Obesity as a risk factor for sustained ventricular tachyarrhythmias in MADIT II patients

Background: Obesity, as defined by body mass index ≥30 kg/m², has been shown to be a risk factor for cardiovascular disease. However, data on the relationship between body mass index (BMI) and the risk of ventricular arrhythmias and sudden cardiac death are limited. The aim of this study was to evaluate the risk of ventricular tachyarrhythmias and sudden death by BMI in patients after myocardial infarction with severe left ventricular dysfunction.
Methods : The risk of appropriate defibrillator therapy for ventricular tachycardia or ventricular fibrillation (VT/VF) by BMI status was analyzed in 476 nondiabetic patients with left ventricular dysfunction who received an implantable cardioverter defibrillator (ICD) in the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT II).
Results : Mean BMI was 27 ± 5 kg/m². Obese patients comprised 25% of the study population. After 2 years of follow-up, the cumulative rates of appropriate ICD therapy for VT/VF were 39% in obese and 24% in nonobese patients, respectively (P = 0.014). In multivariate analysis, there was a significant 64% increase in the risk for appropriate ICD therapy among obese patients as compared with nonobese patients, which was attributed mainly to an 86% increase in the risk of appropriate ICD shocks (P = 0.006). Consistent with these results, the risk of the combined endpoint of appropriate VT/VF therapy or sudden cardiac death (SCD) was also significantly increased among obese patients (Hazard Ratio 1.59; P = 0.01).
Conclusions : Our findings suggest that in nondiabetic patients with ischemic left ventricular dysfunction, a BMI ≥30 kg/m² is an independent risk factor for ventricular tachyarrhythmias.     

潍坊地区329例RhD(-)者Rh表现型、MN、P血型抗原分布

目的探讨潍坊地区RhD阴性献血者Rh表现型、MN及P血型分布特点。方法采用血清学凝集方法对329名RhD阴性献血者的Rh表现型、MN及P血型进行分型。结果Rh表现型:ccdee占58.06%,Ccdee占27.36%,ccdEe占7.6%,CcdEe占3.04%,CCdee占2.43%,ccdEE占0.91%,CCdEe占0.30%,CcdEE占0.30%;MN血:M占22.49%,N占26.45%MN占51.06%;P血型:P1占41.3%,P2占58.7%。结论摸清了潍坊地区RhD阴性献血者红细胞血型分布特点,建立了稀有血型管理档案,为Rh阴性患者储备了宝贵的血液。     

Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome

The polycomb repressive complex (PRC) 1 protein Ring1B is an ubiquitin ligase that modifies nucleosomal histone H2A, a modification which plays a critical role in regulation of gene expression. We have shown that self-ubiquitination of Ring1B generates multiply branched, “noncanonical” polyubiquitin chains that do not target the ligase for degradation, but rather stimulate its activity toward histone H2A. This finding implies that Ring1B is targeted by a heterologous E3. In this study, we identified E6-AP (E6-associated protein) as a ligase that targets Ring1B for “canonical” ubiquitination and subsequent degradation. We further demonstrated that both the self-ubiquitination of Ring1B and its modification by E6-AP target the same lysines, suggesting that the fate of Ring1B is tightly regulated (e.g., activation vs. degradation) by the type of chains and the ligase that catalyzes their formation. As expected, inactivation of E6-AP affects downstream effectors: Ring1B and ubiquitinated H2A levels are increased accompanied by repressed expression of HoxB9, a PRC1 target gene. Consistent with these findings, E6-AP knockout mice display an elevated level of Ring1B and ubiquitinated histone H2A in various tissues, including cerebellar Purkinje neurons, which may have implications to the pathogenesis of Angelman syndrome, a neurodevelopmental disorder caused by deficiency of E6-AP in the brain.     

Crohn＇s disease and risk of fracture： does thyroid disease play a role？

AIM: To assess the role of thyroid disease as a risk for fractures in Crohn‘s patients.METHODS: A cross-sectional study was conducted from 1998 to 2000. The study group consisted of 210 patients with Crohn‘s disease. A group of 206 patients without inflammatory bowel disease served as controls. Primary outcome was thyroid disorder. Secondary outcomes included use of steroids, immunosuppressive medications, surgery and incidence of fracture.RESULTS: The prevalence of hyperthyroidism was similar in both groups. However, the prevalence of hypothyroidism was lower in Crohn‘s patients (3.8 % vs 8.2 %, P=0.05).Within the Crohn‘s group, the use of immunosuppressive agents (0 % vs11%), steroid usage (12.5 % vs37 %), small bowel surgery (12.5 % vs 28 %) and large bowel surgery(12.5 % vs 27 %) were lower in the hypothyroid subset as compared to the euthyroid subset. Seven (3.4 %) Crohn‘s patients suffered fracture, all of whom were euthyroid.CONCLUSION: Thyroid disorder was not found to be associated with Crohn‘s disease and was not found to increase the risk for fractures. Therefore, screening for thyroid disease is not a necessary component in the management of Crohn‘s disease.     

Treatment of arrhythmias and use of implantable cardioverter-defibrillators to improve survival in elderly patients with cardiac disease

Patients who have left ventricular dysfunction and heart failure(HF) are at high risk for ventricular tachyarrhythmias and sudden cardiac death. Randomized clinical trials have demonstrated that pharmacologic management with antiarrhythmic drugs has limited efficacy for the prevention of arrhythmic mortality in this high-risk population, whereas implantation of a defibrillator was shown to be associated with a significant survival benefit. Data on the efficacy of defibrillator therapy in elderly patients, in whom comorbidities are common, are limited. In this article we outline current information on therapeutic modalities for the prevention of arrhythmic mortality in elderly patients who have left ventricular dysfunction and HF, focusing mainly on data on the benefit of device therapy in the older age group.     

Long term omeprazole therapy for reflux esophagitis:follow-up in serum gastrin levels,EC cell hyperplasia and neoplasia

AIM:To evaluate the long-term safety of omeprazole in patients of gastroesophageal reflux disease resistant to treatment with H2 receptor antagonist.METHODS:We prospectively followed 33 patients on omeprazole therapy for severe erosive esophagitis for 5-8 years, with periodic gastrin levels, H. pyloriinfection, gastric biopsies for incidence of ECL cell hyperplasia, carcinoids, gastric atrophy and neoplasia. A total 185 patient follow-up years and 137 gastric biopsies were done.RESULTS:Among the 33 patients, 36% reached their peak gastrin levels in an average of 8 months to one year, then drifted Down slowly over 1-2 year period to just above their baseline level, 24% of the patients had a peak gastrin level above 400ng·L(-1) and one patient had a peak level above 1000ng·L(-1). One patient had a mild ECL cell hyperplasia which was self limiting and did not show any dysplastic changes. Eighteen percent of patients were positive for H. pylori infection. The gastric biopsies did not show gastric atrophy, intestinal metaplasia or neoplastic changes.CONCLUSION:In a series of 33 patients followed for 5-8 years on omeprazole therapy for severe reflux esophagitis, we did not observe any evidence of significant ECL cell hyperplasia, gastric atrophy, intestinal metaplasia, dysplasia or neoplastic changes.     

Oral immune regulation using colitis extracted proteins for treatment of Crohn''s disease: Results of a phase Ⅰ clinical trial

AIM: To evaluate safety and possible efficacy of induction of oral immune regulation using colitis extracted proteins (CEP) in Crohn's disease (CD) subjects. METHODS: Ten CDs were treated orally with autologous CEP thrice weekly for 16 wk. Subjects were monitored for CDAI and IBDQ. Immune modulatory effect was assessed by T-lymphocyte FACS analysis, CEP-specific IFNγ ELISPOT assay and cytokine levels. RESULTS: Induction of oral immune regulation significantly ameliorated disease activity. All (10/10) subjects had clinical response (CDAI ≤ 70) and 7/10 achieved clinical remission (CDAI ≤ 150). Significant increase in mean IBDQ score was noted (134±9 vs 164±12). No treatment-related adverse events were noted. High levels of CEP-specific IFNγ spot forming colonies were detected in five subjects prior to treatment and in all five, a marked decrease was observed. The CD4+/CD8+ lymphocyte ratio and peripheral NKT cell numbers increased significantly, in 7/10 and in 5/10 subjects, respectively. Significant increase in serum IL-10 and IL-4 levels was observed in 7/10 subjects during treatment period.CONCLUSION: Immune regulation via oral administration of CEP is a safe and possibly effective treatment for subjects with moderate CD and may provide means of antigen-specific immune modulation.     

Multiple hematopoietic defects and delayed globin switching in Ikaros null mice

We have previously reported the structure of a chromatin remodeling complex (PYR complex) with Ikaros as its DNA binding subunit that is specifically present in adult murine and human hematopoietic cells. We now show that homozygous Ikaros "knockout" (null) mice lack the PYR complex, demonstrating the requirement for Ikaros in the formation of the complex on DNA. Heterozygous Ikaros null mice have about half as much PYR complex, indicating a dosage effect for both Ikaros and PYR complex. We also show that Ikaros null mice have multiple hematopoietic cell defects including anemia and megakaryocytic abnormalities, in addition to previously reported lymphoid and stem cell defects. The null mice also have a delay in murine embryonic to adult beta-globin switching and a delay in human gamma to beta switching, consistent with a previously suggested role for PYR complex in this process. Lastly, cDNA array analyses indicate that several hematopoietic cell-specific genes in all blood lineages are either up- or down-regulated in 14-day embryos from Ikaros null as compared with wild-type mice. These results indicate that Ikaros and PYR complex function together in vivo at many adult hematopoietic cell-specific genes and at intergenic sites, affecting their expression and leading to pleiotropic hematopoietic defects.     

Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis

OBJECTIVE: To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. METHODS: Human RFC-(over)expressing CEM cells of T cell origin were used to analyze the effect of SSZ on the RFC-mediated cellular uptake of radiolabeled MTX and the natural folate leucovorin. Moreover, both cells with and those without acquired resistance to SSZ were used to assess the antiproliferative effects of MTX in combination with SSZ. RESULTS: Transport kinetic analyses revealed that SSZ was a potent noncompetitive inhibitor of RFC-mediated cellular uptake of MTX and leucovorin, with mean +/- SD K(i) (50% inhibitory concentration) values of 36 +/- 6 microM and 74 +/- 7 microM, respectively. Consistent with the inhibitory interaction of SSZ with RFC, a marked loss of MTX efficacy was observed when MTX was coadministered with SSZ: up to 3.5-fold for CEM cells in the presence of 0.25 mM of SSZ, and >400-fold for SSZ-resistant cells in the presence of 2.5 mM of SSZ. Importantly, along with diminished efficacy of MTX, evidence for cellular folate depletion was obtained by the demonstration of an SSZ dose-dependent decrease in leucovorin accumulation. CONCLUSION: At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these disease-modifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.     

Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC

BACKGROUND/AIMS: We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules. METHODS: Hepatic fibrosis induced by carbon-tetrachloride (CCl4) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice. RESULTS: Hepatic fibrosis significantly increased in all CCl4-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P<0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P<0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin. CONCLUSIONS: During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing.