tbuckley/cabot-search huggingface dataset:
Intra–Sarcoplasmic Reticulum Free [Ca <sup>2+</sup> ] and Buffering in Arrhythmogenic Failing Rabbit Heart
Authors: Tao Guo, Xun Ai, Thomas R. Shannon, Steven M. Pogwizd, Donald M. Bers
Journal: Circulation Research (2007)

Smaller Ca2+ transients and systolic dysfunction in heart failure (HF) can be largely explained by reduced total sarcoplasmic reticulum (SR) Ca2+ content ([Ca]SRT). However, it is unknown whether low [Ca]SRT is manifest as reduced: (1) intra-SR free [Ca2+] ([Ca2+]SR), (2) intra-SR Ca2+ buffering, or (3) SR volume (as percentage of cell volume). Here we assess these possibilities in a well-characterized rabbit model of nonischemic HF. In HF versus control myocytes, diastolic [Ca2+]SR is similar at 0.1-Hz stimulation, but the increase in both [Ca2+]SR and [Ca]SRT as frequency increases to 1 Hz is blunted in HF. Direct measurement of intra-SR Ca2+ buffering (by simultaneous [Ca2+]SR and [Ca]SRT measurement) showed no change in HF. Diastolic [Ca]SRT changes paralleled [Ca2+]SR, suggesting that SR volume is not appreciably altered in HF. Thus, reduced [Ca]SRT in HF is associated with comparably reduced [Ca2+]SR. Fractional [Ca2+]SR depletion increased progressively with stimulation frequency in control but was blunted in HF (consistent with the blunted force-frequency relationship in HF). By studying a range of [Ca2+]SR, analysis showed that for a given [Ca]SR, fractional SR Ca2+ release was actually higher in HF. For both control and HF myocytes, SR Ca2+ release terminated when [Ca2+]SR dropped to 0.3 to 0.5 mmol/L during systole, consistent with a role for declining [Ca2+]SR in the dynamic shutoff of SR Ca2+ release. We conclude that low total SR Ca2+ content in HF, and reduced SR Ca2+ release, is attributable to reduced [Ca2+]SR, not to alterations in SR volume or Ca2+ buffering capacity.
Chemical modification of therapeutic drugs or drug vector systems to achieve targeted therapy: Looking for the grail
Authors: L. Juillerat‐Jeanneret, F. Schmitt
Journal: Medicinal Research Reviews (2006)

Abstract Most therapeutic drugs distribute to the whole body, which results in general toxicity and poor acceptance of the treatments by patients. The targeted delivery of chemotherapeutics to defined cells, either stromal or cancer cells in cancer lesions, or defined inflammatory cells in immunological disorders, is one of the main challenges and a very active field of research in the development of treatment strategies to minimize side‐effects of drugs. Disease‐associated cells express molecules, including proteases, receptors, or adhesion molecules, that are different or differently expressed than their normal counterparts. Therefore one goal in the field of targeted therapies is to develop chemically derivatized drugs or drug vectors able to target defined cells via specific recognition mechanisms and also able to overcome biological barriers. This article will review the approaches which have been explored to achieve these goals and will discuss in more detail three examples (i) the use of nanostructures to take advantage of increased vascular permeability in some human diseases, (ii) the targeting of therapeutic drugs to an organ, the brain, protected against foreign molecules by the blood–brain barrier, and (iii) the use of the folate receptor to target either tumor cells or activated macrophages. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 4, 574–590, 2007
L-Asparagine depletion in plasma and cerebro-spinal fluid of children with acute lymphoblastic leukemia during subsequent exposures to Erwinia L-asparaginase
Authors: D. Gentili, V. Conter, C. Rizzari, B. Tschuemperlin, M. Zucchetti, D. Orlandoni, M. D'Incalci, G. Masera
Journal: Annals of Oncology (1996)
Evolution and respiratory genetics
Authors: P. N. Le Souëf, P. Candelaria, J. Goldblatt
Journal: European Respiratory Journal (2006)

Evolution is a plausible explanation for between-population differences in particular allele frequencies if: the genes involved have related functions; the heterogeneous alleles involved have similar functional consequences; the involved genes are not linked chromosomally; and the patterns observed would result in a biologically plausible, survival-enhancing gene–environment interaction. However, possible evolutionary effects have to be differentiated from founder effects and random genetic drift. The current authors have noted the existence of a consistent pattern of allelic frequencies in genes related to T-helper 2 (Th2) immune responses in humans of different ancestral backgrounds, residing in climatically similar regions. Th2 responses are thought to have evolved in mammals to resist infection by parasites, particularly helminths. Modern man arose in tropical Africa where helminths thrived. Relatively recently, humans migrated to cooler or drier climates where most helminths struggled to reproduce. The genetic tendency to strong Th2 responses may have become a health liability, the reduction in risk from parasites being counterbalanced by an increased inherited propensity to atopic or allergic diseases. The pattern noted by the present authors includes specific alleles of interleukin-4 and its receptor, interleukin-13, interleukin-10, the β chain of the high-affinity receptor for immunoglobulin E, the β 1 -adrenergic receptor, and the alpha chain of tumour necrosis factor. These population-specific polymorphism profiles are likely to be relevant in current disease patterns. The high incidence of asthma in migrants from tropical locations to affluent temperate countries is likely to be related to these patterns. Of even more concern is the possibility that increasing westernisation among the ∼2 billion people living in the tropics will produce rapidly increasing levels of asthma, as these populations have a high genetic predisposition to allergic disease.
Comparative and functional genomics reveals genetic diversity and determinants of host specificity among reference strains and a large collection of Chinese isolates of the phytopathogen Xanthomonas campestris pv. campestris
Authors: Yong-Qiang He, Liang Zhang, Bo-Le Jiang, Zheng-Chun Zhang, Rong-Qi Xu, Dong-Jie Tang, Jing Qin, Wei Jiang, Xia Zhang, Jie Liao, Jin-Ru Cao, Sui-Sheng Zhang, Mei-Liang Wei, Xiao-Xia Liang, Guang-Tao Lu, Jia-Xun Feng, Baoshan Chen, Jing Cheng, Ji-Liang Tang
Journal: Genome biology (2007)

Xanthomonas campestris pathovar campestris (Xcc) is the causal agent of black rot disease of crucifers worldwide. The molecular genetic diversity and host specificity of Xcc are poorly understood.We constructed a microarray based on the complete genome sequence of Xcc strain 8004 and investigated the genetic diversity and host specificity of Xcc by array-based comparative genome hybridization analyses of 18 virulent strains. The results demonstrate that a genetic core comprising 3,405 of the 4,186 coding sequences (CDSs) spotted on the array are conserved and a flexible gene pool with 730 CDSs is absent/highly divergent (AHD). The results also revealed that 258 of the 304 proved/presumed pathogenicity genes are conserved and 46 are AHD. The conserved pathogenicity genes include mainly the genes involved in type I, II and III secretion systems, the quorum sensing system, extracellular enzymes and polysaccharide production, as well as many other proved pathogenicity genes, while the AHD CDSs contain the genes encoding type IV secretion system (T4SS) and type III-effectors. A Xcc T4SS-deletion mutant displayed the same virulence as wild type. Furthermore, three avirulence genes (avrXccC, avrXccE1 and avrBs1) were identified. avrXccC and avrXccE1 conferred avirulence on the hosts mustard cultivar Guangtou and Chinese cabbage cultivar Zhongbai-83, respectively, and avrBs1 conferred hypersensitive response on the nonhost pepper ECW10R.About 80% of the Xcc CDSs, including 258 proved/presumed pathogenicity genes, is conserved in different strains. Xcc T4SS is not involved in pathogenicity. An efficient strategy to identify avr genes determining host specificity from the AHD genes was developed.
Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol
Authors: Xavier Hébuterne, Marc Lémann, Yoram Bouhnik, Olivier Dewit, Jean-Louis Dupas, Michael Mross, Geert D'Haens, Krassimir Mitchev, Étienne Ernault, Séverine Vermeire, Hedia Brixi-Benmansour, Tom G Moreels, Jean-Yves Mary, Philippe Marteau, Jean-Frédéric Colombel
Journal: Gut (2012)

To evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD).This phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in ≥2 intestinal segments with a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≥8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score <6), complete remission (CDEIS score <3) and mucosal healing (no ulcer) at weeks 10 and 54.In the intention-to-treat population (n=89) the mean±SD CDEIS score was 14.5±5.3 at baseline; the mean decrease in CDEIS score at week 10 was 5.7 (95% CI 4.6 to 6.8, p<0.0001). Rates of endoscopic response, endoscopic remission, complete endoscopic remission and mucosal healing at week 10 were 54%, 37%, 10% and 4%, respectively. At week 54 the corresponding rates were 49%, 27%, 14% and 8%, respectively. The safety profile was consistent with that of previous CZP trials.Following CZP treatment in patients with active CD, endoscopic lesions were improved as shown by the decrease in mean CDEIS score and by endoscopic response and remission rates. These benefits were achieved as early as week 10 and were generally maintained through week 54.NCT00297648.
Interleukin 4 and T helper type 2 cells are required for development of experimental onchocercal keratitis (river blindness).
Authors: E Pearlman, J H Lass, D S Bardenstein, M Kopf, F E Hazlett, E Diaconu, J W Kazura
Journal: The Journal of Experimental Medicine (1995)

Inflammation of the corneal stroma (stromal keratitis) is a serious complication of infection with the nematode parasite Onchocerca volvulus. Because stromal keratitis is believed to be immunologically mediated in humans, we used a murine model to examine the role of T cells and T helper cell cytokines in the immunopathogenesis of these eye lesions. BALB/c mice immunized subcutaneously and injected intrastromally with soluble O. volvulus antigens (OvAg) developed pronounced corneal opacification and neovascularization. The corneal stroma was edematous and contained numerous eosinophils and mononuclear cells. Stromal keratitis in immunized mice was determined to be T cell dependent based on the following observations: (a) T cell-deficient nude mice immunized and injected intrastromally with OvAg fail to develop corneal pathology; and (b) adoptive transfer of spleen cells from OvAg-immunized BALB/c mice to naive nude mice before intrastromal injection of OvAg results in development of keratitis. OvAg-stimulated lymph node and spleen cell cytokine production was dependent on CD4 cells and included interleukin (IL)-4 and IL-5, but not interferon gamma, indicating a predominant T helper type 2 cell-like response. Inflamed corneas from immunized BALB/c mice and from reconstituted nude mice had greatly elevated CD4 and IL-4 gene expression compared with interferon gamma. Mice in which the IL-4 gene was disrupted failed to develop corneal disease, demonstrating that IL-4 is essential in the immunopathogenesis of O. volvulus-mediated stromal keratitis.
Currying favor for the heart
Authors: Jonathan A. Epstein
Journal: Journal of Clinical Investigation (2008)

Curcumin, a commonly available spice and alternative medicine, has been tested in the laboratory and the clinic for activity against a wide range of diseases. It is thought to possess antiinflammatory and antioxidant activities and may also function to inhibit histone acetyl transferases, which activate gene expression via chromatin remodeling. Two reports in this issue of the JCI, by Morimoto et al. and Li et al., suggest that curcumin may inhibit cardiac hypertrophy in rodent models and provide beneficial effects after myocardial infarction or in the setting of hypertension (see the related articles beginning on pages 868 and 879, respectively). These results will spur further mechanistic inquiry into the role of chromatin remodeling in the regulation of cardiac homeostasis.
Importance of the echocardiographic evaluation of right ventricular function in patients with AL amyloidosis
Authors: Stefano Ghio, Stefano Perlini, Giovanni Palladini, Nina Ajmone Marsan, Giovanna Faggiano, Monia Vezzoli, Catherine Klersy, Carlo Campana, Giampaolo Merlini, Luigi Tavazzi
Journal: European Journal of Heart Failure (2007)
Nitric oxide synthase plays a role in Chlamydia pneumoniae-induced atherosclerosis
Authors: B Chesebro
Journal: Cardiovascular Research (2003)

Objective:Chlamydia pneumoniae infection has been associated with atherosclerosis, although the mechanisms by which C. pneumoniae contribute to atherogenesis remain unclear. Altered production of nitric oxide, a known bactericidal and anti-inflammatory agent, represents one possible mechanistic link. To examine this issue, a diet-induced, hyperlipidemic mouse model of early atherosclerosis was used. Methods: A series of intranasal inoculations of C. pneumoniae strain AR-39 were administered to mice lacking endothelial or inducible nitric oxide synthase and to normal controls. After 18 weeks on an atherogenic diet, atherosclerotic lesion area in the aortic sinus was measured using computer-assisted morphometry. Results: In the absence of C. pneumoniae infection, diet-fed eNOS−/− mice developed enlarged fatty streak lesions of borderline significance in comparison to uninfected, wild-type mice, while the lesion area in uninfected, diet-fed iNOS−/− mice did not differ significantly from lesion area in wild-type animals. In contrast, lesion area in infected eNOS−/− mice increased slightly, but not significantly in comparison to uninfected eNOS−/− mice. Lesion area in the infected iNOS−/− mice was significantly enlarged when compared to both uninfected iNOS−/− mice as well as to infected wild-type mice. Conclusions: These data suggest that production of nitric oxide by eNOS protects against development of fatty streak lesions in uninfected hyperlipidemic mice, but does not offer additional protection in infected hyperlipidemic mice, while iNOS may play a protective role, thus limiting chlamydial exacerbation of fatty streak lesions.
Methacholine airway hyperresponsiveness is associated with fraction of nitric oxide irrespective of asthma
Authors: Sung-Il Woo, Dae-Hyun Kim, Jae-Young Jang, Youn-Soo Hahn
Journal: European Respiratory Journal (2012)

Background:  Augmented levels of fractional exhaled nitric oxide (FeNO) reflect airway inflammation and associated airway hyperresponsiveness (AHR) in asthma patient. There are many children who had no asthma but increased level of FeNO. We sought to evaluate the correlation between FeNO and AHR in children.   Methods:  Two hundred fourteen children, who had controlled asthma without controller, aged 8 to 16 years were included. Forty seven children without asthma were recruited from community school. Children were evaluated using FeNO measurements, skin prick test, spirometry, and methacholine challenge tests.   Results:  AHR was diagnosed in 153 (71.5%) children with asthma and 27 (57.4%) children without asthma. Geometric mean (GM) of FeNO was significantly higher in children with AHR compared children without AHR in both group (all, p  20  were negatively correlated for both children with asthma and children without asthma (r=-0.364, p   Conclusions:  Airway hyperresponsiveness is associated with level of FeNO irrespective asthma. These findings shows that inflammation of airway is associated with asymptomatic AHR.
Association of Autoimmunity to Autonomic Nervous Structures With Nerve Function in Patients With Type 1 Diabetes: A 16-Year Prospective Study
Authors: Maria M. Zanone, Alessandro Raviolo, Eleonora Coppo, Marina Trento, Martina Trevisan, Franco Cavallo, Enrica Favaro, Pietro Passera, Massimo Porta, Giovanni Camussi
Journal: Diabetes Care (2014)

OBJECTIVE We prospectively evaluated the association between autoimmunity to autonomic nervous structures and autonomic neuropathy in type 1 diabetes in relation to clinical variables. RESEARCH DESIGN AND METHODS A cohort of 112 patients with type 1 diabetes was prospectively followed from adolescence (T0) to approximately 4 (T4) and 16 (T16) years later. Standard cardiovascular (CV) tests and neurological examination were performed and related to the presence of circulating antibodies (Ab) to autonomic nervous structures detected at T0 and T4. Quality of life was assessed by a diabetes-specific questionnaire. RESULTS Sixty-six patients (59% of the cohort) were reexamined at T16 (age 31.4 ± 2 years; disease duration 23.4 ± 3.7 years). Nineteen had circulating Ab to autonomic structures. Prevalence of abnormal tests and autonomic symptoms were higher in Ab-positive (68 and 26%, respectively) than Ab-negative (32 and 4%) patients (P &amp;lt; 0.05). Among Ab-positive patients, the relative risk (RR) of having at least one altered CV test was 5.77 (95% CI 1.56–21.33), and an altered deep breathing (DB) test (&amp;lt;15 bpm) was 14.65 (2.48–86.46). Previous glycemic control was the only other predictor (RR 1.06 [1.002–1.13]/mmol/mol HbA1c increase). Presence of Ab carried over a 68% probability of developing an altered CV test; absence of Ab carried a 91% probability of not having an altered DB test and an 89% probability of not having an altered Valsalva ratio. Autonomic neuropathy was independently associated with worse quality of life. CONCLUSIONS Circulating Ab to autonomic structures are associated with the development of autonomic dysfunction in young diabetic patients independent of glycemic control.
Serum 1,5-Anhydroglucitol Concentrations Are a Reliable Index of Glycemic Control in Type 2 Diabetes With Mild or Moderate Renal Dysfunction
Authors: Won Jun Kim, Cheol-Young Park, Kyu-Beck Lee, Se Eun Park, Eun Jung Rhee, Won Young Lee, Ki Won Oh, Sung Woo Park
Journal: Diabetes Care (2011)

To assess the relationship between 1,5-anhydroglucitol (AG) levels, which are a marker of glycemic control, and stages of chronic kidney disease (CKD).This was a cross-sectional study with 269 subjects with type 2 diabetes who were divided into four groups based on estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (eGFR(MDRD)) formula: 57 in control, 111 in CKD stages 1-2, 78 in stage 3, and 23 in stages 4-5.The study groups differed significantly with respect to 1,5-AG and fasting plasma glucose (FPG), age, duration of diabetes, blood pressure, HDL, and percentage of antihypertension or antidyslipidemia medication use. Stepwise multivariate regression analyses showed that 1,5-AG levels in the control group, the CKD stages 1-2 group, and the CKD stage 3 group could be explained by HbA(1c), age, duration of diabetes, FPG, and antihypertension medication. However, eGFR(MDRD) was the only independent determinant of 1,5-AG levels in CKD stages 4-5. Logarithmic transformed 1,5-AG values (ln[1,5-AG]) had significant inverse correlations with HbA(1c) and FPG levels for CKD stages 1-2 and CKD stage 3 (all P < 0.001). However, associations between ln(1,5-AG) and HbA(1c) or FPG were insignificant for CKD stages 4-5 (P = 0.274 and P = 0.080, respectively).This study demonstrated that 1,5-AG levels do not appear to be influenced by mild or moderate renal dysfunction, suggesting it is a reliable glycemic marker in type 2 diabetes with CKD stages 1-3.
Investigation of signaling pathways that mediate the inotropic effect of urotensin-II in human heart
Authors: F RUSSELL
Journal: Cardiovascular Research (2004)

Objective: This study investigated signaling pathways that may contribute to the potent positive inotropic effect of human urotensin-II (hU-II) in human isolated right atrial trabeculae obtained from patients with coronary artery disease. Methods: Trabeculae were set up in tissue baths and stimulated to contract at 1 Hz. Tissues were incubated with 20 nM hU-II with or without phorbol 12-myristate 13-acetate (PMA, 10 μM) to desensitize PKC, the PKC inhibitor chelerythrine (10 μM), 10 μM 4α-phorbol that does not desensitize PKC, the myosin light chain kinase inhibitor wortmannin (50 nM, 10 μM), or the Rho kinase inhibitor Y-27632 (0.1–10 μM). Activated RhoA was determined by affinity immunoprecipitation, and phosphorylation of signaling proteins was determined by SDS-PAGE. Results: hU-II caused a potent positive inotropic response in atrial trabeculae, and this was concomitant with increased phosphorylation of regulatory myosin light chain (MLC-2, 1.8±0.4-fold, P<0.05, n=6) and PKCα/βII (1.4±0.2-fold compared to non-stimulated controls, P<0.05, n=7). Pretreatment of tissues with PMA caused a marked reduction in the inotropic effect of hU-II, but did not affect hU-II-mediated phosphorylation of MLC-2. The inotropic response was inhibited by chelerythrine, but not 4α-phorbol or wortmannin. Although Y-27632 also reduced the positive inotropic response to hU-II, this was associated with a marked reduction in basal force of contraction. RhoA.GTP was immunoprecipitated in tissues pretreated with or without hU-II, with findings showing no detectable activation of RhoA in the agonist stimulated tissues. Conclusions: The findings indicated that hU-II increased force of contraction in human heart via a PKC-dependent mechanism and increased phosphorylation of MLC-2, although this was independent of PKC. The positive inotropic effect was independent of myosin light chain kinase and RhoA-Rho kinase signaling pathways.
Insights into the Neurobiology of the Nicotinic Cholinergic System and Nicotine Addiction from Mice Expressing Nicotinic Receptors Harboring Gain-of-Function Mutations
Authors: Ryan M. Drenan, Henry A. Lester
Journal: Pharmacological Reviews (2012)

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated, cation-selective ion channels expressed throughout the brain. Although these channels have been investigated for several decades, it is still challenging 1) to identify the important nAChR subunits in cholinergic transmission and nicotine dependence and 2) to develop nAChR subtype-specific ligands. To overcome these challenges, we and others have studied mice expressing mutant, gain-of-function nAChR subunits. In this review, we discuss this research approach and the results it has yielded to date. Gain-of-function mutations, including those in nAChR subunits, provide an approach that is complementary to loss-of-function studies such as gene knockouts; the former allows one to answer questions of sufficiency and the latter addresses questions of necessity. Mutant mice expressing gain-of-function nAChR subunits are commonly produced using traditional gene targeting in embryonic stem cells, but novel approaches such as bacterial artificial chromosome transgenesis have yielded important insights as well. α7 nAChRs were the first nAChRs to be targeted with a gain-of-function mutation, followed by a pair of α4 nAChR gain-of-function mutant mice. These α4 nAChR gain-of-function mice (α4 L9′S mice, followed by α4 L9′A mice) provided an important system to probe α4 nAChR function in vivo, particularly in the dopamine reward system. α6 nAChR gain-of-function mice provided the first robust system allowing specific manipulation of this receptor subtype. Other targeted mutations in various nAChR subunits have also been produced and have yielded important insights into nicotinic cholinergic biology. As nAChR research advances and more details associated with nAChR expression and function emerge, we expect that existing and new mouse lines expressing gain-of-function nAChR subunits will continue to provide new insights.