tbuckley/cabot-search huggingface dataset:
Optical Mapping of Sarcoplasmic Reticulum Ca <sup>2+</sup> in the Intact Heart
Authors: Lianguo Wang, Rachel C. Myles, Nicole M. De Jesus, Alex K.P. Ohlendorf, Donald M. Bers, Crystal M. Ripplinger
Journal: Circulation Research (2014)

Sarcoplasmic reticulum (SR) Ca(2+) cycling is key to normal excitation-contraction coupling but may also contribute to pathological cardiac alternans and arrhythmia.To measure intra-SR free [Ca(2+)] ([Ca(2+)]SR) changes in intact hearts during alternans and ventricular fibrillation (VF).Simultaneous optical mapping of Vm (with RH237) and [Ca(2+)]SR (with Fluo-5N AM) was performed in Langendorff-perfused rabbit hearts. Alternans and VF were induced by rapid pacing. SR Ca(2+) and action potential duration (APD) alternans occurred in-phase, but SR Ca(2+) alternans emerged first as cycle length was progressively reduced (217±10 versus 190±13 ms; P<0.05). Ryanodine receptor (RyR) refractoriness played a key role in the onset of SR Ca(2+) alternans, with SR Ca(2+) release alternans routinely occurring without changes in diastolic [Ca(2+)]SR. Sensitizing RyR with caffeine (200 μmol/L) significantly reduced the pacing threshold for both SR Ca(2+) and APD alternans (188±15 and 173±12 ms; P<0.05 versus baseline). Caffeine also reduced the magnitude of spatially discordant SR Ca(2+) alternans, but not APD alternans, the pacing threshold for discordance, or threshold for VF. During VF, [Ca(2+)]SR was high, but RyR remained nearly continuously refractory, resulting in minimal SR Ca(2+) release throughout VF.In intact hearts, RyR refractoriness initiates SR Ca(2+) release alternans that can be amplified by diastolic [Ca(2+)]SR alternans and lead to APD alternans. Sensitizing RyR suppresses spatially concordant but not discordant SR Ca(2+) and APD alternans. Despite increased [Ca(2+)]SR during VF, SR Ca(2+) release was nearly continuously refractory. This novel method provides insight into SR Ca(2+) handling during cardiac alternans and arrhythmia.
Donor-Specific Antibodies Accelerate Arteriosclerosis after Kidney Transplantation
Authors: Gary S. Hill, Dominique Nochy, Patrick Bruneval, J. P. Duong van Huyen, Denis Glotz, Caroline Suberbielle, Julien Zuber, Dany Anglicheau, Jean-Philippe Empana, Christophe Legendre, Alexandre Loupy
Journal: Journal of the American Society of Nephrology (2011)

In biopsies of renal allografts, arteriosclerosis is often more severe than expected based on the age of the donor, even without a history of rejection vasculitis. To determine whether preformed donor-specific antibodies (DSAs) may contribute to the severity of arteriosclerosis, we examined protocol biopsies from patients with (n=40) or without (n=59) DSA after excluding those with any evidence of vasculitis. Among DSA-positive patients, arteriosclerosis significantly progressed between month 3 and month 12 after transplant (mean Banff cv score 0.65 ± 0.11 to 1.12 ± 0.10, P=0.014); in contrast, among DSA-negative patients, we did not detect a statistically significant progression during the same timeframe (mean Banff cv score 0.65 ± 0.11 to 0.81 ± 0.10, P=not significant). Available biopsies at later time points supported a rate of progression of arteriosclerosis in DSA-negative patients that was approximately one third that in DSA-positive patients. Accelerated arteriosclerosis was significantly associated with peritubular capillary leukocytic infiltration, glomerulitis, subclinical antibody-mediated rejection, and interstitial inflammation. In conclusion, these data support the hypothesis that donor-specific antibodies dramatically accelerate post-transplant progression of arteriosclerosis.
Interleukin-10 production by effector T cells: Th1 cells show self control
Authors: Giorgio Trinchieri
Journal: The Journal of Experimental Medicine (2007)

Interleukin (IL)-10 is a cytokine that modulates both innate and adaptive immunity, primarily by exerting antiinflammatory effects. IL-10 was originally thought to be produced only by T helper (Th)2 cells, but is now known to be made by a variety of cell types. During many infections, CD4+ T cells produce both interferon (IFN)-γ, the signature Th1 cytokine, and IL-10. New data now show that the IL-10 produced by effector Th1 cells helps limit the collateral damage caused by exaggerated inflammation. But this control may also limit the effectiveness of the immune response, resulting in a failure to fully eliminate pathogens.
Trimeric Intracellular Cation Channels and Sarcoplasmic/Endoplasmic Reticulum Calcium Homeostasis
Authors: Xinyu Zhou, Peihui Lin, Daiju Yamazaki, Ki Ho Park, Shinji Komazaki, S.R. Wayne Chen, Hiroshi Takeshima, Jianjie Ma
Journal: Circulation Research (2014)

Trimeric intracellular cation channels (TRIC) represents a novel class of trimeric intracellular cation channels. Two TRIC isoforms have been identified in both the human and the mouse genomes: TRIC-A, a subtype predominantly expressed in the sarcoplasmic reticulum (SR) of muscle cells, and TRIC-B, a ubiquitous subtype expressed in the endoplasmic reticulum (ER) of all tissues. Genetic ablation of either TRIC-A or TRIC-B leads to compromised K(+) permeation and Ca(2+) release across the SR/ER membrane, supporting the hypothesis that TRIC channels provide a counter balancing K(+) flux that reduces SR/ER membrane depolarization for maintenance of the electrochemical gradient that drives SR/ER Ca(2+) release. TRIC-A and TRIC-B seem to have differential functions in Ca(2+) signaling in excitable and nonexcitable cells. Tric-a(-/-) mice display defective Ca(2+) sparks and spontaneous transient outward currents in arterial smooth muscle and develop hypertension, in addition to skeletal muscle dysfunction. Knockout of TRIC-B results in abnormal IP3 receptor-mediated Ca(2+) release in airway epithelial cells, respiratory defects, and neonatal lethality. Double knockout mice lacking both TRIC-A and TRIC-B show embryonic lethality as a result of cardiac arrest. Such an aggravated lethality indicates that TRIC-A and TRIC-B share complementary physiological functions in Ca(2+) signaling in embryonic cardiomyocytes. Tric-a(-/-) and Tric-b(+/-) mice are viable and susceptible to stress-induced heart failure. Recent evidence suggests that TRIC-A directly modulates the function of the cardiac ryanodine receptor 2 Ca(2+) release channel, which in turn controls store-overload-induced Ca(2+) release from the SR. Thus, the TRIC channels, in addition to providing a countercurrent for SR/ER Ca(2+) release, may also function as accessory proteins that directly modulate the ryanodine receptor/IP3 receptor channel functions.
Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle
Authors: Zoltan Arany, Huamei He, Jiandie Lin, Kirsten Hoyer, Christoph Handschin, Okan Toka, Ferhaan Ahmad, Takashi Matsui, Sherry Chin, Pei-Hsuan Wu, Igor I. Rybkin, John M. Shelton, Monia Manieri, Saverio Cinti, Frederick J. Schoen, Rhonda Bassel-Duby, Anthony Rosenzweig, Joanne S. Ingwall, Bruce M. Spiegelman
Journal: Cell Metabolism (2005)
Phase I Study of Vandetanib During and After Radiotherapy in Children With Diffuse Intrinsic Pontine Glioma
Authors: Alberto Broniscer, Justin N. Baker, Michael Tagen, Arzu Onar-Thomas, Richard J. Gilbertson, Andrew M. Davidoff, Atmaram Pai Panandiker, Wing Leung, Thomas K. Chin, Clinton F. Stewart, Mehmet Kocak, Christopher Rowland, Thomas E. Merchant, Sue C. Kaste, Amar Gajjar
Journal: Journal of Clinical Oncology (2010)

Purpose To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. Patients and Methods Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy. Results Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m 2 (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039). Conclusion The recommended phase II dose of vandetanib in children is 145 mg/m 2 per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.
Comparison of T cell receptor alpha, beta, and gamma gene rearrangement and expression in T cell acute lymphoblastic leukemia.
Authors: J Hara, S H Benedict, E Champagne, T W Mak, M Minden, E W Gelfand
Journal: Journal of Clinical Investigation (1988)

We have analyzed the configuration of the T cell receptor (TCR) alpha gene using newly developed genomic joining region (J alpha) probes, which cover approximately 80 kb of the J alpha region upstream from the constant region in 19 patients with T cell acute lymphoblastic leukemia (T-ALL) and in three CD3- leukemic T cell lines (HSB2, CEM, and MOLT4). In parallel, transcription of the TCR-alpha, beta, and gamma genes was examined in 11 of these patients and in the T cell lines. All T-ALL and the three T cell lines exhibited both TCR-gamma and beta gene rearrangements. 8 of 10 T-ALL and all T cell lines expressed TCR-gamma transcripts. All samples tested expressed both TCR-beta and CD3-gamma transcripts. TCR alpha transcripts were only observed in CD3+ T-ALL but not in CD3- T-ALL or the CD3- cell lines. Among the CD3+ T-ALL, eight had TCR-alpha gene rearrangements. In addition, TCR-alpha gene rearrangements were detected in one CD3- T-ALL and all three T cell lines. These leukemic cells may represent a transient stage between rearrangement and expression and provide an opportunity for analyzing the mechanism regulating the expression of the TCR-alpha gene.
The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II
Authors: Lin Wang, Carol J. Soroka, James L. Boyer
Journal: Journal of Clinical Investigation (2002)

PFIC II is a subtype of progressive familial intrahepatic cholestasis (PFIC) that is associated with mutations in the ABCB11 gene encoding the bile salt export pump (BSEP). However it is not known how these mutations cause this disease. To evaluate these mechanisms, we introduced seven PFIC II–associated missense mutations into rat Bsep and assessed their effects on Bsep membrane localization and transport function in MDCK and Sf9 cells, respectively. Five mutations, G238V, E297G, G982R, R1153C, and R1268Q, prevented the protein from trafficking to the apical membrane, and E297G, G982R, R1153C, and R1268Q also abolished taurocholate transport activity, possibly by causing Bsep to misfold. Mutation C336S affected neither Bsep transport activity nor the apical trafficking of Bsep, suggesting that this mutation alone may not cause this disease. D482G did not affect the apical expression but partially decreased the transport activity of Bsep. Mutant G238V was rapidly degraded in both MDCK and Sf9 cells, and proteasome inhibitor resulted in intracellular accumulation of this and other mutants, suggesting proteasome-mediated degradation plays an important role in expression of these PFIC II mutants. Our studies highlight the heterogeneous nature of PFIC II mutations and illustrate the significance of these mutations in the function and expression of Bsep.
Influence of platelet-vessel wall interactions on leukocyte rolling in vivo.
Authors: M G oude Egbrink, G J Tangelder, D W Slaaf, R S Reneman
Journal: Circulation Research (1992)

The influence of platelet-vessel wall interactions on leukocyte rolling was investigated in rabbit mesenteric venules (diameter, 21-40 microns) using intravital videomicroscopy. Puncture of the wall with glass micropipettes (tip, 6-8 microns) evoked the formation of a thrombus in all venules. In most vessels, emboli were produced as well. The rolling of leukocytes (i.e., their movement along the vessel wall at a velocity clearly lower than that of the other blood cells) was quantitated simultaneously in vessel segments upstream and downstream from a thrombus up to 10 minutes after puncture. During embolization the number of rolling leukocytes decreased significantly from the upstream to the downstream vessel segment (median decrease, 45%; p less than or equal to 0.001). It was still decreased by approximately 50% after embolization had stopped, indicating that the decrease in leukocyte rolling was not caused by inclusion of leukocytes in the emboli. In venules without embolization, leukocyte rolling did not change systematically, indicating that fluid dynamic changes induced by the thrombus do not influence leukocyte rolling. Inhibition of prostaglandin formation with aspirin (100 mg/kg) almost completely abolished the influence of the thromboembolic reaction on leukocyte rolling, but blockade of thromboxane A2 receptors with sulotroban (30 mg/kg) had no effect. In conclusion, this is the first report on a functional interaction in vivo, at a site of vessel wall injury, between platelets, vascular cells, and leukocytes. The findings suggest that substances produced by activated platelets and/or damaged vascular cells diminish leukocyte rolling. The identity of these substances is not yet clear, but the present study indicates that prostaglandins other than thromboxane A2 are involved.
HIV–Associated Lipodystrophy: Pathogenesis, Prognosis, Treatment, and Controversies
Authors: Polyxeni Koutkia, Steven Grinspoon
Journal: Annual Review of Medicine (2004)

Potent antiretroviral agents markedly suppress HIV and have dramatically improved the clinical course, prognosis, and survival of HIV-infected patients. Unfortunately, highly active antiretroviral therapy is often compromised by metabolic complications, including insulin resistance, dyslipidemia, and fat redistribution. Together these changes have been termed the HIV-lipodystrophy syndrome, which is estimated to affect a majority of patients treated with potent combination antiretroviral therapy. Routine testing of fasting glucose is recommended for all HIV-infected patients, particularly those who are obese, have a family history of diabetes mellitus, or are receiving protease inhibitor therapy. Preliminary investigations have demonstrated the potential utility of insulin-sensitizing agents and lipid-lowering therapies to ameliorate these metabolic disturbances. Patients with HIV infection who demonstrate fat redistribution and develop hyperinsulinemia and dyslipidemia may be at increased risk of cardiovascular disease. However, the long-term effects on cardiovascular disease have not yet been determined.
Impact of Patient and Provider Characteristics on the Treatment and Outcomes of Colorectal Cancer
Authors: D C Hodgson, C S Fuchs, J Z Ayanian
Journal: JNCI Journal of the National Cancer Institute (2001)

While the management and prognosis of colorectal cancer are largely dependent on clinical features such as tumor stage, there is considerable variation in treatment and outcome not explained by traditional prognostic factors. To guide efforts by researchers and health-care providers to improve quality of care, we review studies of variation in treatment and outcome by patient and provider characteristics. Surgeon expertise and case volume are associated with improved tumor control, although surgeon and hospital factors are not associated consistently with perioperative mortality or long-term survival. Some studies indicate that patients are less likely to undergo permanent colostomy if they are treated by high-volume surgeons and hospitals. Differences in treatment and outcome of patients managed by health maintenance organizations or fee-for-service providers have not generally been found. Older patients are less likely to receive adjuvant therapy after surgery, even after adjustment for comorbid illness. In the United States, black patients with colorectal cancer receive less aggressive therapy and are more likely to die of this disease than white patients, but cancer-specific survival differences are reduced or eliminated when black patients receive comparable treatment. Patients of low socioeconomic status (SES) have worse survival than those of higher SES, although the reasons for this discrepancy are not well understood. Variations in treatment may arise from inadequate physician knowledge of practice guidelines, treatment decisions based on unmeasured clinical factors, or patient preferences. To improve quality of care for colorectal cancer, a better understanding of mechanisms underlying associations between patient and provider characteristics and outcomes is required.
On Being a Doctor Again
Authors: Cathy Liu
Journal: Annals of Internal Medicine (2014)

On Being a Doctor18 February 2014On Being a Doctor AgainCathy Liu, MDCathy Liu, MDFrom University of California, Davis, Sacramento, California.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M13-1105 Audio Reading - “On Being a Doctor Again” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "On Being a Doctor Again," by C. Liu. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail My life changed in an instant.I was in my second week of internal medicine residency at the University of California, Davis, School of Medicine. It was a relatively easy outpatient ambulatory month. On that fateful, sunny Friday in July 2007, I laced up my Asics shoes for my morning run. From my studio apartment, I set out down Freeport Boulevard at a good pace.I don't remember the car that hit me.I awoke from the coma after 1 month in the neurosurgical ICU. Confused, I opened my eyes, could not get oriented, then recognized my family. My parents ... Author, Article, and Disclosure InformationAffiliations: From University of California, Davis, Sacramento, California.Corresponding Author: Cathy Liu, MD, Department of Internal Medicine, University of California, Davis, 4150 V Street, Suite 2400, Sacramento, California 95817-1498; e-mail, 2cathy.[email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “On Being a Doctor Again” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "On Being a Doctor Again," by C. Liu. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics Cited byParadoxes in rehabilitation 18 February 2014Volume 160, Issue 4Page: 286-287KeywordsBrainComaDisabilitiesHemorrhageIntensive care unitsResidencySurgeonsTraumatic brain injuryWilderness ePublished: 18 February 2014 Issue Published: 18 February 2014 Copyright & PermissionsCopyright © 2014 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Anti-CD3 therapy permits regulatory T cells to surmount T cell receptor–specified peripheral niche constraints
Authors: Junko Nishio, Markus Feuerer, Jamie Wong, Diane Mathis, Christophe Benoist
Journal: The Journal of Experimental Medicine (2010)

Treatment with anti-CD3 is a promising therapeutic approach for autoimmune diabetes, but its mechanism of action remains unclear. Foxp3+ regulatory T (T reg) cells may be involved, but the evidence has been conflicting. We investigated this issue in mice derived from the NOD model, which were engineered so that T reg populations were perturbed, or could be manipulated by acute ablation or transfer. The data highlighted the involvement of Foxp3+ cells in anti-CD3 action. Rather than a generic influence on all T reg cells, the therapeutic effect seemed to involve an ∼50–60-fold expansion of previously constrained T reg cell populations; this expansion occurred not through conversion from Foxp3− conventional T (T conv) cells, but from a proliferative expansion. We found that T reg cells are normally constrained by TCR-specific niches in secondary lymphoid organs, and that intraclonal competition restrains their possibility for conversion and expansion in the spleen and lymph nodes, much as niche competition limits their selection in the thymus. The strong perturbations induced by anti-CD3 overcame these niche limitations, in a process dependent on receptors for interleukin-2 (IL-2) and IL-7.
Burden of Comorbid Medical Conditions and Quality of Diabetes Care
Authors: Jewell H. Halanych, Monika M. Safford, Wendy C. Keys, Sharina D. Person, James M. Shikany, Young-Il Kim, Robert M. Centor, Jeroan J. Allison
Journal: Diabetes Care (2007)

With performance-based reimbursement pressures, it is concerning that most performance measurements treat each condition in isolation, ignoring the complexities of patients with multiple comorbidities. We sought to examine the relationship between comorbidity and commonly assessed services for diabetic patients in a managed care organization.In 6,032 diabetic patients, we determined the association between the independent variable medical comorbidity, measured by the Charlson Comorbidity Index (CCI), and the dependent variables A1C testing, lipid testing, dilated eye exam, and urinary microalbumin testing. We calculated predicted probabilities of receiving tests for patients with increasing comorbid illnesses, adjusting for patient demographics.A1C and lipid testing decreased slightly at higher CCI: predicted probabilities for CCI quartiles 1, 2, 3, and 4 were 0.83 (95% CI 0.70-0.91), 0.83 (0.69-0.92), 0.82 (0.68-0.91), and 0.78 (0.61-0.88) for A1C, respectively, and 0.82 (0.69-0.91), 0.81(0.67-0.90), 0.79 (0.64-0.89), and 0.77 (0.61-0.88) for lipids. Dilated eye exam and urinary microalbumin testing did not differ across CCI quartiles: for quartiles 1, 2, 3, and 4, predicted probabilities were 0.48 (0.33-0.63), 0.54 (0.38-0.69), 0.50 (0.34-0.65), and 0.50 (0.34-0.65) for eye exam, respectively, and 0.23 (0.12-0.40), 0.24 (0.12-0.42), 0.24 (0.12-0.41), and 23 (0.11-0.40) for urinary microalbumin.Services received did not differ based on comorbid illness burden. Because it is not clear whether equally aggressive care confers equal benefits to patients with varying comorbid illness burden, more evidence confirming such benefits may be warranted before widespread implementation of pay-for-performance programs using currently available "one size fits all" performance measures.