Early intervention for lactate dehydrogenase elevation improves clinical outcomes in patients with the HeartMate II left ventricular assist device: Insights from the PREVENT study

BACKGROUND: Hemolysis, assessed by elevated serum lactate dehydrogenase (LDH), is strongly associated with HeartMate II pump thrombosis (PT). However, it is unknown whether early intervention for elevated LDH circumvents the risk of serious PT requiring pump exchange. We sought to evaluate the relationship between elevated LDH and clinical outcomes, the effectiveness of early medical intervention, and risk factors for elevated LDH. METHODS: We studied 268 patients in the prospective, multicenter PREVENT study who had 2 or more LDH measurements at ≥30 days post-implant. Elevated LDH was defined as LDH ≥2.5× upper limit of normal (ULN) for 2 consecutive measurements. RESULTS: Fourteen percent of patients had elevated LDH. Stroke-free survival at 6 months was lower in patients with elevated LDH vs patients with normal LDH (83 ± 6% vs 93 ± 2%, p = 0.035). Elevated LDH resolved without intervention in 19% of patients, with intensified medical therapy in 43% and required surgical intervention in 38%. For patients receiving only medical therapy, survival was 94 ± 6% at 6 months post-treatment. In this subgroup, resolution of symptoms with intensified medical therapy was sustained in 15 of 16 patients, with PT occurring in 1 patient at 171 days after initial treatment for elevated LDH (202 days post-implant). Early medical intervention at moderately elevated LDH (2.5× to 3.2× ULN), as compared with higher levels (>3.2× ULN), led to more sustained resolution of symptoms without subsequent PT or need for surgical intervention (91% vs 26% at 6 months post-treatment, p = 0.002). CONCLUSIONS: Early medical intervention can successfully resolve moderate LDH elevations (2.5× to 3.2× ULN) with a low incidence of death or PT at 6 months post-treatment

L-leucine improves anemia and growth in patients with transfusion-dependent Diamond Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond Blackfan Anemia Registry

Background: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA. Procedure: Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595). Results: This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy. Conclusions: L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Building a tuberculosis-free world: The Lancet Commission on tuberculosis

___Key messages___ The Commission recommends five priority investments to achieve a tuberculosis-free world within a generation. These investments are designed to fulfil the mandate of the UN High Level Meeting on tuberculosis. In addition, they answer

The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation

The transcription factor Foxp3 and Stat5 modulate lineage stability and function of regulatory T (Treg) cells to promote immune homeostasis. Here the authors show that O-GlcNAcylation of Foxp3 and Stat5, mediated by O-GlcNAc transferase (OGT), is essential for Treg-mediate immune balance, with Treg-specific deficiency of OGT leading to severe autoimmunity