Citations

Antithymocyte globulin (ATG) has recently been popularized as an effective treatment in myelodysplastic syndrome (MDS). We treated 8 anemic MDS patients (refractory anemia [RA] and refractory anemia with excess blasts [RAEB-1]) with ATG (40 mg/kg/d for 4 days) and prednisone in a phase 2 trial. The study was stopped early according to a preset termination rule because of lack of efficacy. There were no salutary responses. Toxicities included serum sickness (in all patients), transient neutropenia and thrombocytopenia, diarrhea, vomiting, and syncope with a generalized seizure. At least 3 patients had the HLA-DR15 (DR2) allele. We conclude that the risk-benefit ratio of ATG in an unselected population of MDS patients may be unfavorable, and more work is needed to define the subset of patients who will respond to ATG before its widespread use can be recommended.

OBJECTIVEThe goal was to examine the current scope of otolaryngologists’ practices, their geographic distribution, and the roles otolaryngologists and other specialists play in caring for patients with otolaryngic and related conditions of the head and neck.STUDY DESIGNA large national survey and administrative claims databases were examined to develop practice profiles and compile a physician supply for otolaryngology. A focus group of otolaryngologists provided information to model future scenarios.RESULTSThe current and predicted workforce supply and demographics are at a satisfactory level and are decreasing as a proportion of the increasing population. Empiric data analysis supports the diverse nature of an otolaryngologist's practice and the unique role for otolaryngologists that is not shared by many other providers. Together with the focus group results, the study points to areas for which more background and training are warranted.CONCLUSIONSThis study represents a first step in a process to form coherent workforce recommendations for the field of otolaryngology.

The ability to bind immunosuppressive drugs such as cyclosporin and FK506 defines the immunophilin family of proteins, and the FK506-binding proteins form the FKBP subfamily of immunophilins. Some FKBPs, notably FKBP12 (the 12-kDa FK506-binding protein), have defined roles in regulating ion channels or cell signaling, and well established structures. Other FKBPs, especially the larger ones, participate in important biological processes, but their exact roles and the structural bases for these roles are poorly defined. FKBP51 (the 51-kDa FKBP) associates with heat shock protein 90 (Hsp90) and appears in functionally mature steroid receptor complexes. In New World monkeys, FKBP51 has been implicated in cortisol resistance. We report here the x-ray structures of human FKBP51, to 2.7 Å, and squirrel monkey FKBP51, to 2.8 Å, by using multiwavelength anomalous dispersion phasing. FKBP51 is composed of three domains: two consecutive FKBP domains and a three-unit repeat of the TPR (tetratricopeptide repeat) domain. This structure of a multi-FKBP domain protein clarifies the arrangement of these domains and their possible interactions with other proteins. The two FKBP domains differ by an insertion in the second that affects the formation of the progesterone receptor complex.

Abstract Environmental factors play an important role in the rise and manifestation of allergic conditions in genetically predisposed subjects. Increased exposure to indoor/outdoor allergens is a significant factor in the development of allergic sensitization and asthma. Recently, strong relationships between the immune response to several highly purified allergens and specific human leukocyte antigen (HLA)-DQ and -DR haplotypes have been reported. The major antigens from clinically important allergens have been cloned and sequenced. However, whether innate structural features of major allergens or peculiar immune recognition of these molecules contribute to the overly robust immune responses is not known. We generated and used transgenic (tg) mice expressing single HLA class II transgene(s) to characterize the allergen epitopes presented by particular HLA class II molecules. Next, we generated in vivo models for asthma in the HLA tg mice by intranasal challenge with allergenic extracts. Furthermore, we used a single epitope to induce an allergic lung inflammation. Our system offers a sophisticated technique for systematically identifying the genetic (individual human class II) and antigenic (individual allergenic epitopes) basis of asthma sensitivity and has important implications for new treatment strategies.

Objective— C-reactive protein (CRP) is a sensitive marker of inflammation and a prognostic marker in cardiovascular disease. Evidence suggests direct biological activities of CRP within the vascular wall. The study was designed to examine the vasoreactive effects of CRP. Methods and Results— Human internal mammary artery rings were obtained during cardiovascular bypass surgery and suspended in an organ bath chamber. The rings were precontracted with endothelin-1, and response to cumulative concentrations of CRP was obtained. Experiments were repeated after initial incubation with 20, 40, and 60 mmol/L KCl, the potassium channel blockers BaCl, tetraethylammonium chloride, and glibenclamide, and the NO synthase inhibitor N -monomethyl- l -arginine and also after removal of the endothelium. CRP caused dose-dependent relaxation of human internal mammary artery rings, which was not affected by preincubation with N -monomethyl- l -arginine or removal of the endothelium. Maximum relaxation response to CRP (79.5±10%) was attenuated by KCl (2.5±11.5%, P <0.001), BaCl (24.5±7.5%, P <0.001), and tetraethylammonium chloride (34.9±8.25%, P <0.01) but not by glibenclamide. Conclusions– The present study demonstrates that CRP exerts an endothelium-independent vasorelaxing effect via potassium channels. Thus, the study suggests a role of CRP in the regulation of vascular tone.