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.

Background— The risk of ischemic events is high, both early and late after acute coronary syndromes (ACS). We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later (31 days to 12 months) in 12 562 patients with ACS. Methods and Results— A total of 12 562 ACS patients were randomized to receive clopidogrel (300 mg initially followed by 75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30 days was 5.4% in the placebo group and 4.3% in the active group (relative risk 0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3% versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia. Conclusions— Clopidogrel reduces the risk of ischemic vascular events, with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months (mean 9 months) of the study.

Abstract We examined the accuracy of preoperative assessment in predicting postoperative pulmonary risk in a prospective cohort of 272 consecutive patients referred for evaluation before nonthoracic surgery. Outcomes were assessed by an independent investigator who was blinded to the preoperative data. There were 22 (8%) postoperative pulmonary complications. Statistically significant predictors of pulmonary complications (all p ≤ 0.005) were as follows: hypercapnea of 45 mm Hg or more (odds ratio, 61.0), a FVC of less than 1.5 L/minute (odds ratio, 11.1), a maximal laryngeal height of 4 cm or less (odds ratio, 6.9), a forced expiratory time of 9 seconds or more (odds ratio, 5.7), smoking of 40 pack-years or more (odds ratio, 5.7), and a body mass index of 30 or more (odds ratio, 4.1). Multiple regression analyses revealed three preoperative clinical factors that are independently associated with pulmonary complications: an age of 65 years or more (odds ratio, 1.8; p = 0.02), smoking of 40 pack-years or more (odds ratio, 1.9; p = 0.02), and maximum laryngeal height of 4 cm or less (odds ratio, 2.0; p = 0.007). Thus, preoperative factors can identify those patients referred to pulmonologists or internists who are at increased risk for pulmonary complications after nonthoracic surgery.

In cultured endothelial cells, the antioxidant, l -ascorbic acid (vitamin C), increases nitric oxide synthase (NOS) enzyme activity via chemical stabilization of tetrahydrobiopterin. Our objective was to determine the effect of vitamin C on NOS function and tetrahydrobiopterin metabolism in vivo. Twenty-six to twenty-eight weeks of diet supplementation with vitamin C (1%/kg chow) significantly increased circulating levels of vitamin C in wild-type (C57BL/6J) and apolipoprotein E (apoE)–deficient mice. Measurements of NOS enzymatic activity in aortas of apoE-deficient mice indicated a significant increase in total NOS activity. However, this increase was mainly due to high activity of inducible NOS, whereas eNOS activity was reduced. Significantly higher tetrahydrobiopterin levels were detected in aortas of apoE-deficient mice. Long-term treatment with vitamin C restored endothelial NOS activity in aortas of apoE-deficient mice, but did not affect activity of inducible NOS. In addition, 7,8-dihydrobiopterin levels, an oxidized form of tetrahydrobiopterin, were decreased and vascular endothelial function of aortas was significantly improved in apoE-deficient mice. Interestingly, vitamin C also increased tetrahydrobiopterin and NOS activity in aortas of C57BL/6J mice. In contrast, long-term treatment with vitamin E (2000 U/kg chow) did not affect vascular NOS activity or metabolism of tetrahydrobiopterin. In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity.

Activation of CD4+ T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4+CD28null T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4+CD28null T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4+CD28null T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-γ production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH2-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal–regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4+CD28null T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4+CD28null T cells in RA.

Persistent spectral nonphotochemical hole-burning (NPHB) spectroscopy has recently been applied to dye molecules in cells. The sensitivity of NPHB to the nanoenvironment of the probe is well established. It has been shown that NPHB applied to bulk suspensions of cultured human cells can distinguish between normal and cancer cells. Thus, NPHB has potential as a diagnostic cancer tool. For this reason, the methodology is referred to as hole-burning imaging, by analogy with MRI. The optical dephasing time ( T 2 ) of the dye in hole-burning image replaces the proton T 1 relaxation time in MRI. In addition to the T 2 mode of operation, there are four other modes including measurement of the spectral hole growth kinetics (HGK). Reported here is that the selectivity and sensitivity of NPHB operating in the HGK mode allow for distinction between normal and carcinoma cells at the single-cell level. The ovarian cell lines are ovarian surface epithelial cells with temperature-sensitive large T antigens (analogously normal) and ovarian surface epithelial carcinoma (OV167) cells. The mitochondrial specific dye used was rhodamine 800 (Molecular Probes). This carbocationic dye is highly specific for the outer and inner membranes of mitochondria. In line with the results for bulk suspensions of the two cell lines, the hole-burning efficiency for OV167 cells was found to be significantly higher than that for normal cells. Theoretical analysis of the HGK data leads to the conclusion that the degree of structural heterogeneity for the probe–host configurations in OV167 cells is lower than in the normal cells. Possible reasons for this are given.