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Triiodothyronine regulates energy metabolism and thermogenesis. Among triiodothyronine derivatives, 3,5-diiodo-L-thyronine (T2) has been shown to exert marked effects on energy metabolism by acting mainly at the mitochondrial level. Here we investigated the capacity of T2 to affect both skeletal muscle mitochondrial substrate oxidation and thermogenesis within 1h after its injection into hypothyroid rats. Administration of T2 induced an increase in mitochondrial oxidation when palmitoyl-CoA (+ 104%), palmitoylcamitine (+80%), or succinate (+30%) was used as substrate, but it had no effect when pyruvate was used. T2 was able to I) activate the AMPK-ACC-malonyl-CoA metabolic signaling pathway known to direct lipid partitioning toward oxidation and 2) increase the importing of fatty acids into the mitochondrion. These results suggest that T2 stimulates mitochondrial fatty acid oxidation by activating several metabolic pathways, such as the fatty acid import/β-oxidation cycle/FADH2-linked respiratory pathways, where fatty acids are imported. T2 also enhanced skeletal muscle mitochondrial thermogenesis by activating pathways involved in the dissipation of the proton-motive force not associated with ATP synthesis ("proton leak"), the effect being dependent on the presence of free fatty acids inside mitochondria. We conclude that skeletal muscle is a target for T2, and we propose that, by activating processes able to enhance mitochondrial fatty acid oxidation and thermogenesis, T2 could play a role in protecting skeletal muscle against excessive intramyocellular lipid storage, possibly allowing it to avoid functional disorders. [ABSTRACT FROM AUTHOR]

Summary:Severe combined immunodeficiency (SCID) is a heterogeneous group of disorders characterized by a severe defect of both T- and B-cell immunity, which generally require allogeneic bone marrow transplantation (BMT) within the first years of life. We previously reported a patient affected with an X-linked SCID due to L183S hemizygous missense ? chain mutation, whose severe short stature was due to a peripheral growth hormone (GH) hyporesponsiveness associated to abnormal GH receptor (GH-R) signal transduction. In this study, we report the effect of BMT on the GH-R/insulin-like growth factor I (IGF-I) axis. After BMT, the patient showed a significant improvement in linear growth and normalization of basal- and GH-stimulated IGF-I values, which paralleled a fully competent immunological reconstitution. This suggests that cells derived from the hematopoietic stem cell may exert an unexpectedly significant role in producing IGF-I. This may also suggest that stem cell-based therapies may be useful for the correction of non-hematopoietic inherited disorders, such as those of GH-R/IGF-I axis.Bone Marrow Transplantation (2004) 33, 773-775. doi:10.1038/sj.bmt.1704421 Published online 9 February 2004 [ABSTRACT FROM AUTHOR]

Familial hemophagocytic lymphohistiocytosis (FHLH) is a rare, rapidly progressive disorder of early childhood characterized by uncontrolled activation of T cells and macrophages. Although perforin gene mutations have been described in a proportion of patients with FHLH, the genotype/phenotype correlation is still limited. Only a few patients with late onset clinical manifestations have been reported. The biochemical and immunologic alterations in the asymptomatic phase are not well known. We report on a family in which 2 fraternal twins both homozygous for a perforin mutation previously described as causative of the disease, markedly differed in phenotypic expression of FHLH. The twins also had a second novel heterozygous mutation. Natural killer (NK) activity was severely impaired in the patient and was normal in the asymptomatic fraternal twin. Our report highlights that FHLH may present after a long disease-free interval during which biochemical or immunologic alterations may be not evident, thus implying a role for interfering factors.