CD4+ T Cells Reactive to Enteric Bacterial Antigens in Spontaneously Colitic C3H/HeJBir Mice: Increased T Helper Cell Type 1 Response and Ability to Transfer Disease

C3H/HeJBir mice are a new substrain that spontaneously develop colitis early in life. This study was done to determine the T cell reactivity of C3H/HeJBir mice to candidate antigens that might be involved in their disease. C3H/HeJBir CD4⁺ T cells were strongly reactive to antigens of the enteric bacterial flora, but not to epithelial or food antigens. The stimulatory material in the enteric bacteria was trypsin sensitive and restricted by class II major histocompatibility complex molecules, but did not have the properties of a superantigen. The precursor frequency of interleuken (IL)-2–producing, bacterial-reactive CD4⁺ T cells in colitic mice was 1 out of 2,000 compared to 1 out of 20,000–25,000 in noncolitic control mice. These T cells produced predominately IL-2 and interferon γ, consistent with a T helper type 1 cell response and were present at 3–4 wk, the age of onset of the colitis. Adoptive transfer of bacterial-antigen–activated CD4⁺ T cells from colitic C3H/HeJBir but not from control C3H/HeJ mice into C3H/HeSnJ scid/scid recipients induced colitis. These data represent a direct demonstration that T cells reactive with conventional antigens of the enteric bacterial flora can mediate chronic inflammatory bowel disease.The inflammatory bowel diseases (IBD)¹, encompassing Crohn''s disease and ulcerative colitis, are complex chronic inflammatory diseases of the intestine whose etiology and pathogenesis remain unknown. There are multiple etiologic theories, one of which is that a dysregulated CD4 T cell response to the abundant antigens in the lumen may be responsible (1, 2). This hypothesis is based on theoretical grounds and there is only limited supporting data in humans as yet (3, 4). However, support for this hypothesis has come from the results of studies done in a number of recently developed experimental models of IBD, some of which have been the unexpected result of gene deletions by selective gene targeting (5–9). In a number of such models, CD4⁺ T cells have been found to mediate colitis, and most commonly this has involved an exaggerated Th1 response manifested by excessive IFN-γ production in the lesions (10–12). The localization of inflammatory disease to the colon of mice that have global deficiencies of an immune molecule suggests that the bacterial flora is the major immune stimulant leading to chronic intestinal inflammation. Indeed, in some models, animals that are raised germ-free no longer develop colitis (5, 13), and in others rederivation with a defined flora (6, 12) or antibiotic treatment (14) ameliorates the disease. Moreover, reconstitution of intestinal bacteria into germ-free animals can restore intestinal inflammation (15). However, it has remained unclear how the bacterial flora generates chronic intestinal inflammation.Humans with IBD do not have absolute deficiencies of the immune molecules whose deletion in mice has resulted in colitis. For this reason, we have derived and studied a new strain of mice which develop colitis spontaneously, namely the C3H/HeJBir strain (16). C3H/HeJBir mice develop a predominantly right-sided colitis early in life that largely resolves by 3 mo of age. Previous studies on the immunopathogenesis of disease in this mouse strain have found that C3H/HeJBir mice, but not mice of the parenteral C3H/HeJ strain, have high titer serum IgG antibodies to a selected subset of antigens of the enteric bacterial flora (17). These antibodies are mainly of the IgG2a subclass, compatible with a predominant Th1 response to these bacterial antigens. This study was undertaken to define the CD4⁺ T cell response of C3H/HeJBir mice to enteric bacterial antigens. Compatible with our earlier results analyzing antibody responses, strong CD4⁺ Th1 T cell reactivity to protein antigens of the enteric bacterial flora was identified. Moreover, disease could be induced by transfer of enteric bacterial antigen-activated C3H/HeJBir CD4⁺ T cells, but not by control C3H/HeJ T cells, into C3H/ HeSnJ scid/scid recipients. These results demonstrate for the first time that CD4⁺ T cells reactive with conventional antigens of the bacterial flora are able to mediate chronic intestinal inflammation.     

Exercise hemodynamics and catecholamine metabolism after catechol-O-methyltransferase inhibition with nitecapone

The effect of catechol-O-methyltransferase inhibition with nitecapone (OR-462) on the hemodynamic responses to exercise and catecholamine metabolism was studied in 10 healthy male volunteers (aged 19 to 26 years). Nitecapone, a new specific and selective catechol-O-methyltransferase inhibitor, was given at increasing single oral doses up to 100 mg. Nitecapone did not influence resting or exercise heart rate, blood pressure, systolic time intervals, or plasma catecholamine levels. It altered the metabolic profile of catecholamines as shown by (1) an increase of 140% in the plasma concentration of the monoamine oxidase-dependent metabolite 3,4-dihydroxyphenylethyleneglycol (p less than 0.001), (2) a decrease of 27% in the plasma concentration of its methylation product 3-methoxy-4-hydroxyphenylethyleneglycol (p less than 0.05), and (3) a 25% reduction in the urinary excretion of the methylated metabolites 3-methoxy-4-hydroxymandelic acid and homovanillic acid (p less than 0.05). Nitecapone was well tolerated and seemed to be hemodynamically safe in humans.     

Lorcainide in the prophylaxis of ventricular arrhythmias in acute myocardial infarction

Lorcainide, a new class I antiarrhythmic agent, was administered intravenously to eight patients with acute myocardial infarction for 24 hours, and thereafter given by mouth, 200 mg daily for ten days. Ten control infarction patients were given lidocaine 3 mg/min during the first 24 hours and the oral betablocking agent, pindolol, for the following ten days. The two groups were comparable with respect to age, sex, onset-admission interval, and site and size of infarction. Ventricular premature beats were monitored with a 24-hour continuous ECG recording on days 1, 6 and 10. Complex ventricular premature beats were common during the first 24 hours of infarction; their occurrence and severity were similar in both groups, as judged by the Lown grading system. The plasma levels of lorcainide after the 24-hour infusion ranged 72-144 ng/ml (mean 95 ng/ml). On the sixth day, 12 hours after previous oral dose, lorcainide plasma levels ranged 11-82 ng/ml (mean 42 ng/ml). No major adverse effects were noticed, mild insomnia being the most disturbing reaction. It is concluded that lorcainide is an acceptable alternative to lidocaine in the treatment of ventricular arrhythmias in the acute stage of myocardial infarction. It has the advantage of being effective by oral route, too.     

EFFICACY OF RAMIPRIL VERSUS ENALAPRIL IN PATIENTS WITH MILD TO MODERATE ESSENTIAL HYPERTENSION

SUMMARY This double-blind, randomised, cross-over study investigated the antihypertensive efficacy of ramipril and enalapril was completed by 30 patients with mild-to-moderate essential hypertension. After a four-week placebo run-in phase, the patients received either 2.5mg ramipril or 10mg enalapril once daily for four weeks. The dosages were increased to 5mg ramipril and 20mg enalapril for a further four weeks. After a placebo washout phase of four weeks, the patients were crossed over to the alternative treatment. The decrease in average 24-hour ambulatory diastolic blood pressure from week 0 to week 8 was 1.6mmHg greater with ramipril than enalapril (90% confidence interval 0.6-2.7mmHg). The corresponding reduction in for systolic blood pressure was also greater with ramipril than enalapril by 2.4mmHg (90% confidence interval: 0.5-4.2mmHg). For the difference in the drop of 24-hour ambulatory diastolic blood pressure between ramipril and enalapril the lower level of the 90% confidence interval (CI) is above the clinically relevant difference of -3mmHg. This is an indication that ramipril (2.5 and 5mg dose) is at least as effective as enalapril (10 and 20mg dose) in decreasing blood pressure in patients with mild-to-moderate essential hypertension. The duration of adequate antihypertensive effect was relatively long for both ramipril and enalapril; however, ramipril tended to have a more prolonged antihypertensive effect. Ramipril had a higher diastolic and systolic trough/peak ratio than enalapril, resulting in a more uniform antihypertensive effect over the 24-hour treatment period. Both ramipril and enalapril were well tolerated and the two treatment groups had similar safety profiles.     

Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition

Acute graft-versus-host disease (aGVHD) is 1 of the main major complications of post–hematopoietic stem cell transplantation (HSCT). Identifying patients at risk of severe aGVHD may lead to earlier intervention and treatment, resulting in increased survival and a better quality of life. We aimed to identify biomarkers in donor grafts and patient plasma around the time of transplantation that might be predictive of aGVHD development. We build on our previously published methods by using multiplex assays and multicolor flow cytometry. We identified 5 easily assessable cellular markers in donor grafts that combined could potentially be used to calculate risk for severe aGVHD development. Most noteworthy are the T cell subsets expressing IL-7 receptor-α (CD127) and PD-1. Additionally, we identified a potential role for elevated tumor necrosis factor-α levels in both graft and patient before HSCT in development of aGVHD.     

Blood pressure in adult Lapps and Skolts.

Casual blood pressures were recorded in 331 Lapps and 221 Skolts over the age of 20. The systolic pressure was found to rise more with age in women than in men. In neither sex did age affect the diastolic pressure. A general tendency towards higher blood pressure in Lapps than in Skolts was noted up to the age of 50-60 years. Comparison with a Finnish population and one from the Aland Islands revealed similar systolic blood pressures in females, but definitely lower values in male Lapps and Skolts. The Lapps and Skolts did not have the clear age dependence of the diastolic blood pressure as occurs in Finns. These findings, together with other population studies, support the hypothesis that the setting of the resting blood pressure level is influenced by different kinds of stress associated with technological development and with an urbanized way of life.     

Factors related to tobacco use among teenagers

AIM: To examine tobacco use among teenagers, identify factors related to tobacco use, as well as evaluate the outcome of a smoking prevention program. METHODS: From age 7/8 to 14/15, annual questionnaires about asthma and allergy have been completed in the OLIN paediatric study in Northern Sweden. From 12/13 years, questions about tobacco use, i.e. smoking and snuff, were added. A smoking prevention program was performed during 2 years. RESULTS: Any tobacco use increased from 5.0% at age 12/13 years, to 14.4% at age 14/15. At age 14/15 years, the prevalence of tobacco use was significantly higher among boys than girls (16.7 and 12.0%, respectively). More girls than boys smoked (8.9 and 2.8%, respectively), while use of snuff was more common among the boys (15.6 and 4.2%, respectively). Significant risk factors for smoking were any of the family members currently smoking, OR 6.1 (95% CI 4.0-9.3) and a physician-diagnosed asthma at the age of 14/15 years, OR 1.9 (95% CI 1.2-3.0). A protective factor against tobacco use was participation in sports, OR 0.3 (95% CI 0.2-0.4). The prevention program did not result in less tobacco use, although it may have delayed smoking initiation. CONCLUSION: The patterns of tobacco use differed significantly between boys and girls. Though any tobacco use was more common among boys, girls were more likely to smoke, and boys were more likely to use snuff. Having asthma did not prevent the teenagers from smoking. Since having a smoking family member was the major risk factor for tobacco use, prevention programs should be directed at smoking families in addition to the individuals.     

基于7次跨膜受体的药物发现基本方法——细胞检测

随着检测技术进步,含7个跨膜α螺旋结构的受体性质已渐为人们所了解。7次跨膜（7TM）受体不仅具有开关功能,更类似于信息微处理器;特定配体只能参与特定受体介导的部分信号机制,这就为药物发现开拓了一个新领域。为进一步发现7TM受体与配体间的新行为并量化评价药物对这一复杂系统的作用效能,进而指导药物化学研究,药理学检测已成为关注焦点。本文阐述从还原重组体到整体系统测定方法的回归,讨论药物效价与评价其效应的特定检测方法间的联系,强调新的检测方法在药物发现过程中的价值。