Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms.

Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP.

MRI with intraoral orthodontic appliance-a comparative in vitro and in vivo study of image artefacts at 1.5 T.

OBJECTIVES: We investigated artefacts caused from orthodontic appliances at 1.5-T MRI of the head and neck region and whether the image quality can be improved utilizing the artefact-minimizing sequence WARP. METHODS: In vitro tests were performed by phantom measurements of different orthodontic devices applying different types of MR sequences [echoplanar imaging (EPI), turbo spin echo (TSE) and TSE-WARP, gradient echo (GRE)]. Two independent readers determined after calibration the level of artefacts. Subsequently, the interobserver agreement was calculated. The measurement of artefacts was based on the American Society for Testing Materials Standard F 2119-07. For in vivo imaging, one test person was scanned with an inserted multibracket appliance. The level of artefacts for 27 target regions was evaluated. RESULTS: In vitro: ceramic brackets and ferromagnetic steel brackets produced artefact radii up to 1.12 and 7.40 cm, respectively. WARP reduced these artefacts by an average of 32.7%. The Bland-Altman-Plot indicated that maximum measurement differences of 3 mm have to be expected with two calibrated observers. In vivo: the EPI sequence for brain imaging was not analysable. The TSE sequence of the brain did not demonstrate artefacts except for the nasal cavity. Conversely, the TSE sequence of the cervical spine revealed severe artefacts in the midface region. The GRE sequence appeared to be more susceptible to artefacts than did the TSE sequence. CONCLUSIONS: In vitro measurements allow an estimation of the in vivo artefact size. Orthodontic appliances may often remain intraorally when performing MRI. WARP showed a more significant effect in vitro than in vivo.