Distinct enzymatic responses in mice exposed to a range of low doses of ozone.

Short-term exposure of mice to low O3 doses, as defined by the product of concentration and exposure time (ct), was observed to induce alterations in two enzyme systems: first, that leading to changes in hepatic reduced ascorbic acid (RAA) content, and second to changes in plasma creatine phosphokinase (CPK) activity. RAA alterations were noticed immediately, 30 min and 120 min after termination of the exposure period, whereas CPK showed alterations immediately and 15 min after termination of the exposure. Later determinations, i.e., 24 hr after O3 exposure for RAA and 30 min after 03 exposure for CPK, revealed no significant differences when compared to control animals. Although differences in sensitivity existed, the dose response curves for both systems were more or less similar, showing a short decrease for the initial very low O3 doses, followed by a profound rise and a gradual decrease to control levels for subsequent ct doses. Exceptions were the 30 min curve for RAA and the immediate curve for CPK in so far as that both showed an additional depression. Neither plasma histamine nor plasma lactic acid dehydrogenase (LDH3) were observed to be altered by the range of O3 doses employed. These findings were explained on the basis of adaptation of the organism to a potentially noxious O3 stimulus by enhanced metabolic processes: a weak stimulus leading to only a small adjustment, and stronger stimuli to elevated enzyme activity as well. With increasing doses of O3 this elevation in enzyme activity was found to be gradually diminished, possibly due to a steadily growing demand, leaving the overshoot becoming continually smaller until a balanced state is achieved

Long-term comparative effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events:A population-based retrospective inception cohort study in the Netherlands

OBJECTIVE: To determine the long-term effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events.DESIGN: Retrospective inception cohort study covering a 25-year study period.SETTING: University Groningen IADB.nl pharmacy prescription database with data from 1996 to 2020.PARTICIPANTS: Patients aged 18 years or older, free of any cardiovascular disease (CVD) drug therapies prior to initiation of a preventive antihypertensive monotherapy (ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs) and thiazides).OUTCOME MEASURES: Primary outcome was the time to first prescription of acute cardiac drug therapy (CDT) measured by valid drug proxies to identify a first major CVD event in patients without a history of CVD.RESULTS: Among 33 427 initiators, 5205 (15.6%) patients experienced an acute CDT. The average follow-up time was 7.9±5.5 years. The 25-year incidence rate per 1000 person-years were 25.3, 22.4, 18.2, 24.4 and 22.0 for ACEI, ARB, BB, CCB and thiazide starters, respectively. Inverse probability of treatment-weighted Cox regression showed that thiazide starters had lower hazards than the reference BB starters (HR: 0.88, 95% CI: 0.81 to 0.95). Among patients on diabetes drugs, risks were lower (HR: 0.49, 95% CI: 0.28 to 0.85). CCB starters had higher hazards than reference BB (HR: 1.21, 95% CI: 1.07 to 1.36). The overall estimated number needed to treat for thiazides compared with BBs to prevent one acute CDT in 25 years was 26, and four among patients on diabetes drugs.CONCLUSIONS: After adjustments for confounders, patients starting on monotherapy with thiazides had a lower incidence of CDT compared with those starting on BBs, notably among patients on diabetes drugs. Conversely, patients who began CCB monotherapy had a higher incidence of CDT compared with those starting on BBs. Other monotherapies had comparable incidence of cardiovascular disease compared with BBs.</p