Relationships between blood pressure lowering therapy and cardiovascular events in hypertensive patients with coronary artery disease and type 2 diabetes mellitus: The HIJ-CREATE sub-study.

OBJECTIVE: The effects of intensive blood pressure (BP) lowering for hypertensive patients with coronary artery disease (CAD) and diabetes mellitus on their clinical outcomes have not been fully evaluated. The aim was to explore the optimal systolic BP target in such patients in a substudy of a prospective, randomized trial. METHODS: Of a total of 2049 hypertensive patients with CAD who were enrolled in the HIJ-CREATE study, type 2 diabetes was diagnosed in 780 (38.1%). Titration of antihypertensive agents was performed to reach the target BP of <130/85 mmHg. The primary endpoint was the occurrence of a first major adverse cardiovascular event (MACE). Achieved BP was defined as the mean value of systolic BP in patients who did not develop MACEs and as the mean value of systolic BP prior to MACEs in those who developed MACEs during follow-up. RESULTS: During a median follow-up of 4.2 years, the primary outcome occurred in 259 (33.2%) diabetic patients and in 293 (23.1%) non-diabetic patients (p < 0.0001). The diabetic patients were divided into quartiles based on the mean systolic BP during follow-up. The relationships between achieved BP and the incidence of MACEs did not follow a J-shaped curve. Intensive systolic BP lowering to less than 120 mmHg did not correlate with an increased risk of MACEs. CONCLUSIONS: Our results suggest that the intensive BP lowering may not impair patients' clinical courses even in a high-risk population. The establishment of an optimal management strategy for hypertensive patients with diabetes and CAD is essential.

Pokeweed mitogen induces IgE synthesis in the presence of a blocking antibody to the interferon-gamma receptor.

BACKGROUND: Although pokeweed mitogen (PWEM) can induce peripheral blood mononuclear cells (PBMCs) to synthesize IgG, IgA, and IgM, such cultures fail to induce IgE synthesis. The present study examined the possibility that the stimulation of interferon-gamma (IFN-gamma) production plays a role in the failure of PWM to induce IgE synthesis. METHODS: We examined PBMCs from eight normal control subjects for IFN-gamma and IL-4 production. Since IFN-gamma synthesis is known to inhibit IgE synthesis, we also examined the effect of a neutralizing anti-IFN-gamma antibody and of two anti-IFN-gamma receptor antibodies, monoclonal antibody (mAb) GIR208, which blocks cellular binding of IFN-gamma, and mAB GIR94.5, which binds to the IFN-gamma receptor but does not block the binding of IFN-gamma to its receptor on PWM-stimulated PBMCs. RESULTS: After stimulation with PWM, culture supernatants contained significantly more IFN-gamma (p = 0.001) and IL-4 (P = 0.001) compared with supernatants from nonstimulated cultures. PWM-stimulated PBMCs also expressed higher levels of IFN-gamma and IL-4 gene transcripts than unstimulated cells. When cultured in the presence of anti-IFN-gamma, supernatants from PWM-stimulated cultures also induced CD23 on Ramos B cells in an IL-4-dependent manner. In the presence of mAB GIR208 and a neutralizing anti-IFN-gamma antibody, but not mAb GIR94.5, PWM stimulated PBMCs from eight normal control subjects and six patients with atopic dermatitis to produce IgE. Monoclonal antibody GIR208, however, did not enhance IgG synthesis. Furthermore, the exogenous addition of IFN-gamma inhibited the IgE-stimulatory effect of mAb GIR208. Monoclonal antibody GIR208 was unable to induce purified B cells to synthesize IgE in the presence of IL-4. CONCLUSIONS: Thus unlike anti-CD40, mAb GIR208 does not act as a second signal for the induction of IgE synthesis. These results demonstrate that the induction of IFN-gamma production contributes to the failure of PWM to stimulate synthesis of IgE in PBMCs from atopic and nonatopic donors.

Enhanced IL-4 production and IL-4 receptor expression in atopic dermatitis and their modulation by interferon-gamma.

The in vivo and in vitro immunomodulatory effects of interferon gamma (IFN-gamma) treatment on peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis (AD) and elevated IgE levels were studied. As part of a double-blind placebo-controlled clinical trial, 14 AD patients were treated with IFN-gamma (n = 7) or saline (n = 7) for 12 weeks. To assess the in vivo effects of IFN-gamma treatment on interleukin (IL)-4-dependent lymphocyte function, we assessed the proliferation of AD PBMC in response to IL-4. Prior to IFN-gamma treatment, AD PBMC had proportionately decreased proliferative responses to IL-4 when compared to IL-2. After 12 weeks of in vivo treatment with IFN-gamma, there was an increase of IL-4- but not IL-2-induced lymphocyte proliferation in seven of eight AD patients. To further study the immunologic basis of these observations, we studied the expression of IL-4 receptor (IL-4R) mRNA and the production of IL-4 by PBMC from AD patients. PBMC from AD patients expressed higher levels of IL-4R mRNA and produced significantly higher amounts of IL-4 than normal controls (p less than 0.05). More importantly, the in vitro addition of IFN-gamma caused significant reduction in both IL-4R and mRNA expression and IL-4 production of PBMC from AD and non-atopic controls. These data indicate that AD is characterized by an in vivo overstimulation of the IL-4-IL-4R pathway. The poor proliferative responses of untreated AD PBMC to exogenous IL-4 may be due to increased levels of endogenous IL-4 production with constant occupancy on the IL-4R. Furthermore, in vivo and in vitro treatment with IFN-gamma down-regulates this pathway.

Decreased interferon gamma and increased interleukin-4 production in atopic dermatitis promotes IgE synthesis.

The mechanism(s) responsible for increased IgE synthesis in atopic dermatitis (AD) are unknown, but they may be related to either decreased interferon gamma (IFN-gamma) and/or increased interleukin (IL)-4 production. In this study we examined peripheral blood mononuclear cells (PBMCs) from 21 patients with AD, six patients with psoriasis, and 22 nonatopic healthy controls for IFN-gamma and IL-4 production after stimulation with concanavalin A (Con A). The Con A-induced proliferative response of AD PBMCs was similar to the response of healthy controls (p = 0.9). After mitogen stimulation, however, AD culture supernatants contained significantly less IFN-gamma (p = 0.001) but increased IL-4 (p = 0.001) compared with supernatants from nonatopic controls. In contrast, PBMCs from patients with psoriasis produced normal levels of IFN-gamma and IL-4 in vitro. Since IL-4 is known to decrease IFN-gamma synthesis, we examined the effect of neutralizing anti-IL-4 on IFN-gamma production. Anti-IL-4 significantly increased IFN-gamma production in patients with AD (p = 0.008) and nonatopic controls (p = 0.02) but did not normalize IFN-gamma production by AD PBMCs. Supernatants from AD PBMCs, but not supernatants from nonatopic PBMCs, induced IgE synthesis in PBMCs from nonatopic donors (p = 0.02). When an anti-IFN-gamma receptor antibody, which blocks cellular binding of IFN-gamma, was added to supernatants from nonatopic controls their capacity to induce IgE synthesis was significantly greater (p = 0.03). These results demonstrate an imbalance of IL-4 and IFN-gamma production, which may contribute to increased IgE synthesis in AD.

Selective expansion of T cells expressing T-cell receptor variable regions V beta 2 and V beta 8 in Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis complicated by the development of coronary artery abnormalities. The etiology of KD is unknown. Based on the observation that KD is associated with marked activation of T cells and monocyte/macrophages, we hypothesized that KD may be caused by a superantigen [e.g., a bacterial toxin that stimulates T cells expressing particular T-cell receptor beta chain variable (V beta) gene segments]. Peripheral blood T cells from patients in the acute and convalescent phases of KD and from various control groups were analyzed for T-cell receptor V beta gene expression by using a quantitative PCR technique and cytofluorographic analysis with available anti-V beta monoclonal antibodies. Patients with acute KD demonstrated significantly elevated levels of circulating V beta 2+ and V beta 8.1+ T cells compared to the other control groups. none of the other 20 V beta populations analyzed by quantitative PCR were found to be significantly elevated. Using flow cytometry, we confirmed a significant elevation of T cells reactive with anti-V beta 8.1 and the lack of change in several other V beta subsets--i.e. V beta 5.1, -5.2, -6.7, and -12. During the convalescence phase of KD, there was a reduction in the abnormal levels of V beta 2+ and V beta 8.1+ T cells. These observations suggest that KD may be caused by a superantigen and may provide insight into the nature of the etiologic agent.

Hypothalamic-pituitary functions in patients with idiopathic pituitary dwarfism.

To investigate hypothalamic-pituitary functions and the primary site of the lesion in idiopathic pituitary dwarfism, various pituitary function tests, especially the pituitary hormone responses to the hypophysiotropic hormones were studied in 23 patients with idiopathic pituitary dwarfism. A few cases showed slight responses of GH to GH stimulation tests. Gonadotropin deficiencies were most frequently noted among pituitary hormones. The basal levels and the responses of plasma LH and FSH to LH-RH test were diminished markedly in all of the cases except in 5 cases with isolated GH deficiency. Responses of LH and FSH to LH-RH improved markedly after a long term administration of LH-RH for a period of one month in 2 patients with gonadotropin deficiency. As to TSH axis, half of the cases accompanied hypothyroidism. However, the responses of TSH to TRH were normal in all of the cases regardless of the thyroid function. The basal levels and the responses of plasma cortisol and 11-deoxycortisol to the rapid metopirone test were also impaired in about half of the cases. Basal levels of plasma prolactin were normal in all of the cases and the responses of prolactin to TRH were normal in cases with normal thyroid function, but slightly delayed in cases with hypothyroidism. It is concluded from the above observations that the incidences of various pituitary hormone deficiencies were quite high in this disorder and hypophysiotropic hormone deficiencies may cause pituitary hormone deficiencies. Therefore, it is suggested that the primary site of the lesion in this disorder might be at the hypothalamus.