Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism.

https://science.sciencemag.org/content/sci/226/4674/544.full.pdf

Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

Calcineurin Inhibitor Nephrotoxicity

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840020516

Evolution of Liver Transplantation

Type I diabetes may be an autoimmune disorder, although the evidence is largely circumstantial. The natural history of the disease after diagnosis includes partial remission in most patients, but only about 3 percent achieve transient insulin independence. beta Cell function, as indicated by the plasma concentration of C-peptide, is lost over 6 to 30 months and islet cell antibodies disappeared over 1 to 2 years. This article describes a pilot study in which 41 patients were treated with the immunosuppressive agent cyclosporine for 2 to 12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8 to 44 weeks after diagnosis, two achieved this state. These results indicate that a controlled trial of the effects of cyclosporine in type I diabetes should be conducted.

https://science.sciencemag.org/content/sci/223/4643/1362.full.pdf

Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset

https://escholarship.org/content/qt16g3d6mk/qt16g3d6mk.pdf

Nuclear magnetic resonance of laser-polarized noble gases in molecules, materials, and organisms.

Plasma alkaline phosphatase activity in preterm neonates.

Development of rickets in vitamin-D supplemented very-low-birthweight (VLBW) infants can be associated with low Phosphorus (P) and Calcium (Ca) intake Therefore, we estimated P and Ca intake of three VLBW-infants who were fed pooled human milk after birth and then switched to an adapted formula We measured P, Ca, activity of alkaline phosphatase and parathormone in serum and P and Ca excretion in urine P and Ca intake was below the estimated requirement for prematures with pooled human milk as well as with the adapted formula, on the other hand, Ca and especially P intake increased when infants were switched to the adapted formula When fed human milk we found evidence for a P deficiency in the body with signs of inadequate bone mineralisation On the adapted formula infants showed Ca deficiency but bone mineralisation improved From our findings we conclude that on pooled human milk VLBW-infants do not receive the required amount of P and Ca The signs of Ca deficiency on the adapted formula might be related to low Ca intake or to the P: Ca ratio of the formula which could be inadequate for VLBW-infants

Schilling R

Papers

Plasma alkaline phosphatase activity in preterm neonates.

Phosphorus and calcium metabolism of premature infants fed human milk and formulated milk