Case Report Short Stature in Chronic Kidney Disease Treated with Growth Hormone and an Aromatase Inhibitor

We describe an alternative strategy for management of severe growth failure in a 14-year-old child who presented with advanced chronic kidney disease close to puberty. The patient was initially treated with growth hormone for a year until kidney transplantation, followed immediately by a year-long course of an aromatase inhibitor, anastrozole, to prevent epiphyseal fusion and prolong the period of linear growth. Outcome was excellent, with successful transplant and anticipated complete correction of height deficit. This strategy may be appropriate for children with chronic kidney disease and short stature who are in puberty

A Novel Gene Deletion Associated With Xeroderma Pigmentosum And Type IA Growth Hormone Deficiency. 611

A 15 year old Chilean male, the product of a nonsanguineous uncle-niece marriage, has type IA GH deficiency and xeroderma pigmentosum (XP), both rare autosomal recessive disorders. Type IA growth hormone (GH) deficiency which is due to a 6.7 or 7.6 kb GH gene deletion is associated with production of antibodies in response to growth hormone therapy. XP causes freckling, xerosis and a variety of skin cancers. The underlying defect is abnormal DNA repair. Eight complementation groups A through G exist for XP. The chromosomal location of most of these genes has been identified (except for the `variant' type). None of these genes are known to map to the the GH locus on chromosome 17q22-q24. The XP in our patient is associated with skin freckling, actinic keratosis and basal cell carcinoma of the face. Fibroblast DNA repair studies following exposure to mitomycin C and ultraviolet C are compatible with`variant' XP. Molecular studies of the growth hormone gene locus show a novel deletion extending 5′ from the GH gene cluster and including the GH gene. GH deficiency and XP appear to be co-segregating in this family. One male sibling with GH deficiency died at the age of 4 years. He was not old enough to have developed XP and none of the remaining 6 brothers have GH deficiency or XP. We postulate that the unique gene deletion causing GH deficiency in this family, is also the location of a previously unmapped`variant' XP gene

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+ CCR7- CD45RA- effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T(CM)) cells. In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4(+)CCR7(−)CD45RA(−) effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T(CM)) cells. In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca(2+)-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted