models are developed for cell cycle specific (CS) and cell cycle nonspecific (CNS) drugs to identify the schedule of drug application that balances this tradeoff. The models predict that a CS drug may be applied most effectively by splitting the cumulative dose intomore » many (>40) fractions applied by long-term chemotherapy, while CNS drugs may be better applied in fewer than 10 fractions applied over a shorter term. The model suggests that administering each fraction by continuous infusion may be more effective than giving the drug as a bolus, whether the drug is CS or CNS. In addition, tumors with a low growth fraction or slow rate of cell division are predicted to be controlled more easily with CNS drugs, while those with a high proliferative fraction or fast cell division rate may respond better to CS drugs.« less

Validation of PR interval length as a criterion for development of atrial fibrillation in non-Hispanic whites, African Americans and Hispanics.

PubMed

Shulman, Eric; Aagaard, Philip; Kargoli, Faraj; Hoch, Ethan; Zheng, Laura; Di Biase, Luigi; Fisher, John; Gross, Jay; Kim, Soo; Ferrick, Kevin; Krumerman, Andrew

2015-01-01

PR interval prolongation on electrocardiogram (ECG) increases the risk of atrial fibrillation (AF). Non-Hispanic Whites are at higher risk of AF compared to African Americans and Hispanics. However, it remains unknown if prolongation of the PR interval for the development of AF varies by race/ethnicity. Therefore, we determined whether race affects the PR interval length's ability to predict AF and if the commonly used criterion of 200 ms in AF prediction models can continue to be used for non-White cohorts. This is a retrospective epidemiological study of consecutive inpatient and outpatients. An ECG database was initially interrogated. Patients were included if their initial ECG demonstrated sinus rhythm and had two or more electrocardiograms and declared a race and/or ethnicity as non-Hispanic White, African American or Hispanic. Development of AF was stratified by race/ethnicity along varying PR intervals. Cox models controlled for age, gender, race/ethnicity, systolic blood pressure, BMI, QRS, QTc, heart rate, murmur, treatment for hypertension, heart failure and use of AV nodal blocking agents to assess PR interval's predictive ability for development of AF. 50,870 patients met inclusion criteria of which 5,199 developed AF over 3.72 mean years of follow-up. When the PR interval was separated by quantile, prolongation of the PR interval to predict AF first became significant in Hispanic and African Americans at the 92.5th quantile of 196-201 ms (HR: 1.42, 95% CI: 1.09-1.86, p=0.01; HR: 1.32, 95% CI: 1.07-1.64, p=0.01, respectively) then in non-Hispanic Whites at the 95th quantile at 203-212 ms (HR: 1.24, 95% CI: 1.24-1.53, p=0.04). For those with a PR interval above 200 ms, African Americans had a lower risk than non-Hispanic Whites to develop AF (HR: 0.80, 95% CI: 0.64-0.95, p=0.012), however, no significant difference was demonstrated in Hispanics. This is the first study to validate a PR interval value of 200 ms as a criterion in African Americans and Hispanics for the development of AF. However, a value of 200 ms may be less sensitive as a predictive measure for the development of AF in African Americans compared to non-Hispanic Whites. Copyright © 2015 Elsevier Inc. All rights reserved.

Making better scar: Emerging approaches for modifying mechanical and electrical properties following infarction and ablation.

PubMed

Holmes, Jeffrey W; Laksman, Zachary; Gepstein, Lior

2016-01-01

Following myocardial infarction (MI), damaged myocytes are replaced by collagenous scar tissue, which serves an important mechanical function - maintaining integrity of the heart wall against enormous mechanical forces - but also disrupts electrical function as structural and electrical remodeling in the infarct and borderzone predispose to re-entry and ventricular tachycardia. Novel emerging regenerative approaches aim to replace this scar tissue with viable myocytes. Yet an alternative strategy of therapeutically modifying selected scar properties may also prove important, and in some cases may offer similar benefits with lower risk or regulatory complexity. Here, we review potential goals for such modifications as well as recent proof-of-concept studies employing specific modifications, including gene therapy to locally increase conduction velocity or prolong the refractory period in and around the infarct scar, and modification of scar anisotropy to improve regional mechanics and pump function. Another advantage of scar modification techniques is that they have applications well beyond MI. In particular, ablation treats electrical abnormalities of the heart by intentionally generating scar to block aberrant conduction pathways. Yet in diseases such as atrial fibrillation (AF) where ablation can be extensive, treating the electrical disorder can significantly impair mechanical function. Creating smaller, denser scars that more effectively block conduction, and choosing the location of those lesions by balancing their electrical and mechanical impacts, could significantly improve outcomes for AF patients. We review some recent advances in this area, including the use of computational models to predict the mechanical effects of specific lesion sets and gene therapy for functional ablation. Overall, emerging techniques for modifying scar properties represents a potentially important set of tools for improving patient outcomes across a range of heart diseases, whether used in place of or as an adjunct to regenerative approaches. Copyright © 2015 Elsevier Ltd. All rights reserved.

Understanding the Mechanism of Thermotolerance Distinct From Heat Shock Response Through Proteomic Analysis of Industrial Strains of Saccharomyces cerevisiae*

PubMed Central

Shui, Wenqing; Xiong, Yun; Xiao, Weidi; Qi, Xianni; Zhang, Yong; Lin, Yuping; Guo, Yufeng; Zhang, Zhidan; Wang, Qinhong; Ma, Yanhe

2015-01-01

Saccharomyces cerevisiae has been intensively studied in responses to different environmental stresses such as heat shock through global omic analysis. However, the S. cerevisiae industrial strains with superior thermotolerance have not been explored in any proteomic studies for elucidating the tolerance mechanism. Recently a new diploid strain was obtained through evolutionary engineering of a parental industrial strain, and it exhibited even higher resistance to prolonged thermal stress. Herein, we performed iTRAQ-based quantitative proteomic analysis on both the parental and evolved industrial strains to further understand the mechanism of thermotolerant adaptation. Out of ∼2600 quantifiable proteins from biological quadruplicates, 193 and 204 proteins were differentially regulated in the parental and evolved strains respectively during heat-stressed growth. The proteomic response of the industrial strains cultivated under prolonged thermal stress turned out to be substantially different from that of the laboratory strain exposed to sudden heat shock. Further analysis of transcription factors underlying the proteomic perturbation also indicated the distinct regulatory mechanism of thermotolerance. Finally, a cochaperone Mdj1 and a metabolic enzyme Adh1 were selected to investigate their roles in mediating heat-stressed growth and ethanol production of yeasts. Our proteomic characterization of the industrial strain led to comprehensive understanding of the molecular basis of thermotolerance, which would facilitate future improvement in the industrially important trait of S. cerevisiae by rational engineering. PMID:25926660

Activation of respiratory muscles during weaning from mechanical ventilation.

PubMed

Walterspacher, Stephan; Gückler, Julia; Pietsch, Fabian; Walker, David Johannes; Kabitz, Hans-Joachim; Dreher, Michael

2017-04-01

Respiratory muscle dysfunction is a key component of weaning failure. Balancing respiratory muscle loading and unloading by applying different ventilation modes along with spontaneous breathing episodes are established weaning strategies. However, the effects of body positioning on the respiratory muscles during weaning remains unclear. This study aimed at assessing respiratory drive by surface electromyography (EMG) of the diaphragm (EMG dia ) and parasternal muscles (EMG para ) in tracheotomized patients during prolonged weaning in 3 randomized body positions-supine, 30° semirecumbent, and 80° sitting-during mechanical ventilation and spontaneous breathing. Nine patients were included for analysis. Cardiorespiratory parameters (heart rate, blood pressure, arterial oxygen saturation, dyspnea) did not change under each condition (all P>.05). EMG para and EMG dia did not change under mechanical ventilation (both P>.05). EMG dia changed under spontaneous breathing from supine to sitting (0.45±0.26 vs 0.32±0.19; P=.012) and between semirecumbent to sitting (0.41±0.23 vs 0.32±0.19; P=.039), whereas EMG para did not change. This is the first study to show that body positioning influences respiratory drive to the diaphragm in tracheotomized patients with prolonged weaning from mechanical ventilation during unassisted breathing. Sitting position reduces respiratory drive compared with semirecumbent and supine positioning and might therefore be favored during spontaneous breathing trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Intermittent fasting promotes prolonged associative interactions during synaptic tagging/capture by altering the metaplastic properties of the CA1 hippocampal neurons.

PubMed

Dasgupta, Ananya; Kim, Joonki; Manakkadan, Anoop; Arumugam, Thiruma V; Sajikumar, Sreedharan

2017-12-19

Metaplasticity is the inherent property of a neuron or neuronal population to undergo activity-dependent changes in neural function that modulate subsequent synaptic plasticity. Here we studied the effect of intermittent fasting (IF) in governing the interactions of associative plasticity mechanisms in the pyramidal neurons of rat hippocampal area CA1. Late long-term potentiation and its associative mechanisms such as synaptic tagging and capture at an interval of 120 min were evaluated in four groups of animals, AL (Ad libitum), IF12 (daily IF for 12 h), IF16 (daily IF for 16 h) and EOD (every other day IF for 24 h). IF had no visible effect on the early or late plasticity but it manifested a critical role in prolonging the associative interactions between weak and strong synapses at an interval of 120 min in IF16 and EOD animals. However, both IF12 and AL did not show associativity at 120 min. Plasticity genes such as Bdnf and Prkcz, which are well known for their expressions in late plasticity and synaptic tagging and capture, were significantly upregulated in IF16 and EOD in comparison to AL. Specific inhibition of brain derived neurotropic factor (BDNF) prevented the prolonged associativity expressed in EOD. Thus, daily IF for 16 h or more can be considered to enhance the metaplastic properties of synapses by improving their associative interactions that might translate into animprovedmemoryformation. Copyright © 2017. Published by Elsevier Inc.

Evidence for a crucial modulating role of the sodium channel in the QTc prolongation related to antipsychotics.

PubMed

Silvestre, Jordi S; O'Neill, Michael F; Prous, Josep R

2014-04-01

Blockade of the cardiac hERG channel is recognized as the main mechanism underlying the QT prolongation induced by many classes of drugs, including antipsychotics. However, antipsychotics interact with a variety of other pharmacological targets that could also modulate cardiac function. The present study aims to identify those key factors involved in the QT prolongation induced by antipsychotics. The interactions of 28 antipsychotics were measured on a variety of pharmacological targets. Binding affinity (K(i)), functional channel blockade (IC₅₀), and the corresponding ratios to total and free plasma drug concentration were compared with the corrected QT changes (QTc) associated with the therapeutic use of these drugs by multivariable linear regression analysis to determine the best predictors of QTc. Besides confirming hERG as the primary predictor of QTc, all analyses consistently show the concomitant involvement of Na(V)1.5 channel as modulating factor of the QTc related to hERG blockade. In particular, the hERG/Na(V)1.5 ratio explains the 57% of the overall QTc variability associated with antipsychotics. Since it is known that inhibition of late I Na could offset the dysfunctional effects of hERG blockade, we hypothesize the inhibition of late I(Na) as a crucial compensatory mechanism of the QTc associated with antipsychotics and hence an important factor to consider concomitantly with hERG blockade to appraise the arrhythmogenic risk of these drugs more accurately.

Recovery from impaired muscle growth arises from prolonged postnatal accretion of myonuclei in Atrx mutant mice

PubMed Central

Yan, Keqin; Price-O’Dea, Tina

2017-01-01

Reduced muscle mass due to pathological development can occur through several mechanisms, including the loss or reduced proliferation of muscle stem cells. Muscle-specific ablation of the α-thalassemia mental retardation syndrome mutant protein, Atrx, in transgenic mice results in animals with a severely reduced muscle mass at three weeks of age; yet this muscle mass reduction resolves by adult age. Here, we explore the cellular mechanism underlying this effect. Analysis of Atrx mutant mice included testing for grip strength and rotorod performance. Muscle fiber length, fiber volume and numbers of myofiber-associated nuclei were determined from individual EDL or soleus myofibers isolated at three, five, or eight weeks. Myofibers from three week old Atrx mutant mice are smaller with fewer myofiber-associated nuclei and reduced volume compared to control animals, despite similar fiber numbers. Nonetheless, the grip strength of Atrx mutant mice was comparable to control mice when adjusted for body weight. Myofiber volume remained smaller at five weeks, becoming comparable to controls by 8 weeks of age. Concomitantly, increased numbers of myofiber-associated nuclei and Ki67+ myoblasts indicated that the recovery of muscle mass likely arises from the prolonged accretion of new myonuclei. This suggests that under disease conditions the muscle satellite stem cell niche can remain in a prolonged active state, allowing for the addition of a minimum number of myonuclei required to achieve a normal muscle size. PMID:29095838

The Effect of Optokinetic Stimulation on Perceptual and Postural Symptoms in Visual Vestibular Mismatch Patients.

PubMed

Van Ombergen, Angelique; Lubeck, Astrid J; Van Rompaey, Vincent; Maes, Leen K; Stins, John F; Van de Heyning, Paul H; Wuyts, Floris L; Bos, Jelte E

2016-01-01

Vestibular patients occasionally report aggravation or triggering of their symptoms by visual stimuli, which is called visual vestibular mismatch (VVM). These patients therefore experience discomfort, disorientation, dizziness and postural unsteadiness. Firstly, we aimed to get a better insight in the underlying mechanism of VVM by examining perceptual and postural symptoms. Secondly, we wanted to investigate whether roll-motion is a necessary trait to evoke these symptoms or whether a complex but stationary visual pattern equally provokes them. Nine VVM patients and healthy matched control group were examined by exposing both groups to a stationary stimulus as well as an optokinetic stimulus rotating around the naso-occipital axis for a prolonged period of time. Subjective visual vertical (SVV) measurements, posturography and relevant questionnaires were assessed. No significant differences between both groups were found for SVV measurements. Patients always swayed more and reported more symptoms than healthy controls. Prolonged exposure to roll-motion caused in patients and controls an increase in postural sway and symptoms. However, only VVM patients reported significantly more symptoms after prolonged exposure to the optokinetic stimulus compared to scores after exposure to a stationary stimulus. VVM patients differ from healthy controls in postural and subjective symptoms and motion is a crucial factor in provoking these symptoms. A possible explanation could be a central visual-vestibular integration deficit, which has implications for diagnostics and clinical rehabilitation purposes. Future research should focus on the underlying central mechanism of VVM and the effectiveness of optokinetic stimulation in resolving it.

Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception.

PubMed

Cao, Jing; Wang, Po-Kai; Tiwari, Vinod; Liang, Lingli; Lutz, Brianna Marie; Shieh, Kun-Ruey; Zang, Wei-Dong; Kaufman, Andrew G; Bekker, Alex; Gao, Xiao-Qun; Tao, Yuan-Xiang

2015-12-02

Chronic stress has been reported to increase basal pain sensitivity and/or exacerbate existing persistent pain. However, most surgical patients have normal physiological and psychological health status such as normal pain perception before surgery although they do experience short-term stress during pre- and post-operative periods. Whether or not this short-term stress affects persistent postsurgical pain is unclear. In this study, we showed that pre- or post-surgical exposure to immobilization 6 h daily for three consecutive days did not change basal responses to mechanical, thermal, or cold stimuli or peak levels of incision-induced hypersensitivity to these stimuli; however, immobilization did prolong the duration of incision-induced hypersensitivity in both male and female rats. These phenomena were also observed in post-surgical exposure to forced swimming 25 min daily for 3 consecutive days. Short-term stress induced by immobilization was demonstrated by an elevation in the level of serum corticosterone, an increase in swim immobility, and a decrease in sucrose consumption. Blocking this short-term stress via intrathecal administration of a selective glucocorticoid receptor antagonist, RU38486, or bilateral adrenalectomy significantly attenuated the prolongation of incision-induced hypersensitivity to mechanical, thermal, and cold stimuli. Our results indicate that short-term stress during the pre- or post-operative period delays postoperative pain recovery although it does not affect basal pain perception. Prevention of short-term stress may facilitate patients' recovery from postoperative pain.

Abnormal reflex activation of hamstring muscles in dogs with cranial cruciate ligament rupture.

PubMed

Hayes, Graham M; Granger, Nicolas; Langley-Hobbs, Sorrel J; Jeffery, Nick D

2013-06-01

The mechanisms underlying cranial cruciate ligament rupture (CCLR) in dogs are poorly understood. In this study hamstring muscle reflexes in response to cranial tibial translation were analysed to determine whether these active stabilisers of the stifle joint are differently activated in dogs with CCLR compared to control dogs. In a prospective clinical study reflex muscle activity from the lateral and medial hamstring muscles (biceps femoris and semimembranosus) was recorded using surface electrodes in control dogs (n=21) and dogs with CCLR (n=22). These electromyographic recordings were analysed using an algorithm previously validated in humans. The hamstring reflex was reliably and reproducibly recorded in normal dogs. Both a short latency response (SLR, 17.6±2.1ms) and a medium latency response (MLR, 37.7±2.7ms) could be identified. In dogs with unilateral CCLR, the SLR and MLR were not significantly different between the affected and the unaffected limbs, but the MLR latency of both affected and unaffected limbs in CCLR dogs were significantly prolonged compared to controls. In conclusion, the hamstring reflex can be recorded in dogs and the MLR is prolonged in dogs with CCLR. Since both affected and unaffected limbs exhibit prolonged MLR, it is possible that abnormal hamstring reflex activation is a mechanism by which progressive CCL damage may occur. The methodology allows for further investigation of the relationship between neuromuscular imbalance and CCLR or limitations in functional recovery following surgical intervention. Copyright © 2012 Elsevier Ltd. All rights reserved.

Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

PubMed

Liu, Fang; Rainosek, Shuo W; Frisch-Daiello, Jessica L; Patterson, Tucker A; Paule, Merle G; Slikker, William; Wang, Cheng; Han, Xianlin

2015-10-01

Sevoflurane is a volatile anesthetic that has been widely used in general anesthesia, yet its safety in pediatric use is a public concern. This study sought to evaluate whether prolonged exposure of infant monkeys to a clinically relevant concentration of sevoflurane is associated with any adverse effects on the developing brain. Infant monkeys were exposed to 2.5% sevoflurane for 9 h, and frontal cortical tissues were harvested for DNA microarray, lipidomics, Luminex protein, and histological assays. DNA microarray analysis showed that sevoflurane exposure resulted in a broad identification of differentially expressed genes (DEGs) in the monkey brain. In general, these genes were associated with nervous system development, function, and neural cell viability. Notably, a number of DEGs were closely related to lipid metabolism. Lipidomic analysis demonstrated that critical lipid components, (eg, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol) were significantly downregulated by prolonged exposure of sevoflurane. Luminex protein analysis indicated abnormal levels of cytokines in sevoflurane-exposed brains. Consistently, Fluoro-Jade C staining revealed more degenerating neurons after sevoflurane exposure. These data demonstrate that a clinically relevant concentration of sevoflurane (2.5%) is capable of inducing and maintaining an effective surgical plane of anesthesia in the developing nonhuman primate and that a prolonged exposure of 9 h resulted in profound changes in gene expression, cytokine levels, lipid metabolism, and subsequently, neuronal damage. Generally, sevoflurane-induced neuronal damage was also associated with changes in lipid content, composition, or both; and specific lipid changes could provide insights into the molecular mechanism(s) underlying anesthetic-induced neurotoxicity and may be sensitive biomarkers for the early detection of anesthetic-induced neuronal damage. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by a US Government employee and is in the public domain in the US.

Evaluation and expression analysis of alfalfa genotypes in response to prolonged salt stress

USDA-ARS?s Scientific Manuscript database

Salinity is one of the most important abiotic stresses that adversely affect plant growth and productivity globally. In order to tackle this complex problem, it is important to link the biochemical and physiological responses with the underlying genetic mechanisms. In this study, we used 12 previous...

Membrane module assembly

DOEpatents

Kaschemekat, J.

1994-03-15

A membrane module assembly is described which is adapted to provide a flow path for the incoming feed stream that forces it into prolonged heat-exchanging contact with a heating or cooling mechanism. Membrane separation processes employing the module assembly are also disclosed. The assembly is particularly useful for gas separation or pervaporation. 2 figures.

The use of tracheostomy speaking valves in mechanically ventilated patients results in improved communication and does not prolong ventilation time in cardiothoracic intensive care unit patients.

PubMed

Sutt, Anna-Liisa; Cornwell, Petrea; Mullany, Daniel; Kinneally, Toni; Fraser, John F

2015-06-01

The aim of this study was to assess the effect of the introduction of in-line tracheostomy speaking valves (SVs) on duration of mechanical ventilation and time to verbal communication in patients requiring tracheostomy for prolonged mechanical ventilation in a predominantly cardiothoracic intensive care unit (ICU). We performed a retrospective preobservational-postobservational study using data from the ICU clinical information system and medical record. Extracted data included demographics, diagnoses and disease severity, mechanical ventilation requirements, and details on verbal communication and oral intake. Data were collected on 129 patients. Mean age was 59 ± 16 years, with 75% male. Demographics, case mix, and median time from intubation to tracheostomy (6 days preimplementation-postimplementation) were unchanged between timepoints. A significant decrease in time from tracheostomy to establishing verbal communication was observed (18 days preimplementation and 9 days postimplementation, P <.05). There was no difference in length of mechanical ventilation (20 days preimplementation-post) or time to decannulation (14 days preimplementation-postimplementation). No adverse events were documented in relation to the introduction of in-line SVs. In-line SVs were successfully implemented in mechanically ventilated tracheostomized patient population. This resulted in earlier verbal communication, no detrimental effect on ventilator weaning times, and no change in decannulation times. The purpose of the study was to compare tracheostomy outcomes in mechanically ventilated patients in a cardiothoracic ICU preintroduction and postintroduction of in-line SVs. It was hypothesized that in-line SVs would improve communication and swallowing specific outcomes with no increase in average time to decannulation or the number of adverse events. Copyright © 2015 Elsevier Inc. All rights reserved.

Association between QRS Duration and Obstructive Sleep Apnea

PubMed Central

Gupta, Shuchita; Cepeda-Valery, Beatriz; Romero-Corral, Abel; Shamsuzzaman, Abu; Somers, Virend K.; Pressman, Gregg S.

2012-01-01

Background: Both obstructive sleep apnea (OSA) and prolonged QRS duration are associated with hypertension, heart failure, and sudden cardiac death. However, possible links between QRS duration and OSA have not been explored. Methods: Cross-sectional study of 221 patients who underwent polysomnography at our center. Demographics, cardiovascular risk factors and ECG were collected to explore a relationship between OSA and QRS duration. Results: The apnea-hypopnea index (AHI) was positively correlated with QRS duration (r = 0.141, p = 0.03). Patients were divided into 3 groups: AHI < 5 (61), AHI 5-29 (104), and AHI > 30 (55). The mean QRS duration prolonged significantly as OSA worsened (AHI < 5, 85 ± 9.5; AHI 5-29, 89 ± 11.9; and AHI > 30, 95 ± 19.9 ms, p = 0.001). QRS ≥ 100 ms was present in 12.7% of patients with severe OSA compared with 0% in the rest of the sample (p < 0.0001). After adjustment for age, race, and cardiovascular risk factors, this association remained significant in women but not in men. Conclusion: QRS duration and OSA were significantly associated. Severity of OSA independently predicted prolonged QRS in women but not men. Nevertheless, prolongation of QRS duration in either sex may potentiate arrhythmic risks associated with OSA. Citation: Gupta S; Cepeda-Valery B; Romero-Corral A; Shamsuzzaman A; Somers VK; Pressman GS. Association between QRS duration and obstructive sleep apnea. J Clin Sleep Med 2012;8(6):649-654. PMID:23243398

Spatial variability of excess mortality during prolonged dust events in a high-density city: a time-stratified spatial regression approach.

PubMed

Wong, Man Sing; Ho, Hung Chak; Yang, Lin; Shi, Wenzhong; Yang, Jinxin; Chan, Ta-Chien

2017-07-24

Dust events have long been recognized to be associated with a higher mortality risk. However, no study has investigated how prolonged dust events affect the spatial variability of mortality across districts in a downwind city. In this study, we applied a spatial regression approach to estimate the district-level mortality during two extreme dust events in Hong Kong. We compared spatial and non-spatial models to evaluate the ability of each regression to estimate mortality. We also compared prolonged dust events with non-dust events to determine the influences of community factors on mortality across the city. The density of a built environment (estimated by the sky view factor) had positive association with excess mortality in each district, while socioeconomic deprivation contributed by lower income and lower education induced higher mortality impact in each territory planning unit during a prolonged dust event. Based on the model comparison, spatial error modelling with the 1st order of queen contiguity consistently outperformed other models. The high-risk areas with higher increase in mortality were located in an urban high-density environment with higher socioeconomic deprivation. Our model design shows the ability to predict spatial variability of mortality risk during an extreme weather event that is not able to be estimated based on traditional time-series analysis or ecological studies. Our spatial protocol can be used for public health surveillance, sustainable planning and disaster preparation when relevant data are available.

Impact of demographic and clinical parameters on video capsule transit time.

PubMed

Niv, Eva; Pinchasovich, Hadassa; Yanai, Henit

2016-10-01

Small bowel (SB) capsule endoscopy (CE) studies provide data on both gastric and SB transit times (GTT and SBTT, respectively). This study aimed to evaluate the influence of demographic and clinical parameters on the GTT and SBTT. Transit times for two generations of capsules (Pillcam SB2 and SB3) were also compared. Consecutive adult patients undergoing CE were included. GTT, SBTT, and cecum arrival rates were calculated and correlated to demographics and clinical characteristics. A total of 332 CE studies were analyzed. Neither GTT nor SBTT were impacted by age or sex. SBTT was prolonged in newly diagnosed Crohn's disease (CD) patients compared with all other patients (303.1±90.3 vs. 243.6±83.6 min, P=0.02 for SB2, 267.8±63 vs. 228.6±72.3, P=0.01 for SB3, respectively). Moreover, CD patients had higher incomplete study rates compared with patients with all other diagnoses (29.4 vs. 7.3%, respectively, P=0.0116) in the SB2 subgroup. Higher cecum arrival rates were achieved by the SB3 capsule compared with SB2 (97 vs. 91%, P=0.04). Patients with prolonged gastric time or patients with incomplete studies had similar demographic and clinical characteristics as others. Age and sex apparently do not influence intestinal kinetics. Newly diagnosed CD patients have relatively prolonged SBTTs. Demographic and clinical parameters cannot predict prolonged GTT or cecum nonarrival.

When hope and grief intersect: rates and risks of prolonged grief disorder among bereaved individuals and relatives of disappeared persons in Colombia.

PubMed

Heeke, Carina; Stammel, Nadine; Knaevelsrud, Christine

2015-03-01

Forced disappearance is a frequent phenomenon in violent conflicts and regimes, yet little is known about unresolved grief processes as a possible outcome of the disappearance of a loved one. This study investigates prolonged grief disorder (PGD) and its risk factors in a sample of persons who lost a significant other to disappearance as compared with a sample of bereaved individuals, both groups having experienced displacement due to the armed conflict in Colombia. In a cross-sectional study conducted in four Colombian provinces, 73 persons who lost a significant other to disappearance and 222 bereaved individuals completed measures of PGD (PG-13), depression (HSCL-25), and PTSD (PCL-C) via face-to-face interviews. Trauma- and loss-related variables, including the extent to which significant others of disappeared persons hoped that their loved one was still alive, were assessed. Results indicated that 23% of participants who lost a significant other to disappearance met criteria for PGD as compared to 31.5% in bereaved participants. No differences were found between the two groups in terms of symptom severity of PGD, depression, posttraumatic stress disorder, or traumatic exposure. Regression analysis indicated that, among relatives and friends of disappeared persons, the extent of hope predicted PGD above and beyond depression severity whereas among bereaved persons, PGD was predicted by time since the loss, the number of traumatic events and symptom severity of PTSD and depression. The instruments were not validated for use in Colombia; generalizability of findings is limited. Forced disappearance is related to prolonged grief reactions, particularly when those left behind maintain hope that the disappeared person is still alive. Copyright © 2014 Elsevier B.V. All rights reserved.

Challenges at work and financial rewards to stimulate longer workforce participation.

PubMed

Proper, Karin I; Deeg, Dorly J H; van der Beek, Allard J

2009-08-11

Because of the demographic changes, appropriate measures are needed to prevent early exit from work and to encourage workers to prolong their working life. To date, few studies have been performed on the factors motivating continuing to work after the official age of retirement. In addition, most of those studies were based on quantitative data. The aims of this study were to examine, using both quantitative and qualitative data: (1) the reasons for voluntary early retirement; (2) the reasons for continuing working life after the official retirement age; and (3) the predictive value of the reasons mentioned. Quantitative data analyses were performed with a prospective cohort among persons aged 55 years and older. Moreover, qualitative data were derived from interviews with workers together with discussions from a workshop among occupational physicians and employers. Results showed that the presence of challenging work was among the most important reasons for not taking early retirement. In addition, this motive appeared to positively predict working status after three years. The financial advantages of working and the maintenance of social contacts were the reasons reported most frequently for not taking full retirement, with the financial aspect being a reasonably good predictor for working status after three years. From the interviews and the workshop, five themes were identified as important motives to prolong working life: challenges at work, social contacts, reward and appreciation, health, and competencies and skills. Further, it was brought forward that each stakeholder can and should contribute to the maintenance of a healthy and motivated ageing workforce. Based on the findings, it was concluded that measures that promote challenges at work, together with financial stimuli, seem to be promising in order to prolong workforce participation.

PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation.

PubMed

Fonzo, Gregory A; Goodkind, Madeleine S; Oathes, Desmond J; Zaiko, Yevgeniya V; Harvey, Meredith; Peng, Kathy K; Weiss, M Elizabeth; Thompson, Allison L; Zack, Sanno E; Lindley, Steven E; Arnow, Bruce A; Jo, Booil; Gross, James J; Rothbaum, Barbara O; Etkin, Amit

2017-12-01

Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but many patients do not respond. Brain functions governing treatment outcome are not well characterized. The authors examined brain systems relevant to emotional reactivity and regulation, constructs that are thought to be central to PTSD and exposure therapy effects, to identify the functional traits of individuals most likely to benefit from treatment. Individuals with PTSD underwent functional MRI (fMRI) while completing three tasks assessing emotional reactivity and regulation. Participants were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30). A random subset of the prolonged exposure group (N=17) underwent single-pulse transcranial magnetic stimulation (TMS) concurrent with fMRI to examine whether predictive activation patterns reflect causal influence within circuits. Linear mixed-effects modeling in line with the intent-to-treat principle was used to examine how baseline brain function moderated the effect of treatment on PTSD symptoms. At baseline, individuals with larger treatment-related symptom reductions (compared with the waiting list condition) demonstrated 1) greater dorsal prefrontal activation and 2) less left amygdala activation, both during emotion reactivity; 3) better inhibition of the left amygdala induced by single TMS pulses to the right dorsolateral prefrontal cortex; and 4) greater ventromedial prefrontal/ventral striatal activation during emotional conflict regulation. Reappraisal-related activation was not a significant moderator of the treatment effect. Capacity to benefit from prolonged exposure in PTSD is gated by the degree to which prefrontal resources are spontaneously engaged when superficially processing threat and adaptively mitigating emotional interference, but not when deliberately reducing negative emotionality.

Potential Cost-Effectiveness of Ambulatory Cardiac Rhythm Monitoring After Cryptogenic Stroke.

PubMed

Yong, Jean Hai Ein; Thavorn, Kednapa; Hoch, Jeffrey S; Mamdani, Muhammad; Thorpe, Kevin E; Dorian, Paul; Sharma, Mike; Laupacis, Andreas; Gladstone, David J

2016-09-01

Prolonged ambulatory ECG monitoring after cryptogenic stroke improves detection of covert atrial fibrillation, but its long-term cost-effectiveness is uncertain. We estimated the cost-effectiveness of noninvasive ECG monitoring in patients aged ≥55 years after a recent cryptogenic stroke and negative 24-hour ECG. A Markov model used observed rates of atrial fibrillation detection and anticoagulation from a randomized controlled trial (EMBRACE) and the published literature to predict lifetime costs and effectiveness (ischemic strokes, hemorrhages, life-years, and quality-adjusted life-years [QALYs]) for 30-day ECG (primary analysis) and 7-day or 14-day ECG (secondary analysis), when compared with a repeat 24-hour ECG. Prolonged ECG monitoring (7, 14, or 30 days) was predicted to prevent more ischemic strokes, decrease mortality, and improve QALYs. If anticoagulation reduced stroke risk by 50%, 30-day ECG (at a cost of USD $447) would be highly cost-effective ($2000 per QALY gained) for patients with a 4.5% annual ischemic stroke recurrence risk. Cost-effectiveness was sensitive to stroke recurrence risk and anticoagulant effectiveness, which remain uncertain, especially at higher costs of monitoring. Shorter duration (7 or 14 days) monitoring was cost saving and more effective than an additional 24-hour ECG; its cost-effectiveness was less sensitive to changes in ischemic stroke risk and treatment effect. After a cryptogenic stroke, 30-day ECG monitoring is likely cost-effective for preventing recurrent strokes; 14-day monitoring is an attractive value alternative, especially for lower risk patients. These results strengthen emerging recommendations for prolonged ECG monitoring in secondary stroke prevention. Cost-effectiveness in practice will depend on careful patient selection. © 2016 American Heart Association, Inc.

Young age as a modifying factor in sports concussion management: what is the evidence?

PubMed

Foley, Cassidy; Gregory, Andrew; Solomon, Gary

2014-01-01

In 2008, the Concussion in Sport Group (CISG) published its third consensus statement and introduced 10 'modifying' factors that were presumed clinically to influence the investigation and management of concussions in sports. Young age was listed as one of the modifying factors. In some cases, these modifiers were thought to be predictive of prolonged or persistent symptoms. These same modifying factors were retained in the fourth iteration of the CISG consensus statement (2013), although mention was made of possible limitations of their efficacy. The CISG statements provided several empirical references regarding young age as a modifying factor. We reviewed the published sports concussion literature with the purpose of determining empirical studies that support or refute the inclusion of young age as a modifier of concussive injury in sports. We performed a systematic review of the PubMed database utilizing the keywords concussion, sports, mild traumatic brain injury, youth, adolescents, and children. English language studies were extracted by the authors and summarized for review. Multiple empirical studies were found indicating that younger athletes may take longer to recover from a sports-related concussion (SRC) than their older peers. However, studies did not indicate that younger athletes were at more risk for prolonged recovery (>4 wk). Empirical evidence supports the inclusion of young age as a modifying factor in sports concussion. However, the difference in recovery time seems relatively small (a few days) and young age does not predict prolonged recovery (>4 wk). The findings support the inclusion of young age as a specific modifier in the treatment of SRC and have implications for the clinical management of this common injury.

F247. INTERNALIZED STIGMA HAS A STRONGER RELATIONSHIP WITH INTRINSIC MOTIVATION COMPARED TO AMOTIVATION IN EARLY PHASE AND PROLONGED SCHIZOPHRENIA

PubMed Central

Firmin, Ruth; Luther, Lauren; Lysaker, Paul; Vohs, Jennifer

2018-01-01

Abstract Background Motivation deficits predict decreased functioning in schizophrenia. Recent work suggests deficits reflect challenges in separate domains: intrinsic motivation (one’s internal drive to engage in a behavior out of enjoyment or interest) and amotivation (one’s broader decrease in motivated behavior linked to avolition and anhedonia). Internalized stigma is another determinant of functioning for people with schizophrenia that may impact motivation. However, little is known about these relationships, including which aspects of motivation it may impact nor when these links emerge. Identifying the link between these constructs may help to identify whether internalized stigma may be a novel treatment target to facilitate improvements in motivation. Methods Forty adults with early phase schizophrenia and 66 adults with prolonged schizophrenia completed measures of internalized stigma, intrinsic motivation, and amotivation. Pearson’s correlations were examined followed by Fischer’s r-to-z transformations to compare differences in the magnitude of associations between internalized stigma and intrinsic motivation and internalized stigma and amotivation among the first episode and prolonged samples. Next, we conducted stepwise regressions to examine whether internalized stigma was associated with intrinsic motivation above and beyond associations with amotivation in each sample. Results In the early phase sample, the association between internalized stigma was greater with intrinsic motivation (r=-0.48, p=.00) compared to amotivation (r=0.27, p=0.10). Associations with internalized stigma in the prolonged sample were also greater with intrinsic motivation (r=-0.30, p=0.02) versus amotivation (r=0.19, p=0.12). The magnitude of the associations between internalized stigma and intrinsic motivation (z=1.03, p=0.15) and between internalized stigma and amotivation (z=0.41, p = 0.34) did not significantly differ when comparing phase of illness. Regression analyses indicated that, controlling for amotivation, internalized stigma predicted intrinsic motivation in both the prolonged sample (R2=0.09, F(1,64) =6.18, p=0.02) and the early phase schizophrenia sample (R2=0.23, F(1,37)=10.98, p=.00). Discussion Results suggest internalized stigma has a stronger relationship with intrinsic motivation separate from, and above and beyond, its association with amotivation. Findings support models of intrinsic and amotivation being distinct domains. Links between internalized stigma and motivation appear to emerge and persist from the early stages of schizophrenia, suggesting that targeting stigma in early intervention services may help to improve intrinsic motivation in people with schizophrenia.

Anger and guilt in treatment for chronic posttraumatic stress disorder.

PubMed

Clifton, Erin G; Feeny, Norah C; Zoellner, Lori A

2017-03-01

Feelings of anger and guilt are important to consider when treating PTSD as they are related to higher PTSD severity and may be related to avoidance during treatment. Avoidance may impede emotional engagement, the process of connecting with distressing, fear-related emotions during imaginal exposure, which is considered an important mechanism for successful PTSD treatment in prolonged exposure (PE). Yet, little research has examined possible complications in achieving emotional engagement, such as anger and guilt. The present study utilized data from 116 individuals with PTSD who received PE to investigate whether anger and guilt were associated with poorer emotional engagement, as captured by pre, peak, post, and mean subjective units of distress (SUDs), during the initial imaginal exposure, and whether anger and guilt predicted worse treatment outcome generally and as a result of lessened emotional engagement. Neither initial anger nor guilt hindered engagement nor predicted worse outcome. Contrary to hypotheses, higher guilt was predictive of greater anticipatory distress and slightly better PTSD outcome. The relationship between pre-treatment guilt cognitions and post-treatment PTSD severity was not mediated by engagement. This study used a trauma-specific measure of guilt and general measure for anger, however both are commonly used. In addition, this study examined emotional engagement during imaginal exposure to the exclusion of engagement with other therapy components, such as in vivo exposure. These findings help dispel concerns that those with higher anger and guilt will avoid emotionally engaging during the initial imaginal exposure due to feeling distressed by intense negative emotionality. Copyright © 2016 Elsevier Ltd. All rights reserved.

Risk Factors for Prolonged Length of Stay or Complications During Pediatric Respiratory Hospitalizations.

PubMed

Kaiser, Sunitha V; Bakel, Leigh-Anne; Okumura, Megumi J; Auerbach, Andrew D; Rosenthal, Jennifer; Cabana, Michael D

2015-09-01

Respiratory illnesses are the leading cause of pediatric hospitalizations in the United States, and a major focus of efforts to improve quality of care. Understanding factors associated with poor outcomes will allow better targeting of interventions for improving care. The objective of this study was to identify patient and hospital factors associated with prolonged length of stay (LOS) or complications during pediatric hospitalizations for asthma or lower respiratory infection (LRI). Cross-sectional study of hospitalizations of patients <18 years with asthma or LRI (bronchiolitis, influenza, or pneumonia) by using the nationally representative 2012 Kids Inpatient Database. We used multivariable logistic regression models to identify factors associated with prolonged LOS (>90th percentile) or complications (noninvasive ventilation, mechanical ventilation, or death). For asthma hospitalizations(n = 85 320), risks for both prolonged LOS and complications were increased with each year of age (adjusted odds ratio [AOR] 1.06, 95% confidence interval [CI] 1.05-1.07; AOR 1.05, 95% CI 1.03-1.07, respectively for each outcome) and in children with chronic conditions (AOR 4.87, 95% CI 4.15-5.70; AOR 21.20, 95% CI 15.20-29.57, respectively). For LRI hospitalizations (n = 204 950), risks for prolonged LOS and complications were decreased with each year of age (AOR 0.98, 95% CI 0.97-0.98; AOR 0.95, 95% CI 0.94-0.96, respectively) and increased in children with chronic conditions (AOR 9.86, 95% CI 9.03-10.76; AOR 56.22, 95% CI 46.60-67.82, respectively). Risks for prolonged LOS for asthma were increased in large hospitals (AOR 1.67, 95% CI 1.32-2.11) and urban-teaching hospitals (AOR 1.62, 95% CI 1.33-1.97). Older children with asthma, younger children with LRI, children with chronic conditions, and those hospitalized in large urban-teaching hospitals are more vulnerable to prolonged LOS and complications. Future research and policy efforts should evaluate and support interventions to improve outcomes for these high-risk groups (eg, hospital-based care coordination for children with chronic conditions). Copyright © 2015 by the American Academy of Pediatrics.

Impact of Diverse Hydrologic Pathways, 3D Failure Geometries, and Unsaturated Soil Suctions on Shallow Landsliding

NASA Astrophysics Data System (ADS)

Reid, M. E.; Iverson, R. M.; Brien, D. L.; Iverson, N. R.; Lahusen, R. G.; Logan, M.

2016-12-01

Shallow landslides and ensuing debris flows can be triggered by diverse hydrologic phenomena such as groundwater inflow, prolonged moderate-intensity precipitation, or bursts of high-intensity precipitation. However, hazard assessments typically rely on simplistic hydrologic models that disregard this diversity. We used the USGS debris-flow flume to conduct controlled, field-scale slope failure experiments designed to investigate the effects of diverse hydrologic pathways, as well as the effects of 3D landslide geometries and suction stresses in unsaturated soil. Using overhead sprinklers or groundwater injectors on the flume bed, we induced failures in 6 m3 (0.65-m thick and 2-m wide) prisms of loamy sand on a 31º slope. We used 50 sensors to monitor soil deformation, variably saturated pore pressures, and moisture changes. We also determined shear strength, hydraulic conductivity, and unsaturated moisture retention characteristics from ancillary tests. The three hydrologic scenarios noted above led to different behaviors. Groundwater injection and prolonged infiltration created differing soil moisture patterns. Intense sprinkling bursts caused rapid failure without development of widespread positive pore pressures. We simulated these observed differences numerically by coupling 2D variably saturated groundwater flow modeling and 3D limit-equilibrium analysis. We also simulated the time evolution of changes in factors of safety, and quantified the mechanical effects of 3D geometry and unsaturated soil suction on stability. When much of the soil became relatively wet, effects of 3D geometry and soil suction produced slight increases ( 10-20%) in factors of safety. Suction effects were more pronounced with drier soils. Our results indicate that simplistic models cannot consistently predict the timing of slope failure, and that high frequency monitoring (with sampling periods < 60 s) is needed to measure and interpret the effects of rapid hydrologic triggers.

Not all droughts are created equal: The impacts of interannual drought pattern and magnitude on grassland carbon cycling

USGS Publications Warehouse

Hoover, David L.; Rogers, Brendan M.

2016-01-01

Climate extremes, such as drought, may have immediate and potentially prolonged effects on carbon cycling. Grasslands store approximately one-third of all terrestrial carbon and may become carbon sources during droughts. However, the magnitude and duration of drought-induced disruptions to the carbon cycle, as well as the mechanisms responsible, remain poorly understood. Over the next century, global climate models predict an increase in two types of drought: chronic but subtle ‘press-droughts’, and shorter term but extreme ‘pulse-droughts’. Much of our current understanding of the ecological impacts of drought comes from experimental rainfall manipulations. These studies have been highly valuable, but are often short term and rarely quantify carbon feedbacks. To address this knowledge gap, we used the Community Land Model 4.0 to examine the individual and interactive effects of pulse- and press-droughts on carbon cycling in a mesic grassland of the US Great Plains. A series of modeling experiments were imposed by varying drought magnitude (precipitation amount) and interannual pattern (press- vs. pulse-droughts) to examine the effects on carbon storage and cycling at annual to century timescales. We present three main findings. First, a single-year pulse-drought had immediate and prolonged effects on carbon storage due to differential sensitivities of ecosystem respiration and gross primary production. Second, short-term pulse-droughts caused greater carbon loss than chronic press-droughts when total precipitation reductions over a 20-year period were equivalent. Third, combining pulse- and press-droughts had intermediate effects on carbon loss compared to the independent drought types, except at high drought levels. Overall, these results suggest that interannual drought pattern may be as important for carbon dynamics as drought magnitude and that extreme droughts may have long-lasting carbon feedbacks in grassland ecosystems.

Multi-walled carbon nanotube structural instability with/without metal nanoparticles under electron beam irradiation

NASA Astrophysics Data System (ADS)

Khan, Imran; Huang, Shengli; Wu, Chenxu

2017-12-01

The structural transformation of multi-walled carbon nanotubes (MWCNT) under electron beam (e-beam) irradiation at room temperature is studied, with respect to a novel passivation effect due to gold nanoparticles (Au NPs). MWCNT structural evolution induced by energetic e-beam irradiation leads to faster shrinkage, as revealed via in situ transmission electron microscopy, while MWCNT surface modification with Au NPs (Au-MWCNT) slows down the shrinkage by impeding the structural evolution process for a prolonged time under the same irradiation conditions. The new relationship between MWCNT and Au-MWCNT shrinking radii and irradiation time illustrates that the MWCNT shrinkage rate is faster than either theoretical predictions or the same process in Au-MWCNTs. As compared with the outer surface energy (positive curvature), the inner surface energy (negative curvature) of the MWCNT contributes more to the athermal evaporation of tube wall atoms, leading to structural instability and shrinkage under e-beam irradiation. Conversely, Au NPs possess only outer surface energy (positive curvature) compared with the MWCNT. Their presence on MWCNT surfaces retards the dynamics of MWCNT structural evolution by slowing down the evaporation process of carbon atoms, thus restricting Au-MWCNT shrinkage. Au NP interaction and growth evolves athermally on MWCNT surfaces, exhibits increase in their size, and indicates the association of this mechanism with the coalescence induced by e-beam activated electronic excitations. Despite their growth, Au NPs show extreme structural stability, and remain crystalline under prolonged irradiation. It is proposed that the surface energy of MWCNTs and Au NPs, together with e-beam activated soft modes or lattice instability effects, predominantly govern all the above varieties of structural evolution.

Prolonged QRS duration on surface electrocardiogram is associated with left ventricular restrictive filling pattern.

PubMed

Erdoğan, Turan; Durakoğlugil, Murtaza Emre; Çiçek, Yüksel; Çetin, Mustafa; Duman, Hakan; Şatiroğlu, Ömer; Çelik, Şükrü

2017-03-01

Prolonged QRS duration is associated with decreased left ventricular (LV) systolic function. However, the relation between LV restrictive filling pattern (RFP) and QRS duration has not been investigated yet. The purpose of our study was to assess this relationship. We analyzed standard 12-lead surface electrocardiogram (ECG) of 155 consecutive patients. Mitral inflow and septal tissue velocities were obtained using the apical 4-chamber view with pulsed Doppler echocardiography. Patients were divided into 2 groups according to measured deceleration time (DT): restrictive (with DT ≤130 ms) or non-restrictive (with DT >130 ms). QRS duration was significantly longer in the restrictive group than in the non-restrictive group (0.101 vs. 0.090 s, p  < 0.0001). QRS duration of >0.10 s was highly specific (82.6%), but modestly sensitive (64.7%), for the prediction of LV RFP. Multivariate analyses demonstrated that E/A ratio, peak E, peak A, septal e', and a' velocities were significantly associated with RFP. Prolonged QRS duration (>0.10 s) obtained from a standard resting 12-lead ECG is associated with LV RFP. However, the relationship of QRS duration with RFP was not independent of echocardiographic parameters.

Review and Outcome of Prolonged Cardiopulmonary Resuscitation

PubMed Central

Youness, Houssein; Al Halabi, Tarek; Hussein, Hussein; Awab, Ahmed; Jones, Kellie; Keddissi, Jean

2016-01-01

The maximal duration of cardiopulmonary resuscitation (CPR) is unknown. We report a case of prolonged CPR. We have then reviewed all published cases with CPR duration equal to or more than 20 minutes. The objective was to determine the survival rate, the neurological outcome, and the characteristics of the survivors. Measurements and Main Results. The CPR data for 82 patients was reviewed. The median duration of CPR was 75 minutes. Patients mean age was 43 ± 21 years with no significant comorbidities. The main causes of the cardiac arrests were myocardial infarction (29%), hypothermia (21%), and pulmonary emboli (12%). 74% of the arrests were witnessed, with a mean latency to CPR of 2 ± 6 minutes and good quality chest compression provided in 96% of the cases. Adjunct therapy included extracorporeal membrane oxygenation (18%), thrombolysis (15.8%), and rewarming for hypothermia (19.5%). 83% were alive at 1 year, with full neurological recovery reported in 63 patients. Conclusion. Patients undergoing prolonged CPR can survive with good outcome. Young age, myocardial infarction, and potentially reversible causes of cardiac arrest such as hypothermia and pulmonary emboli predict a favorable result, especially when the arrest is witnessed and followed by prompt and good resuscitative efforts. PMID:26885387

Kinetics of Chronic Oxidation of NBG-17 Nuclear Graphite by Water Vapor

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

Contescu, Cristian I; Burchell, Timothy D; Mee, Robert

2015-05-01

This report presents the results of kinetic measurements during accelerated oxidation tests of NBG-17 nuclear graphite by low concentration of water vapor and hydrogen in ultra-high purity helium. The objective is to determine the parameters in the Langmuir-Hinshelwood (L-H) equation describing the oxidation kinetics of nuclear graphite in the helium coolant of high temperature gas-cooled reactors (HTGR). Although the helium coolant chemistry is strictly controlled during normal operating conditions, trace amounts of moisture (predictably < 0.2 ppm) cannot be avoided. Prolonged exposure of graphite components to water vapor at high temperature will cause very slow (chronic) oxidation over the lifetimemore » of graphite components. This behavior must be understood and predicted for the design and safe operation of gas-cooled nuclear reactors. The results reported here show that, in general, oxidation by water of graphite NBG-17 obeys the L-H mechanism, previously documented for other graphite grades. However, the characteristic kinetic parameters that best describe oxidation rates measured for graphite NBG-17 are different than those reported previously for grades H-451 (General Atomics, 1978) and PCEA (ORNL, 2013). In some specific conditions, certain deviations from the generally accepted L-H model were observed for graphite NBG-17. This graphite is manufactured in Germany by SGL Carbon Group and is a possible candidate for the fuel elements and reflector blocks of HTGR.« less

Meta-analysis of Magnetic Marker Monitoring Data to Characterize the Movement of Single Unit Dosage Forms Though the Gastrointestinal Tract Under Fed and Fasting Conditions.

PubMed

Hénin, Emilie; Bergstrand, Martin; Weitschies, Werner; Karlsson, Mats O

2016-03-01

To develop a model predicting movement of non-disintegrating single unit dosage forms (or "tablet") through the gastrointestinal tract and characterizing the effect of food intake, based on Magnetic Marker Monitoring data, allowing real-time location of a magnetically labeled formulation. Five studies including 30 individuals in 94 occasions under 3 food status were considered. The mean residence time (MRT) of the tablet and the effect of food intake in proximal (PS) and distal stomach (DS), small intestine (SI), ascending (AC), transverse (TC) and descending colon (DC) were estimated using a Markov model for probabilities of movement. Under fasting conditions, tablet MRTs were 9.4 min in PS, 10.4 in DS, 246 in SI, 545 in AC, 135 in TC, and 286 in DC. A meal taken simultaneous to tablet intake prolonged tablet MRT to 99 min in PS and to 232 in DS; probability of gastric emptying increased of 89% each hour from 2.25 h after meal. The effect of a gastroileac reflex, caused by a secondary meal, accelerated the transit from terminal SI to AC. This model-based knowledge can be used as a part of mechanism-based models for drug absorption, applied for bottom-up predictions and/or top-down estimation.

Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

PubMed

Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Ray; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

2017-04-04

Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide ( r =0.55; 95% confidence interval, 0.09-0.81; P =0.02), 23% in response to quinidine ( r =0.48; 95% confidence interval, -0.03 to 0.79; P =0.06), and 27% in response to ranolazine ( r =0.52; 95% confidence interval, 0.05-0.80; P =0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls ( r 2 =12%, P =1×10 -7 ). We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950. © 2017 American Heart Association, Inc.

Severe Neutropenia in Dengue Patients: Prevalence and Significance

PubMed Central

Thein, Tun-Linn; Lye, David C.; Leo, Yee-Sin; Wong, Joshua G. X.; Hao, Ying; Wilder-Smith, Annelies

2014-01-01

Studies on severe neutropenia in dengue are scarce, and its clinical significance is uncertain. We analyzed a cohort of 1,921 reverse transcription polymerase chain reaction-confirmed adult dengue patients admitted to the Communicable Disease Center in Singapore between 2005 and 2008. Time trend analyses for daily absolute neutrophil counts (ANCs) were done using Bayesian hierarchical and Markov models. We found that severe neutropenia, defined as ANC ≤ 0.5 × 109/L, was found in 11.8% with a median duration of 1 day. ANC nadir occurred on illness day 5. Severe neutropenia was not predictive of more severe disease and not associated with secondary bacterial infections, prolonged hospital stay, prolonged fever, or fatal outcome. We concluded that prophylactic antibiotics are not indicated in patients with severe neutropenia without indication for bacterial infection. PMID:24732460

Clinician perceptions of using a smartphone app with prolonged exposure therapy.

PubMed

Kuhn, Eric; Eftekhari, Afsoon; Hoffman, Julia E; Crowley, Jill J; Ramsey, Kelly M; Reger, Greg M; Ruzek, Josef I

2014-11-01

Clinician perceptions of clinical innovations affect their adoption and spread. This study investigated mental health clinicians' (n = 163) perceptions of a patient-facing smartphone application (app) for prolonged exposure (PE) therapy for posttraumatic stress disorder, before its public release. After reading a description of the app, participants rated perceptions of it based on diffusion of innovations theory constructs. Perceptions were generally favorable regarding the app's relative advantage over existing PE practices, compatibility with their values and needs, and complexity. Age (<40 years), smartphone ownership, and having used apps in care related to more favorable perceptions. Smartphone ownership, relative advantage, and complexity significantly predicted intention to use the app if it were available. These findings suggest that clinicians are receptive to using a PE app and that dissemination efforts should target sub-groups of PE clinicians to maximize adoption.

Carotid Baroreflex Function During Prolonged Exercise

NASA Technical Reports Server (NTRS)

Raven, P. B.

1999-01-01

Astronauts are often required to work (exercise) at moderate to high intensities for extended periods while performing extra-vehicular activities (EVA). Although the physiologic responses associated with prolonged exercise have been documented, the mechanisms involved in blood pressure regulation under these conditions have not yet been fully elucidated. An understanding of this issue is pertinent to the ability of humans to perform work in microgravity and complies with the emphasis of NASA's Space Physiology and Countermeasures Program. Prolonged exercise at a constant workload is know to result in a progressive decrease in mean arterial pressure (MAP) concomitant with a decrease in stroke volume and a compensatory increase in heart rate. The continuous decrease in MAP during the exercise, which is related to the thermoregulatory redistribution of circulating blood volume to the cutaneous circulation, raises the question as to whether there is a loss of baroreflex regulation of arterial blood pressure. We propose that with prolongation of the exercise to 60 minutes, progressive increases on central command reflect a progressive upward resetting of the carotid baroreflex (CBR) such that the operating point of the CBR is shifted to a pressure below the threshold of the reflex rendering it ineffectual in correcting the downward drift in MAP. In order to test this hypothesis, experiments have been designed to uncouple the global hemodynamic response to prolonged exercise from the central command mediated response via: (1) continuous maintenance of cardiac filling volume by intravenous infusion of a dextran solution; and (2) whole body surface cooling to counteract thermoregulatory cutaneous vasodialation. As the type of work (exercise) performed by astronauts is inherently arm and upper body dependent, we will also examine the physiologic responses to prolonged leg cycling and arm ergometry exercise in the supine positions with and without level lower body negative pressure (-10 torr) to mimic spaceflight- related decreases in cardiac filling volumes.

Strategies for maximizing your chances for weaning success. Limitations--and advantages--of common predictive indices.

PubMed

Patel, R G; Petrini, M F; Norman, J R

1995-06-01

Using indices to predict weaning outcome can avoid premature extubation and unnecessary prolongation of ventilatory support. Unfortunately, none of the indices is consistently able to predict outcome. The key to successful weaning is to assess respiratory function repeatedly with several indices, not just one. The patient should be able to sustain spontaneous breathing for at least 24 hours on minimal partial ventilatory support (a pressure support or a continuous positive airway pressure of 5 cm H2O or a T piece, for example). Indices of maximal inspiratory pressure; work of breathing; and rapid, shallow breathing are useful in evaluating a patient's respiratory muscle performance; airway occlusion pressure is helpful as well when increased neuromuscular drive is a problem.

Tardive dyskinesia successfully treated with alprazolam.

PubMed Central

Jordan, H. W.; Williams, B. C.

1990-01-01

Tardive dyskinesia is a disorder secondary to prolonged treatment (from 18 months to 3 years) with antipsychotic agents, affecting approximately 15% to 20% of patients. Tardive dyskinesia is characterized by difficulty controlling involuntary movements of the small muscle groups, producing tic-like reactions, muscle rigidity, and difficulty maintaining muscle tone. It is a chronic and unrelenting disorder which may be permanent if not successfully treated. The mechanism of action is thought to be secondary to dopamine hypersensitivity resulting from prolonged deprivation of dopamine on the part of dopamine-sensitive receptors. Theoretically, these receptors have been deprived of the neurotransmitter by chronic treatment with antipsychotic drugs, which are recognized as dopamine-blocking agents. We present a case in which alprazolam was successfully used in treating tardive dyskinesia. PMID:2213917

Photocurrent generation in SnO2 thin film by surface charged chemisorption O ions

NASA Astrophysics Data System (ADS)

Lee, Po-Ming; Liao, Ching-Han; Lin, Chia-Hua; Liu, Cheng-Yi

2018-06-01

We report a photocurrent generation mechanism in the SnO2 thin film surface layer by the charged chemisorption O ions on the SnO2 thin film surface induced by O2-annealing. A critical build-in electric field in the SnO2 surface layer resulted from the charged O ions on SnO2 surface prolongs the lifetime and reduces the recombination probability of the photo-excited electron-hole pairs by UV-laser irradiation (266 nm) in the SnO2 surface layer, which is the key for the photocurrent generation in the SnO2 thin film surface layer. The critical lifetime of prolonged photo-excited electron-hole pair is calculated to be 8.3 ms.

On integrability of the Killing equation

NASA Astrophysics Data System (ADS)

Houri, Tsuyoshi; Tomoda, Kentaro; Yasui, Yukinori

2018-04-01

Killing tensor fields have been thought of as describing the hidden symmetry of space(-time) since they are in one-to-one correspondence with polynomial first integrals of geodesic equations. Since many problems in classical mechanics can be formulated as geodesic problems in curved space and spacetime, solving the defining equation for Killing tensor fields (the Killing equation) is a powerful way to integrate equations of motion. Thus it has been desirable to formulate the integrability conditions of the Killing equation, which serve to determine the number of linearly independent solutions and also to restrict the possible forms of solutions tightly. In this paper, we show the prolongation for the Killing equation in a manner that uses Young symmetrizers. Using the prolonged equations, we provide the integrability conditions explicitly.

Hippocampal cell proliferation regulation by repeated stress and antidepressants.

PubMed

Chen, Hu; Pandey, Ghanshyam N; Dwivedi, Yogesh

2006-06-26

A recent hypothesis suggests reduced hippocampal neurogenesis in depression. Here, we examined cell proliferation in the dentate gyrus and the subventricular zone of rats given repeated stress, a paradigm that prolongs learned helplessness behavior, and whether antidepressants modulate the learned helplessness-associated altered cell proliferation. Decreased cell proliferation, number of clusters, and cells/cluster were noted in the dentate gyrus, but not in the subventricular zone, of learned helplessness rats. Both fluoxetine and desipramine reversed the learned helplessness behavior and increased the cell proliferation and the number of clusters in learned helplessness rats; only fluoxetine did so significantly. Both fluoxetine and desipramine significantly increased the number of cells/cluster. Our results suggest modified hippocampal neurogenesis in prolonged depression and in the mechanism of antidepressant action.

The Major Histocompatibility Complex–related Fc Receptor for IgG (FcRn) Binds Albumin and Prolongs Its Lifespan

PubMed Central

Chaudhury, Chaity; Mehnaz, Samina; Robinson, John M.; Hayton, William L.; Pearl, Dennis K.; Roopenian, Derry C.; Anderson, Clark L.

2003-01-01

The inverse relationship between serum albumin concentration and its half-life suggested to early workers that albumin would be protected from a catabolic fate by a receptor-mediated mechanism much like that proposed for IgG. We show here that albumin binds FcRn in a pH dependent fashion, that the lifespan of albumin is shortened in FcRn-deficient mice, and that the plasma albumin concentration of FcRn-deficient mice is less than half that of wild-type mice. These results affirm the hypothesis that the major histocompatibility complex–related Fc receptor protects albumin from degradation just as it does IgG, prolonging the half-lives of both. PMID:12566415

Transient decrease in nociceptor GRK2 expression produces long–term enhancement in inflammatory pain

PubMed Central

Ferrari, Luiz F.; Bogen, Oliver; Alessandri–Haber, Nicole; Levine, Emma; Gear, Robert W.; Levine, Jon D.

2012-01-01

In heterozygous mice, attenuation of G-protein-coupled receptor kinase 2 (GRK2) level in nociceptors is associated with enhanced and prolonged inflammatory hyperalgesia. To further elucidate the role of GRK2 in nociceptor function we reversibly decreased GRK2 expression using intrathecal antisense oligodeoxynucleotide (AS-ODN). GRK2 AS-ODN administration led to an enhanced and prolonged hyperalgesia induced by prostaglandin E 2, epinephrine and carrageenan. Morover, this effect persisted unattenuated 2 weeks after the last dose of antisense, well after GRK2 protein recovered, suggesting that transient attenuation of GRK2 produced neuroplastic changes in nociceptor function. Unlike hyperalgesic priming induced by transient attenuation of GRK2 produced neuroplastic changes in nociceptor function. Unlike hyperalgesic priming induced by transient activation of protein kinase C epsilon (PKCε), (Aley et al., 2000, Parada et al., 2003b), the enhanced and prolonged hyperalgesia following attenuation of GRK2 is PKCε- and cytoplasmic polyadenylation element binding protein (CPEB)-independent and is protein kinase A (PKA)- and Src tyrosine kinase (Src)-dependent. Finally, rats treated with GRK2 AS-ODN exhibited enhanced and prolonged hyperalgesia induced by direct activation of second messengers, adenyl cyclase, Epac or PKA, suggesting changes downstream of G-protein-coupled receptors. Because inflammation can produce a decrease in GRK2, such a mechanism could help explain a predilection to develop chronic pain, after resolution of acute inflammation. PMID:22796071

Short and prolonged exposure to hyperglycaemia in human fibroblasts and endothelial cells: metabolic and osmotic effects.

PubMed

Moruzzi, Noah; Del Sole, Marianna; Fato, Romana; Gerdes, Jantje M; Berggren, Per-Olof; Bergamini, Christian; Brismar, Kerstin

2014-08-01

High blood glucose levels are the main feature of diabetes. However, the underlying mechanism linking high glucose concentration to diabetic complications is still not fully elucidated, particularly with regard to human physiology. Excess of glucose is likely to trigger a metabolic response depending on the cell features, activating deleterious pathways involved in the complications of diabetes. In this study, we aim to elucidate how acute and prolonged hyperglycaemia alters the biology and metabolism in human fibroblasts and endothelial cells. We found that hyperglycaemia triggers a metabolic switch from oxidative phosphorylation to glycolysis that is maintained over prolonged time. Moreover, osmotic pressure is a major factor in the early metabolic response, decreasing both mitochondrial transmembrane potential and cellular proliferation. After prolonged exposure to hyperglycaemia we observed decreased mitochondrial steady-state and uncoupled respiration, together with a reduced ATP/ADP ratio. At the same time, we could not detect major changes in mitochondrial transmembrane potential and reactive oxygen species. We suggest that the physiological and metabolic alterations observed in healthy human primary fibroblasts and endothelial cells are an adaptive response to hyperglycaemia. The severity of metabolic and bioenergetics impairment associated with diabetic complications may occur after longer glucose exposure or due to interactions with cell types more sensitive to hyperglycaemia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sprint training shortens prolonged action potential duration in postinfarction rat myocyte: mechanisms.

PubMed

Zhang, X Q; Zhang, L Q; Palmer, B M; Ng, Y C; Musch, T I; Moore, R L; Cheung, J Y

2001-05-01

Two electrophysiological manifestations of myocardial infarction (MI)-induced myocyte hypertrophy are prolongation of action potential duration (APD) and reduction of transient outward current (I(to)) density. Because high-intensity sprint training (HIST) ameliorated myocyte hypertrophy and improved myocyte Ca(2+) homeostasis and contractility after MI, the present study evaluated whether 6-8 wk of HIST would shorten the prolonged APD and improve the depressed I(to) in post-MI myocytes. There were no differences in resting membrane potential and action potential amplitude (APA) measured in myocytes isolated from sham-sedentary (Sed), MI-Sed, and MI-HIST groups. Times required for repolarization to 50 and 90% APA were significantly (P < 0.001) prolonged in MI-Sed myocytes. HIST reduced times required for repolarization to 50 and 90% APA to values observed in Sham-Sed myocytes. The fast and slow components of I(to) were significantly (P < 0.0001) reduced in MI-Sed myocytes. HIST significantly (P < 0.001) enhanced the fast and slow components of I(to) in MI myocytes, although not to levels observed in Sham-Sed myocytes. There were no significant differences in steady-state I(to) inactivation and activation parameters among Sham-Sed, MI-Sed, and MI-HIST myocytes. Likewise, recovery from time-dependent inactivation was also similar among the three groups. We suggest that normalization of APD after MI by HIST may be mediated by restoration of I(to) toward normal levels.

Effect of fluid ingestion on neuromuscular function during prolonged cycling exercise.

PubMed

Vallier, J-M; Grego, F; Basset, F; Lepers, R; Bernard, T; Brisswalter, J

2005-04-01

To investigate the effects of fluid ingestion on neuromuscular function during prolonged cycling exercise. Eight well trained subjects exercised for 180 minutes in a moderate environment at a workload requiring approximately 60% maximal oxygen uptake. Two conditions, fluid (F) and no fluid (NF) ingestion, were investigated. During maximal voluntary isometric contraction (MVC), prolonged cycling exercise reduced (p<0.05) the maximal force generating capacity of quadriceps muscles (after three hours of cycling) and root mean square (RMS) values (after two hours of cycling) with no difference between the two conditions despite greater body weight loss (p<0.05) in NF. The mean power frequency (MPF) for vastus lateralis muscle was reduced (p<0.05) and the rate of force development (RFD) was increased (p<0.05) only during NF. During cycling exercise, integrated electromyographic activity and perceived exertion were increased in both conditions (p<0.05) with no significant effect of fluid ingestion. The results suggest that fluid ingestion did not prevent the previously reported decrease in maximal force with exercise duration, but seems to have a positive effect on some indicators of neuromuscular fatigue such as mean power frequency and rate of force development during maximal voluntary contraction. Further investigations are needed to assess the effect of change in hydration on neural mechanisms linked to the development of muscular fatigue during prolonged exercise.

Providing a diet containing only maintenance levels of energy and protein during the latter stages of pregnancy resulted in a prolonged delivery time during parturition in rats.

PubMed

Tanaka, Y; Kadokawa, H

2012-01-01

In mammals, a prolonged delivery time during parturition is dangerous for both mother and fetus, although the mechanisms that prolong delivery are unclear. To investigate whether nutrition affects delivery time, we administered two feeds containing maintenance (L-feed) or higher (H-feed) levels of energy and protein at different points during the latter half of pregnancy and compared the effects of the various treatments on delivery time in rats. After the rats had been maintained on the L-feed and then copulated on pro-oestrus (Day 0), pregnant females were randomly allocated to one of three groups: (1) the no-improvement group, which was fed L-feed throughout gestation; (2) the early group, which was fed L-feed until Day 11 of gestation and then switched to H-feed; and (3) the late group, which was fed L-feed until Day 16 of gestation and then switched to H-feed. There was no significant difference in the number of pups among the three groups. However, delivery time was significantly longer in the no-improvement group (73.7±5.2 min) than the early (46.9±5.6 min) and late (55.4±5.5 min) groups. Consuming a maintenance diet during the latter half of pregnancy resulted in a prolonged delivery time.

Light-Induced Translocation of RGS9-1 and Gβ5L in Mouse Rod Photoreceptors

PubMed Central

Tian, Mei; Zallocchi, Marisa; Wang, Weimin; Chen, Ching-Kang; Palczewski, Krzysztof; Delimont, Duane; Cosgrove, Dominic; Peng, You-Wei

2013-01-01

The transducin GTPase-accelerating protein complex, which determines the photoresponse duration of photoreceptors, is composed of RGS9-1, Gβ5L and R9AP. Here we report that RGS9-1 and Gβ5L change their distribution in rods during light/dark adaptation. Upon prolonged dark adaptation, RGS9-1 and Gβ5L are primarily located in rod inner segments. But very dim-light exposure quickly translocates them to the outer segments. In contrast, their anchor protein R9AP remains in the outer segment at all times. In the dark, Gβ5L's interaction with R9AP decreases significantly and RGS9-1 is phosphorylated at S475 to a significant degree. Dim light exposure leads to quick de-phosphorylation of RGS9-1. Furthermore, after prolonged dark adaptation, RGS9-1 and transducin Gα are located in different cellular compartments. These results suggest a previously unappreciated mechanism by which prolonged dark adaptation leads to increased light sensitivity in rods by dissociating RGS9-1 from R9AP and redistributing it to rod inner segments. PMID:23555598

Death by acid rain: VAP or EXIT?

PubMed

Thorburn, Kentigern; Darbyshire, Andrew

2009-01-01

Ventilator-associated pneumonia (VAP) is a new (nosocomial) lower respiratory tract infection diagnosed in mechanically ventilated patients 48 or more hours after intubation. There is no gold standard for establishing the diagnosis and its pathogenesis is iatrogenic and multifactorial. Gastro-oesophageal reflux is common in mechanically ventilated children, but its role in VAP remains speculative. VAP is associated with increased mortality and morbidity, prolonged duration of ventilation and hospital stay, and escalated costs of hospitalisation. VAP 'bundles' are championed as the antidote.

Indoor mold spore exposure: characteristics of 127 homes in southern California with endogenous mold problems.

PubMed

Gallup, J; Kozak, P; Cummins, L; Gillman, S

1987-01-01

We are constantly being exposed to molds in our environment. Indoor mold problems occur after prolonged or chronic water damage to a variety of organic materials such as unfinished wood, jutebacked carpeting, wallpaper, books, cardboard, leather, cork, paper, wallboard, and wicker baskets. Mechanisms for spore dispersal (such as air currents or foot traffic on carpets) must also be present. The presence of these organic materials and dispersal mechanisms leads to significant increases in indoor spore levels.

Consequences of contamination of the spacecraft environment: immunologic consequences

NASA Technical Reports Server (NTRS)

Shearer, W. T.

2001-01-01

Long-term space voyages pose numerous known and unknown health hazards, to the human immune system. Well-studied clinical examples of secondary immunodeficiencies created on Earth, lead one to predict that the conditions of prolonged space flight would weaken the human immune responses that normally hold infection and cancer in check. From evidence gathered from humans flown for prolonged periods in space and from human models of space flight studied on Earth it is reasonable to suspect that space travelers to the planet Mars would experience a weakening of immunity. Subtle defects of immune cell structure and function have been observed in astronauts, such as weakening of specific T-lymphocyte recall of specific antigens. Ground-based models also have demonstrated alterations of immune function, such as the elevation of neuroendocrine immune system messengers, interleukin-6, and soluble tumor necrosis factor-alpha receptor in sleep deprivation. Since severe immune compromise the clinical consequences of reactivation of latent virus infections and the development of cancer, has yet to be seen in space flight or in the Earth models, it is extremely important to begin to quantify early changes in immunity to predict the development of immune system collapse with poor clinical outcomes. This approach is designed to validate a number of surrogate markers that will predict trouble ahead. Inherent in this research is the development of countermeasures to reduce the risks of infection and cancer in the first humans going to Mars.

Laboratory and Molecular Characterization of Dengue Viruses in a 2014 Outbreak in Guangfo Region, Southern China.

PubMed

Luo, Zhao-Fan; Hu, Bo; Zhang, Feng-Yi; Lin, Xiang-Hua; Xie, Xiao-Ying; Pan, Kun-Yi; Li, Hong-Yu; Ren, Rui-Wen; Zhao, Wen-Zhong

2017-09-25

Non-specific symptoms and low viremia levels make early diagnosis of dengue virus (DENV) infection challenging. This study aimed to i) identify laboratory markers that can be used to predict a DENV-positive diagnosis and ii) perform a molecular characterization of DENVs from the 2014 Guangdong epidemic. This retrospective study analyzed 1,044 patients from the Guangdong epidemic who were clinically suspected cases of dengue. Viral RNA was detected by real-time RT-PCR, and viral-specific NS1 antigen was detected using enzyme-linked immuno sorbent assay. A molecular phylogenetic analysis was performed for the with the DENV C-prM gene junction. Patients with dengue infection had leukopenia (2.8 × 10 9 /L), thrombocytopenia (109.0 × 10 9 /L), elevated aspartate aminotransferase (56.0 IU/L) and alanine aminotransferase (43.5 IU/L), and prolonged activated partial thromboplastin time (APTT, 33.5 s) (all P ＜ 0.001) compared to patients without dengue. The positive predictive value of leukopenia and thrombocytopenia for DENV infection were 96.9% and 93.0%, respectively. Leukopenia, thrombocytopenia, elevated aminotransferases, and prolonged APTT were useful predictive markers for an early diagnosis of DENV infection. Phylogenetic analysis indicated that the DENVs from the 2014 epidemic were closely related to a 2010 New Delhi strain and a 2013 Guangzhou strain. The 2014 epidemic consisted of co-circulating DENV-1 genotypes I and V from multiple origins. Efficient dengue surveillance can facilitate rapid response to future outbreaks.

Patient and family perceptions of physical therapy in the medical intensive care unit.

PubMed

Sottile, Peter D; Nordon-Craft, Amy; Malone, Daniel; Schenkman, Margaret; Moss, Marc

2015-10-01

Patient and family member perceptions of physical therapy (PT) in the intensive care unit and the factors that influence their degree of satisfaction have not been described. A panel of experts developed a questionnaire that assessed patient and family perceptions of PT. Critically ill patients and their family members were asked to complete the survey. Patient and family member scores were compared and stratified by age, sex, and mechanical ventilation for greater than 14 days compared to 14 days or less. A total of 55 patients and 49 family members completed the survey. Patients and family members reported that PT was necessary and beneficial to recovery, despite associating PT with difficulty, exertion, and discomfort. Patient perceptions were similar regardless of age or sex. Family members underestimated a patient's enjoyment of PT (P = .03). For individuals who required prolonged mechanical ventilation (>14 days), patients reported that PT was more difficult (P = .03) and less enjoyable (P = .049), and family members reported PT as causing greater discomfort (P = .005). In addition, family members of patients who required prolonged mechanical ventilation felt that PT was less beneficial (P = .01). Physical therapy is perceived as necessary and beneficial to recovery by critically ill patients and family members. Copyright © 2015 Elsevier Inc. All rights reserved.

Heat stress protects against mechanical ventilation-induced diaphragmatic atrophy.

PubMed

Ichinoseki-Sekine, Noriko; Yoshihara, Toshinori; Kakigi, Ryo; Sugiura, Takao; Powers, Scott K; Naito, Hisashi

2014-09-01

Mechanical ventilation (MV) is a life-saving intervention in patients who are incapable of maintaining adequate pulmonary gas exchange due to respiratory failure or other disorders. However, prolonged MV is associated with the development of respiratory muscle weakness. We hypothesized that a single exposure to whole body heat stress would increase diaphragm expression of heat shock protein 72 (HSP72) and that this treatment would protect against MV-induced diaphragmatic atrophy. Adult male Wistar rats (n = 38) were randomly assigned to one of four groups: an acutely anesthetized control group (CON) with no MV; 12-h controlled MV group (CMV); 1-h whole body heat stress (HS); or 1-h whole body heat stress 24 h prior to 12-h controlled MV (HSMV). Compared with CON animals, diaphragmatic HSP72 expression increased significantly in the HS and HSMV groups (P < 0.05). Prolonged MV resulted in significant atrophy of type I, type IIa, and type IIx fibers in the costal diaphragm (P < 0.05). Whole body heat stress attenuated this effect. In contrast, heat stress did not protect against MV-induced diaphragm contractile dysfunction. The mechanisms responsible for this heat stress-induced protection remain unclear but may be linked to increased expression of HSP72 in the diaphragm. Copyright © 2014 the American Physiological Society.

Understanding Epileptiform After-Discharges as Rhythmic Oscillatory Transients.

PubMed

Baier, Gerold; Taylor, Peter N; Wang, Yujiang

2017-01-01

Electro-cortical activity in patients with epilepsy may show abnormal rhythmic transients in response to stimulation. Even when using the same stimulation parameters in the same patient, wide variability in the duration of transient response has been reported. These transients have long been considered important for the mapping of the excitability levels in the epileptic brain but their dynamic mechanism is still not well understood. To investigate the occurrence of abnormal transients dynamically, we use a thalamo-cortical neural population model of epileptic spike-wave activity and study the interaction between slow and fast subsystems. In a reduced version of the thalamo-cortical model, slow wave oscillations arise from a fold of cycles (FoC) bifurcation. This marks the onset of a region of bistability between a high amplitude oscillatory rhythm and the background state. In vicinity of the bistability in parameter space, the model has excitable dynamics, showing prolonged rhythmic transients in response to suprathreshold pulse stimulation. We analyse the state space geometry of the bistable and excitable states, and find that the rhythmic transient arises when the impending FoC bifurcation deforms the state space and creates an area of locally reduced attraction to the fixed point. This area essentially allows trajectories to dwell there before escaping to the stable steady state, thus creating rhythmic transients. In the full thalamo-cortical model, we find a similar FoC bifurcation structure. Based on the analysis, we propose an explanation of why stimulation induced epileptiform activity may vary between trials, and predict how the variability could be related to ongoing oscillatory background activity. We compare our dynamic mechanism with other mechanisms (such as a slow parameter change) to generate excitable transients, and we discuss the proposed excitability mechanism in the context of stimulation responses in the epileptic cortex.

Home tracheotomy mechanical ventilation in patients with amyotrophic lateral sclerosis: causes, complications and 1-year survival.

PubMed

Sancho, Jesús; Servera, Emilio; Díaz, José Luis; Bañuls, Pilar; Marín, Julio

2011-11-01

Home tracheotomy mechanical ventilation (HTMV) can prolong survival in patients with amyotrophic lateral sclerosis (ALS) when non-invasive ventilation (NIV) fails, but knowledge about HTMV is scarce. The aim of this study was to determine the causes of tracheotomy and the main issues of 1-year HTMV in a cohort of patients with ALS. A prospective study of all patients needing HTMV was performed in a referral respiratory care unit (RCU) from April 2001 to January 2010. Patients' informed decisions about HTMV were fully respected. Caregivers were trained and could telephone the RCU. Hospital staff made home visits. All patients (n=116) agreed to participate and a tracheotomy was needed for 76, mainly due to bulbar dysfunction. Of the 38 who had a tracheotomy, in 21 it was performed in an acute setting and in 17 as a non-emergency procedure. In 19 patients the tracheotomy was related to the inadequacy of mechanically assisted coughing (MAC) to maintain normal oxygen saturation. During HTMV, 19 patients required hospitalisation, 12 with respiratory problems. The 1-year survival rate was 78.9%, with a mean survival of 10.39 months (95% CI 9.36 to 11.43). Sudden death was the main cause of death (n=9) and only one patient died from respiratory causes. No predictive factors for survival were found. Besides NIV inadequacy, the ineffectiveness of mechanically assisted coughing appears to be a relevant cause of tracheotomy for patients with ALS with severe bulbar dysfunction. Patients choosing HTMV provided by a referral RCU could have a good 1-year survival rate, respiratory problems being the main cause of hospitalisation but not of death.

Transient rolling friction model for discrete element simulations of sphere assemblies

NASA Astrophysics Data System (ADS)

Kuhn, Matthew R.

2014-03-01

The rolling resistance between a pair of contacting particles can be modeled with two mechanisms. The first mechanism, already widely addressed in the DEM literature, involves a contact moment between the particles. The second mechanism involves a reduction of the tangential contact force, but without a contact moment. This type of rotational resistance, termed creep-friction, is the subject of the paper. Within the creep-friction literature, the term “creep” does not mean a viscous mechanism, but rather connotes a slight slip that accompanies rolling. Two extremes of particle motions bound the range of creep-friction behaviors: a pure tangential translation is modeled as a Cattaneo-Mindlin interaction, whereas prolonged steady-state rolling corresponds to the traditional wheel-rail problem described by Carter, Poritsky, and others. DEM simulations, however, are dominated by the transient creep-friction rolling conditions that lie between these two extremes. A simplified model is proposed for the three-dimensional transient creep-friction rolling of two spheres. The model is an extension of the work of Dahlberg and Alfredsson, who studied the two-dimensional interactions of disks. The proposed model is applied to two different systems: a pair of spheres and a large dense assembly of spheres. Although creep-friction can reduce the tangential contact force that would otherwise be predicted with Cattaneo-Mindlin theory, a significant force reduction occurs only when the rate of rolling is much greater than the rate of translational sliding and only after a sustained period of rolling. When applied to the deviatoric loading of an assembly of spheres, the proposed creep-friction model has minimal effect on macroscopic strength or stiffness. At the micro-scale of individual contacts, creep-friction does have a modest influence on the incremental contact behavior, although the aggregate effect on the assembly's behavior is minimal.

Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias.

PubMed

Lu, H R; Hortigon-Vinagre, M P; Zamora, V; Kopljar, I; De Bondt, A; Gallacher, D J; Smith, G

2017-09-01

Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (T rise ) of the optical action potential duration (oAPD). Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with I Ca -antagonists, I Kr -activator or ATP-sensitive K + channel (K ATP )-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase. Copyright © 2017 Elsevier Inc. All rights reserved.

PTEN Loss Does Not Predict for Response to RAD001 (Everolimus) in a Glioblastoma Orthotopic Xenograft Test Panel

PubMed Central

Yang, Lin; Clarke, Michelle J.; Carlson, Brett L.; Mladek, Ann C.; Schroeder, Mark A.; Decker, Paul; Wu, Wenting; Kitange, Gaspar J.; Grogan, Patrick T.; Goble, Jennie M.; Uhm, Joon; Galanis, Evanthia; Giannini, Caterina; Lane, Heidi A.; James, C. David; Sarkaria, Jann N.

2014-01-01

Purpose Hyperactivation of the phosphatidylinositol 3-kinase/Akt signaling through disruption of PTEN function is common in glioblastoma multiforme, and these genetic changes are predicted to enhance sensitivity to mammalian target of rapamycin (mTOR) inhibitors such as RAD001 (everolimus). Experimental Design To test whether PTEN loss could be used as a predictive marker for mTOR inhibitor sensitivity, the response of 17 serially transplantable glioblastoma multiforme xenografts was evaluated in an orthotopic therapy evaluation model. Of these 17 xenograft lines, 7 have either genomic deletion or mutation of PTEN. Results Consistent with activation of Akt signaling, there was a good correlation between loss of PTEN function and elevated levels of Akt phosphorylation. However, of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival). Relative to placebo, 5 days of RAD001 treatment was associated with a marked 66% reduction in the MIB1 proliferation index in the sensitive GBM10 line (deleted PTEN) compared with a 25% and 7% reduction in MIB1 labeling index in the insensitive GBM14 (mutant PTEN) and GBM15 (wild-type PTEN) lines, respectively. Consistent with a cytostatic antitumor effect, bioluminescent imaging of luciferase-transduced intracranial GBM10 xenografts showed slowed tumor growth without significant tumor regression during RAD001 therapy. Conclusion These data suggest that loss of PTEN function is insufficient to adequately predict responsiveness to mTOR inhibitors in glioblastoma multiforme. PMID:18559622

Failure to Rescue Rates After Coronary Artery Bypass Grafting: An Analysis From The Society of Thoracic Surgeons Adult Cardiac Surgery Database.

PubMed

Edwards, Fred H; Ferraris, Victor A; Kurlansky, Paul A; Lobdell, Kevin W; He, Xia; O'Brien, Sean M; Furnary, Anthony P; Rankin, J Scott; Vassileva, Christina M; Fazzalari, Frank L; Magee, Mitchell J; Badhwar, Vinay; Xian, Ying; Jacobs, Jeffrey P; Wyler von Ballmoos, Moritz C; Shahian, David M

2016-08-01

Failure to rescue (FTR) is increasingly recognized as an important quality indicator in surgery. The Society of Thoracic Surgeons National Database was used to develop FTR metrics and a predictive FTR model for coronary artery bypass grafting (CABG). The study included 604,154 patients undergoing isolated CABG at 1,105 centers from January 2010 to January 2014. FTR was defined as death after four complications: stroke, renal failure, reoperation, and prolonged ventilation. FTR was determined for each complication and a composite of the four complications. A statistical model to predict FTR was developed. FTR rates were 22.3% for renal failure, 16.4% for stroke, 12.4% for reoperation, 12.1% for prolonged ventilation, and 10.5% for the composite. Mortality increased with multiple complications and with specific combinations of complications. The multivariate risk model for prediction of FTR demonstrated a C index of 0.792 and was well calibrated, with a 1.0% average difference between observed/expected (O/E) FTR rates. With centers grouped into mortality terciles, complication rates increased modestly (11.4% to 15.7%), but FTR rates more than doubled (6.8% to 13.9%) from the lowest to highest terciles. Centers in the lowest complication rate tercile had an FTR O/E of 1.14, whereas centers in the highest complication rate tercile had an FTR O/E of 0.91. CABG mortality rates vary directly with FTR, but complication rates have little relation to death. FTR rates derived from The Society of Thoracic Surgeons data can serve as national benchmarks. Predicted FTR rates may facilitate patient counseling, and FTR O/E ratios have promise as valuable quality metrics. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

An idealised study for the long term evolution of crescentic bars

NASA Astrophysics Data System (ADS)

Chen, W. L.; Dodd, N.; Tiessen, M. C. H.; Calvete, D.

2018-01-01

An idealised study that identifies the mechanisms in the long term evolution of crescentic bar systems in nature is presented. Growth to finite amplitude (i.e., equilibration, sometimes referred to as saturation) and higher harmonic interaction are hypothesised to be the leading nonlinear effects in long-term evolution of these systems. These nonlinear effects are added to a linear stability model and used to predict crescentic bar development along a beach in Duck, North Carolina (USA) over a 2-month period. The equilibration prolongs the development of bed patterns, thus allowing the long term evolution. Higher harmonic interaction enables the amplitude to be transferred from longer to shorter lengthscales, which leads to the dominance of shorter lengthscales in latter post-storm stages, as observed at Duck. The comparison with observations indicates the importance of higher harmonic interaction in the development of nearshore crescentic bar systems in nature. Additionally, it is concluded that these nonlinear effects should be included in models simulating the development of different bed patterns, and that this points a way forward for long-term morphodynamical modelling in general.

Adult cyclical vomiting syndrome: a disorder of allostatic regulation?

PubMed

Levinthal, D J; Bielefeldt, K

2014-08-01

Cyclic vomiting syndrome (CVS) is an idiopathic illness characterized by stereotypic and sudden-onset episodes of intense retching and repetitive vomiting that are often accompanied by severe abdominal pain. Many associated factors that predict CVS attacks, such as prolonged periods of fasting, sleep deprivation, physical and emotional stress, or acute anxiety, implicate sympathetic nervous system activation as a mechanism that may contribute to CVS pathogenesis. Furthermore, adult patients with CVS tend to have a history of early adverse life events, mood disorders, chronic stress, and drug abuse-all associations that may potentiate sympathetic neural activity. In this review, we set forth a conceptual model in which CVS is viewed as a brain disorder involving maladaptive plasticity within central neural circuits important for allostatic regulation of the sympathetic nervous system. This model not only can account for the varied clinical observations that are linked with CVS, but also has implications for potential therapeutic interventions. Thus, it is likely that cognitive behavioral therapy, stress management ("mind-body") interventions, regular exercise, improved sleep, and avoidance of cannabis and opiate use could have positive influences on the clinical course for patients with CVS.

Gene Expression Dynamics Accompanying the Sponge Thermal Stress Response.

PubMed

Guzman, Christine; Conaco, Cecilia

2016-01-01

Marine sponges are important members of coral reef ecosystems. Thus, their responses to changes in ocean chemistry and environmental conditions, particularly to higher seawater temperatures, will have potential impacts on the future of these reefs. To better understand the sponge thermal stress response, we investigated gene expression dynamics in the shallow water sponge, Haliclona tubifera (order Haplosclerida, class Demospongiae), subjected to elevated temperature. Using high-throughput transcriptome sequencing, we show that these conditions result in the activation of various processes that interact to maintain cellular homeostasis. Short-term thermal stress resulted in the induction of heat shock proteins, antioxidants, and genes involved in signal transduction and innate immunity pathways. Prolonged exposure to thermal stress affected the expression of genes involved in cellular damage repair, apoptosis, signaling and transcription. Interestingly, exposure to sublethal temperatures may improve the ability of the sponge to mitigate cellular damage under more extreme stress conditions. These insights into the potential mechanisms of adaptation and resilience of sponges contribute to a better understanding of sponge conservation status and the prediction of ecosystem trajectories under future climate conditions.

Metagenomic Insights into Evolution of a Heavy Metal-Contaminated Groundwater Microbial Community

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

Hemme, Christopher L.; Deng, Ye; Gentry, Terry J.

2010-02-15

Understanding adaptation of biological communities to environmental change is a central issue in ecology and evolution. Metagenomic analysis of a stressed groundwater microbial community reveals that prolonged exposure to high concentrations of heavy metals, nitric acid and organic solvents (~;;50 years) have resulted in a massive decrease in species and allelic diversity as well as a significant loss of metabolic diversity. Although the surviving microbial community possesses all metabolic pathways necessary for survival and growth in such an extreme environment, its structure is very simple, primarily composed of clonal denitrifying ?- and ?-proteobacterial populations. The resulting community is over-abundant inmore » key genes conferring resistance to specific stresses including nitrate, heavy metals and acetone. Evolutionary analysis indicates that lateral gene transfer could be a key mechanism in rapidly responding and adapting to environmental contamination. The results presented in this study have important implications in understanding, assessing and predicting the impacts of human-induced activities on microbial communities ranging from human health to agriculture to environmental management, and their responses to environmental changes.« less

The evolution of prestige: freely conferred deference as a mechanism for enhancing the benefits of cultural transmission.

PubMed

Henrich, J; Gil-White, F J.

2001-05-01

This paper advances an "information goods" theory that explains prestige processes as an emergent product of psychological adaptations that evolved to improve the quality of information acquired via cultural transmission. Natural selection favored social learners who could evaluate potential models and copy the most successful among them. In order to improve the fidelity and comprehensiveness of such ranked-biased copying, social learners further evolved dispositions to sycophantically ingratiate themselves with their chosen models, so as to gain close proximity to, and prolonged interaction with, these models. Once common, these dispositions created, at the group level, distributions of deference that new entrants may adaptively exploit to decide who to begin copying. This generated a preference for models who seem generally "popular." Building on social exchange theories, we argue that a wider range of phenomena associated with prestige processes can more plausibly be explained by this simple theory than by others, and we test its predictions with data from throughout the social sciences. In addition, we distinguish carefully between dominance (force or force threat) and prestige (freely conferred deference).

Status of Chronic Oxidation Studies of Graphite

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

Contescu, Cristian I.; Mee, Robert W.

Graphite will undergo extremely slow, but continuous oxidation by traces of moisture that will be present, albeit at very low levels, in the helium coolant of HTGR. This chronic oxidation may cause degradation of mechanical strength and thermal properties of graphite components if a porous oxidation layer penetrates deep enough in the bulk of graphite components during the lifetime of the reactor. The current research on graphite chronic oxidation is motivated by the acute need to understand the behavior of each graphite grade during prolonged exposure to high temperature chemical attack by moisture. The goal is to provide the elementsmore » needed to develop predictive models for long-time oxidation behavior of graphite components in the cooling helium of HTGR. The tasks derived from this goal are: (1) Oxidation rate measurements in order to determine and validate a comprehensive kinetic model suitable for prediction of intrinsic oxidation rates as a function of temperature and oxidant gas composition; (2) Characterization of effective diffusivity of water vapor in the graphite pore system in order to account for the in-pore transport of moisture; and (3) Development and validation of a predictive model for the penetration depth of the oxidized layer, in order to assess the risk of oxidation caused damage of particular graphite grades after prolonged exposure to the environment of helium coolant in HTGR. The most important and most time consuming of these tasks is the measurement of oxidation rates in accelerated oxidation tests (but still under kinetic control) and the development of a reliable kinetic model. This report summarizes the status of chronic oxidation studies on graphite, and then focuses on model development activities, progress of kinetic measurements, validation of results, and improvement of the kinetic models. Analysis of current and past results obtained with three grades of showed that the classical Langmuir-Hinshelwood model cannot reproduce all data collected so far. Starting from here we propose a modification of the LH model to include temperature activation of graphite surface as a Boltzmann activation function. The enhanced Boltzmann-Langmuir-Hinshelwood model (BLH) was tested successfully on three grades of graphite. The model is a robust, comprehensive mathematical function that allows better fitting of experimental results spanning a wide range of temperature and partial pressures of water vapor and hydrogen. However, the model did not fit satisfactorily the data extracted from the old report on graphite H-451 oxidation by water.« less

Reach-to-grasp movement as a minimization process.

PubMed

Yang, Fang; Feldman, Anatol G

2010-02-01

It is known that hand transport and grasping are functionally different but spatially coordinated components of reach-to-grasp (RTG) movements. As an extension of this notion, we suggested that body segments involved in RTG movements are controlled as a coherent ensemble by a global minimization process associated with the necessity for the hand to reach the motor goal. Different RTG components emerge following this process without pre-programming. Specifically, the minimization process may result from the tendency of neuromuscular elements to diminish the spatial gap between the actual arm-hand configuration and its virtual (referent) configuration specified by the brain. The referent configuration is specified depending on the object shape, localization, and orientation. Since the minimization process is gradual, it can be interrupted and resumed following mechanical perturbations, at any phase during RTG movements, including hand closure. To test this prediction of the minimization hypothesis, we asked subjects to reach and grasp a cube placed within the reach of the arm. Vision was prevented during movement until the hand returned to its initial position. As predicted, by arresting wrist motion at different points of hand transport in randomly selected trials, it was possible to halt changes in hand aperture at any phase, not only during hand opening but also during hand closure. Aperture changes resumed soon after the wrist was released. Another test of the minimization hypothesis was made in RTG movements to an object placed beyond the reach of the arm. It has previously been shown (Rossi et al. in J Physiol 538:659-671, 2002) that in such movements, the trunk motion begins to contribute to hand transport only after a critical phase when the shifts in the referent arm configuration have finished (at about the time when hand velocity is maximal). The minimization rule suggests that when the virtual contribution of the arm to hand transport is completed, guidance of hand aperture switches from the arm to the trunk control system. As a consequence, hand aperture changes can be halted by trunk arrests but only if they are prolonged beyond a critical phase. As predicted, hand transport and hand aperture in RTG movements beyond the reach of the arm were halted by trunk arrests only if they were prolonged beyond the time of peak hand velocity. Hand motion and aperture changes resumed only when the trunk was released. While supporting the minimization hypothesis, our findings imply that not only spatial but also temporal characteristics of each component, including the shortest, hand closure component of RTG movements, are controlled in a flexible, task-specific way.

Involuntary Subordination and Its Relation to Personality, Mood, and Submissive Behavior

ERIC Educational Resources Information Center

Sturman, Edward D.

2011-01-01

According to social rank theory, involuntary subordination may be adaptive in species that compete for resources as a mechanism to switch off fighting behaviors when loss is imminent (thus saving an organism from injury). In humans, major depression is thought to occur when involuntary subordination becomes prolonged. The present study sought to…

Inactivation of Escherichia coli on blueberries using cold plasma with chemical augmentation inside a partial vacuum

USDA-ARS?s Scientific Manuscript database

Justification: The mechanism by which cold plasma inactivates pathogens is through the production of free reactive chemical species. Unfortunately, the most reactive chemical species have the shortest half-life. In a vacuum their half-life is believed to be prolonged. Additionally, these reactive sp...

Sepsis and Inflammatory Response Mechanisms: An Activity Stress Model in Humans

DTIC Science & Technology

2001-01-31

anaerobic threshold yielded the reactions most typical of trauma. However, no mode of laboratory exercise induced a sustained and prolonged inflammatory...mobilization ....................................................................................... 9 8. Anaerobic threshold as a marker of the critical...after epmnephriei injection. Lymphocyte retention by lymph nodes, however, may contribute to post-injection lymphopenia. 8. Anaerobic Threshold as a

Teacher Burnout: Is It Real? Can We Prevent It?

ERIC Educational Resources Information Center

Terry, Paul M.

Excessive, prolonged stress can alter the body's normal physiologic function. If adequate coping mechanisms are not instituted, this extreme state can lead to burnout. Burnout can be experienced with physical, intellectual, social, psycho-emotional, and spiritual adaptations. It has been estimated that up to 40 percent of U.S. teachers will not be…

Emotional and Physiological Responses of Fluent Listeners while Watching the Speech of Adults Who Stutter

ERIC Educational Resources Information Center

Guntupalli, Vijaya K.; Everhart, D. Erik; Kalinowski, Joseph; Nanjundeswaran, Chayadevie; Saltuklaroglu, Tim

2007-01-01

Background: People who stutter produce speech that is characterized by intermittent, involuntary part-word repetitions and prolongations. In addition to these signature acoustic manifestations, those who stutter often display repetitive and fixated behaviours outside the speech producing mechanism (e.g. in the head, arm, fingers, nares, etc.).…

[State of neuro-humoral regulation in workers with intensive psychologic strain].

PubMed

Khaĭbullina, A Z

2005-01-01

Acitvities of internal affairs officers are associated with law machinery and power establishment and therefore carry prolonged psychoemotional strain. Necessity of higher occupational ability and reliability of internal affairs officers in significant functional strain determines importance and expedience of studying responses, adaptational mechanisms and their break in these individuals.

The Association Between Nutritional Adequacy and Long-Term Outcomes in Critically Ill Patients Requiring Prolonged Mechanical Ventilation: A Multicenter Cohort Study.

PubMed

Wei, Xuejiao; Day, Andrew G; Ouellette-Kuntz, Hélène; Heyland, Daren K

2015-08-01

To examine the association between short-term nutritional adequacy received while in the ICU and long-term outcomes including 6-month survival and health-related quality of life in critically ill patients requiring prolonged mechanical ventilation. Retrospective analysis of data prospectively collected in the context of a multicenter randomized controlled trial. An international sample of ICUs. Adult patients who were mechanically ventilated for more than 8 days in the ICU. None. Nutritional adequacy was obtained from the average proportion of prescribed calories received over the amount prescribed during the first 8 days. Survival status and health-related quality of life as assessed using the Short-Form 36 v2 were obtained at 3- and 6 months post ICU admission. Of the 1,223 patients enrolled in the randomized controlled trial, 475 met the inclusion criteria for this study. At 6-month follow-up, 302 of the 475 patients (64%) were alive. Survival time in those who received low nutritional adequacy was significantly shorter than those who received high nutritional adequacy while adjusting for important covariates (adjusted hazard ratio, 1.7; 95% CI, 1.1-2.6). At 3-month follow-up, a 25% increase in nutritional adequacy was associated with improvements in Physical Functioning and Role Physical of 7.3 (p = 0.02) and 8.3 (p = 0.004) points, respectively. At 6-month follow-up, adjusted increases in Physical Functioning and Role Physical scores for every 25% increase in nutrition adequacy became smaller and were no longer statistically significant (adjusted estimate for Physical Functioning = 4.2, p = 0.14; for Role Physical = 3.2, p = 0.25). Greater amounts of nutritional intake received during the first week in the ICU were associated with longer survival time and faster physical recovery to 3 months but not 6 months post ICU discharge in critically ill patients requiring prolonged mechanical ventilation. Current recommendations to underfeed critically ill patients may cause harm in some long-stay patients.

Delayed and Temporally Imprecise Neurotransmission in Reorganizing Cortical Microcircuits

PubMed Central

Barnes, Samuel J.; Cheetham, Claire E.; Liu, Yan; Bennett, Sophie H.; Albieri, Giorgia; Jorstad, Anne A.; Knott, Graham W.

2015-01-01

Synaptic neurotransmission is modified at cortical connections throughout life. Varying the amplitude of the postsynaptic response is one mechanism that generates flexible signaling in neural circuits. The timing of the synaptic response may also play a role. Here, we investigated whether weakening and loss of an entire connection between excitatory cortical neurons was foreshadowed in the timing of the postsynaptic response. We made electrophysiological recordings in rat primary somatosensory cortex that was undergoing experience-dependent loss of complete local excitatory connections. The synaptic latency of pyramid–pyramid connections, which typically comprise multiple synapses, was longer and more variable. Connection strength and latency were not correlated. Instead, prolonged latency was more closely related to progression of connection loss. The action potential waveform and axonal conduction velocity were unaffected, suggesting that the altered timing of neurotransmission was attributable to a synaptic mechanism. Modeling studies indicated that increasing the latency and jitter at a subset of synapses reduced the number of action potentials fired by a postsynaptic neuron. We propose that prolonged synaptic latency and diminished temporal precision of neurotransmission are hallmarks of impending loss of a cortical connection. PMID:26085628

Intracellular recordings from isolated rabbit retinal Müller (glial) cells.

PubMed

Reichenbach, A; Eberhardt, W

1986-09-01

Müller (glial) cells were isolated from rabbit retinae by papaine and mechanical dissociation. The cells were fixed on a gelatine-covered glass slide by means of concanavalin A, and the slide was mounted in a perfusion chamber under a light microscope with modified optics. Besides the recording microelectrode, two other micropipettes could be adjusted with their tips near the cell. These micropipettes were used for application of test solutions into the environment of the cells. On application of high K+ solutions, the cell depolarized strongly but during prolonged application there was a marked repolarization. After the end of high K+ application the cells showed a hyperpolarization which was enhanced in both amplitude and duration with prolongation of the K+ exposure. Both repolarization and afterhyperpolarization disappeared under ouabain. Ouabain application itself caused a small reversible depolarization. Na+ free solution caused hyperpolarization. The results suggest the existence of an active membrane pump mechanism in our cells. This pump seems to be electrogenic under our experimental conditions and seems to be activated even in the absence of sodium. The cell membrane is demonstrated to contain a significant Na+ conductance.

Surface reaction mechanisms during ozone and oxygen plasma assisted atomic layer deposition of aluminum oxide.

PubMed

Rai, Vikrant R; Vandalon, Vincent; Agarwal, Sumit

2010-09-07

We have elucidated the reaction mechanism and the role of the reactive intermediates in the atomic layer deposition (ALD) of aluminum oxide from trimethyl aluminum in conjunction with O(3) and an O(2) plasma. In situ attenuated total reflection Fourier transform infrared spectroscopy data show that both -OH groups and carbonates are formed on the surface during the oxidation cycle. These carbonates, once formed on the surface, are stable to prolonged O(3) exposure in the same cycle. However, in the case of plasma-assisted ALD, the carbonates decompose upon prolonged O(2) plasma exposure via a series reaction kinetics of the type, A (CH(3)) --> B (carbonates) --> C (Al(2)O(3)). The ratio of -OH groups to carbonates on the surface strongly depends on the oxidizing agent, and also the duration of the oxidation cycle in plasma-assisted ALD. However, in both O(3) and O(2) plasma cycles, carbonates are a small fraction of the total number of reactive sites compared to the hydroxyl groups.

Priapism - etiology, pathophysiology and management.

PubMed

Van der Horst, C; Stuebinger, Henrik; Seif, Christoph; Melchior, Diethild; Martínez-Portillo, F J; Juenemann, K P

2003-01-01

The understanding of erectile physiology has improved the prompt diagnosis and treatment of priapism. Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation and failure to subside despite orgasm. Numerous etiologies of this condition are considered. Among others a disturbed detumescence mechanism, which may due to excess release of contractile neurotransmitters, obstruction of draining venules, malfunction of the intrinsic detumescence mechanism or prolonged relaxation of intracavernosal smooth muscle are postulated. Treatment of priapism varies from a conservative medical to a drastic surgical approach. Two main types of priapism; veno-occlusive low flow (ischemic) and arterial high flow (non-ischemic), must be distinguished to choose the correct treatment option for each type. Patient history, physical examination, penile hemodynamics and corporeal metabolic blood quality provides distinction between a static or dynamic pathology. Priapism can be treated effectively with intracavernous vasoconstrictive agents or surgical shunting. Alternative options, such as intracavernous injection of methylene blue (MB) or selective penile arterial embolization (SPEA), for the management of high and low flow priapism are described and a survey on current treatment modalities is given.

Prolonged Particulate Hexavalent Chromium Exposure Suppresses Homologous Recombination Repair in Human Lung Cells.

PubMed

Browning, Cynthia L; Qin, Qin; Kelly, Deborah F; Prakash, Rohit; Vanoli, Fabio; Jasin, Maria; Wise, John Pierce

2016-09-01

Genomic instability is one of the primary models of carcinogenesis and a feature of almost all cancers. Homologous recombination (HR) repair protects against genomic instability by maintaining high genomic fidelity during the repair of DNA double strand breaks. The defining step of HR repair is the formation of the Rad51 nucleofilament, which facilitates the search for a homologous sequence and invasion of the template DNA strand. Particulate hexavalent chromium (Cr(VI)), a human lung carcinogen, induces DNA double strand breaks and chromosome instability. Since the loss of HR repair increases Cr(VI)-induced chromosome instability, we investigated the effect of extended Cr(VI) exposure on HR repair. We show acute (24 h) Cr(VI) exposure induces a normal HR repair response. In contrast, prolonged (120 h) exposure to particulate Cr(VI) inhibited HR repair and Rad51 nucleofilament formation. Prolonged Cr(VI) exposure had a profound effect on Rad51, evidenced by reduced protein levels and Rad51 mislocalization to the cytoplasm. The response of proteins involved in Rad51 nuclear import and nucleofilament formation displayed varying responses to prolonged Cr(VI) exposure. BRCA2 formed nuclear foci after prolonged Cr(VI) exposure, while Rad51C foci formation was suppressed. These results suggest that particulate Cr(VI), a major chemical carcinogen, inhibits HR repair by targeting Rad51, causing DNA double strand breaks to be repaired by a low fidelity, Rad51-independent repair pathway. These results further enhance our understanding of the underlying mechanism of Cr(VI)-induced chromosome instability and thus, carcinogenesis. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Antibiotic Therapy for Very Low Birth Weigh Newborns in NICU

PubMed Central

Afjeh, Seyyed-Abolfazl; Sabzehei, Mohammad-Kazem; Fahimzad, Seyyed-Ali-Reza; Shiva, Farideh; Shamshiri, Ahmad-Reza; Esmaili, Fatemeh

2016-01-01

Background Prolonged empiric antibiotics therapy in neonates results in several adverse consequences including widespread antibiotic resistance, late onset sepsis (LOS), necrotizing enterocolitis (NEC), prolonged hospital course (HC) and increase in mortality rates. Objectives To assess the risk factors and the outcome of prolonged empiric antibiotic therapy in very low birth weight (VLBW) newborns. Materials and Methods Prospective study in VLBW neonates admitted to NICU and survived > 2 W, from July 2011 - June 2012. All relevant perinatal and postnatal data including duration of antibiotics therapy (Group I < 2W vs Group II > 2W) and outcome up to the time of discharge or death were documented and compared. Results Out of 145 newborns included in the study, 62 were in group I, and 83 in Group II. Average duration of antibiotic therapy was 14 days (range 3 - 62 days); duration in Group I and Group II was 10 ± 2.3 vs 25.5 ± 10.5 days. Hospital stay was 22.3 ± 11.5 vs 44.3 ± 14.7 days, respectively. Multiple regression analysis revealed following risk factors as significant for prolonged empiric antibiotic therapy: VLBW especially < 1000 g, (P < 0.001), maternal Illness (P = 0.003), chorioamnionitis (P = 0.048), multiple pregnancy (P = 0.03), non-invasive ventilation (P < 0.001) and mechanical ventilation (P < 0.001). Seventy (48.3%) infants developed LOS; 5 with NEC > stage II, 12 (8.3%) newborns died. Infant mortality alone and with LOS/NEC was higher in group II as compared to group I (P < 0.002 and < 0.001 respectively). Conclusions Prolonged empiric antibiotic therapy caused increasing rates of LOS, NEC, HC and infant mortality. PMID:27307961

Intravenous dexamethasone and perineural dexamethasone similarly prolong the duration of analgesia after supraclavicular brachial plexus block: a randomized, triple-arm, double-blind, placebo-controlled trial.

PubMed

Abdallah, Faraj W; Johnson, James; Chan, Vincent; Murgatroyd, Harry; Ghafari, Mohammad; Ami, Noam; Jin, Rongyu; Brull, Richard

2015-01-01

Perineural dexamethasone prolongs the duration of single-injection peripheral nerve block when added to the local anesthetic solution. Postulated systemic mechanisms of action along with theoretical safety concerns have prompted the investigation of intravenous dexamethasone as an alternative, with decidedly mixed results. We aimed to confirm that addition of intravenous dexamethasone will prolong the duration of analgesia after single-injection supraclavicular block compared with conventional long-acting local anesthetic alone or in combination with perineural dexamethasone for ambulatory upper extremity surgery. Seventy-five patients were randomized to receive supraclavicular block using 30-mL bupivacaine 0.5% alone (Control), with concomitant intravenous dexamethasone 8 mg (DexIV), or with perineural dexamethasone 8 mg (DexP). Duration of analgesia was designated as the primary outcome. To test our hypothesis, the superiority of DexIV was first compared with Control and then with DexP. Motor block duration, pain scores, opioid consumption, opioid-related side effects, patient satisfaction, and block-related complications were also analyzed. Twenty-five patients per group were analyzed. The duration of analgesia (mean [95% confidence interval]) was prolonged in the DexIV group(25 hours [17.6–32.4]) compared with Control (13.2 hours [11.5–15.0]; P < 0.001) but similar to the DexP group (25 hours[19.5–30.5]; P = 1). [corrected] Both DexIV and DexP had reduced pain scores, reduced postoperative opioid consumption, and improved satisfaction compared with Control. In a single-injection supraclavicular block with long-acting local anesthetic, the effectiveness of intravenous dexamethasone in prolonging the duration of analgesia seems similar to perineural dexamethasone.

Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival

PubMed Central

Fujitsuka, N; Asakawa, A; Uezono, Y; Minami, K; Yamaguchi, T; Niijima, A; Yada, T; Maejima, Y; Sedbazar, U; Sakai, T; Hattori, T; Kase, Y; Inui, A

2011-01-01

Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia. PMID:22832525

Partial Support Ventilation and Mitochondrial-Targeted Antioxidants Protect against Ventilator-Induced Decreases in Diaphragm Muscle Protein Synthesis.

PubMed

Hudson, Matthew B; Smuder, Ashley J; Nelson, W Bradley; Wiggs, Michael P; Shimkus, Kevin L; Fluckey, James D; Szeto, Hazel H; Powers, Scott K

2015-01-01

Mechanical ventilation (MV) is a life-saving intervention in patients in respiratory failure. Unfortunately, prolonged MV results in the rapid development of diaphragm atrophy and weakness. MV-induced diaphragmatic weakness is significant because inspiratory muscle dysfunction is a risk factor for problematic weaning from MV. Therefore, developing a clinical intervention to prevent MV-induced diaphragm atrophy is important. In this regard, MV-induced diaphragmatic atrophy occurs due to both increased proteolysis and decreased protein synthesis. While efforts to impede MV-induced increased proteolysis in the diaphragm are well-documented, only one study has investigated methods of preserving diaphragmatic protein synthesis during prolonged MV. Therefore, we evaluated the efficacy of two therapeutic interventions that, conceptually, have the potential to sustain protein synthesis in the rat diaphragm during prolonged MV. Specifically, these experiments were designed to: 1) determine if partial-support MV will protect against the decrease in diaphragmatic protein synthesis that occurs during prolonged full-support MV; and 2) establish if treatment with a mitochondrial-targeted antioxidant will maintain diaphragm protein synthesis during full-support MV. Compared to spontaneously breathing animals, full support MV resulted in a significant decline in diaphragmatic protein synthesis during 12 hours of MV. In contrast, diaphragm protein synthesis rates were maintained during partial support MV at levels comparable to spontaneous breathing animals. Further, treatment of animals with a mitochondrial-targeted antioxidant prevented oxidative stress during full support MV and maintained diaphragm protein synthesis at the level of spontaneous breathing animals. We conclude that treatment with mitochondrial-targeted antioxidants or the use of partial-support MV are potential strategies to preserve diaphragm protein synthesis during prolonged MV.

Cardiovascular and Postural Control Interactions during Hypergravity: Effects on Cerebral Autoregulation in Males and Females

NASA Astrophysics Data System (ADS)

Goswami, Nandu; Blaber, Andrew; Bareille, Marie-Pierre; Beck, Arnaud; Avan, Paul; Bruner, Michelle; Hinghofer-Szalkay, Helmut

2012-07-01

Orthostatic intolerance remains a problem upon return to Earth from the microgravity environment of spaceflight. A variety of conditions including hypovolemia, cerebral vasoconstriction, cerebral or peripheral vascular disease, or cardiac arrhythmias may result in syncope if the person remains upright. Current research indicates that there is a greater dependence on visual and somatosensory information at the beginning of space flight with a decreased otolith gain during prolonged space flight (Herault et al., 2002). The goal of the research is to further our understanding of the fundamental adaptive homeostatic mechanisms involved in gravity related changes in cardiovascular and postural function. Cardiovascular, cerebrovascular, and postural sensory motor control systems in male and female participants before, during, and after exposure to graded levels of hyper-G were investigated. Hypotheses: 1) Activation of skeletal muscle pump will be directly related to the degree of orthostatic stress. 2) Simultaneous measurement of heart rate, blood pressure and postural sway will predict cardio-postural stability. Blood pressure and heart rate (means and variability), postural sway, center of pressure (COP), baroreflex function, calf blood flow, middle cerebral artery blood flow, non-invasive intracranial pressure measurements, and two-breath CO2 were measured. Results from the study will be used to provide an integrated insight into mechanisms of cardio-postural control and cerebral autoregulation, which are important aspects of human health in flights to Moon, Mars and distant planets.

Suboxic conditions at the Permian-Triassic boundary in the NE Panthalassic Ocean suggest a different extinction mechanism compared to Paleotethys anoxia

NASA Astrophysics Data System (ADS)

Foriel, J.; Shen, Y.; Algeo, T. J.; Henderson, C. M.; Ward, P. D.

2008-12-01

The Permian-Triassic boundary marks the most important mass extinction event recorded in Earth history. Based on numerous studies of Permian-Triassic sites, most of them located around the Paleotethys, an anoxic event has been assumed to be the most likely killing mechanism. Here we present a high-resolution study of a Permian-Triassic section on the north- eastern shore of the Panthalassic Ocean. The Opal Creek shale section in SW Alberta was sampled over 40 m with a 50 cm resolution and at a 10 cm-scale around the extinction event; paleontological and geochemical data were collected. The extinction event is correlated by conodont biostratigraphy and a ~5‰ carbon isotope negative trend. The onset of suboxic/euxinic conditions is suggested by trace elements (V, Mo, U) and organic carbon data and a negative trend of non-acid volatile sulfur isotope data to a minimum of -31.2‰ just above the extinction horizon. However, this episode appears to be very short-lived as all geochemical tracers return to background values over a ~50 cm interval. Our results from the Opal Creek section seem to argue against the model of a prolonged euxinic ocean as seen in Paleotethys sections. Such discrepancy may be explained by contrasting geography and climate. The semi-closed, equatorial Paleotethys would have been much more prone to reaching euxinic conditions because of high continental nutrient delivery. On the open shore of the Panthalassic global ocean, with a much lower terrigenous input, lower temperatures and hence presumably lower bioproductivity, sustaining euxinia would have been difficult. In spite of the lack of evidence for strong prolonged anoxia, extinction does occur at Opal Creek, albeit at a lesser scale than in the Paleotethys, which may imply a different mechanism for the prolonged delay in biotic recovery.

Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction.

PubMed

Troupes, Constantine D; Wallner, Markus; Borghetti, Giulia; Zhang, Chen; Mohsin, Sadia; von Lewinski, Dirk; Berretta, Remus M; Kubo, Hajime; Chen, Xiongwen; Soboloff, Jonathan; Houser, Steven

2017-07-07

Pathological increases in cardiac afterload result in myocyte hypertrophy with changes in myocyte electrical and mechanical phenotype. Remodeling of contractile and signaling Ca 2+ occurs in pathological hypertrophy and is central to myocyte remodeling. STIM1 (stromal interaction molecule 1) regulates Ca 2+ signaling in many cell types by sensing low endoplasmic reticular Ca 2+ levels and then coupling to plasma membrane Orai channels to induce a Ca 2+ influx pathway. Previous reports suggest that STIM1 may play a role in cardiac hypertrophy, but its role in electrical and mechanical phenotypic alterations is not well understood. To define the contributions of STIM1-mediated Ca 2+ influx on electrical and mechanical properties of normal and diseased myocytes, and to determine whether Orai channels are obligatory partners for STIM1 in these processes using a clinically relevant large animal model of hypertrophy. Cardiac hypertrophy was induced by slow progressive pressure overload in adult cats. Hypertrophied myocytes had increased STIM1 expression and activity, which correlated with altered Ca 2 + -handling and action potential (AP) prolongation. Exposure of hypertrophied myocytes to the Orai channel blocker BTP2 caused a reduction of AP duration and reduced diastolic Ca 2+ spark rate. BTP2 had no effect on normal myocytes. Forced expression of STIM1 in cultured adult feline ventricular myocytes increased diastolic spark rate and prolonged AP duration. STIM1 expression produced an increase in the amount of Ca 2+ stored within the sarcoplasmic reticulum and activated Ca 2+ /calmodulin-dependent protein kinase II. STIM1 expression also increased spark rates and induced spontaneous APs. STIM1 effects were eliminated by either BTP2 or by coexpression of a dominant negative Orai construct. STIM1 can associate with Orai in cardiac myocytes to produce a Ca 2+ influx pathway that can prolong the AP duration and load the sarcoplasmic reticulum and likely contributes to the altered electromechanical properties of the hypertrophied heart. © 2017 American Heart Association, Inc.

Cardiovascular magnetic resonance assessment of acute cardiovascular effects of voluntary apnoea in elite divers.

PubMed

Eichhorn, L; Doerner, J; Luetkens, J A; Lunkenheimer, J M; Dolscheid-Pommerich, R C; Erdfelder, F; Fimmers, R; Nadal, J; Stoffel-Wagner, B; Schild, H H; Hoeft, A; Zur, B; Naehle, C P

2018-06-18

Prolonged breath holding results in hypoxemia and hypercapnia. Compensatory mechanisms help maintain adequate oxygen supply to hypoxia sensitive organs, but burden the cardiovascular system. The aim was to investigate human compensatory mechanisms and their effects on the cardiovascular system with regard to cardiac function and morphology, blood flow redistribution, serum biomarkers of the adrenergic system and myocardial injury markers following prolonged apnoea. Seventeen elite apnoea divers performed maximal breath-hold during cardiovascular magnetic resonance imaging (CMR). Two breath-hold sessions were performed to assess (1) cardiac function, myocardial tissue properties and (2) blood flow. In between CMR sessions, a head MRI was performed for the assessment of signs of silent brain ischemia. Urine and blood samples were analysed prior to and up to 4 h after the first breath-hold. Mean breath-hold time was 297 ± 52 s. Left ventricular (LV) end-systolic, end-diastolic, and stroke volume increased significantly (p < 0.05). Peripheral oxygen saturation, LV ejection fraction, LV fractional shortening, and heart rate decreased significantly (p < 0.05). Blood distribution was diverted to cerebral regions with no significant changes in the descending aorta. Catecholamine levels, high-sensitivity cardiac troponin, and NT-pro-BNP levels increased significantly, but did not reach pathological levels. Compensatory effects of prolonged apnoea substantially burden the cardiovascular system. CMR tissue characterisation did not reveal acute myocardial injury, indicating that the resulting cardiovascular stress does not exceed compensatory physiological limits in healthy subjects. However, these compensatory mechanisms could overly tax those limits in subjects with pre-existing cardiac disease. For divers interested in competetive apnoea diving, a comprehensive medical exam with a special focus on the cardiovascular system may be warranted. This prospective single-centre study was approved by the institutional ethics committee review board. It was retrospectively registered under ClinicalTrials.gov (Trial registration: NCT02280226 . Registered 29 October 2014).

Akt2 knockout alleviates prolonged caloric restriction-induced change in cardiac contractile function through regulation of autophagy.

PubMed

Zhang, Yingmei; Han, Xuefeng; Hu, Nan; Huff, Anna F; Gao, Feng; Ren, Jun

2014-06-01

Caloric restriction leads to changes in heart geometry and function although the underlying mechanism remains elusive. Autophagy, a conserved pathway for degradation of intracellular proteins and organelles, preserves energy and nutrient in the face of caloric insufficiency. This study was designed to examine the role of Akt2 in prolonged caloric restriction-induced change in cardiac homeostasis and the underlying mechanism(s) involved. Wild-type (WT) and Akt2 knockout mice were calorie restricted (by 40%) for 30weeks. Echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties, autophagy and its regulatory proteins were evaluated. Caloric restriction compromised echocardiographic indices (decreased left ventricular mass, left ventricular diameters and cardiac output), cardiomyocyte contractile and intracellular Ca(2+) properties associated with dampened SERCA2a phosphorylation, upregulated phospholamban and autophagy (Beclin-1, Atg7, LC3BII-to-LC3BI ratio), increased autophagy adaptor protein p62, elevated phosphorylation of AMPK, Akt2 and the Akt downstream signal molecule TSC2, the effects of which with the exception of autophagy protein markers (Beclin-1, Atg7, LC3B) and AMPK were mitigated or significantly alleviated by Akt2 knockout. Lysosomal inhibition using bafilomycin A1 negated Akt2 knockout-induced protective effect on p62. Evaluation of downstream signaling molecules of Akt and AMPK including mTOR and ULK1 revealed that caloric restriction suppressed and promoted phosphorylation of mTOR and ULK1, respectively, without affecting total mTOR and ULK1 expression. Akt2 knockout significantly augmented caloric restriction-induced responses on mTOR and ULK1. Taken together, these data suggest a beneficial role of Akt2 knockout in preservation of cardiac homeostasis against prolonged caloric restriction-induced pathological changes possibly through facilitating autophagy. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy." Copyright © 2013 Elsevier Ltd. All rights reserved.

Intermittent vibration protects aged muscle from mechanical and oxidative damage under prolonged compression.

PubMed

Wong, Sing Wan; Cheung, Brian Chun Ho; Pang, Bruce Tak Keung; Kwong, Ateline; Chung, Anna; Lee, Kenneth Ka Ho; Mak, Arthur Fut Tak

2017-04-11

Deep tissue pressure ulcers, a serious clinical challenge originating in the muscle layer, are hardly detectable at the beginning. The challenge apparently occurs in aged subjects more frequently. As the ulcer propagates to the skin surface, it becomes very difficult to manage and can lead to fatal complications. Preventive measures are thus highly desirable. Although the complex pathological mechanisms have not been fully understood, prolonged and excessive physical challenges and oxidative stress are believed to be involved in the ulcer development. Previous reports have demonstrated that oxidative stress could compromise the mechanical properties of muscle cells, making them easier to be damaged when physical challenges are introduced. In this study, we used senescence accelerated (SAMP8) mice and its control breed (SAMR1) to examine the protective effects of intermittent vibration on aged and control muscle tissues during prolonged epidermal compression under 100mmHg for 6h. Results showed that an application of 35Hz, 0.25g intermittent vibration during compression decreased the compression-induced muscle breakdown in SAMP8 mice, as indicated histologically in terms of number of interstitial nuclei. The fact that no significant difference in muscle damage could be established in the corresponding groups in SAMR1 mice suggests that SAMR1 mice could better accommodate the compression insult than SAMP8 mice. Compression-induced oxidative damage was successfully curbed using intermittent vibration in SAMP8 mice, as indicated by 8-OHdG. A possible explanation is that the anti-oxidative defense could be maintained with intermittent vibration during compression. This was supported by the expression level of PGC-1-alpha, catalase, Gpx-1 and SOD1. Our data suggested intermittent vibration could serve as a preventive measure for deep tissue ulcer, particularly in aged subjects. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice

PubMed Central

Withey, Sarah L.; Hill, Rob; Lyndon, Abigail; Dewey, William L.; Kelly, Eamonn

2017-01-01

Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine. PMID:28130265

The Effect of Optokinetic Stimulation on Perceptual and Postural Symptoms in Visual Vestibular Mismatch Patients

PubMed Central

Van Rompaey, Vincent; Maes, Leen K.; Stins, John F.; Van de Heyning, Paul H.

2016-01-01

Background Vestibular patients occasionally report aggravation or triggering of their symptoms by visual stimuli, which is called visual vestibular mismatch (VVM). These patients therefore experience discomfort, disorientation, dizziness and postural unsteadiness. Objective Firstly, we aimed to get a better insight in the underlying mechanism of VVM by examining perceptual and postural symptoms. Secondly, we wanted to investigate whether roll-motion is a necessary trait to evoke these symptoms or whether a complex but stationary visual pattern equally provokes them. Methods Nine VVM patients and healthy matched control group were examined by exposing both groups to a stationary stimulus as well as an optokinetic stimulus rotating around the naso-occipital axis for a prolonged period of time. Subjective visual vertical (SVV) measurements, posturography and relevant questionnaires were assessed. Results No significant differences between both groups were found for SVV measurements. Patients always swayed more and reported more symptoms than healthy controls. Prolonged exposure to roll-motion caused in patients and controls an increase in postural sway and symptoms. However, only VVM patients reported significantly more symptoms after prolonged exposure to the optokinetic stimulus compared to scores after exposure to a stationary stimulus. Conclusions VVM patients differ from healthy controls in postural and subjective symptoms and motion is a crucial factor in provoking these symptoms. A possible explanation could be a central visual-vestibular integration deficit, which has implications for diagnostics and clinical rehabilitation purposes. Future research should focus on the underlying central mechanism of VVM and the effectiveness of optokinetic stimulation in resolving it. PMID:27128970

Glucose delays the insulin-induced increase in thyroid hormone-mediated signaling in adipose of prolong-fasted elephant seal pups

PubMed Central

Soñanez-Organis, José G.; Viscarra, Jose A.; Jaques, John T.; MacKenzie, Duncan S.; Crocker, Daniel E.; Ortiz, Rudy M.

2016-01-01

Prolonged food deprivation in mammals typically reduces glucose, insulin, and thyroid hormone (TH) concentrations, as well as tissue deiodinase (DI) content and activity, which, collectively, suppress metabolism. However, in elephant seal pups, prolonged fasting does not suppress TH levels; it is associated with upregulation of adipose TH-mediated cellular mechanisms and adipose-specific insulin resistance. The functional relevance of this apparent paradox and the effects of glucose and insulin on TH-mediated signaling in an insulin-resistant tissue are not well defined. To address our hypothesis that insulin increases adipose TH signaling in pups during extended fasting, we assessed the changes in TH-associated genes in response to an insulin infusion in early- and late-fasted pups. In late fasting, insulin increased DI1, DI2, and THrβ-1 mRNA expression by 566%, 44%, and 267% at 60 min postinfusion, respectively, with levels decreasing by 120 min. Additionally, we performed a glucose challenge in late-fasted pups to differentiate between insulin- and glucose-mediated effects on TH signaling. In contrast to the insulin-induced effects, glucose infusion did not increase the expressions of DI1, DI2, and THrβ-1 until 120 min, suggesting that glucose delays the onset of the insulin-induced effects. The data also suggest that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. These responses appear to be unique among mammals and to have evolved in elephant seals to facilitate their adaptation to tolerate an extreme physiological condition. PMID:26739649

Intermittent food restriction initiated late in life prolongs lifespan and retards the onset of age-related markers in the annual fish Nothobranchius guentheri.

PubMed

Wang, Xia; Du, Xiaoyuan; Zhou, Yang; Wang, Su; Su, Feng; Zhang, Shicui

2017-06-01

Two of the most studied and widely accepted conjectures on possible aging mechanisms are the oxidative stress hypothesis and the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway. Intermittent fasting (IF) is known to modulate aging and to prolong lifespan in a variety of organisms, but the mechanisms are still under debate. In this study, we first demonstrated that late-onset two consecutive days a week fasting, a form of IF, termed intermittent food restriction (IFR), exhibited a time-dependent effect, and long-term late-onset IFR extended the mean lifespan and maximum lifespan by approximately 3.5 and 3 weeks, respectively, in the annual fish Nothobranchius guentheri. We also showed that IFR reduced the accumulation of lipofuscin in the gills and the protein oxidation and lipid peroxidation levels in the muscles. Moreover, IFR was able to enhance the activities of antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase in the fish. Finally, IFR was also able to decelerate the decrease of SirT1 and Foxo3A, but accelerate the decrease of IGF-1. Collectively, our findings suggest that late-onset IFR can retard the onset of age-related markers, and prolong the lifespan of the aging fish, via a synergistic action of an anti-oxidant system and the IIS pathway. It also proposes that the combined assessment of anti-oxidant system and IIS pathway will contribute to providing a more comprehensive view of anti-aging process.

Adverse ventricular-ventricular interactions in right ventricular pressure load: Insights from pediatric pulmonary hypertension versus pulmonary stenosis.

PubMed

Driessen, Mieke M P; Hui, Wei; Bijnens, Bart H; Dragulescu, Andreea; Mertens, Luc; Meijboom, Folkert J; Friedberg, Mark K

2016-06-01

Right ventricular (RV) pressure overload has a vastly different clinical course in children with idiopathic pulmonary arterial hypertension (iPAH) than in children with pulmonary stenosis (PS). While RV function is well recognized as a key prognostic factor in iPAH, adverse ventricular-ventricular interactions and LV dysfunction are less well characterized and the pathophysiology is incompletely understood. We compared ventricular-ventricular interactions as hypothesized drivers of biventricular dysfunction in pediatric iPAH versus PS Eighteen iPAH, 16 PS patients and 18 age- and size-matched controls were retrospectively studied. Cardiac cycle events were measured by M-mode and Doppler echocardiography. Measurements were compared between groups using ANOVA with post hoc Dunnet's or ANCOVA including RV systolic pressure (RVSP; iPAH 96.8 ± 25.4 mmHg vs. PS 75.4 ± 18.9 mmHg; P = 0.011) as a covariate. RV-free wall thickening was prolonged in iPAH versus PS, extending beyond pulmonary valve closure (638 ± 76 msec vs. 562 ± 76 msec vs. 473 ± 59 msec controls). LV and RV isovolumetric relaxation were prolonged in iPAH (P < 0.001; LV 102.8 ± 24.1 msec vs. 63.1 ± 13.7 msec; RV 95 [61-165] vs. 28 [0-43]), associated with adverse septal kinetics; characterized by rightward displacement in early systole and leftward displacement in late RV systole (i.e., early LV diastole). Early LV diastolic filling was decreased in iPAH (73 ± 15.9 vs. PS 87.4 ± 14.4 vs. controls 95.8 ± 12.5 cm/sec; P = 0.004). Prolonged RVFW thickening, prolonged RVFW isovolumetric times, and profound septal dyskinesia are associated with interventricular mechanical discoordination and decreased early LV filling in pediatric iPAH much more than PS These adverse mechanics affect systolic and diastolic biventricular efficiency in iPAH and may form the basis for worse clinical outcomes. We used clinically derived data to study the pathophysiology of ventricular-ventricular interactions in right ventricular pressure overload, demonstrating distinct differences between pediatric pulmonary arterial hypertension (iPAH) and pulmonary stenosis (PS). Altered timing of right ventricular free wall contraction and profound septal dyskinesia are associated with interventricular mechanical discoordination and decreased early LV filling in iPAH much more than PS These adverse mechanics affect systolic and diastolic biventricular efficiency, independent of right ventricular systolic pressure. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells.

PubMed

Neumann, Avidan U; Phillips, Sandra; Levine, Idit; Ijaz, Samreen; Dahari, Harel; Eren, Rachel; Dagan, Shlomo; Naoumov, Nikolai V

2010-09-01

Antibodies are thought to exert antiviral activities by blocking viral entry into cells and/or accelerating viral clearance from circulation. In particular, antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) confer protection, by binding circulating virus. Here, we used mathematical modeling to gain information about viral dynamics during and after single or multiple infusions of a combination of two human monoclonal anti-HBs (HepeX-B) antibodies in patients with chronic hepatitis B. The antibody HBV-17 recognizes a conformational epitope, whereas antibody HBV-19 recognizes a linear epitope on the HBsAg. The kinetic profiles of the decline of serum HBV DNA and HBsAg revealed partial blocking of virion release from infected cells as a new antiviral mechanism, in addition to acceleration of HBV clearance from the circulation. We then replicated this approach in vitro, using cells secreting HBsAg, and compared the prediction of the mathematical modeling obtained from the in vivo kinetics. In vitro, HepeX-B treatment of HBsAg-producing cells showed cellular uptake of antibodies, resulting in intracellular accumulation of viral particles. Blocking of HBsAg secretion also continued after HepeX-B was removed from the cell culture supernatants. These results identify a novel antiviral mechanism of antibodies to HBsAg (anti-HBs) involving prolonged blocking of the HBV and HBsAg subviral particles release from infected cells. This may have implications in designing new therapies for patients with chronic HBV infection and may also be relevant in other viral infections.

Usefulness of simultaneous and sequential monitoring of glucose level and electrocardiogram in monkeys treated with gatifloxacin under conscious and nonrestricted conditions.

PubMed

Yoshimatsu, Yu; Ishizaka, Tomomichi; Chiba, Katsuyoshi; Mori, Kazuhiko

2018-05-10

Drug-induced cardiac electrophysiological abnormalities accompanied by hypoglycemia or hyperglycemia increase the risk for life-threatening arrhythmia. To assess the drug-induced cardiotoxic potential associated with extraordinary blood glucose (GLU) levels, the effect of gatifloxacin (GFLX) which was frequently associated with GLU abnormality and QT/QTc prolongations in the clinic on blood GLU and electrocardiogram (ECG) parameters was investigated in cynomolgus monkeys (n=4) given GFLX orally in an ascending dose regimen (10, 30, 60 and 100 mg/kg). Simultaneous and sequential GLU and ECG monitoring with a continuous GLU monitoring system and Holter ECG, respectively, were conducted for 24 h under free-moving conditions. Consequently, GFLX at 30 and 60 mg/kg dose-dependently induced a transient decrease in GLU without any ECG abnormality 2-4 h postdose. Highest dose of 100 mg/kg caused severe hypoglycemia with a mean GLU of <30 mg/dL, accompanied by remarkable QT/QTc prolongations by 20-30% in all animals. In contrast, hyperglycemia without QT/QTc prolongations was noted 24 h after dosing in one animal. A close correlation between GLU and QTc values was observed in animals treated with 100 mg/kg, suggesting that GFLX-induced hypoglycemia enhanced QT/QTc prolongations. Furthermore, the 24-h sequential GLU monitoring data clearly distinguished between GFLX-induced GLU abnormality and physiological GLU changes influenced by feeding throughout the day. In conclusion, the combined assessment of continuous GLU and ECG monitoring is valuable in predicting the drug-induced cardio-electrophysiological risk associated with both GLU and ECG abnormalities.

Chronic restraint stress after injury and shock is associated with persistent anemia despite prolonged elevation in erythropoietin levels.

PubMed

Bible, Letitia E; Pasupuleti, Latha V; Gore, Amy V; Sifri, Ziad C; Kannan, Kolenkode B; Mohr, Alicia M

2015-07-01

Following severe traumatic injury, critically ill patients have a prolonged hypercatacholamine state that is associated with bone marrow (BM) dysfunction and persistent anemia. However, current animal models of injury and shock result in a transient anemia. Daily restraint stress (chronic stress [CS]) has been shown to increase catecholamines. We hypothesize that adding CS following injury or injury and shock in rats will prolong the hypercatecholaminemia and prolong the initial anemia, despite elevated erythropoietin (EPO) levels. Male Sprague-Dawley rats (n = 6-8 per group) underwent lung contusion (LC) or combined LC/hemorrhagic shock (LCHS) followed by 6 days of CS. CS consisted of a 2-hour restraint period interrupted with repositioning and alarms every 30 minutes. At 7 days, urine was assessed for norepinephrine (NE) levels, blood for EPO and hemoglobin (Hgb), and BM for erythroid progenitor growth. Animals undergoing LC or combined LCHS predictably recovered by Day 7; urine NE, EPO, and Hgb levels were normal. The addition of CS to LC and LCHS models was associated with a significant elevation in NE on Day 6. The addition of CS to LC led to a persistent 20% to 25% decrease in the growth of BM hematopoietic progenitor cells. These findings were further exaggerated when CS was added following LCHS, resulting in a 20%q to 40% reduction in BM erythroid progenitor colony growth and a 20% decrease in Hgb when compared with LCHS alone. Exposing injured animals to CS results in prolonged elevation of NE and EPO, which is associated with worsening BM erythroid function and persistent anemia. Chronic restraint stress following injury and shock provides a clinically relevant model to further evaluate persistent injury-associated anemia seen in critically ill trauma patients. Furthermore, alleviating CS after severe injury is a potential therapeutic target to improve BM dysfunction and anemia.

Chronic Restraint Stress after Injury and Shock is Associated with Persistent Anemia despite Prolonged Elevation in Erythropoietin Levels

PubMed Central

Bible, Letitia E.; Pasupuleti, Latha V.; Gore, Amy V.; Sifri, Ziad C.; Kannan, Kolenkode B.; Mohr, Alicia M.

2015-01-01

Background Following severe traumatic injury, critically ill patients have a prolonged hypercatacholamine state that is associated with bone marrow (BM) dysfunction and persistent anemia. However, current animal models of injury and shock result in a transient anemia. Daily restraint stress (CS) has been shown to increase catecholamines. We hypothesize that adding CS following injury or injury and shock in rats will prolong the hypercatecholaminemia, and prolong the initial anemia, despite elevated erythropoietin levels. Methods Male Sprague-Dawley Rats (N=6–8/group) underwent lung contusion (LC) or combined lung contusion/hemorrhagic shock (LCHS) followed by six days of chronic stress (CS). CS consisted of a two hour restraint period interrupted with repositioning and alarms every 30 minutes. At seven days, urine was assessed for norepinephrine (NE) levels, blood for erythropoietin (EPO) and hemoglobin (Hgb), and BM for erythroid progenitor growth. Results Animals undergoing LC or combined LCHS predictably recovered by day seven; urine NE, EPO and Hgb levels were normal. The addition of CS to LC and LCHS models was associated with a significant elevation in NE on day six. The addition of CS to LC led to a persistent 20–25% decrease in the growth of BM HPCs. These findings were further exaggerated when CS was added following LCHS, resulting in a 20–40% reduction in BM erythroid progenitor colony growth and a 20% decrease in Hgb when compared to LCHS alone. Conclusions Exposing injured animals to CS results in prolonged elevation of norepinephrine and erythropoietin which is associated with worsening BM erythroid function and persistent anemia. Chronic restraint stress following injury and shock provides a clinically relevant model to further evaluate persistent injury-associated anemia seen in critically ill trauma patients. Furthermore, alleviating chronic stress after severe injury is a potential therapeutic target to improve BM dysfunction and anemia. PMID:26091320

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia

PubMed Central

Lon, Chanthap; Spring, Michele; Sok, Sommethy; Ta-aksorn, Winita; Kodchakorn, Chanikarn; Pann, Sut-Thang; Chann, Soklyda; Ittiverakul, Mali; Sriwichai, Sabaithip; Buathong, Nillawan; Kuntawunginn, Worachet; So, Mary; Youdaline, Theng; Milner, Erin; Wojnarski, Mariusz; Lanteri, Charlotte; Manning, Jessica; Prom, Satharath; Haigney, Mark; Cantilena, Louis; Saunders, David

2017-01-01

ABSTRACT Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.) PMID:28193647

Translating QT interval prolongation from conscious dogs to humans.

PubMed

Dubois, Vincent F S; Smania, Giovanni; Yu, Huixin; Graf, Ramona; Chain, Anne S Y; Danhof, Meindert; Della Pasqua, Oscar

2017-02-01

In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms μM -1 and 6.1 ms μM -1 in dogs and -10 ms μM -1 and 90 ms μM -1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R 2  = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans. © 2016 The British Pharmacological Society.

Comparative toxicity of diphacinone to northern bobwhite (Colinus virginianus) and American kestrels (Falco sparverius)

USGS Publications Warehouse

Rattner, Barnett A.; Horak, Katherine E.; Warner, Sarah E.; Day, Daniel D.; Johnston, John J.

2010-01-01

The acute oral toxicity of the anticoagulant rodenticide diphacinone was found to be about 20 times greater to American kestrels (LD50=97 mg/kg) than to northern bobwhite (LD50=2,014 mg/kg). Several precise and sensitive clotting assays (prothrombin time, Russell's Viper venom time, thrombin clotting time) were adapted for use in these species, and this combination of assays is recommended to detect effects of diphacinone and other rodenticides on coagulation. Oral administration of diphacinone over a range of doses (sublethal to the extrapolated LD15) prolonged prothrombin time and Russell's Viper venom time within 24 to 48 hrs post-exposure. Prolongation of in vitro clotting time reflects impaired coagulation complex activity and was detected before or at the onset of overt signs of toxicity and lethality. These data will assist in the development of a pharmacodynamic model to assess and predict rodenticide toxicity to non-target avian species.

Psycholegal abilities and restoration of competence to stand trial.

PubMed

Morris, Douglas R; Deyoung, Nathaniel J

2012-01-01

Criminal defendants adjudicated incompetent to stand trial are typically hospitalized for competence restoration in state institutions. Prolonged restoration hospitalizations involve civil rights concerns and increasing financial costs, and there remains interest in determining which individuals are likely to be successfully restored. We retrospectively reviewed hospital records of 455 male defendants admitted to a forensic treatment center for competence restoration in an effort to determine whether psychiatric diagnoses, demographic factors, or psycholegal abilities were predictive of successful or failed restoration. At varying stages of restoration efforts, psychotic disorder, mental retardation, and previous state hospitalization predicted unsuccessful restoration, while substance use and personality disorders were predictive of successful restoration. Psycholegal abilities were predictive of successful restoration and appeared to form a continuum, with basic behavior and outlook, factual legal understanding, and rational attorney assistance factors demonstrating progressively increased importance in successful restoration. Copyright © 2012 John Wiley & Sons, Ltd.

Challenges of Electronic Medical Surveillance Systems

DTIC Science & Technology

2004-06-01

More sophisticated approaches, such as regression models and classical autoregressive moving average ( ARIMA ) models that make estimates based on...with those predicted by a mathematical model . The primary benefit of ARIMA models is their ability to correct for local trends in the data so that...works well, for example, during a particularly severe flu season, where prolonged periods of high visit rates are adjusted to by the ARIMA model , thus

The Usefulness of Clinical-Practice-Based Laboratory Data in Facilitating the Diagnosis of Dengue Illness

PubMed Central

Liu, Jien-Wei; Lee, Ing-Kit; Wang, Lin; Chen, Rong-Fu; Yang, Kuender D.

2013-01-01

Alertness to dengue and making a timely diagnosis is extremely important in the treatment of dengue and containment of dengue epidemics. We evaluated the complementary role of clinical-practice-based laboratory data in facilitating suspicion/diagnosis of dengue. One hundred overall dengue (57 dengue fever [DF] and 43 dengue hemorrhagic fever [DHF]) cases and another 100 nondengue cases (78 viral infections other than dengue, 6 bacterial sepsis, and 16 miscellaneous diseases) were analyzed. We separately compared individual laboratory variables (platelet count [PC] , prothrombin time [PT], activated partial thromboplastin time [APTT], alanine aminotransferase [ALT], and aspartate aminotransferase [AST]) and varied combined variables of DF and/or DHF cases with the corresponding ones of nondengue cases. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) in the diagnosis of DF and/or DHF were measured based on these laboratory variables. While trade-off between sensitivity and specificity, and/or suboptimal PPV/NPV was found at measurements using these variables, prolonged APTT + normal PT + PC < 100 × 109 cells/L had a favorable sensitivity, specificity, PPV, and NPV in diagnosis of DF and/or DHF. In conclusion, these data suggested that prolonged APTT + normal PT + PC < 100 × 109 cells/L is useful in evaluating the likelihood of DF and/or DHF. PMID:24455678

Antibacterial activity of silver-killed bacteria: the "zombies" effect

NASA Astrophysics Data System (ADS)

Wakshlak, Racheli Ben-Knaz; Pedahzur, Rami; Avnir, David

2015-04-01

We report a previously unrecognized mechanism for the prolonged action of biocidal agents, which we denote as the zombies effect: biocidally-killed bacteria are capable of killing living bacteria. The concept is demonstrated by first killing Pseudomonas aeruginosa PAO1 with silver nitrate and then challenging, with the dead bacteria, a viable culture of the same bacterium: Efficient antibacterial activity of the killed bacteria is observed. A mechanism is suggested in terms of the action of the dead bacteria as a reservoir of silver, which, due to Le-Chatelier's principle, is re-targeted to the living bacteria. Langmuirian behavior, as well as deviations from it, support the proposed mechanism.

Variation and Grey GM(1, 1) Prediction of Melting Peak Temperature of Polypropylene During Ultraviolet Radiation Aging

NASA Astrophysics Data System (ADS)

Chen, K.; Y Zhang, T.; Zhang, F.; Zhang, Z. R.

2017-12-01

Grey system theory regards uncertain system in which information is known partly and unknown partly as research object, extracts useful information from part known, and thereby revealing the potential variation rule of the system. In order to research the applicability of data-driven modelling method in melting peak temperature (T m) fitting and prediction of polypropylene (PP) during ultraviolet radiation aging, the T m of homo-polypropylene after different ultraviolet radiation exposure time investigated by differential scanning calorimeter was fitted and predicted by grey GM(1, 1) model based on grey system theory. The results show that the T m of PP declines with the prolong of aging time, and fitting and prediction equation obtained by grey GM(1, 1) model is T m = 166.567472exp(-0.00012t). Fitting effect of the above equation is excellent and the maximum relative error between prediction value and actual value of T m is 0.32%. Grey system theory needs less original data, has high prediction accuracy, and can be used to predict aging behaviour of PP.