AimSerum paraoxonase 1 (PON1) is an HDL-associated lipolactonase and its association with hypertension is controversial. We studied the possible role of PON1 in blood pressure (BP) regulation, by using PON1 knockout (PON1KO) mice.Methods and resultsBoth, systolic and diastolic BPs were lower in PON1KO compared to WT mice. Hypotension detected in PON1KO is probably neither related to nitric oxide/guanylate cyclase-mediated vasodilation nor to angiotensin II or aldosterone-mediated vasoconstriction. Surprisingly, when challenged by high-salt diet, BP was further reduced in PON1KO mice. The later, pointed to a possible involvement of transient receptor potential vanilloid 4 (TRPV4), and indeed, administration of ruthenium red, a TRPV4 blocker, resulted in a sharp rise in BP. The protein levels of TRPV4 in kidneys of PON1KO were not higher than in WT. However, the renal level of 5,6-epoxyeicosatrienoic acid (5,6-EET), a TRPV4 specific agonist, was significantly higher in PON1KO compared with WT mice. 5,6-EET levels were further elevated under high-salt diet or administration of arachidonic acid. Injection of inhibitor of CYP450 epoxygenase resulted in increased BP in PON1KO mice. Injection of recombinant human PON1 resulted in elevation of BP and a concomitant reduction in renal content of 5,6-EET. PON1, in vitro, metabolized 5,6-EET, but not other EETs, to its corresponding diol. Vasodilation, blocked by excess of dietary K+ but not reversed by depletion of cellular Ca2+ stores, point to endothelial-derived hyperpolarization-like response.ConclusionThe present study shows causal, direct relationship between PON1 and blood pressure which is mediated, at least in part, by the regulation of 5,6-EET. 相似文献
West syndrome constitutes the most frequent of all seizure types in infants with Down syndrome. We retrospectively reviewed records of 12 infants with Down syndrome and West syndrome, accounting for 5% of 239 infants with West syndrome from a comprehensive epilepsy database during a 17-year period. All demonstrated classic hypsarrhythmia on video electroencephalograms. One had clinically responded to clonazepam, and one was not treated because the parents refused any treatment. Seven of 10 infants demonstrated a complete response to high-dose natural adrenocorticotrophic hormone. Four (57%) of these seven infants relapsed. Relapses occurred as long as 2 years after cessation of the initial presentation of infantile spasms. At most recent follow-up (median age, 5 years), 8/12 (67%) were seizure-free, and seven were off any medications. Two of three nonresponders manifested intractable epilepsy and profound mental retardation. Developmentally, 6/8 who could be assessed met criteria for autistic spectrum disorder. Close follow-up is necessary even after successful initial treatment, because relapses are frequent and can occur as long as 2 years later. 相似文献
ObjectiveTo evaluate the association between bezafibrate, a drug used to treat hypertriglyceridemia, and long-term cancer incidence in patients with coronary artery disease (CAD).Patients and MethodsThe study comprised 2980 patients with CAD (mean age, 60 years; 2729 [91.6%] men) who were free of cancer and were enrolled in the Bezafibrate Infarction Prevention study, a double-blind trial conducted between May 1, 1990, and January 31, 1993, in 18 cardiology departments in Israel. Patients randomized to receive 400 mg of bezafibrate (n=1486) or placebo (n=1494) daily for a median of 6.2 years (range, 4.7-7.6 years) were followed up for incidence of cancer through the Israeli National Cancer Registry and all-cause death through the Population Registry of the State of Israel until December 31, 2013. Cox proportional hazards and Fine and Gray survival models were used to assess the bezafibrate-cancer association.ResultsClinical characteristics and laboratory values were well balanced between the 2 groups at the study entry. Over a median follow-up of 22.5 years (range, 21.2-23.9 years), cancer developed in 753 patients. With death considered a competing event, the cumulative incidence of cancer at the end of the follow-up was lower in the bezafibrate vs the placebo group (23.9%; 95 CI, 21.9%-26.1% vs 27.2%; 95 CI, 25.1%-29.4%; P=.04). The hazard ratio for cancer in the bezafibrate vs placebo groups was 0.86 (95% CI, 0.74-0.99). In mediation analysis, the association between bezafibrate treatment and cancer incidence was not sensitive to adjustment for on-trial lipid levels but was attenuated on adjustment for on-trial fibrinogen levels.ConclusionBezafibrate treatment is associated with reduced risk of cancer among patients with CAD. Fibrinogen, but not lipid lowering, is linked to this association. 相似文献
The oxy-form of sickle hemoglobin (Hb S) is abnormally unstable and precipitates at a 10-fold faster rate than does oxyhemoglobin A (oxy-Hb A) during mechanical shaking. The apparent rate of precipitation of heterozygous hemolysate (AS) is approximately half that of oxy-Hb S. The deoxy-form of Hb S, on the other hand, is resistant to the mechanical treatment. This stabilization is attributed to the conformational change of hemoglobin rather than the lack of oxygen, because carbonmonoxide hemoglobin S, which is known to have conformational properties similar to those of oxy-Hb, is unstable even under anaerobic conditions. Methemoglobin S is most unstable, although addition of cyanide stabilizes the protein. The precipitation of oxy-Hb S is inhibited by ethanol and other organic solvents. The relationship of the mechanical instability of sickle oxyhemoglobin to intraerythrocytic denaturation and vaso-occlusive phenomena in sickle cell disease to be determined. 相似文献
Background: Elevation of acute phase proteins [C-reactive protein (CRP) and serum amyloid type A (SAA)] has been demonstrated in unstable angina with an adverse clinical prognosis. Hypothesis: The study was undertaken to determine the effect of angioplasty on the levels of SAA and the correlation with postangioplasty restenosis. Methods: In a university-affiliated tertiary medical center, a prospective case study was undertaken in 55 patients who underwent successful percutaneous transluminal coronary angioplasty (PTCA) of a single coronary lesion for angina pectoris. Three groups of patients were clinically characterized according to Braunwald's classification of anginal syndrome: Group A: class III; Group B: class I; Group C: stable angina. Serum amyloid type A was measured by an ELISA method before PICA and after 24 h, 1, and 3 months. Patients were followed clinically for 12 months. A thallium stress perfusion scan was performed 3 months after PTCA and coronary angiography was repeated in patients with an abnormal thallium perfusion scan. Results: Serum amyloid type A levels >100 m?/ml could identify Group A patients with a high sensitivity and specificity (r = 0.85 and 0.86, respectively). Of the patients studied. 75% increased their SAA level 24 h after angioplasty. An increase of SAA by >100% was associated with an increased risk of restenosis, with a relative risk of 6.4 (p < 0.05). Conclusion: Increased levels of SAA characterize patients with unstable angina pectoris with a high specificity and sensitivity. Levels of SAA that increase > 100% 24 h after angioplasty may serve as a marker of restenosis. 相似文献
Objectives: To investigate the nature of the association of normal levels of total cholesterol with cognitive function and the contribution of age to this association.
Methods: A sample of 61 senior executives, who were summoned for an annual medical examination with approximately four measurements of total cholesterol during 4 years, were examined with a computerized cognitive battery assessing mental processing speed as a sensitive measure of cognitive decline. We examined the association of total cholesterol with processing speed and the moderating effect of age on this association.
Results: A multiple regression analysis yielded a significant interaction between cholesterol and age for processing speed (p = .045). In order to examine the source of the interaction, simple slope analysis was performed. A significant negative high correlation was found for young subjects (p = .021), while no significant correlation was observed at middle (p = .286) or older (p = .584) age. The difference in slopes was robust to adjustment for potential confounding factors, including body mass index, and fasting glucose.
Conclusions: Within the normal range, higher total cholesterol levels were associated with better processing speed in younger ages and this association diminished with increasing age. Our findings highlight the important role of brain cholesterol in good cognitive functioning. 相似文献