Autoimmune enteropathy with a CD8+ CD7- T-cell small bowel intraepithelial lymphocytosis: case report and literature review

<p>Abstract</p> <p>Background</p> <p>Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, are uncertain. We present a unique case of AIE associated with a CD8+CD7- lymphocytosis and review the literature to characterize the histologic and immunologic abnormalities, and the autoantibodies and autoimmune conditions associated with AIE.</p> <p>Case Presentation</p> <p>We present a case of immune mediated enteropathy distinguished by the CD8+CD7- intra-epithelial and lamina propria lymphocytosis. Twenty-nine cases of AIE have been reported. The majority of patients had auto-antibodies (typically anti-enterocyte), preferential small bowel involvement, and predominately CD3+ CD4+ infiltrates. Common therapies included steroids or immuno-suppressive agents and clinical response with associated with histologic improvement.</p> <p>Conclusions</p> <p>AIE is most often characterized (1) IgG subclass anti-epithelial cell antibodies, (2) preferential small bowel involvement, and (3) CD3+ alphabeta TCR+ infiltrates; there is insufficient evidence to conclude CD4+ T-cells are solely responsible in all cases of AIE.</p

Expression of Human Frataxin Is Regulated by Transcription Factors SRF and TFAP2

Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression.We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2.We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia

Kv7 Channels Can Function without Constitutive Calmodulin Tethering

M-channels are voltage-gated potassium channels composed of Kv7.2-7.5 subunits that serve as important regulators of neuronal excitability. Calmodulin binding is required for Kv7 channel function and mutations in Kv7.2 that disrupt calmodulin binding cause Benign Familial Neonatal Convulsions (BFNC), a dominantly inherited human epilepsy. On the basis that Kv7.2 mutants deficient in calmodulin binding are not functional, calmodulin has been defined as an auxiliary subunit of Kv7 channels. However, we have identified a presumably phosphomimetic mutation S511D that permits calmodulin-independent function. Thus, our data reveal that constitutive tethering of calmodulin is not required for Kv7 channel function

Caring Agent for the Call: The Lived Experience of Nurses as Call Center Agents

A number of registered nurses are working as call center agents instead of practicing their profession. This phenomenological inquiry aimed to understand and provide perspective on the lived experience of seven registered nurses, who worked as a call center agent for at least two years. Through intensive recorded interviews, the responses were initially clustered in ten. The initial five clusters were categorized into textural themes such a) ceasing opportunities vs chasing pavements; b) learning to adjust; c) deception and false images: seeing from inside out; d) reflection on the derailed career path ; e) self-fulfillment in the chosen path.&nbsp; The final five clusters were categorized into structural theme such as f) making ends meet; becoming the breadwinner; g) change vs tradition; h) gaining strength through challenges; i) eyes on the patient, ears on the phone; j) vulnerability of the strong.&nbsp; In conclusion, the lived experience of nurses working as call center agents provided self-fulfillment, through financial stability that enable them to provide for their family, personality and career growth, and the benefits received. They cope with the challenges encountered on this job by being competitive and having a strong personality, though two of the participants resorted to vices

Toll-like Receptor 4 Activation Promotes Cardiac Arrhythmias By Decreasing The Transient Outward Potassium Current (ito) Through An Irf3-dependent And Myd88-independent Pathway

Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll-like receptors (TLRs) seem to be involved in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias, and the signaling pathway involved in these effects. Membrane potential was recorded in Wistar rat ventricle. Ca2+ transients, as well as the L-type Ca2+ current (ICaL) and the transient outward K+ current (Ito), were recorded in isolated myocytes after 24h exposure to the TLR4 agonist, lipopolysaccharide (LPS, 1μg/ml). TLR4 stimulation in vitro promoted a cardiac electrical remodeling that leads to action potential prolongation associated with arrhythmic events, such as delayed afterdepolarization and triggered activity. After 24h LPS incubation, Ito amplitude, as well as Kv4.3 and KChIP2 mRNA levels were reduced. The Ito decrease by LPS was prevented by inhibition of interferon regulatory factor 3 (IRF3), but not by inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4) or nuclear factor kappa B (NF-κB). Extrasystolic activity was present in 25% of the cells, but apart from that, Ca2+ transients and ICaL were not affected by LPS; however, Na+/Ca2+ exchanger (NCX) activity was apparently increased. We conclude that TLR4 activation decreased Ito, which increased AP duration via a MyD88-independent, IRF3-dependent pathway. The longer action potential, associated with enhanced Ca2+ efflux via NCX, could explain the presence of arrhythmias in the LPS group.767075Murray, C.J., Lopez, A.D., Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study (1997) Lancet, 349, pp. 1498-1504Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) (1994) Lancet, 344, pp. 1383-1389Algra, A., Tijssen, J.G., Roelandt, J.R., Pool, J., Lubsen, J., QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest (1991) Circulation, 83, pp. 1888-1894Casis, O., Gallego, M., Iriarte, M., Sánchez-Chapula, J.A., Effects of diabetic cardiomyopathy on regional electrophysiologic characteristics of rat ventricle (2000) Diabetologia, 43, pp. 101-109Kang, Y.J., Cardiac hypertrophy: a risk factor for QT-prolongation and cardiac sudden death (2006) Toxicol Pathol, 34, pp. 58-66Leurs, R., Church, M.K., Taglialatela, M., H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects (2002) Clin Exp Allergy, 32, pp. 489-498Monnerat-Cahli, G., Trentin-Sonoda, M., Guerra, B., Manso, G., Ferreira, A.C., Silva, D.L., Bone marrow mesenchymal stromal cells rescue cardiac function in streptozotocin-induced diabetic rats (2013) Int J Cardiol, 171, pp. 199-208Danesh, J., Wheeler, J.G., Hirschfield, G.M., Eda, S., Eiriksdottir, G., Rumley, A., C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease (2004) N Engl J Med, 350, pp. 1387-1397Scheruebel, S., Koyani, C.N., Hallström, S., Lang, P., Platzer, D., Mächler, H., If blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes (2014) J Mol Cell Cardiol, 72, pp. 64-73Devaraj, S., Dasu, M.R., Rockwood, J., Winter, W., Griffen, S.C., Jialal, I., Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state (2008) J Clin Endocrinol Metab, 93, pp. 578-583Casey, L.C., Balk, R.A., Bone, R.C., Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome (1993) Ann Intern Med, 119, pp. 771-778Nozaki, N., Shishido, T., Takeishi, Y., Kubota, I., Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice (2004) Circulation, 110, pp. 2869-2874Shishido, T., Nozaki, N., Yamaguchi, S., Shibata, Y., Nitobe, J., Miyamoto, T., Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction (2003) Circulation, 108, pp. 2905-2910Fallach, R., Shainberg, A., Avlas, O., Fainblut, M., Chepurko, Y., Porat, E., Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia (2010) J Mol Cell Cardiol, 48, pp. 1236-1244Panama, B.K., Latour-Villamil, D., Farman, G.P., Zhao, D., Bolz, S.-S., Kirshenbaum, L.A., Nuclear factor κB downregulates the transient outward potassium current Ito, f through control of KChIP2 expressionnovelty and significance (2011) Circ Res, 108, pp. 537-543Medei, E.H., Nascimento, J.H., Pedrosa, R.C., Barcellos, L., Masuda, M.O., Sicouri, S., Antibodies with beta-adrenergic activity from chronic chagasic patients modulate the QT interval and M cell action potential duration (2008) Europace, 10, pp. 868-876Penna, L.B., Bassani, R.A., Increased spontaneous activity and reduced inotropic response to catecholamines in ventricular myocytes from footshock-stressed rats (2010) Stress, 13, pp. 73-82Bassani, R.A., Ricardo, R.A., Bassani, J.W., Estimation of the fractional sarcoplasmic reticulum Ca2+ release in intact cardiomyocytes using integrated Ca2+ fluxes (2012) Gen Physiol Biophys, 31, pp. 401-408Bassani, R.A., Bassani, J.W., Bers, D.M., Mitochondrial and sarcolemmal Ca2+ transport reduce [Ca2+]i during caffeine contractures in rabbit cardiac myocytes (1992) J Physiol, 453, pp. 591-608Voigt, N., Heijman, J., Wang, Q., Chiang, D.Y., Li, N., Karck, M., Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation (2014) Circulation, 129, pp. 145-156Boyd, J.H., Mathur, S., Wang, Y., Bateman, R.M., Walley, K.R., Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response (2006) Cardiovasc Res, 72, pp. 384-393Oyama, J., Blais, C., Liu, X., Pu, M., Kobzik, L., Kelly, R.A., Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice (2004) Circulation, 109, pp. 784-789Zheng, Z.J., Croft, J.B., Giles, W.H., Mensah, G.A., Sudden cardiac death in the United States, 1989 to 1998 (2001) Circulation, 104, pp. 2158-2163Friedman, R.A., Kearney, D.L., Moak, J.P., Fenrich, A.L., Perry, J.C., Persistence of ventricular arrhythmia after resolution of occult myocarditis in children and young adults (1994) J Am Coll Cardiol, 24, pp. 780-783Wondergem, R., Graves, B.M., Ozment-Skelton, T.R., Li, C., Williams, D.L., Lipopolysaccharides directly decrease Ca2+ oscillations and the hyperpolarization-activated nonselective cation current If in immortalized HL-1 cardiomyocytes (2010) Am J Physiol Cell Physiol, 299, pp. C665-C671Medei, E., Marocolo, M., Rodrigues, D., Arantes, P.C., Takiya, C.M., Silva, J., Chronic treatment with anabolic steroids induces ventricular repolarization disturbances: cellular, ionic and molecular mechanism (2010) J Mol Cell Cardiol, 49, pp. 165-175Zhou, C., Ziegler, C., Birder, L.A., Stewart, A.F., Levitan, E.S., Angiotensin II and stretch activate NADPH oxidase to destabilize cardiac Kv4.3 channel mRNA (2006) Circ Res, 98, pp. 1040-1047Zhang, G., Ghosh, S., Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity (2001) J Clin Invest, 107, pp. 13-19Takeda, K., Akira, S., TLR signaling pathways (2004) Semin Immunol, 16, pp. 3-9Schlotthauer, K., Bers, D.M., Sarcoplasmic reticulum Ca(2+) release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials (2000) Circ Res, 87, pp. 774-780Ter Keurs, H.E., Boyden, P.A., Calcium and arrhythmogenesis (2007) Physiol Rev, 87, pp. 457-506Boer, D.C., Bassani, J.W., Bassani, R.A., Functional antagonism of β-adrenoceptor subtypes in the catecholamine-induced automatism in rat myocardium (2011) Br J Pharmacol, 162, pp. 1314-1325Carvalho, B.M., Bassani, R.A., Franchini, K.G., Bassani, J.W., Enhanced calcium mobilization in rat ventricular myocytes during the onset of pressure overload-induced hypertrophy (2006) Am J Physiol Heart Circ Physiol, 291, pp. H1803-H1813Pogwizd, S.M., Bers, D.M., Cellular basis of triggered arrhythmias in heart failure (2004) Trends Cardiovasc Med, 14, pp. 61-66Milberg, P., Pott, C., Fink, M., Frommeyer, G., Matsuda, T., Baba, A., Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3 (2008) Heart Rhythm, 5, pp. 1444-145