The Journal of laboratory and clinical medicine
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Review Historical Article
Smallpox in history: the birth, death, and impact of a dread disease.
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3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitors are widely used to decrease plasma cholesterol levels in patients with heterozygous familial hypercholesterolemia (FH) who are at increased risk of premature coronary artery disease. Tissue-culture and animal studies have indicated that administration of HMG CoA reductase inhibitors (eg, lovastatin, simvastatin, etc) induces a compensatory increase in the activity of HMG CoA reductase, both by increasing its synthesis and decreasing catabolism. ⋯ Similarly, the 24-hour urinary excretion of mevalonic acid was reduced during treatment with lovastatin or simvastatin and increased promptly on discontinuation of drug but did not increase to levels exceeding those found at baseline when the patients were receiving dietary therapy only. We conclude that cessation of treatment with HMG CoA reductase inhibitors in patients with FH does not result in a rebound increase in cholesterol biosynthesis and that no rebound overshoot occurs in plasma concentrations of low-density-lipoprotein cholesterol.
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The effects of selective alpha(2)-adrenergic agonist alpha-methylnorepinephrine on the initial success of resuscitation and postresuscitation myocardial function were compared with nonselective alpha- and beta-adrenergic epinephrine in a swine model of cardiac arrest. Epinephrine, the primary pharmacological intervention in the treatment of cardiac arrest, improves immediate outcome. However, epinephrine increases the severity of myocardial dysfunction after cardiac resuscitation. ⋯ Ejection fraction was reduced by 35% and 14% by epinephrine and alpha-MNE, respectively, after resuscitation. Epinephrine and alpha-MNE increased postresuscitation heart rate by 38% and 15%, respectively. Accordingly, significantly less postresuscitation impairment followed the administration of alpha-MNE. alpha-MNE, a selective alpha-adrenergic agonist, was as effective as epinephrine in restoring spontaneous circulation after 7 minutes of untreated VF in a porcine model for CPR and demonstrated lesser postresuscitation myocardial injury.
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Investigations on the effects of serotonin (5-HT) and the serotonin transporter (5-HTT) on the pulmonary circulation are of special interest because of the reported increased risk of primary pulmonary hypertension (PPH) in patients who used some appetite suppressants that interfere with 5-HT. In addition to its vasoactive effects, 5-HT exerts mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PASMCs). These mitogenic and comitogenic effects require 5-HT internalization by the high-affinity 5-HTT, which can be competitively inhibited by specific drugs such as fluoxetine and paroxetine. ⋯ An increase in the levels of 5-HTT messenger ribonucleic acid was observed in smooth-muscle cells from remodeled pulmonary arteries in rats subjected to long-term hypoxia. Two series of especially relevant data further support the idea that 5-HT plays a key role in PASMC proliferation in vivo: (1) treatments that increase plasma 5-HT levels aggravate pulmonary hypertension in rats subjected to long-term hypoxia, and this effect can be prevented by combined simultaneous treatment with 5-HTT inhibitors; and (2) knockout mice with disruption of the 5-HTT gene exhibit lesser degree of hypoxic pulmonary hypertension and pulmonary vascular remodeling than control mice despite increased hypoxic pulmonary vasoconstriction. These observations indicate that 5-HTT expression, activity, or both in PASMCs contribute to pulmonary vascular remodeling and that the inducing effects of some appetite suppressants on pulmonary hypertension may be related to possible effects of these drugs on 5-HTT expression, activity, or both.
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We investigated the pathogenic mechanism(s) of small intestinal injury during acidosis in relation to circulating nitric oxide (NO) in an experimental rat model. Rats were anesthetized, paralyzed, and mechanically ventilated with room air. Hydrochloric acid (0.16 mmol bolus followed by 0.132 mmol/kg/h) was infused through the jugular vein for 5 hours. ⋯ Pretreatment with an iNOS inhibitor, aminoguanidine (AG, 50 mg/kg), reversed HCl-induced hypotension without a change in blood pH. HCl-induced lesions, MPO activity, TBARS, and plasma NOx production were decreased by AG. Our data show that the pathogenic mechanisms of acidosis-induced small intestinal lesions involve up-regulation of NO production by increased expression of iNOS and augmentation of superoxide radicals and MPO activity.