The recent development of haploid cell lines has facilitated forward genetic screenings in mammalian cells. These lines include nearhaploid human cell lines isolated from a patient with chronic myelogenous leukemia (KBM7 and HAP1), as well as haploid embryonic stem cells derived from several organisms. In all cases, haploidy was shown to be an unstable state, so that cultures of mammalian haploid cells rapidly become enriched in diploids. Here we show that the observed diploidization is due to a proliferative disadvantage of haploid cells compared with diploid cells. Accordingly, single-cell-sorted haploid mammalian cells maintain the haploid state for prolonged periods, owing to the absence of competing diploids. Although the duration of interphase is similar in haploid and diploid cells, haploid cells spend longer in mitosis, indicative of problems in chromosome segregation. In agreement with this, a substantial proportion of the haploids die at or shortly after the last mitosis through activation of a p53-dependent cytotoxic response. Finally, we show that p53 deletion stabilizes haploidy in human HAP1 cells and haploid mouse embryonic stem cells. We propose that, similar to aneuploidy or tetraploidy, haploidy triggers a p53-dependent response that limits the fitness of mammalian cells.haploidy | embryonic stem cells | p53 | HAP1 | chromosome segregation T he main advantage of yeast as a model organism for genetic studies is the availability of haploid cells, so that the mutation of a single allele can suffice to reveal a phenotype. This approach has been of enormous importance for biomedical research in recent decades, as exemplified by the number of Nobel Prizes awarded to discoveries that used yeast as a model system, including the discovery of autophagy, telomeres, and the cell cycle (1). In any case, there are questions intrinsic to mammalian biology, such as stemness or differentiation, that are difficult to address using yeast as a model, and that could be answered by the availability of mammalian haploid cell lines.

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Development of tuberculosis infection in a renal transplant patient is infrequent in Spain, although the prevalence is higher than in the general population. These patients usually receive calcineurin inhibitors as the main component of their immunosuppressive treatment. The metabolism of these drugs, whether cyclosporine or tacrolimus, involves cytochrome P-450 3A. Rifampin, a widely used agent in the treatment of tuberculosis, is also an important inducer of cytochrome P-450 3A metabolism and has the capacity to decrease serum levels of the calcineurin inhibitors. This metabolic interaction makes pharmacologic management of tuberculosis-infected transplant patients more complex and can result in a higher risk of acute rejection caused by decreased levels of the immunosuppressant in the blood. The authors present a case of a renal transplant patient with a soft tissue infection caused by Mycobacterium tuberculosis who was treated with rifabutin instead of rifampin, with excellent results in terms of graft survival and overall survival. The use of rifabutin allowed the authors to achieve better control of circulating immunosuppressant levels and a lower probability of acute graft rejection.

Simultaneous pancreas kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and end-stage renal disease. Rapamycin and mycophenolate mofetil (MMF) have been used for maintenance immunosuppression with tacrolimus in SPKT; however, long-term outcomes are lacking. From September 2000 through December 2009, 170 SPKT recipients were enrolled in a randomized, prospective trial receiving Rapamycin (n = 84) or MMF (n = 86). All patients received dual induction therapy with thymoglobulin and daclizumab, and low-dose maintenance tacrolimus and corticosteroids. Compared to MMF, rates of freedom from first biopsy-proven acute kidney or pancreas rejection were superior for Rapamycin at year 1 (kidney: 100% vs. 88%; P = 0.001; pancreas: 99% vs. 92%; P = 0.04) and at year 10 (kidney: 88% vs. 71%, P = 0.01; pancreas: 99% vs. 89%, P = 0.01). The higher rates of rejection were associated with withholding MMF (vs. Rapamycin, p = 0.009), generally for gastrointestinal or bone marrow toxicity. There was no significant difference in creatinine, proteinuria, c-peptide, viral infections, lymphoproliferative disorders or posttransplant diabetes. HbA1C and lipid levels were normal in both groups, although higher in the Rapamycin arm. There were no significant differences in patient or allograft survival. In this 10-year SPKT study, Rapamycin in combination with tacrolimus was better tolerated and more effective than MMF. Overall, the patient and allograft survival were equivalent.