Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice

KARAP/DAP12 is a transmembrane polypeptide with an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). KARAP/DAP12 is associated with several activating cell surface receptors in hematopoietic cells. Here, we report that knockin mice bearing a nonfunctional KARAP/DAP12 ITAM present altered innate immune responses. Although in these mice NK cells are present and their repertoire of inhibitory MHC class I receptors is intact, the NK cell spectrum of natural cytotoxicity toward tumor cell targets is restricted. KARAP/DAP12 loss-of-function mutant mice also exhibit a dramatic accumulation of dendritic cells in muco-cutaneous epithelia, associated with an impaired hapten-specific contact sensitivity. Thus, despite its homology with CD3zeta and FcRgamma, KARAP/DAP12 plays a specific role in innate immunity, emphasizing the nonredundancy of these ITAM-bearing polypeptides in hematopoietic cells.     

Comparative study of time-course of hemodynamic effect of isosorbide dinitrate spray and sublingual tablets in patients with pulmonary congestion

Summary We compared the time-course of the hemodynamic effect of isosorbide dinitrate (ISDN), 5 mg, in the form of sublingual tablet and oral spray, in 15 patients with isolated chronic pulmonary congestion (pulmonary arterial end-diastolic pressure of 15 mmHg or more in the presence of normal or only slightly reduced cardiac index). Both formulations produced significant reductions in the pulmonary arterial end-diastolic pressure. The effect of ISDN tablet (sublingually) became evident at 10 minutes after administration and was maximal at 30 minutes. The effect of ISDN oral spray became evident at 3 minutes and reached a peak at 10 minutes. The magnitude of hemodynamic response was similar. These findings indicate that ISDN oral spray is superior to ISDN sublingual tablets for rapid relief of pulmonary congestion     

Abciximab therapy improves 1-month survival rate in unselected patients with acute myocardial infarction undergoing routine infarct artery stent implantation

Background The impact of abciximab therapy on mortality in unselected patients with acute myocardial infarction (AMI) undergoing routine primary infarct-related artery (IRA) stent implantation is not yet defined, and previous randomized studies have produced conflicting results. Methods A strategy of IRA stenting alone as opposed to IRA stenting plus abciximab was compared in a series of 561 consecutive unselected patients with AMI. Abciximab tretament was strongly encouraged for all patients. The contraindication for abciximab therapy was a high risk of major bleeding as assessed by the operator before mechanical intervention. Results Of 561 patients, 348 patients underwent abciximab therapy and 213 underwent primary IRA stenting alone. The 1-month overall mortality rate was 2.9% in the abciximab group and 10.8% in the stent alone group (P < .001). The relative reduction in mortality rate was 73% for patients overall, 77% in the subset of patients aged ≤70 years (mortality rate, 1.2% vs 5.2%, P = .020), 57% in patients aged >70 years (7.7% vs 18%, P = .043), 63% in patients with cardiogenic shock (17% vs 46%, P = .022), and 77% in patients without cardiogenic shock (1.3% vs 5.6%, P = .002). Multivariate analyses on the basis of all patients, and on the subset of patients aged ≤70 years, showed that abciximab therapy was independently related to the risk of death at 1 month. No differences were seen between groups in the procedural success rate (99.1% vs 98.1%) or in the incidence rates of nonfatal reinfarction (0.3% vs 1.9%) or repeat target vessel revascularization (1.7% vs 1.9%). Conclusion The results of this study strongly support the use of abciximab therapy in nonselected patients with AMI undergoing routine IRA stent implantation. The mechanism of the clinical benefit of abciximab was not related to the patency of the IRA. (Am Heart J 2002;144:315-22.)     

Multifactor‐dimensionality reduction reveals interaction of important gene variants involved in allergy

Elevated IgE levels in the atopic triad of asthma, allergic rhinitis and atopic dermatitis is a multifactorial condition whose genetic component involves interaction of several gene loci. One hundred and two matched pairs of allergic and nonallergic individuals were phenotyped for total serum IgE level using enzyme‐linked immunosorbent assay (ELISA). Atopic status was defined by serum IgE concentration ≥100 IU mL^?1. SNPs genotyped include the IL4 ‐590C>T (rs2243250), FCER1B E237G (rs569108), CD14 ‐159C>T (rs2569190), IL4RA Q551R (rs1801275) and ADRB2 R16G (rs1042713). Gene–gene interaction was analysed using multifactor‐dimensionality reduction (MDR). Significant association between atopic allergy and the IL4 ‐590C>T polymorphism was confirmed in three genetic models. Interaction among the 5 gene variants was validated by MDR. The five‐locus model was chosen as the best to describe the interaction of the SNPs within the context of atopy. The strongest interaction was between IL4 ‐590C>T and IL4RA Q551R and between FCER1B E237G and ADRB2 R16G. The IL4 variant also interacts synergistically with the FCER1B and ADRB2 coding variants. CD14 ‐159C>T, in general, interacts antagonistically with the rest of the SNPs. In conclusion, a five‐locus interaction exists among IL4 ‐590C>T, FCER1B E237G, CD14 ‐159C>T, IL4RA Q551R and ADRB2 R16G in Filipino cases of atopic allergy.     

Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies

This prospective study investigated the efficacy, safety, and response duration of low-dose rituximab (100 mg fixed dose for 4 weekly infusions) together with a short course of steroids as first- or second-line therapy in 23 patients with primary autoimmune hemolytic anemia (AIHA). The overall response was 82.6% at month +2, and subsequently stabilized to ～ 90% at months +6 and +12; the response was better in warm autoimmune hemolytic anemia (WAIHA; overall response, 100% at all time points) than in cold hemagglutinin disease (CHD; average, 60%); the relapse-free survival was 100% for WAIHA at +6 and +12 months versus 89% and 59% in CHD, respectively, and the estimated relapse-free survival at 2 years was 81% and 40% for the warm and cold forms, respectively. The risk of relapse was higher in CHD and in patients with a longer interval between diagnosis and enrollment. Steroid administration was reduced both as cumulative dose (～ 50%) and duration compared with the patient's past history. Treatment was well tolerated and no adverse events or infections were recorded; retreatment was also effective. The clinical response was correlated with amelioration biologic markers such as cytokine production (IFN-γ, IL-12, TNF-α, and IL-17), suggesting that low-dose rituximab exerts an immunomodulating activity. This study is registered at www.clinicaltrials.gov as NCT01345708.     

HPLC同时测定生物样品中新乌头碱、乌头碱、次乌头碱的含量

 目的建立同时测定血液、肝组织中新乌头碱(mesaconitine)、乌头碱(aconitine)、次乌头碱(hypaconitine)含量的HPLC分析方法。方法采用Welchrom C₁₈柱(4.6mm×250mm,5μm),以乙腈-0.03%四丁基氢氧化铵(用冰醋酸调至pH9.74)(58∶42)为流动相,流速为1.0mL·min^-1,检测波长为230nm。结果生物样品中新乌头碱在0.077～23mg·L^-1内线性关系良好(r=0.9998),乌头碱在0.083～25mg·L^-1内线性关系良好(r=0.9998),次乌头碱在0.08～24mg·L^-1内线性关系良好(r=0.9996)。生物样品中新乌头碱、乌头碱、次乌头碱的回收率不低于83.6%。生物样品中新乌头碱、乌头碱、次乌头碱的日内精密度和日间精密度分别在5.1%和9.3%以内。结论本方法简便、灵敏、准确,适用于血液、肝组织中新乌头碱、乌头碱、次乌头碱的分析。     

Systematic treatment of acute myocardial infarction with primary angioplasty. Early clinical and angiographic results and after 6 months

Starting in 1995, at our institution all patients with acute myocardial infarction (AMI) who gave informed consent were treated by primary percutaneous transluminal coronary angioplasty (PTCA) without limitations in entry criteria. This report presents early and six-month clinical and angiographic results of the 720 patients (77% male, median age 64 years) treated by direct PTCA between January 1, 1995 and July 31, 1998. On admission, 33% of patients were in Killip class > 1, and 101 patients (14%) were in early cardiogenic shock. Optimal acute angiographic success (TIMI grade 3 flow with residual stenosis < 30%) was achieved in 683 patients (95%). Primary or unplanned stenting of infarct related artery (IRA) for a suboptimal or poor angiographic result after primary PTCA was performed in 454 patients (63%). The mean time from hospital arrival to recanalization was 62 +/- 28 min. At 30 days, the mortality rate was 4.9% (1.8% in Killip class < 4 patients and 24% in patients with cardiogenic shock). The reinfarction rate was 1.2%. At 30 days, coronary angiography showed restenosis or reocclusion of the IRA in 55 patients (8.9%). During the six-month follow-up (30-180 days), there were 11 deaths (1.5%) and 2 non-fatal reinfarctions (0.3%). At six months, the IRA patency rate was 95%, while the mean ejection fraction improvement in 422 patients with paired ventriculograms was 7%. Recurrent ischemia occurred in 144 patients (20%) and resulted in 7 deaths, 11 non-fatal reinfarctions and 126 repeat targeted vessel revascularization. CONCLUSIONS: The major finding of our experience is that direct coronary angioplasty may result in excellent early and late outcome in a population without limitations in entry criteria. The low mortality and the few recurrent myocardial ischemic events are connected with the high patency rate at 6 months. The extensive use of stents improves the angiographic results and the clinical outcome.