The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T₃) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen‐replete, 46 estrogen‐deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone‐specific alkaline phosphatase (BAP), cross‐linking terminal C‐telopeptide of type I collagen (CTX), procollagen type 1 amino‐terminal propeptide (P1NP), and cross‐linked N‐telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25‐hydroxyvitamin D, parathyroid hormone (PTH), thyroid‐stimulating hormone (TSH), and free triiodothyroxine (T₄) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild‐type subjects (p = .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone. © 2010 American Society for Bone and Mineral Research     

Mitral valve surgery for mitral regurgitation caused by Libman-Sacks endocarditis: a report of four cases and a systematic review of the literature

Libman-Sacks endocarditis of the mitral valve was first described by Libman and Sacks in 1924. Currently, the sterile verrucous vegetative lesions seen in Libman-Sacks endocarditis are regarded as a cardiac manifestation of both systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). Although typically mild and asymptomatic, complications of Libman-Sacks endocarditis may include superimposed bacterial endocarditis, thromboembolic events, and severe valvular regurgitation and/or stenosis requiring surgery. In this study we report two cases of mitral valve repair and two cases of mitral valve replacement for mitral regurgitation (MR) caused by Libman-Sacks endocarditis. In addition, we provide a systematic review of the English literature on mitral valve surgery for MR caused by Libman-Sacks endocarditis. This report shows that mitral valve repair is feasible and effective in young patients with relatively stable SLE and/or APS and only localized mitral valve abnormalities caused by Libman-Sacks endocarditis. Both clinical and echocardiographic follow-up after repair show excellent mid- and long-term results.     

Different causes of Reduced Sensitivity to Thyroid Hormone: Diagnosis and Clinical management

Normal thyroid hormone (TH) metabolism and action require adequate cellular TH signalling. This entails proper function of TH transporters in the plasma membrane, intracellular deiodination of TH and action of the bioactive hormone T3 at its nuclear receptors (TRs). The present review summarizes the discoveries of different syndromes with reduced sensitivity at the cellular level. Mutations in the TH transporter MCT8 cause psychomotor retardation and abnormal thyroid parameters. Mutations in the SBP2 protein, which is required for normal deiodination, give rise to a multisystem disorder including abnormal thyroid function tests. Mutations in TRβ1 are a well‐known cause of resistance to TH with mostly a mild phenotype, while only recently, patients with mutations in TRα1 were identified. The latter patients have slightly abnormal TH levels, growth retardation and cognitive defects. This review will describe the mechanisms of disease, clinical phenotype, diagnostic testing and suggestions for treatment strategies for each of these syndromes.     

Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung

BACKGROUND: We investigated CD4(+) memory T cell responses to influenza virus (FLU), respiratory syncytial virus (RSV), and nontypeable Haemophilus influenzae (NTHi). METHODS: The precursor frequencies of antigen-specific CD4(+) cells were determined by in vitro expansion of peripheral blood mononuclear cells from healthy individuals (n=9) and patients with chronic obstructive pulmonary disease (COPD; n=16). The expression of CD27 and CCR7 and the production of interferon (IFN)- gamma and interleukin-2 was measured directly ex vivo. Furthermore, the phenotypic and functional properties of CD4(+) T cells residing in the lung were analyzed and compared with those of circulating CD4(+)memory cells from the same donors (n=8). RESULTS: FLU-, RSV-, and NTHi-specific CD4(+) memory T cells circulated at low frequencies in the peripheral blood of healthy individuals and patients. RSV- and NTHi-specific CD4(+) T cells had a memory phenotype with moderate to high CD27 and CCR7 expression. In contrast to the low frequencies of circulating FLU-specific CD4(+) T cells, we found an enrichment of differentiated CD4(+) FLU-specific cells and high IFN- gamma expression in CD4(+) memory cells in lung tissue. CONCLUSION: No gross defects were found in circulating CD4(+) memory cells specific for pathogens associated with COPD. However, the large differentiated CD4(+) memory T cell pool residing in the lung may contribute to a large extent to local antiviral immunological protection.     

Absence of donor T-cell-derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity

Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-alpha converting enzyme (TACE). To study the contribution of donor T-cell-derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNF(Delta/Delta)) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.