Placental expression of interferon-gamma (IFN-gamma) and its receptor IFN-gamma R2 fail to switch from early hypoxic to late normotensive development in preeclampsia

The inability of the mother to switch from T helper cell type 1 (Th1) to Th2 cytokine profiles at the fetal-maternal interface has been proposed as one of the primary causes of miscarriage, intrauterine growth restriction (IUGR), and preeclampsia (PE). The Th1 [interferon-gamma (IFN-gamma), TNF-alpha, and IL-12] and Th2 (IL-4 and IL-10) cytokines have opposite effects on human pregnancy. Leukemia inhibitory factor (LIF) promotes embryo implantation and sustains pregnancy, whereas IFN-gamma and TNF-alpha are detrimental to pregnancy. Both IFN-gamma and LIF are produced by maternal cells and tissues at the fetal-maternal interface, whereas the IFN-gamma receptors (IFN-gamma R1 and IFN-gamma R2) and LIF receptor are abundantly expressed on the surface of placental trophoblasts. The effect of IFN-gamma on T lymphocyte activation is influenced by the relative membrane density of its two receptors, particularly IFN-gamma R2. In this study we report that in PE (25-40 wk gestation) and PE complicated by IUGR, IFN-gamma R2 protein expression is severely down-regulated and is similar to that observed in early placenta (7-10 wk gestation) developing under low O(2) tension. IFN-gamma production was found to be inversely related to the IFN-gamma R2 protein expression, and LIF receptor protein expression in PE mimicked that in early placental development. These results show that in PE, placental trophoblasts fail to establish an early to late switch with respect to IFN-gamma and IFN-gamma R2 expression. This supports the hypothesis that trophoblasts control the polarization of maternal immune effectors and cytokine profiles at the fetal-maternal interface that could be subject to oxidative stress in PE.     

Arrhythmogenic right ventricular dysplasia: an uncommon cause of ventricular tachycardia in young and old?

Right ventricular dysplasia is a little understood condition and is almost certainly underdiagnosed as an important cause of recurrent ventricular tachycardia and sudden death. This report describes two patients with right ventricular dysplasia. Their clinical presentation reflects the remarkable diversity of the disease while the potentially life-threatening nature of their arrhythmias and their lack of response to medical treatment justified the antiarrhythmic surgical procedure of right ventricular disarticulation.     

Estrogen can protect splenocytes from the toxic effects of the environmental pollutant 4-tert-octylphenol

Four-tert-octylphenol (OP), an environmental pollutant, exerts apoptotic effects on cultured mouse splenocytes. Although OP binds to estrogen receptors, these apoptotic effects are not exerted by 17β-estradiol (E). It remained possible that OP might bind to estrogen receptors and subsequently exert apoptotic effects not exerted by E after it binds to the same receptors. It also remained possible that E-primed splenocytes might respond to OP differently than splenocytes not exposed to E. Thus, we investigated OP and E interactions on the viability of mouse splenocytes in culture. The total number of splenocytes (cells stained and not stained with trypan blue) was not altered or altered slightly after incubation with any agent for 24 h. Incubation of splenocytes in medium containing 5×10⁻⁵ or 5×10⁻⁷ M OP decreased the percentage of viable cells by approx 47% and 25%, respectively. The addition of 0.8×10⁻⁵ to 0.8×10⁻⁹ M E to cultures was without effect or decreased the percentage of viable cells by only approx 5%. The addition of these concentrations of E simultaneously with or at 2 h after the addition of 5×10⁻⁵ M or 5×10⁻⁷ M OP to cultures did not interfere with the OP-induced decreases in cell viability. By contrast, incubation of splenocytes in medium containing E for 2 h prior to the subsequent addition of either dose of OP blocked the OP-induced decreases in cell viability in a dose-response manner. There was a marked reduction in the percentage of viable cells (70%) when splenocytes were incubated with 0.5×10⁻⁵ M dexamethasone. The addition of 0.8×10⁻⁵ M E at 2 h prior to the addition of dexamethasone did not prevent the decreased cell viability. Incubation of cells in medium with 0.8×10⁻⁵ M testosterone caused a small decrease in splenocyte viability similar to that observed with E. However, unlike E, the addition of testosterone at 2 h prior to the addition of 5×10⁻⁵ M OP did not prevent the OP-induced decrease in cell viability. These data suggest the presence of estrogen receptors in some splenocytes. They also suggest that if OP binds to these estrogen receptors or other receptors in the absence or initial presence of E, the resulting effect is toxic to the cells. By contrast, exposure of splenocytes to E prior to their exposure to OP can prevent the toxicity of OP. A portion of this work has been published in abstract form in Molecular Biology of the Cell, Supplement to Vol. 7, 1996, Abstract 3843.     

Circadian Variation and Waking Hour Dynamics of the QT Interval

Background: The incidence of sudden cardiac death is maximal in the morning hours. Although ventricular arrhythmias have been implicated as a potential mechanism, and several neurohumoral factors affecting myocardial excitability have been shown to be raised in the early morning hours, it is not known if there is any circadian variation in the dynamics of ventricular repolarization when studied on a beat-to-beat basis. The objective of this study was to examine the range, diurnal variations, and circadian distribution of the variability of the QT interval in healthy subjects. Method: We developed and validated a new method for continuous measurement of QT intervals from 24-hour Holter recordings. The QT intervals measured semi-automatically were corrected by a linear regression formula derived independently for each patient from his own QT and RR values in 32 healthy males (20 ± 0.4 years). QT variability was assessed by the mean standard deviation of the average of consecutive uncorrected QT intervals (SDA-QT Index) and corrected QT intervals (SDA-QTc index) over 5-minute segments. The rate-dependent changes of the QT interval were studied as a function of the slope of the regression line between the QT and RR values. Results: The average QTc range was mean (SD) 79 (± 28) ms; the average maximal QTc interval was 481 (± 24) ms. The 95% upper confidence limit for the mean 24-hour QTc interval was 443 ms. The RR, QT, and QTc intervals were longer, while the SDA-QT and SDA-QTc indices were shorter during sleep. Hourly averages of the SDA-QT and SDA- QTc index revealed a sudden increase in QT variability in the first hour of waking (P < 0.0001 and P = 0.006). Conclusion: The dynamic behavior of the QT interval shows significant diurnal variations. The maximal QTc interval over 24 hours is longer than previously assumed. The period shortly following awakening is characterized by a peak in the variability of the QT interval. These changes may be indicative of autonomic instability during the early waking hours and correspond with the peak incidence of sudden arrhythmic death.     

Treatment of erosive reflux esophagitis resistant to H2-receptor antagonist therapy

Fifty-four patients with endoscopically documented therapy-resistant erosive reflux esophagitis were treated with lansoprazole, a new proton pump inhibitor, for up to 12 weeks. Prior to entry, all had remained unhealed after treatment with at least two histamine₂-receptor antagonists, at therapeutic doses or higher, for at least 12 weeks. Patients were randomized to receive either 30 or 60 mg lansoprazole once daily. Endoscopy was performed and symptoms assessed at weeks 2, 4, 6, 8, and 12. Fifty-nine percent of the 50 evaluable patients were healed (ie, no evidence of erosions) after only two weeks of lansoprazole. Cumulative endoscopic healing rates were 82% and 92% by week 4 and week 8, respectively, and the two doses were equally effective in healing. The 30- and 60-mg doses effected a decrease in the overall symptom score from 5.30 and 4.85 to 2.35 and 1.67, respectively, by the final treatment visit (P=0.001). No clinically significant adverse events or changes in laboratory parameters were observed, and no patients withdrew prematurely from the study. This study demonstrates that lansoprazole therapy is highly effective in healing erosive reflux esophagitis resistant to therapy with histamine H₂-receptor antagonists.Supported by a grant from TAP Pharmaceuticals Inc., Deerfield, Illinois.     

Beef and soy-based food supplements differentially affect serum lipoprotein-lipid profiles because of changes in carbohydrate intake and novel nutrient intake ratios in older men who resistive-train

OBJECTIVE: We examined if the predominant source of dietary protein influenced the lipoprotein-lipid profile in older men who performed resistive exercise training (RT). DESIGN: This is a 14-week, randomized, repeated-measures study with a 12-week period of RT with supplementation of different sources of dietary protein (beef and soy). SETTING: Nutrition, Metabolism, and Exercise Laboratory, Central Arkansas Veteran's Healthcare System, North Little Rock, Ark. Subjects Twenty-six healthy men were recruited, and 21 men (age 65 +/- 5 years, body mass index 28.2 +/- 2.6 kg/m 2 ) completed the study. Interventions For 14 weeks, all men were counseled to self-select a lacto-ovo-vegetarian diet. For 2 weeks (baseline), all men also consumed 0.6 g-protein/kg per day from portioned quantities of soy-based texturized vegetable protein foods. For the next 12 weeks, 11 men were randomized to continue with texturized vegetable protein foods (VEG group), whereas 10 men were randomized to receive 0.6 g-protein/kg per day from portioned quantities of beef (BEEF group) and continue their otherwise lacto-ovo-vegetarian diet. All men participated in RT 3 d/wk during this 12-week period. Assessments of upper and lower body muscle strength and power, serum lipoprotein-lipid profile, and dietary nutrient intakes were made at baseline and week 12 of RT (POST). RESULTS: The BEEF and VEG groups increased ( P < .05) overall muscle strength and muscle power with RT, with no differences between groups. From baseline to POST, the BEEF group had increased concentrations of high-density lipoprotein cholesterol ( P = .025; HDL-C), low-density lipoprotein cholesterol ( P = .027; LDL-C), and total cholesterol ( P = .015: CHOL), with no changes ( P > .05) in triacylglycerol (TG), the CHOL/HDL-C ratio, or the TG/HDL-C ratio. The VEG group did not experience within-group changes ( P > .05) in any lipoprotein-lipid parameter. At POST, the concentrations of HDL-C, LDL-C, and CHOL were greater in the BEEF group compared with the VEG group. There were significant interaction effects for HDL-C ( P = .004) and the TG/HDL-C ratio ( P = .022). Multiple regression analysis determined that, regardless of intervention, change in the saturated fat/fiber ratio (SF/fiber) predicted CHOL (adjusted R 2 = 0.34); the SF/fiber ratio predicted LDL-C (adjusted R 2 = 0.36); the cholesterol/fiber intake ratio predicted HDL-C (adjusted R 2 = 0.26), and the change in carbohydrate intake predicted the CHOL/HDL-C ratio (adjusted R 2 = 0.37) and TG (adjusted R 2 = 0.44). CONCLUSIONS: These results suggest that the lipoprotein-lipid profile in these older men was differentially affected by supplementation with beef versus soy-based foods during RT. Regardless of group, the lipoprotein-lipid changes were predicted by differences in the SF/fiber ratio and cholesterol/fiber ratio and increases in carbohydrate intake over time.