The taurine transporter: mechanisms of regulation.

Taurine transport undergoes an adaptive response to changes in taurine availability. Unlike most amino acids, taurine is not metabolized or incorporated into protein but remains free in the intracellular water. Most amino acids are reabsorbed at rates of 98-99%, but reabsorption of taurine may range from 40% to 99.5%. Factors that influence taurine accumulation include ionic environment, electrochemical charge, and post-translational and transcriptional factors. Among these are protein kinase C (PKC) activation and transactivation or repression by proto-oncogenes such as WT1, c-Jun, c-Myb and p53. Renal adaptive regulation of the taurine transporter (TauT) was studied in vivo and in vitro. Site-directed mutagenesis and the oocyte expression system were used to study post-translational regulation of the TauT by PKC. Reporter genes and Northern and Western blots were used to study transcriptional regulation of the taurine transporter gene (TauT). We demonstrated that (i) the body pool of taurine is controlled through renal adaptive regulation of TauT in response to taurine availability; (ii) ionic environment, electrochemical charge, pH, and developmental ontogeny influence renal taurine accumulation; (iii) the fourth segment of TauT is involved in the gating of taurine across the cell membrane, which is controlled by PKC phosphorylation of serine 322 at the post-translational level; (iv) expression of TauT is repressed by the p53 tumour suppressor gene and is transactivated by proto-oncogenes such as WT1, c-Jun, and c-Myb; and (v) over-expression of TauT protects renal cells from cisplatin-induced nephrotoxicity.

Regulation of TauT by cisplatin in LLC-PK1 renal cells.

Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. Since cisplatin-induced renal injury is mainly confined to the S3 segment of renal proximal tubules-the primary site for renal adaptive regulation of TauT-we hypothesize that TauT functions as an anti-apoptotic gene and plays a role in protecting renal cells from drug-induced nephrotoxicity. In the present study we demonstrated that expression of TauT was significantly reduced by cisplatin (50 muM) in LLC-PK1 cells. Down-regulation of TauT by cisplatin occurs at the transcriptional level in a dose-dependent manner, as demonstrated through a reporter gene driven by the TauT promoter. It appears that cisplatin down-regulates TauT expression, at least in part, through the p53-dependent pathway, since cisplatin induces the p53 expression, which, in turn, represses TauT. Cisplatin induces apoptosis of LLC-PK1 cells in a dose-dependent manner. However, forced over-expression of TauT by stable transfection of a taurine transporter cDNA (pNCT) in LLC-PK1 cells was able to attenuate cisplatin-induced down-regulation of taurine uptake by LLC-PK1 cells and protect renal tubular cells from apoptosis. The mechanism by which TauT serves as an anti-apoptotic gene in cisplatin-induced renal injury remains to be determined, but could relate to taurine-dependent cell volume regulation.

Promoting education, mentorship, and support for pediatric research.

Pediatricians have an important role to play in the advancement of child health research and should be encouraged and supported to pursue research activities. Education and training in child health research should be part of every level of pediatric training. Continuing education and access to research advisors should be available to practitioners and academic faculty. Recommendations to promote additional research education and support at all levels of pediatric training, from premedical to continuing medical education, as well as suggestions for means to increase support and mentorship for research activities, are outlined in this statement.

Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1alpha-hydroxyvitamin D(2)) in dialysis patients with secondary hyperparathyroidism: a sequential comparison.

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and >/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

Final report of the FOPE II Education of the Pediatrician Workgroup.

This report from the FOPE II Education of the Pediatrician Workgroup assesses the current status and future trends of pediatric education. The attributes of each level of the education process (undergraduate, residency, fellowship, continuing medical education [CME]) are considered within the framework of lifelong learning. The pediatric education of nonpediatrician providers is carefully considered. The Workgroup proposes and describes a new model for pediatric education that encompasses educational needs assessment, curriculum development and outcomes evaluation. Particular attention is paid to CME, with a review of the strengths and problems of the current system. The proposal for improving CME in the 21st century highlights the need for each pediatrician to have a "CME home," and several models and scenarios are explored. Appendices summarize the results of several surveys conducted on behalf of the Workgroup, and list societal trends and advances in pediatric health care that will influence pediatric education in the future. Pediatrics 2000;106(suppl):1175-1198; pediatric education, educational needs assessment, curriculum development, outcomes evaluation.

Final report of the FOPE II Pediatric Generalists of the Future Workgroup.

The Future of Pediatric Education II (FOPE II) Project was a 3-year, grant-funded initiative, which continued the work begun by the 1978 Task Force on the Future of Pediatric Education. Its primary goal was to proactively provide direction for pediatric education for the 21st century. To achieve this goal, 5 topic-specific workgroups were formed: 1) the Pediatric Generalists of the Future Workgroup, 2) the Pediatric Specialists of the Future Workgroup, 3) the Pediatric Workforce Workgroup, 4) the Financing of Pediatric Education Workgroup, and 5) the Education of the Pediatrician Workgroup. The FOPE II Final Report was recently published as a supplement to Pediatrics (The Future of Pediatric Education II: organizing pediatric education to meet the needs of infants, children, adolescents, and young adults in the 21st century. Pediatrics. 2000;105(suppl):161-212). It is also available on the project web site at: This report reflects the deliberations and recommendations of the Pediatric Generalists of the Future Workgroup of the Task Force on FOPE II. The report looks at 5 factors that have led to changes in child health needs and pediatric practice over the last 2 decades. The report then presents a vision for the role and scope of the pediatrician of the future and the core attributes, skills, and competencies pediatricians caring for infants, children, adolescents, and young adults will need in the 21st century. Pediatrics 2000;106(suppl):1199-1223; pediatrics, medical education, children, adolescents, health care delivery.

Final report of the FOPE II Pediatric Subspecialists of the Future Workgroup.

The report of the Pediatric Subspecialists of the Future Workgroup of the Second Task Force on Pediatric Education reviews the critical changes of the past 2 decades that have affected the provision of pediatric subspecialty services, education of pediatric health care providers, and the acquisition and application of new knowledge. The report considers the future needs that will determine the ability of pediatric subspecialists to meet identified goals. Recommendations for change in the education, role, and financing of the pediatric subspecialist are reported together with those of other workgroups. Pediatrics 2000;106(suppl):1224-1244; pediatric subspecialist, pediatric subspecialist workforce, education pediatric subspecialist, research pediatric subspecialist.

Final report of the FOPE II Pediatric Workforce Workgroup.

From the inception of the Future of Pediatric Education II (FOPE II) Project, it was acknowledged that any discussion of pediatric education would need to encompass a review of the pediatric workforce. This report looks at the current trends in pediatric workforce and draws some conclusions regarding future growth and composition. In addition to looking at demographic trends, ranging from geography to gender, the report explores influences including managed care, telemedicine, and others. Models for determining workforce needs are described and scenarios and projections are discussed. Pediatrics 2000;106(suppl):1245-1255; pediatric workforce.

Final report of the FOPE II Financing of Pediatric Education Workgroup.

Some of the challenges of financing pediatric medical education are shared with all medical education; others are specific to pediatrics. The general disadvantage that funding of graduate medical education (GME) is linked to reimbursement for clinical care has uniquely negative consequences for freestanding children's hospitals because they therefore receive little Medicare GME support. This represents both a competitive disadvantage for such hospitals and an aggregate federal underinvestment in children's health care that now amounts to billions of dollars. The need to subsidize medical student and subspecialty education with clinical practice revenue jeopardizes both activities in pediatric departments already burdened by inadequate reimbursement for children's health care and the extra costs of ambulatory care. The challenges of funding are complicated by rising costs as curriculum expands and clinical education moves to ambulatory settings. Controversies over prioritization of resources are inevitable. Solutions require specification of costs of education and a durable mechanism for building consensus within the pediatric community. Pediatrics 2000;106(suppl):1256-1269; medical student education, continuing medical education, medical subspecialties, children, pediatrics, health maintenance organizations, managed care, hospital finances, children's hospitals.

Peripheral gangrene complicating idiopathic and recessive hemolytic uremic syndromes.

Three patients with hemolytic uremic syndrome (HUS) developed peripheral gangrene. Bilateral carotid artery thromboses occurred in one of these patients after recovery from HUS. One patient had a long history of juvenile rheumatoid arthritis. In the second patient, a flu-like illness preceded the onset of HUS. The third was one of two sisters, with the HUS appearing more than 1 year apart. None had evidence of disseminated intravascular coagulation or infection with Streptococcus pneumoniae. The patient with rheumatoid arthritis had renal cortical necrosis but recovered moderate renal function after treatment with dialysis and plasmapheresis for 6 months. The child with a genetic form of HUS died of renal failure and had massive cortical necrosis and vascular thrombosis at autopsy. This is the first report of peripheral gangrene in children with idiopathic HUS and autosomal recessive HUS.

Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

The taurine transporter gene and its role in renal development.

This paper examines a unique hypothesis regarding an important role for taurine in renal development. Taurine-deficient neonatal kittens show renal developmental abnormalities, one of several lines of support for this speculation. Adaptive regulation of the taurine transporter gene is critical in mammalian species because maintenance of adequate tissue levels of taurine is essential to the normal development of the retina and the central nervous system. Observations of the remarkable phenotypic similarity that exists between children with deletion of bands p25-pter of chromosome 3 and taurine-deficient kits led us to hypothesize that deletion of the renal taurine transporter gene (TauT) might contribute to some features of the 3p-syndrome. Further, the renal taurine transporter gene is down-regulated by the tumor suppressor gene p53, and up-regulated by the Wilms tumor (WT-1) and early growth response-1 (EGR-1) genes. It has been demonstrated using WT-1 gene knockout mice that WT-1 is critical for normal renal development. In contrast, transgenic mice overexpressing the p53 gene have renal development defects, including hypoplasia similar to that observed in the taurine-deficient kitten. This paper reviews evidence that altered expression of the renal taurine transporter may result in reduced intracellular taurine content, which in turn may lead to abnormal cell volume regulation, cell death and, ultimately, defective renal development.