Hassinen M, Paajanen V, Haverinen J, Eronen H, Vornanen M. Cloning and expression of cardiac Kir2.1 and Kir2.2 channels in thermally acclimated rainbow trout. Am J Physiol Regul Integr Comp Physiol 292: R2328-R2339, 2007. First published February 8, 2007 doi:10.1152/ajpregu.00354.2006.-Potassium currents are plastic entities that modify electrical activity of the heart in various physiological conditions including chronic thermal stress. We examined the molecular basis of the inward rectifier K ϩ current (IK1) in rainbow trout acclimated to cold (4°C, CA) and warm (18°C, WA) temperature. Inward rectifier K ϩ channel (Kir)2.1 and Kir2.2 transcripts were expressed in atrium and ventricle of the trout heart, K ir2.1 being the major component in both cardiac chambers. The relative expression of K ir2.2 was, however, higher (P Ͻ 0.05) in atrium than ventricle. The density of ventricular I K1 was ϳ25% larger (P Ͻ 0.05) in WA than CA trout. Furthermore, the I K1 of the WA trout was 10 times more sensitive to Ba 2ϩ (IC50 0.18 Ϯ 0.42 M) than the IK1 of the CA trout (1.17 Ϯ 0.44 M) (P Ͻ 0.05), and opening kinetics of single K ir2 channels was slower in WA than CA trout (P Ͻ 0.05). When expressed in COS-1 cells, the homomeric K ir2.2 channels demonstrated higher Ba 2ϩ sensitivity (2.88 Ϯ 0.42 M) than Kir2.1 channels (24.99 Ϯ 7.40 M) (P Ͻ 0.05). In light of the different Ba 2ϩ sensitivities of rainbow trout (om)Kir2.1 and omKir2.2 channels, it is concluded that warm acclimation increases either number or activity of the omKir2.2 channels in trout ventricular myocytes. The functional changes in I K1 are independent of omKir2 transcript levels, which remained unaltered by thermal acclimation. Collectively, these findings suggest that thermal acclimation modifies functional properties and subunit composition of the trout K ir2 channels, which may be needed for regulation of cardiac excitability at variable temperatures.inward rectifier potassium channels; atrial myocytes; ventricular myocytes; thermal plasticity STRONG INWARD RECTIFIER POTASSIUM (K ir ) channels conduct inward currents at membrane potentials negative to the K ϩ reversal potential but permit only limited K ϩ efflux at more positive voltages (18, 37) based on the voltage-dependent block of the channels by intracellular Mg 2ϩ and polyamines (8,9,17). The small outward current is physiologically important, since it sets resting membrane potential (RMP), controls excitability, and participates in diverse body functions in various organs. In the heart, the inward rectifier current (I K1 ) clamps the RMP close to K ϩ equilibrium potential and contributes to the late phase 3 repolarization of the action potential (AP) and thereby participates in the regulation of AP duration (18).On the basis of sequence homology, inward rectifier K ϩ channels have been classified into seven subfamilies, K ir 1-K ir 7 (5, 18). Inward rectifiers of the mammalian heart are homoor heterotetrameric assemblies of K ir 2.1-3 subunits (16,26,31,36,40) with substantial variation between spe...

Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients. It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator (SERM). To test these hypotheses, we have established novel MCF-7 cell line-derived in vitro models of anti-estrogen-and progestin-resistant and estrogen-independent breast cancer by long-term culture in the presence of toremifene and medroxyprogesterone acetate (MPA) and in the absence of estradiol, respectively. Using cell growth and multiprobe ribonuclease protection assays, the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied. Progesterone receptor (PR) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors (SMRT) and amplified in breast cancer-1 (AIB1) expression increased in antiestrogen-resistant cells. Estrogen caused PR and ERb upregulation in all cell lines, but we did not observe increased agonist activity of anti-estrogen measured by regulation of these estrogen target genes. Basal ERa levels and estrogenic growth response were decreased and p300/CBP-associated factor (pCAF) and AIB1 upregulated by estrogen in progestin-resistant cells, but coregulator levels were unchanged. Estrogen-independent cells were still estrogen-responsive and PR, nuclear receptor corepressor (NCoR) and SMRT expression was increased whereas steroid receptor coactivator-1 (SRC-1a) and CBP-related protein p300 (p300) expression decreased. Their growth was inhibited by toremifene, but estradiol was able to abrogate this effect, which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy. ' 2005 Wiley-Liss, Inc.

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Background and aims: Every fifth patient with ulcerative colitis (UC) experiences severe acute flare at some point in the course of the disease. Corticosteroids (Cs) remain the treatment of choice in acute flare. Data on the efficacy of first intravenous Cs in the long-term prognosis of UC are scarce and were investigated here. Materials and methods: All episodes of patients with acute UC admitted to Tampere University Hospital and treated with intravenous Cs between January 2007 and January 2016 were identified from patient records and reviewed. The risks for colectomy and for continuous use of Cs were evaluated. Predictive factors were analysed. Results: The study comprised 217 patients of whom 184 (85%) responded to intravenous Cs at index flare. Of the 33 non-responders, 31 (94%) were treated with intravenous cyclosporine A and 28 responded. Five (2.3%) patients needed emergency colectomy. Twenty-six (12%) patients underwent colectomy within 1 year of index flare. Overall colectomy rate was 56 (26%) during follow-up (median 7.5 years, range 0.1-10.5). Six months after index flare 66 (30%) patients were still on steroids. In this series 149 (69%) required further Cstherapy and 104 (48%) needed rehospitalization for new flare at some point during follow-up. Overall 155 patients were treated with thiopurines, of whom 72% within the first year after admission. A total of 36 patients had infliximab as a first-line biological treatment, nine needed second-line therapy with adalimumab or vedolizumab after infliximab failed. Conclusion: Although intravenous Cs were efficient in inducing clinical response in patients with severe acute UC, only one fifth maintained remission in the long term. Two-thirds of patients required further Cs and the overall colectomy rate remained at 26%. High relapse rate indicates the need for closer monitoring of these patients. Enhancement of maintenance therapy should be considered at early stage after acute flare.

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