Long-term study of steroid avoidance in renal transplant patients: a single-center experience.

OBJECTIVES: Steroids have played a major role in renal transplantation for more than 4 decades. However, chronic use of steroids is associated with many comorbidities. This study aimed to assess the costs and benefits of a steroid-free immunosuppression regimen in a prospective randomized controlled study of living-donor renal transplantation, which was lacking in the literature. MATERIALS AND METHODS: In our study, 428 patients were enrolled to receive tacrolimus (Tac), mycophenolic acid (MPA), basiliximab (Simulect, Novartis, Basel, Switzerland) induction and steroids only for 3 days (214 patients, study group) and steroid maintenance (214 patients, control group). Median follow-up was 66 ± 41 months. RESULTS: We found that both groups showed comparable graft and patient survival, rejection episodes, and graft function. Posttransplantation hypertension was detected in 40% of the steroid-free group and 80% of the steroid maintenance group (P = .05), whereas posttransplantation diabetes mellitus was detected in 5% and 15% of these 2 groups, respectively (P = .3). CONCLUSIONS: Among low-immunological-risk recipients of living-donor renal transplants, steroid avoidance was feasible, safe, and had less morbidity outcome using Simulect induction, then Tac and MPA as maintenance immunosuppression. Steroid avoidance was associated with a lower total cost despite comparable immunosuppression cost, which was attributed to the lower cost of associated morbidities.

cSox3 expression and neurogenesis in the epibranchial placodes.

Epibranchial placodes are local thickenings of the surface ectoderm, which give rise to sensory neurons of the distal cranial ganglia. The development of these placodes has remained unclear due to the lack of any definitive marker for these structures. We show here that the chick transcription factor, cSox3, is expressed in four lateral patches at the rostral edge of the epibranchial arches and that these mark the epibranchial placodes. These patches of cSox3 expression arise by gradual thinning from broader areas of cSox3 expression with concomitant loss of cSox3 in nonplacodal regions. Cells leaving the epithelial placodes as they initiate neurogenesis, lose cSox3 expression and sequentially express Ngn1, NeuroD, NeuroM, and Phox2a, but do not express Ngn2. This is in contrast to studies in the mouse where it is Ngn2, rather than Ngn1, that is predominantly expressed in epibranchial-derived neuroblasts. Overexpression of cSox3 interferes with normal neuroblast migration and results in changes in ectodermal morphology. Thus, cSox3 provides a useful tool for the study of placode formation, and loss of cSox3 expression appears to be a necessary event in normal neurogenesis from the epibranchial placodes.

Sox3 expression defines a common primordium for the epibranchial placodes in chick.

The epibranchial placodes are ectodermal thickenings that generate sensory neurons of the distal ganglia of the branchial nerves. Although significant advances in our understanding of neurogenesis from the placodes have recently been made, the events prior to the onset of neurogenesis remain unclear. We found that chick Sox3 (cSox3) shows a highly dynamic pattern of expression before becoming confined to the final placodes: one pre-otic (geniculate) and three post-otic (one petrosal and two nodose) placodes. A fate-mapping study using lipophilic dyes revealed that all post-otic placodes arise within a single broad cSox3-positive domain, where cSox3 expression and epithelial thickness will be retained only in much smaller final neurogenic placodes. The data presented here suggest that post-otic placodes are remnants of a common primordium defined as a discrete domain of cSox3 expression.

Roles of Sox4 in central nervous system development.

The transcription factor-encoding gene, Sox4, is expressed in a wide range of tissues and has been shown to be functionally involved in heart, B-cell and reproductive system development. Sox4 shows a high degree of sequence homology with another group C Sox gene, Sox11, which is predominantly expressed in the CNS. Since the expression of Sox4 in the CNS has not been described we have carried out such a study. Sox4 and Sox11 expression increased simultaneously in the same early differentiating cells of the developing CNS except in the external granule layer of the cerebellum where Sox11 expression preceded that of Sox4. As development proceeded, their expression always appeared to relate to the maturational stage of the cell population, with Sox11 expression more transient than Sox4, except in the spinal cord where the reverse was true. Sox4 knock-out mice have been shown to die of a heart defect half way through gestation with no observable CNS phenotype. Our more detailed analysis showed no abnormality in the spatial restriction of expression of Sox2, Sox11, Mash1, neurogenin1 or neurogenin2, although the level of expression of Sox11 and Mash1 appeared a little different from the wild-type, implying that Sox4 might indeed have a functional role in CNS development. However, since Sox4 and Sox11 expression is so similar, we propose that Sox11 might compensate for the loss of Sox4 function in the CNS such that the phenotype is extremely mild in the Sox4 null mutant.

Chick sox10, a transcription factor expressed in both early neural crest cells and central nervous system.

Human SOX10 and mouse Sox10 have been cloned and shown to be expressed in the neural crest derivatives that contribute to formation of the peripheral nervous system during embryogenesis. Mutations in Sox10 have been identified as a cause of the Dominant megacolon mouse and Waardenburg-Shah syndrome in human, both of which include defects in the enteric nervous system and pigmentation (and in the latter, sometimes hearing). We have cloned a chick Sox10 ortholog (cSox10) in order to study its role in neural crest cell development. This cDNA reveals a 1383 bp open reading frame encoding 461 amino acids which is highly conserved with human SOX10 and mouse Sox10. In situ hybridization showed cSox10 is expressed in migrating neural crest cells just after the zinc finger transcription factor Slug, but is lost as cells undergo neuronal differentiation in ganglia of the peripheral nervous system. In addition, cSox10 is expressed in the developing otic vesicle, the developing central nervous system and pineal gland.