tbuckley/cabot-search huggingface dataset:
Influence of immunogenicity on the efficacy of longterm treatment of spondyloarthritis with infliximab
Authors: Chamaida Plasencia, Dora Pascual-Salcedo, Laura Nuño, Gema Bonilla, Alejandro Villalba, Diana Peiteado, Jesús Díez, Daniel Nagore, Ainhoa Ruiz del Agua, Rosario Moral, Emilio Martin-Mola, Alejandro Balsa
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Infliximab (IFX) is a monoclonal antibody against tumour necrosis factor α that is effective for treating spondyloarthritis (SpA). However, after initial success of the drug some patients lose responsiveness or develop infusion reactions, which may be related to the development of antibodies against the drug. <h3>Objective</h3> To investigate the clinical relevance of antibodies to infliximab (ATI) formation in patients with SpA undergoing IFX treatment over a prolonged period. <h3>Methods</h3> 94 patients with SpA treated with IFX from 1999 to 2010 were studied. Their clinical characteristics, serum trough IFX levels and ATI status were evaluated for a mean of 6.99 (95% CI:6.28 to 7.7) years. Clinical activity and improvement were measured using the Ankylosing Spondylitis Disease Activity Score (ASDAS): inactive &lt;1.3, moderate ≥1.3 and &lt;2.1, high ≥2.1–≤3.5, and very high &gt;3.5 at three time points (6 months, 12 months and &gt;4 years). <h3>Results</h3> ATI were detected in 24 (25.5%) patients. The patients with ATI had higher ASDAS scores than those without ATI (2.55±0.89 vs 1.79±1.04, p=0.038 at 6 months; 1.95±0.67 vs 1.67±0.71, p=0.042 at 1 year; 2.52±0.99 vs 1.53±0.81, p=0.024 at &gt;4 years). Eleven patients (12%) developed infusion-related reactions, and of these, ATI were present in eight patients (73%). The patients with infusion-related reactions had higher ATI titres (median 12 931 AU/ml, IQR 853–82 437) vs median 2454 AU/ml, IQR 449–7718, p=0.028) and shorter survival (4.25 years vs 8.19 years, p&lt;0.001). ATI development occurred more frequently in the patients not receiving methotrexate (20/58 (34.5%) vs 4/36 (11.1%), p=0.011). <h3>Conclusion</h3> In patients with SpA treated with IFX, ATI formation is associated with a poor clinical response, the appearance of infusion reactions and the discontinuation of treatment.
Oxidative Stress and Antioxidant Defense in Relation to the Severity of Diabetic Polyneuropathy and Cardiovascular Autonomic Neuropathy
Authors: Dan Ziegler, Christoph G.H. Sohr, Jaffar Nourooz-Zadeh
Journal: Diabetes Care (2004)

OBJECTIVE—Oxidative stress resulting from enhanced free-radical formation and/or a defect in antioxidant defenses has been implicated in the pathogenesis of experimental diabetic neuropathy. The objective of this study was to evaluate plasma levels of various biomarkers of oxidative stress in diabetic subjects in relation to the presence or absence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN). RESEARCH DESIGN AND METHODS—Plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), superoxide anion (O2·−) generation, lag phase to peroxidation by peroxynitrite (ONOO−), vitamin E-to-lipid ratio, and vitamin C were measured in nonsmoking diabetic patients without PN and CAN (PN−/CAN− group; n = 62), in a group with PN but without CAN (PN+/CAN− group; n = 105), in those with both PN and CAN (PN+/CAN+ group; n = 22), and in healthy control subjects (n = 85). RESULTS—All three markers of oxidative stress were significantly increased, and both markers of antioxidant defense were decreased in the PN+/CAN− group compared with the control group (all P &amp;lt; 0.05). PN−/CAN− subjects showed a significant increase compared with control subjects for 8-iso-PGF2α, O2·−, and ONOO− and a decrease for the vitamin E-to-lipid ratio (all P &amp;lt; 0.05). In the PN+/CAN− group, a significant increase compared with the PN−/CAN− group was noted for O2·−, whereas the vitamin E-to-lipid ratio and vitamin C were reduced (all P &amp;lt; 0.05). No significant differences were noted between the PN+/CAN− and PN+/CAN+ groups for each of the five markers of oxidative stress. In multivariate models, O2·− and ONOO− were independently associated with neuropathic deficits, but diabetes duration and triglyceride levels were also independent determinants. CONCLUSIONS—Oxidative stress is enhanced in diabetic patients before the development of PN but to an even higher degree in those with PN, without further significant increase in relation to superimposed autonomic neuropathy. However, apart from oxidative stress, diabetes duration and triglyceride levels are also related to the severity of PN.
Obstructive sleep apnea is associated with alterations in markers of feto-placental wellbeing
Authors: Jennifer Fung, Geralyn Messerlian, Patrizia Curran, Kristen Butterfield, Susan Martin, Ghada Bourjeily
Journal: European Respiratory Journal (2013)

Background: Sleep disordered breathing (SDB) has been associated with adverse pregnancy and fetal outcomes. As the placenta plays a central role in mediating many of these outcomes, we hypothesized that markers of feto-placental wellbeing are altered in women with obstructive sleep apnea (OSA).  Methods: A retrospective case-control study was performed. Cases were identified by ICD-9 codes. Controls were identified from a sample of women screened for symptoms of SDB by using questions from the multivariable apnea prediction index. Women who scored zero (never) on snoring, gasping and apneas were selected as controls. Women with available feto-placental screening markers (estriol (uE3) and alpha-fetoprotein (AFP)) were then selected. Standard statistical analyses were used.  Results: Twenty six OSA cases and 165 controls were identified. Median age and body mass index (BMI) were 27.0 and 28.5, p=0.5, and 37.7 and 22.9, p  Conclusion: OSA is associated with alterations in markers of feto-placental wellbeing. Prospective studies need to elucidate this association further.
Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions
Authors: Charles N. Serhan, Rong Yang, Kimberly Martinod, Kie Kasuga, Padmini S. Pillai, Timothy F. Porter, Sungwhan F. Oh, Matthew Spite
Journal: The Journal of Experimental Medicine (2008)

The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MΦs). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MΦs converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MΦ mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MΦs in tissue homeostasis, inflammation resolution, wound healing, and host defense.
The First M.O.H
Authors: C. F. Brockington
Journal: BMJ (1948)

Accurate dry weight assessment is difficult in pediatric hemodialysis patients but is essential to prevent chronic fluid overload, hypertension, and cardiovascular morbidity. A noninvasive monitoring (NIVM) of hematocrit-guided ultrafiltration algorithm was studied prospectively in 20 pediatric hemodialysis patients. The algorithm targeted the first 50% of total goal ultrafiltration to be removed during the first hour of dialysis with a maximum blood volume change of 8 to 12% per hour. The second 50% was removed during the remaining treatment time with a maximum blood volume change of 5% per hour. Data that were collected at baseline and 6 mo included weight, BP, number of antihypertensive medications, 24-h ambulatory BP monitoring (ABPM), echocardiogram, and ultrafiltration-associated symptoms. Sixteen of 20 enrolled patients completed the study. No difference was seen between baseline and 6-mo weight, predialysis casual BP, nighttime ABPM, or left ventricular mass index. There was a decrease in postdialysis casual systolic BP, daytime ABPM, number of antihypertensive medications prescribed, and rate of intradialytic events related to ultrafiltration (all <i>P</i> ≤ 0.05). Adoption of a standardized NIVM-guided algorithm led to (<i>1</i>) improved ABPM profiles, (<i>2</i>) decreased antihypertensive medication burden, and (<i>3</i>) decreased ultrafiltration-associated symptoms. Wider use of NIVM-guided ultrafiltration may decrease cardiovascular morbidity in pediatric hemodialysis patients.
Overactivated Neddylation Pathway as a Therapeutic Target in Lung Cancer
Authors: Lihui Li, Mingsong Wang, Guangyang Yu, Ping Chen, Hui Li, Dongping Wei, Ji Zhu, Li Xie, Huixun Jia, Jieyi Shi, Chunjie Li, Wantong Yao, Yanchun Wang, Qiang Gao, Lak Shin Jeong, Hyuk Woo Lee, Jinha Yu, Fengqing Hu, Ju Mei, Ping Wang, Yiwei Chu, Hui Qi, Meng Yang, Ziming Dong, Yi Sun, Robert M. Hoffman, Lijun Jia
Journal: JNCI Journal of the National Cancer Institute (2014)

A number of oncoproteins and tumor suppressors are known to be neddylated, but whether the neddylation pathway is entirely activated in human cancer remains unexplored.NEDD8-activating enzyme (NAE) (E1) and NEDD8-conjugating enzyme (E2) expression and global-protein neddylation were examined by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction analysis. Cell proliferation, clonogenic survival, migration, and motility in vitro, as well as tumor formation and metastasis in vivo, were determined upon neddylation inhibition by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Survival was analyzed with Kaplan-Meier methods and compared by the log-rank test. All statistical tests were two-sided.The entire neddylation pathway, including NEDD8-activating enzyme E1, NEDD8-conjugating enzyme E2, and global-protein neddylation, is overactivated in both lung adenocarcinoma and squamous-cell carcinoma. Compared with lung adenocarcinoma patients with low expression, those with high expression had worse overall survival (NEDD8-activating enzyme E1 subunit 1 [NAE1]: hazard ratio [HR] = 2.07, 95% confidence interval [CI] = 0.95 to 4.52, P = .07; ubiquitin-conjugating enzyme E2M (UBC12): HR = 13.26, 95% CI = 1.77 to 99.35, P = .01; global protein neddylation: HR = 3.74, 95% CI = 1.65 to 8.47, P = .002). Moreover, inhibition of neddylation by the NAE inhibitor MLN4924 statistically significantly suppressed proliferation, survival, migration, and motility of lung cancer cells in vitro and tumor formation and metastasis in vivo. At the molecular level, MLN4924 inactivated Cullin-RING E3 ligases, led to accumulation of tumor-suppressive Cullin-RING E3 ligase substrates and induced phorbol-12-myristate-13-acetate-induced protein 1 (NOXA)-dependent apoptosis or cellular senescence.Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.
Primary angioplasty versus intravenous thrombolysis in acute myocardial infarction: can we define subgroups of patients benefiting most from primary angioplasty?
Authors: Ralf Zahn, Rudolf Schiele, Steffen Schneider, Anselm K Gitt, Harm Wienbergen, Karlheinz Seidl, Thomas Voigtländer, Martin Gottwik, Gunther Berg, Ernst Altmann, Werner Rosahl, Jochen Senges
Journal: Journal of the American College of Cardiology (2001)
Imaging Dispersion of Myocardial Repolarization, I
Authors: John E. Burnes, Raja N. Ghanem, Albert L. Waldo, Yoram Rudy
Journal: Circulation (2001)

Background Body-surface ECG measures (QT dispersion [QTd], QRST integrals) have been used as indices of myocardial repolarization abnormalities with the goal of identifying patients at risk of fatal arrhythmias. The clinical utility of these measures has been questioned. We investigate the complex relationship between epicardial and body-surface potentials in the context of regionally abnormal myocardial repolarization. Methods and Results Epicardial potentials were recorded with a 224-electrode sock from an open-chest dog during control, regional epicardial warming, cooling, and adjacent warming and cooling to induce localized alterations in myocardial repolarization and regions of increased repolarization dispersion. Body-surface potentials were generated from these epicardial potentials in a human torso model. Epicardial estimates of repolarization (activation recovery intervals [ARIs] and QRST integrals) were evaluated for their ability to identify regions with increased repolarization dispersion. Body-surface QRST integrals and QTd in 12-lead ECG and 64-lead body-surface potential maps were evaluated for their ability to detect increased dispersion of myocardial repolarization. Epicardial ARI and QRST integral maps successfully located epicardial regions with increased dispersion of repolarization. The increased dispersion was not consistently reflected in the 12-lead or 64-lead ECG QTd or in the body-surface QRST integral maps. Conclusions This study demonstrates the inadequacy of body-surface measures that are thought to reflect myocardial dispersion of repolarization. In contrast, measures based on epicardial electrograms (ARI or epicardial QRST integral maps) provide physiologically relevant information about myocardial repolarization and can locate regions of increased dispersion.
Desmosterol in human nonalcoholic steatohepatitis
Authors: Marko Simonen, Ville Männistö, Joel Leppänen, Dorota Kaminska, Vesa Kärjä, Sari Venesmaa, Pirjo Käkelä, Johanna Kuusisto, Helena Gylling, Markku Laakso, Jussi Pihlajamäki
Journal: Hepatology (2013)

Dysregulation of the cholesterol synthesis pathway and accumulation of cholesterol in the liver are linked to the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, we investigated the association of serum and liver levels of cholesterol precursors with NASH. Liver histology was assessed in 110 obese patients (Kuopio Obesity Surgery Study [KOBS] study, age 43.7 ± 8.1 years [mean ± standard deviation, SD], body mass index [BMI] 45.0 ± 6.1 kg/m 2 ). Serum and liver levels of cholesterol precursors were measured with gas-liquid chromatography. The association between cholesterol precursors and serum alanine aminotransferase (ALT), as a marker of liver disease, was also investigated in a population cohort of 717 men (Metabolic Syndrome in Men Study [METSIM] study, age 57.6 ± 5.8 years, BMI 27.1 ± 4.0 kg/m 2 ). Serum desmosterol levels and the desmosterol-to-cholesterol ratio were higher in individuals with NASH, but not in individuals with simple steatosis, compared to obese subjects with normal liver histology ( P = 0.002 and P = 0.003, respectively). Levels of serum and liver desmosterol correlated strongly ( r = 0.667, P = 1 × 10 −9 ), suggesting a shared regulation. Both serum and liver desmosterol levels correlated positively with steatosis and inflammation in the liver ( P &lt; 0.05). Serum desmosterol had a higher correlation with the accumulation of cholesterol in the liver than serum cholesterol. Serum desmosterol levels ( P = 2 × 10 −6 ) and the serum desmosterol-to-cholesterol ratio ( P = 5 × 10 −5 ) were associated with serum ALT in the population study. Conclusion : Levels of desmosterol in serum and the liver were associated with NASH. These results suggest that serum desmosterol is a marker of disturbed cholesterol metabolism in the liver. Whether desmosterol has a more specific role in the pathophysiology of NASH compared to other cholesterol precursors needs to be investigated. (Hepatology 2013;53:976–982)
Does Patient Cognition Predict Time Off From Work After Life-Threatening Accidents?
Authors: Ulrich Schnyder, Hanspeter Moergeli, Richard Klaghofer, Tom Sensky, Stefan Buchi
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Accidental injuries are frequent and their socioeconomic consequences enormous. The present study aimed to identify predictors of the number of days of leave taken in a consecutively selected group of accident victims who sustained severe, mostly life-threatening physical trauma. METHOD: One hundred patients with severe accidental injuries who were referred to a trauma surgeons' intensive care unit were followed up for 12 months. The main outcome measure was the number of days of leave taken that were attributable to the accident 1 year after the trauma. RESULTS: Multiple regression analysis explained 30% of the variance in the number of days of leave taken that were attributable to the accident. Factors contributing to the predictive model were injury severity, type of accident and, most significantly, the patients' subjective self-assessment of accident severity and of their abilities to cope with the accident and its job-related consequences. Patients who perceived the severity of their accident as relatively low and judged their coping abilities as high took a mean 121 days of leave compared to 287 days of leave taken by those who perceived the trauma as relatively severe and were less optimistic regarding their coping abilities. A two-factor analysis of variance showed that patient perceptions of accident severity and their appraisal of their coping abilities made independent contributions to the predicted amount of leave taken. CONCLUSIONS: In severely injured accident victims, leave taken because of the accident depended to a considerable degree on the patients' accident-related self-assessment.
Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial
Authors: Michael R Migden, Alexander Guminski, Ralf Gutzmer, Luc Dirix, Karl D Lewis, Patrick Combemale, Robert M Herd, Ragini Kudchadkar, Uwe Trefzer, Sven Gogov, Celine Pallaud, Tingting Yi, Manisha Mone, Martin Kaatz, Carmen Loquai, Alexander J Stratigos, Hans-Joachim Schulze, Ruth Plummer, Anne Lynn S Chang, Frank Cornélis, John T Lear, Dalila Sellami, Reinhard Dummer
Journal: The Lancet Oncology (2015)
Inflammation, Metabolic Dysregulation, and Pulmonary Function among Obese Urban Adolescents with Asthma
Authors: Deepa Rastogi, Sasha Fraser, Jamie Oh, Ashley M. Huber, Yael Schulman, Renuka H. Bhagtani, Zeeshan S. Khan, Lydia Tesfa, Charles B. Hall, Fernando Macian
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Insulin resistance and low high-density lipoprotein (HDL) are associated with pulmonary morbidity, including asthma, but the underlying mechanisms are not well elucidated.To investigate whether systemic inflammation underlies the association of metabolic abnormalities with pulmonary function among urban adolescents.Th-cell responses and monocyte subsets, and their association with serum homeostatic model assessment of insulin resistance (HOMA-IR) and HDL, and pulmonary function were quantified in 168 adolescents, including 42 obese subjects with asthma, 42 normal-weight subjects with asthma, 40 obese subjects without asthma, and 44 healthy control subjects. Th-cell responses (Th1 [CD4(+)IFNγ(+)] and Th2 [CD4(+)IL4(+)] cells) to stimulation with phytohemagglutinin, leptin, and dust mite, and classical (CD14(+)CD16(-)), resident (CD14(+)CD16(+)), and patrolling (CD14dimCD16(+)) monocytes, and their C-C chemokine receptor type-2 (CCR2) expression were quantified by flow cytometry.Th1/Th2 ratio to all three stimuli was higher in obese subjects with asthma than normal-weight subjects with asthma and directly correlated with HOMA-IR. Classical monocytes inversely associated with Th1/Th2 ratio to phytohemagglutinin (r = -0.43; P = 0.01) and directly with Asthma Control Test score (β = 1.09; P = 0.04), while patrolling monocytes correlated with Composite Asthma Severity Index score (β = 1.11; P = 0.04) only among obese subjects with asthma. HDL was inversely associated with patrolling monocytes and directly associated with CCR2 expression on resident monocytes. CCR2 expression on patrolling monocytes predicted residual volume (RV), RV/TLC ratio, and FRC, after adjusting for HDL, but not after adjusting for body mass index. Association of Th1/Th2 ratio with RV, FRC, and inspiratory capacity was attenuated after adjusting for HOMA-IR.Th1 polarization and monocyte activation among obese subjects with asthma correlates with metabolic abnormalities. Association of monocyte activation with pulmonary function is mediated by body mass index, whereas that of Th1 polarization is mediated by insulin resistance.
The effect of the pericardium on ventricular systolic function in man.
Authors: D T Mangano
Journal: Circulation (1980)

To determine the role of the pericardium in man, ventricular function was studied in 20 patients who underwent pericardiotomy during coronary artery bypass surgery. Left and right ventricular function curves were generated before and after pericardiotomy by changing body position to alter venous pressure. Central venous (0--14 mm Hg) and pulmonary wedge pressures (1--25 mm Hg) ranged over normal and moderately elevated values. Pericardiotomy did not alter the relationship between left ventricular stroke work index and pulmonary wedge pressure, between right ventricular stroke work index and central venous pressure, or between pulmonary wedge pressure and central venous pressure. These data suggest that in patients with normal and moderately elevated filling pressures, the pericardium does not influence right or left ventricular systolic function or the coupling between the right and left ventricles.