Belatacept and Eculizumab for Treatment of Calcineurin Inhibitor-induced Thrombotic Microangiopathy After Kidney Transplantation: Case Report.

Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome. Belatacept, an inhibitor of T cell costimulatory protein CTLA-4 has been used in immunosuppression strategies aimed at minimization of CNI. Here we report the first case of treatment of CNI-associated TMA/hemolytic uremic syndrome with withdrawal of tacrolimus and initiation of both belatacept and eculizumab. The case describes a favorable clinical course for both graft and patient, and is accompanied by a review of the literature.

De Novo Belatacept in a Human Immunodeficiency Virus-Positive Kidney Transplant Recipient.

Benefits of belatacept-based immunosuppressive regimens in human immunodeficiency virus (HIV)-positive renal transplant recipients include avoidance of drug interactions between calcineurin inhibitors and highly active antiretroviral agents and decreased likelihood or severity of nonimmune toxicities such as new-onset diabetes after transplant, hyperlipidemia and hypertension. We report a successful case of de novo belatacept at >18 mo from transplant in an HIV-positive black man aged 50 years who received his first transplant from a living related kidney donor. To our knowledge, this case is the first reported of belatacept use in an HIV-positive renal transplant recipient.

Crystal structure of the carbapenem intrinsic resistance protein CarG.

In the Gram-negative enterobacterium Erwinia (Pectobacterium) and Serratia sp. ATCC 39006, intrinsic resistance to the carbapenem antibiotic 1-carbapen-2-em-3-carboxylic acid is mediated by the CarF and CarG proteins, by an unknown mechanism. Here, we report a high-resolution crystal structure for the Serratia sp. ATCC 39006 carbapenem resistance protein CarG. This structure of CarG is the first in the carbapenem intrinsic resistance (CIR) family of resistance proteins from carbapenem-producing bacteria. The crystal structure shows the protein to form a homodimer, in agreement with results from analytical gel filtration. The structure of CarG does not show homology with any known antibiotic resistance proteins nor does it belong to any well-characterised protein structural family. However, it is a close structural homologue of the bacterial inhibitor of invertebrate lysozyme, PliI-Ah, with some interesting structural variations, including the absence of the catalytic site responsible for lysozyme inhibition. Both proteins show a unique ß-sandwich fold with short terminal α-helices. The core of the protein is formed by stacked anti-parallel sheets that are individually very similar in the two proteins but differ in their packing interface, causing the splaying of the two sheets in CarG. Furthermore, a conserved cation binding site identified in CarG is absent from the homologue.

Dissolution and spectrophotometric determination of astaxanthin in aqueous solutions.

The poor solubility of astaxanthin in water can cause problems during dissolution tests of dosage forms because they are usually performed in water-based media. The aim of this study was the development of a convenient dissolution medium and a method for a spectrophotometric determination of astaxanthin in an aqueous solution. Three surfactants in different concentrations were tested as solubility-improving substances: sodium lauryl sulfate (SLS), polysorbate 80 (PS 80) and macrogolglycerol hydroxystearate (Cremophor RH 40, CR 40). Optimal conditions were determined. The dissolution of astaxanthin from solid dosage form is performed into 1000 g of a solution of sodium lauryl sulfate with the concentration 1.0% (w/w) at 37 degrees C by paddle method, 100 rotations per minute, dissolution time 30 minutes. The procedure is convenient for solid dosage forms with a content of 4 to 12 mg of astaxanthin. The spectrophotometric determination of astaxanthin in aqueous solution from the dissolution test is measured at 486 nm. The specific absorbance A(1%) 1cm for astaxanthin in water is 2000, a sodium lauryl sulfate solution (1%) was used as a blank.

Evolution of the role of the transplant pharmacist on the multidisciplinary transplant team.

Transplant pharmacists have been recognized as an essential part of the transplant team by their colleagues along with several governing and professional organizations. The specific education, training and responsibilities of the transplant pharmacist have not been clearly delineated in the literature. Various pharmacists across the country have been called upon to serve on the transplant team necessitating standardization of their fundamental and desirable activities. Therefore, the purpose of this manuscript is to describe the training and role of a transplant pharmacist on the patient care team and provide a roadmap to implementation of novel transplant pharmacy services.

Indomethacin release in relation to the concentration of pharmaceutical excipients.

Indomethacin in vitro release was investigated in relation to the concentration of the pharmaceutical excipients, such as ethanol and propylene glycol. Drug release was studied from gels containing Sepigel 305 as a gelling agent. Not only the concentration of ethanol and propylene glycol influence the rate of indomethacin release, but also Sepigel 305 significantly increased the amount of indomethacin release.

Protecting genomic integrity in somatic cells and embryonic stem cells.

Mutation frequencies at some loci in mammalian somatic cells in vivo approach 10(-4). The majority of these events occur as a consequence of loss of heterozygosity (LOH) due to mitotic recombination. Such high levels of DNA damage in somatic cells, which can accumulate with age, will cause injury and, after a latency period, may lead to somatic disease and ultimately death. This high level of DNA damage is untenable for germ cells, and by extrapolation for embryonic stem (ES) cells, that must recreate the organism. ES cells cannot tolerate such a high frequency of damage since mutations will immediately impact the altered cell, and subsequently the entire organism. Most importantly, the mutations may be passed on to future generations. ES cells, therefore, must have robust mechanisms to protect the integrity of their genomes. We have examined two such mechanisms. Firstly, we have shown that mutation frequencies and frequencies of mitotic recombination in ES cells are about 100-fold lower than in adult somatic cells or in isogenic mouse embryonic fibroblasts (MEFs). A second complementary protective mechanism eliminates those ES cells that have acquired a mutational burden, thereby maintaining a pristine population. Consistent with this hypothesis, ES cells lack a G1 checkpoint, and the two known signaling pathways that mediate the checkpoint are compromised. The checkpoint kinase, Chk2, which participates in both pathways is sequestered at centrosomes in ES cells and does not phosphorylate its substrates (i.e. p53 and Cdc25A) that must be modified to produce a G1 arrest. Ectopic expression of Chk2 does not rescue the p53-mediated pathway, but does restore the pathway mediated by Cdc25A. Wild type ES cells exposed to ionizing radiation do not accumulate in G1 but do so in S-phase and in G2. ES cells that ectopically express Chk2 undergo cell cycle arrest in G1 as well as G2, and appear to be protected from apoptosis.

Effect of beta-(1,3)-glucan on rheological properties and stability of topical formulations.

The paper deals with an effect of insoluble fungal beta-(1,3)-glucan on rheological properties of topical preparations. Two types of hydrogels (based on carbomer and polyacrylamide) and two types of hydrocreams (based on polysorbate 80/Span 80 and Brij 721TM/Brij 72) were prepared and investigated. The rheological properties of all these preparations were compared with the properties of placebos and they were measured after preparation and after 5 months of storage under different conditions: at 20 degrees C and 35 degrees C and after a triplicate freeze-thaw cycling process (-20 degrees C/+20 degrees C). In general it can be stated that with the exception of polyacrylamide hydrogel the beta-(1,3)-glucan presence increased the apparent viscosity of assessed preparations by approximately 10-20%. In the case of hydrocreams it was observed that the triplicate freeze-thaw cycling process increased the apparent viscosity of beta-(1,3)-glucan preparations by about 20-30%.