KAP Degradation by Calpain Is Associated with CK2 Phosphorylation and Provides a Novel Mechanism for Cyclosporine A-Induced Proximal Tubule Injury

The use of cyclosporine A (CsA) is limited by its severe nephrotoxicity that includes reversible vasoconstrictor effects and proximal tubule cell injury, the latter associated whith chronic kidney disease progression. The mechanisms of CsA-induced tubular injury, mainly on the S3 segment, have not been completely elucidated. Kidney androgen-regulated protein (KAP) is exclusively expressed in kidney proximal tubule cells, interacts with the CsA-binding protein cyclophilin B and its expression diminishes in kidneys of CsA-treated mice. Since we reported that KAP protects against CsA toxicity in cultured proximal tubule cells, we hypothesized that low KAP levels found in kidneys of CsA-treated mice might correlate with proximal tubule cell injury. To test this hypothesis, we used KAP Tg mice developed in our laboratory and showed that these mice are more resistant to CsA-induced tubular injury than control littermates. Furthermore, we found that calpain, which was activated by CsA in cell cultures and kidney, is involved in KAP degradation and observed that phosphorylation of serine and threonine residues found in KAP PEST sequences by protein kinase CK2 enhances KAP degradation by calpain. Moreover, we also observed that CK2 inhibition protected against CsA-induced cytotoxicity. These findings point to a novel mechanism for CsA-induced kidney toxicity that might be useful in developing therapeutic strategies aimed at preventing tubular cell damage while maintaining the immunosuppressive effects of CsA

Off-Label Biologic Regimens in Psoriasis: A Systematic Review of Efficacy and Safety of Dose Escalation, Reduction, and Interrupted Biologic Therapy

Objectives: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment

Feeding Very-Low-Birth-Weight Infants: Our Aspirations versus the Reality in Practice

Recently, new guidelines for enteral feedings in premature infants were issued by the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition. Nevertheless, practice proves difficult to attain suggested intakes at all times, and occurrence of significant potential cumulative nutritional deficits 'lies in wait' in the neonatal intensive care unit. This review describes several aspects that are mandatory for optimizing nutritional intake in these vulnerable infants. These aspects range from optimal infrastructure to the initiation of parenteral nutrition with proper transition to enteral breast or formula feedings. Proper monitoring of nutritional tolerance includes serum biochemistry although proper specific markers are unknown and safety reference values are lacking. Although a lot of progress has been made through research during the last few decades, numerous questions still remain unanswered as to what would be the optimal quantity and quality of the various macronutrients. The inevitable suboptimal intake may, however, contribute significantly to the incidence of neonatal diseases, including impaired neurodevelopment. Therefore, it is pivotal that all hospital staff acknowledges that preterm birth is a nutritional emergency and that all must be done, both in clinical practice as well as in research, to reduce nutritional deficit