tbuckley/cabot-search huggingface dataset:
High Vesicular Monoamine Transporter Binding in Asymptomatic Bipolar I Disorder: Sex Differences and Cognitive Correlates
Authors: Jon-Kar Zubieta, Philippe Huguelet, Linda E. Ohl, Robert A. Koeppe, Michael R. Kilbourn, Jodie M. Carr, Bruno J. Giordani, Kirk A. Frey
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: It has been hypothesized that anomalies in monoaminergic function underlie some of the manifestations of bipolar disorder. In this study the authors examined the possibility that trait-related abnormalities in the concentration of monoaminergic synaptic terminals may be present in patients with asymptomatic bipolar disorder type I. METHOD: The concentration of a stable presynaptic marker, the vesicular monoamine transporter protein (VMAT2), was quantified with (+)[11C]dihydrotetrabenazine (DTBZ) and positron emission tomography. Sixteen asymptomatic patients with bipolar I disorder who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. Correlational analyses were conducted to examine the relationship between regional VMAT2 binding, cognitive function, and clinical variables. RESULTS: VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than that in the comparison subjects. VMAT2 concentrations in these regions correlated with performance on measures of frontal, executive function. In addition, sex differences in VMAT2 binding were detected in the thalamus of the bipolar patients; the male patients had higher binding than the women. No sex differences in binding were observed in the healthy comparison group. CONCLUSIONS: These initial results suggest that higher than normal VMAT2 expression and, by extension, concentration of monoaminergic synaptic terminals, may represent a trait-related abnormality in patients with bipolar I disorder and that male and female patients show different patterns. Also, VMAT2 concentrations may be associated with some of the cognitive deficits encountered in euthymic bipolar disorder.
Comparative effectiveness of switching to alternative tumour necrosis factor (TNF) antagonists versus switching to rituximab in patients with rheumatoid arthritis who failed previous TNF antagonists: the MIRAR Study
Authors: Juan J Gomez-Reino, Jose Ramon Maneiro, Jorge Ruiz, Rosa Roselló, Raimon Sanmarti, Ana Belen Romero
Journal: Annals of the Rheumatic Diseases (2012)

Objective To compare the effectiveness of switching to rituximab (RTX) with switching to alternative tumour necrosis factor (TNF) antagonists in patients with rheumatoid arthritis (RA) failing on TNF antagonists. Methods A multicentre prospective 3-year observational study was performed in patients with RA treated with RTX or an alternative TNF antagonist. The baseline 28-joint disease activity score (DAS28) and Health Assessment Questionnaire (HAQ) score were compared with 6, 9 and 12 month values, adjusting for propensity score quintiles. Propensity scores were estimated for each patient using logistic regression with treatment as the dependent variable and baseline prior number of TNFs &gt;1, years from diagnosis &gt;5, extra-articular manifestations, previous toxicity, use of ≥2 disease-modifying antirheumatic drugs, age and sex as independent variables. Results 1124 patients were treated with either RTX (n=591, 52.6%) or alternative TNF antagonists (n=533, 47.4%). RTX-treated patients had longer disease duration (p=0.0001), larger numbers of previous TNF antagonists (p&lt;0.0001) and tender and swollen joints (p&lt;0.0001). There was no significant difference in the reduction in DAS28 at 6, 9 and 12 months between RTX-treated patients and those treated with TNF antagonists. However, the reduction in DAS28 was significantly different between RTX-treated patients and adalimumab/infliximab-treated patients (p=0.001 and p=0.05, respectively). There was a marginally significant difference at any time period in the proportion of patients achieving an improvement in the HAQ score of &gt;0.22 (p=0.06). Conclusions Optimal treatment for patients with RA failing on treatment with TNF antagonists may include RTX. This study suggests that the improvement in DAS28 is larger in patients treated with RTX than in those treated with monoclonal anti-TNF agents.
Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction
Authors: L. Tiret, V. Nicaud, F. Kee, A. Evans, J.P. Cambou, D. Arveiler, G. Luc, P. Amouyel, O. Poirier, L. Lecerf, F. Cambien
Journal: The Lancet (1993)
STUDIES ON THE MODE OF ACTION OF DIPHTHERIA TOXIN
Authors: D. Michael Gill, A. M. Pappenheimer, Robin Brown, James T. Kurnick
Journal: The Journal of Experimental Medicine (1969)

When diphtheria toxin and NAD are added to soluble fractions containing aminoacyl transfer enzymes isolated from rabbit reticulocytes or from HeLa cells, free nicotinamide is released and, simultaneously, an inactive ADP ribose derivative of transferase II is formed. The reaction is reversible, and in the presence of excess nicotinamide, toxin catalyzes the restoration of aminoacyl transfer activity in intoxicated preparations. In living cultures of HeLa cells, the internal NAD concentration is sufficiently high to account for the rapid conversion, catalyzed by a few toxin molecules located in the cell membrane, of the entire cell content of free transferase II to its inactive ADP ribose derivative. Completely inactive ammonium sulfate fractions containing soluble proteins isolated from cells that have been exposed for several hours to excess toxin, can be reactivated to full aminoacyl transfer activity by addition of nicotinamide together with diphtheria toxin. Transferase II appears to be a highly specific substrate for the toxin-stimulated splitting of NAD and thus far no other protein acceptor for the ADP ribose moiety has been found.
Phase I/II Study of Oncolytic HSVGM-CSF in Combination with Radiotherapy and Cisplatin in Untreated Stage III/IV Squamous Cell Cancer of the Head and Neck
Authors: Kevin J. Harrington, Mohan Hingorani, Mary Anne Tanay, Jennifer Hickey, Shreerang A. Bhide, Peter M. Clarke, Louise C. Renouf, Khin Thway, Amen Sibtain, Iain A. McNeish, Kate L. Newbold, Howard Goldsweig, Robert Coffin, Christopher M. Nutting
Journal: Clinical Cancer Research (2010)

Abstract Purpose: This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN). Experimental Design: Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m2 on days 1, 22, and 43) and dose-escalating (106, 106, 106, 106 pfu/mL for cohort 1; 106, 107, 107, 107 for cohort 2; 106, 108, 108, 108 for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored. Results: Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months). Conclusions: JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 106, 108, 108, 108. Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN. Clin Cancer Res; 16(15); 4005–15. ©2010 AACR.
Prognostic Value of Dobutamine Stress Echocardiography in Patients With Diabetes
Authors: Fabiola B. Sozzi, Abdou Elhendy, Jos R.T.C. Roelandt, Ron T. van Domburg, Arend F.L. Schinkel, Eleni C. Vourvouri, Jeroen J. Bax, Johan De Sutter, Alberico Borghetti, Don Poldermans
Journal: Diabetes Care (2003)

The aim of this study was to assess the incremental value of dobutamine stress echocardiography (DSE) for the risk stratification of diabetic patients who are unable to perform an adequate exercise stress test. Exercise capacity is frequently impaired in patients with diabetes. The role of pharmacologic stress echocardiography in the risk stratification of diabetic patients has not been well defined.We studied 396 diabetic patients (mean age 61 +/- 11 years, 252 men [64%]) with limited exercise capacity who underwent DSE for evaluation of known or suspected coronary artery disease (CAD). End points were hard cardiac events (cardiac death and nonfatal myocardial infarction) and all causes of mortality.During a median follow-up of 3 years, 97 patients (24%) died (55 cardiac deaths), and 27 patients had nonfatal myocardial infarction. In an incremental multivariate analysis model, clinical predictors of hard cardiac events were history of congestive heart failure, previous myocardial infarction, hypercholesterolemia, and ejection fraction at rest. The percentage of ischemic segments was incremental to the clinical model in the prediction of hard cardiac events (chi(2) = 37 vs. 18, P < 0.05). Clinical predictors of all causes of mortality were history of congestive heart failure, age, hypercholesterolemia, and ejection fraction at rest. Wall motion score index at peak stress was incremental to the clinical model in the prediction of mortality (chi(2) = 52 vs. 43, P < 0.05).DSE provides incremental data for the prediction of mortality and hard cardiac events in patients with diabetes who are unable to perform an adequate exercise stress test.
Correlation Between Palmar Hyperlinearity and Early Childhood Atopic Dermatitis with Filaggrin Gene Null Mutations
Authors: Tatsuki Fukuie, Ryuhei Yasuoka, Jun-ichi Sakabe, Toshiharu Fujiyama, Yoshiki Tokura, Tomohide Taguchi
Journal: Journal of Allergy and Clinical Immunology (2015)
The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: a review
Authors: G.F. Homan, M. Davies, R. Norman
Journal: Human Reproduction Update (2007)

This evidence-based review focuses on the impact of potentially modifiable, non-communicable lifestyle factors on reproductive performance in the general population and the infertile population undergoing assisted reproductive technology (ART) treatment. The impact of several lifestyle factors including; age, weight, smoking, diet, exercise, psychological stress, caffeine consumption, alcohol consumption and exposure to environmental pollutants are included in the review. The databases of Medline, PubMed and Cinahl were searched to identify relevant publications. There is strong evidence that age, weight and smoking impact on general health and adversely on reproductive performance. However there is a need for further research focusing specifically on the relationship between diet and various levels of exercise on reproductive performance. There are several other factors such as psychological stress, caffeine consumption, alcohol consumption and exposure to environmental pollutants that have been implicated but the evidence is equivocal. It is concluded that lifestyle modification can assist couples to conceive spontaneously or optimize their chances of conception with ART treatment.
Increasing functional avidity of TCR-redirected T cells by removing defined <i>N</i>-glycosylation sites in the TCR constant domain
Authors: Jürgen Kuball, Beate Hauptrock, Victoria Malina, Edite Antunes, Ralf-Holger Voss, Matthias Wolfl, Roland Strong, Matthias Theobald, Philip D. Greenberg
Journal: The Journal of Experimental Medicine (2009)

Adoptive transfer of T lymphocytes transduced with a T cell receptor (TCR) to impart tumor reactivity has been reported as a potential strategy to redirect immune responses to target cancer cells (Schumacher, T.N. 2002. Nat. Rev. Immunol. 2:512–519). However, the affinity of most TCRs specific for shared tumor antigens that can be isolated is usually low. Thus, strategies to increase the affinity of TCRs or the functional avidity of TCR-transduced T cells might be therapeutically beneficial. Because glycosylation affects the flexibility, movement, and interactions of surface molecules, we tested if selectively removing conserved N-glycoslyation sites in the constant regions of TCR α or β chains could increase the functional avidity of T cells transduced with such modified TCRs. We observed enhanced functional avidity and improved recognition of tumor cells by T cells harboring TCR chains with reduced N-glycosylation (ΔTCR) as compared with T cells with wild-type (WT) TCR chains. T cells transduced with WT or ΔTCR chains bound tetramer equivalently at 4°C, but tetramer binding was enhanced at 37°C, predominantly as a result of reduced tetramer dissociation. This suggested a temperature-dependent mechanism such as TCR movement in the cell surface or structural changes of the TCR allowing improved multimerization. This strategy was effective with mouse and human TCRs specific for different antigens and, thus, should be readily translated to TCRs with any specificity.
Ice and modern sports physiotherapy: still cool?
Authors: Mario Bizzini
Journal: British Journal of Sports Medicine (2012)

Respiratory syncytial virus (RSV) bronchiolitis causes severe respiratory tract infection in infants, frequently necessitating mechanical ventilatory support. However, life-saving, mechanical ventilation aggravates lung inflammation. We set up a model to dissect the host molecular response to mechanical ventilation in RSV infection. Furthermore, the response to induced hypercapnic acidosis, reported to dampen the inflammatory response to mechanical ventilation in non-infectious models, was assessed. BALB/c mice were inoculated with RSV or mock-suspension and ventilated for 5 h on day 5 post inoculation. Mechanical ventilation of infected mice resulted in enhanced cellular influx and increased concentrations of pro-inflammatory cytokines in the bronchoalveolar space. Microarray analysis showed that enhanced inflammation was associated with a molecular signature of a stress response to mechanical ventilation with little effect on the virus-induced innate immune response. Hypercapnic acidosis during mechanical ventilation of infected mice did not change host transcript profiles. We conclude that mechanical ventilation during RSV infection adds a robust but distinct molecular stress response to virus-induced innate immunity activation, emphasising the importance of lung-protective mechanical ventilation strategies. Induced hypercapnic acidosis has no major effect on host transcription profiles during mechanical ventilation for RSV infection, suggesting that this is a safe approach to minimise ventilator-induced lung injury.
Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease
Authors: Yu-Hsin Chen, Ko-Lin Kuo, Szu-Chun Hung, Chih-Cheng Hsu, Ying-Hwa Chen, Der-Cherng Tarng
Journal: Journal of the American Society of Nephrology (2014)

The length polymorphism of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with cardiovascular events and mortality in high-risk populations. Experimental data suggest that heme oxygenase-1 protects against kidney disease. However, the association between this polymorphism and long-term risk of CKD in high-risk patients is unknown. We analyzed the allelic frequencies of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter in 386 patients with coronary artery disease recruited from January 1999 to July 2001 and followed until August 31, 2012. The S allele represents short repeats (<27), and the L allele represents long repeats (≥27). The primary renal end points consisted of sustained serum creatinine doubling and/or ESRD requiring long-term RRT. The secondary end points were major adverse cardiovascular events and mortality. At the end of study, the adjusted hazard ratios (95% confidence intervals) for each L allele in the additive model were 1.99 (1.27 to 3.14; P=0.003) for the renal end points, 1.70 (1.27 to 2.27; P<0.001) for major adverse cardiovascular events, and 1.36 (1.04 to 1.79; P=0.03) for mortality. With cardiac events as time-dependent covariates, the adjusted hazard ratio for each L allele in the additive model was 1.91 (1.20 to 3.06; P=0.01) for the renal end points. In conclusion, a greater number of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with higher risk for CKD, cardiovascular events, and mortality among patients with coronary artery disease.
Mechanism of the impairment of the glucagon-stimulated phosphoenolpyruvate carboxykinase gene expression by interleukin-6 in rat hepatocytes: Inhibition of the increase in cyclic 3',5' adenosine monophosphate and the downstream cyclic 3',5' adenosine monophosphate action
Authors: B Christ, A Nath, K Jungermann
Journal: Hepatology (1997)

In cultured rat hepatocytes, the gluconeogenic key enzyme, phosphoenolpyruvate carboxykinase (PCK), is induced by glucagon via elevation of cyclic 3',5' adenosine monophosphate (cAMP). The proinflammatory cytokine, interleukin-6 (IL-6), which in the liver together with IL-1beta and tumor necrosis factor alpha triggers the acute-phase response, had been shown to attenuate the glucagon-induced increase in PCK gene transcription, messenger (mRNA) levels, and enzyme activity. The molecular mechanism of this inhibition was investigated in the present study. Glucagon increased cyclic cAMP and PCK mRNA levels to a transient maximum twofold and fivefold, respectively. The increases were attenuated by IL-6. Forskolin, which stimulates adenylate cyclase activity, increased cAMP and PCK mRNA levels 1.6-fold and fivefold, respectively. However, IL-6 attenuated the forskolin- stimulated increase in PCK mRNA but not the increase in cAMP. This showed that IL-6 inhibited PCK mRNA increase in part by the attenuation of cAMP increase, but also beyond cAMP formation. This was confirmed in experiments in which PCK mRNA levels were increased by the nonhydrolyzable cAMP-analogue, chlorophenylthio (CPT)-cAMP. The increase in PCK mRNA was again attenuated by IL-6. In pertussis toxin- and in isobutylmethylxanthine-treated hepatocytes, IL-6 still inhibited the glucagon-stimulated increase in cAMP, indicating that IL-6 did not activate an inhibitory G-protein or phosphodiesterase, which could cause the impairment of cAMP increase. To demonstrate whether the inhibition of PCK gene expression by IL-6 beyond cAMP might be caused by the inhibition of the activation of the PCK gene promoter by cAMP, cultured rat hepatocytes were transfected with a luciferase reporter gene construct under the control of a PCK gene promoter fragment (base - 979 to base +32). Luciferase activity was determined after stimulation of the cells with CPT-cAMP in the absence or presence of IL-6. CPT-cAMP increased luciferase activity by 1.7-fold, which was inhibited in the presence of IL-6. It is concluded that IL-6 had a dual inhibitory effect on the stimulation of PCK gene expression by glucagon. It inhibited the increase in cAMP at a site before cAMP formation by adenylate cyclase and at a site after cAMP formation, the activation of the PCK gene promoter by cAMP. (Hepatology 1997 Jul;26(1):73-80)
Effect of high versus low ambient humidity on the severity of obstructive sleep apnoea
Authors: R. Jokic, L. Bhagchandani, T. Zintel, M. Baetz, M. F Fitzpatrick
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Surface tension forces appear to make a significant contribution to upper airway closure in patients with obstructive sleep apnoea (OSA). It is possible that drying of the upper airway mucosa at night might contribute to these surface tension forces and the severity of OSA might therefore change with alteration of the ambient humidity. <h3>METHODS</h3> A randomised single blind crossover study of high ambient relative humidity (HRH) versus low ambient relative humidity (LRH) was performed in 12 men of mean (SD) age 49 (9) years with mild OSA (apnoea/hypopnoea index (AHI) 14 (5.2)). On one night patients slept in continuous HRH (85 (4)%, range 80–93%) and on the other in LRH (16 (4)%, range 11–22%). <h3>RESULTS</h3> The AHI was similar on the HRH and LRH nights (mean difference 3; 95% CI –2 to 9, p = 0.20) and no statistically significant differences in AHI were observed on the two nights after standardising for body position and sleep stage. Sleep stage distribution and the proportion of time spent in the supine position were similar on the HRH and LRH nights. The number of non-respiratory arousals was also similar on the two nights. <h3>CONCLUSION</h3> Altering ambient humidity alone has no significant impact on the severity of OSA.
Genetic Susceptibility and Loss of Nr4a1 Enhances Macrophage-Mediated Renal Injury in CKD
Authors: Lindsey Westbrook, Ashley C. Johnson, Kevin R. Regner, Jan M. Williams, David L. Mattson, Patrick B. Kyle, Jeffery R. Henegar, Michael R. Garrett
Journal: Journal of the American Society of Nephrology (2014)

Nuclear hormone receptors of the NR4A subgroup have been implicated in cancer, atherosclerosis, and metabolic disease. However, little is known about the role of these receptors in kidney health or disease. Nr4a1-deficient rats (Nr4a1−/−) developed on a genetic background susceptible to kidney injury (fawn-hooded hypertensive rat [FHH]) were evaluated for BP, proteinuria, renal function, and metabolic parameters from 4 to 24 weeks-of-age. By week 24, Nr4a1−/− rats exhibited significantly higher proteinuria (approximately 4-fold) and decreased GFR compared with FHH controls. The severity of tubular atrophy, tubular casts, and interstitial fibrosis increased significantly in Nr4a1−/− rats and was accompanied by a large increase in immune cell infiltration, predominantly macrophages and to a lesser extent T cells and B cells. Global transcriptome and network analyses at weeks 8, 16, and 24 identified several proinflammatory genes and pathways differentially regulated between strains. Bone marrow crosstransplantation studies demonstrated that kidney injury in Nr4a1−/− rats was almost completely rescued by bone marrow transplanted from FHH controls. In vitro, macrophages isolated from Nr4a1−/− rats demonstrated increased immune activation compared with FHH-derived macrophages. In summary, the loss of Nr4a1 in immune cells appears to cause the increased kidney injury and reduced renal function observed in the Nr4a1−/− model.