Citations

Abstract The prognostic heterogeneity of the World Health Organization category of “systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease” (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.

Rationale: Tissue factor pathway inhibitor (TFPI) is a potent regulator of the tissue factor pathway and is found in plasma in association with lipoproteins. Objective: To determine the role of TFPI in the development of atherosclerosis, we bred mice which overexpress TFPI into the apolipoprotein E–deficient (apoE −/− ) background. Methods and Results: On a high-fat diet, smooth muscle 22α (SM22α)-TFPI/apoE −/− mice were shown to have less aortic plaque burden compared to apoE −/− mice. Unexpectedly, SM22α-TFPI/apoE −/− had lower plasma cholesterol levels compared to apoE −/− mice. Furthermore, SM22α-TFPI mice fed a high-fat diet had lower cholesterol levels than did wild-type mice. Because TFPI is associated with lipoproteins and its carboxyl terminus (TFPIct) has been shown to be a ligand for the very-low-density lipoprotein (VLDL) receptor, we hypothesized that TFPI overexpression may regulate lipoprotein distribution. We quantified VLDL binding and uptake in vitro in mouse aortic smooth muscle cells from SM22α-TFPI and wild-type mice. Mouse aortic smooth muscle cells from SM22α-TFPI mice demonstrated higher VLDL binding and internalization compared to those from wild-type mice. Because SM22α-TFPI mice have increased circulating levels of TFPI antigen, we examined whether TFPIct may act to alter lipoprotein distribution. In vitro, TFPIct increased VLDL binding, uptake, and degradation in murine embryonic fibroblasts. Furthermore, this effect was blocked by heparinase treatment. In vivo, systemic administration of TFPIct reduced plasma cholesterol levels in apoE −/− mice. Conclusions: These studies suggest that overexpression of TFPI lowers plasma cholesterol through the interaction of its carboxyl terminus with lipoproteins and heparan sulfate proteoglycans.

This review discusses the use of extracorporeal membrane oxygenation (ECMO) for the treatment of respiratory failure in neonates. After briefly reviewing the early history of neonatal ECMO, the authors describe the respiratory diagnoses most often treated with ECMO and the manner in which affected neonates are deemed to have “failed” conventional therapies and thus require ECMO. After reviewing the most common indications for ECMO, factors that influence the timing of conversion to extracorporeal life support, as well as criteria that may exclude patients from receiving ECMO therapy, are described. At the conclusion of this article, the authors discuss the long-term outcomes of neonates whose respiratory disease was treated with ECMO and the costs associated with that care.

Since the first successful application of extracorporeal membrane oxygenation (ECMO) in 1972, ECMO’s role in the management of respiratory and circulatory collapse continues to be refined and debated. Randomized clinical trials aimed at establishing efficacy and patient selection criteria have been fraught with ethical challenges. Growing concerns over rising health care costs require that careful evaluations of cost, utilization, and ethical issues surrounding heroic life-saving interventions such as ECMO are undertaken. Continued analyses of ECMO’s place in the medical management of respiratory and circulatory failure will help ensure that ECMO is used for not only prolonging life but also for providing a chance for “quality of life” following recovery from near-fatal illnesses.

Abstract Agonists of TLR have been explored as vaccine adjuvants for tumor immunotherapy. However, their immunological consequences are not fully understood. Although TLR signaling increases the functional potential of dendritic cells (DCs) for priming T cells, coinduction of potentially negative immunoregulatory capacities may impair effector T cell generation. We examined the expression and function of B7 family costimulatory molecules on DCs after activation with the TLR3 agonist, polyinosinic:polycytidylic acid. We demonstrated that polyinosinic:polycytidylic acid consistently up-regulated both B7-2 and B7-H1 molecules on resident, migratory DCs from spleen and lymph nodes. Depletion or blockade of B7-H1 on activated DCs increased the magnitude of effector CD8 T cell expansion. DC-based or protein-based tumor vaccines, in combination with B7-H1 blockade, induced strong effector CD8 T cell responses, resulting in protective immunity against newly established tumors. Our studies suggest that TLR3 signaling has the potential to up-regulate both positive and negative coregulatory molecules on APCs. Selective blockade of negative regulatory molecules in combination with TLR3 agonist may be an effective strategy for increasing the efficacy of tumor vaccines.

Objectives: To assess the clinical effectiveness of Low Level Laser Therapy (LLLT) in the treatment of tendinopathy. Secondary objectives were to determine the relevance of irradiation parameters to outcomes, and the validity of current dosage recommendations for the treatment of tendinopathy. Background: LLLT is proposed as a possible treatment for tendon injuries. However, the clinical effectiveness of this modality remains controversial, with limited agreement on the most efficacious dosage and parameter choices. Method: The following databases were searched from inception to 1 st August 2008: MEDLINE, PubMed, CINAHL, AMED, EMBASE, All EBM reviews, PEDro (Physiotherapy Evidence Database), SCOPUS. Controlled clinical trials evaluating LLLT as a primary intervention for any tendinopathy were included in the review. Methodological quality was classified as: high (≥6 out of 10 on the PEDro scale) or low (<6) to grade the strength of evidence. Accuracy and clinical appropriateness of treatment parameters were assessed using established recommendations and guidelines. Results: Twenty-five controlled clinical trials met the inclusion criteria. There were conflicting findings from multiple trials: 12 showed positive effects and 13 were inconclusive or showed no effect. Dosages used in the 12 positive studies would support the existence of an effective dosage window that closely resembled current recommended guidelines. In two instances where pooling of data was possible, LLLT showed a positive effect size; in studies of lateral epicondylitis that scored ≥6 on the PEDro scale, participants' grip strength was 9.59 kg higher than that of the control group; for participants with Achilles tendinopathy, the effect was 13.6 mm less pain on a 100 mm visual analogue scale. Conclusion: LLLT can potentially be effective in treating tendinopathy when recommended dosages are used. The 12 positive studies provide strong evidence that positive outcomes are associated with the use of current dosage recommendations for the treatment of tendinopathy.

Background— KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I K1 . KCNJ2 mutations are associated with Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia. The aim of this study was to characterize the biophysical and cellular phenotype of a KCNJ2 missense mutation, V227F, found in a patient with catecholaminergic polymorphic ventricular tachycardia. Methods and Results— Kir2.1-wild-type (WT) and V227F channels were expressed individually and together in Cos-1 cells to measure I K1 by voltage clamp. Unlike typical Andersen-Tawil syndrome-associated KCNJ2 mutations, which show dominant negative loss of function, Kir2.1WT+V227F coexpression yielded I K1 indistinguishable from Kir2.1-WT under basal conditions. To simulate catecholamine activity, a protein kinase A (PKA)-stimulating cocktail composed of forskolin and 3-isobutyl-1-methylxanthine was used to increase PKA activity. This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I K1 compared with Kir2.1-WT. PKA-induced reduction in I K1 was eliminated by mutating the phosphorylation site at serine 425 (S425N). Conclusions— Heteromeric Kir2.1-V227F and WT channels showed an unusual latent loss of function biophysical phenotype that depended on PKA-dependent Kir2.1 phosphorylation. This biophysical phenotype, distinct from typical Andersen-Tawil syndrome mutations, suggests a specific mechanism for PKA-dependent I K1 dysfunction for this KCNJ2 mutation, which correlates with adrenergic conditions underlying the clinical arrhythmia.