赛庚啶对离体大鼠心脏缺钙/复钙损伤(钙反常)的保护作用

离体大鼠心脏经无钙灌流(灌流液为不含Ca²⁺的K-H液,通以95%O₂和5%CO₂的混合气体)5min后,用正常K-H液进行复钙灌流20min,可导致心肌细胞内酶(CPK,LDH)及蛋白的大量漏出,心脏变苍白,甚至出现心脏挛缩,心肌组织抗氧自由基酶(SOD,GSH-Px)活性明显降低,但MDA含量无明显改变。赛庚啶(2.5～5μmol/L)能明显减少心脏Ca²⁺反常时心肌组织内酶及蛋白的漏出,显著保护心肌组织抗氧自由基酶的活性。     

Nucleic acid composition of bone marrow mononuclear cells in cobalamin deficiency

Recent studies using anion exclusion chromatography have suggested that uracil is misincorporated into the DNA of patients with megaloblastic anemia to levels detectable by nonradioactive methods. We have investigated the nucleotide composition of DNA from the bone marrow mononuclear cells of eight patients with cobalamin deficiency and compared this with that found in normal subjects. The median level of uracil in the megaloblastic group was 0.082 mol% of cytosine (approx. 0.02 mol% of all bases in DNA), which was similar to that found in the control group (median 0.085 mol% of cytosine) and may be attributable, at least in part, to artefactual deamination of deoxycytidine monophosphate during the DNA hydrolysis. Our findings give no support for the view that, by overwhelming the uracil N-glycosidase mechanism, the degree of uracil misincorporation in megaloblastic anemia is sufficient to increase the steady state level of uracil in the DNA by amounts detectable by nonradioactive methods. Using high performance liquid chromatography, we have also demonstrated normal levels of methylcytosine in the DNA of megaloblastic subjects.     

Effect of axial loading on neural foramina and nerve roots in the lumbar spine

The hypothesis that the neural foramina in some patients are critically narrowed by axial compression of the spine has not been studied with direct imaging techniques. Frozen cadaveric motion segments of the lumbar spine (intervertebral disk and contiguous vertebrae) were imaged with computed tomography (CT). The segments were thawed and compressed in a hydrostatic press to simulate axial loading, and then the segments were frozen and imaged again. The motion segments were subsequently sectioned with a cryomicrotome, and the chronic degenerative changes present in the disks were classified. Pre- and post-compression CT images were compared, and anatomic relationships were studied. In 41 randomly selected segments (some with preexisting radial, transverse, and concentric annular tears), compression diminished the diameters and cross-sectional areas of the spinal canal and neural foramina. In no cases were nerve roots displaced, distorted, or compressed by axial loading. This study suggests that axial loading, such as that produced by ordinary weight bearing, does not critically compromise the neural foramina even in the presence of chronic degenerative disk changes.     

Blood pressure control in dialysis patients: importance of the lag phenomenon

Failure by the world dialysis community to understand and use the dry-weight method of blood pressure (BP) control has resulted in an increasing incidence of treatment-resistant hypertension, which remains the principal cause of cardiovascular morbidity and mortality. This failure may in part be because the relationship between the extracellular volume (ECV) and BP is not simple and linear, but complex, because of a lag of several weeks between the normalization of the time-averaged ECV and the decrease in BP. Another cause for this failure may be the unwillingness to taper and stop all antihypertensive medications during the transition from hypertension to normotension. In this report, we describe in detail the lag phenomenon, document its presence during treatment in other populations, and describe how this knowledge is used in the application of the dry-weight method of drug-free BP control in the dialysis population.     

Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo

N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose. It is thought to provide cysteine for glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, and other mechanisms of action such as reduction of the quinoneimine might be responsible for the clinical efficacy of N-acetylcysteine. After the administration to rats of acetaminophen (1 g/kg) intraduodenally (i.d.) and of [³⁵S]-N-acetylcysteine (1.2 g/kg i.d.), the specific activity of the N-acetylcysteine adduct of acetaminophen (mercapturic acid) isolated from urine and assayed by high pressure liquid chromatography averaged 76±6% of the specific activity of the glutathione-acetaminophen adduct excreted in bile, indicating that virtually all N-acetylcysteine-acetaminophen originated from the metabolism of the glutathione-acetaminophen adduct rather than from a direct reaction with the toxic metabolite. N-Acetylcysteine promptly reversed the acetaminophen-induced depletion of glutathione by increasing glutathione synthesis from 0.54 to 2.69 μmol/g per h. Exogenous N-acetylcysteine did not increase the formation of the N-acetylcysteine and glutathione adducts of acetaminophen in fed rats. However, when rats were fasted before the administration of acetaminophen, thereby increasing the stress on the glutathione pool, exogenous N-acetylcysteine significantly increased the formation of the acetaminophen-glutathione adduct from 57 to 105 nmol/min per 100 g. Although the excretion of acetaminophen sulfate increased from 85±15 to 211±17 μmol/100 g per 24 h after N-acetylcysteine, kinetic simulations showed that increased sulfation does not significantly decrease formation of the toxic metabolite. Reduction of the benzoquinoneimine by N-acetylcysteine should result in the formation of N-acetylcysteine disulfides and glutathione disulfide via thiol-disulfide exchange. Acetaminophen alone depleted intracellular glutathione, and led to a progressive decrease in the biliary excretion of glutathione and glutathione disulfide. N-Acetylcysteine alone did not affect the biliary excretion of glutathione disulfide. However, when administered after acetaminophen. N-acetylcysteine produced a marked increase in the biliary excretion of glutathione disulfide from 1.2±0.3 nmol/min per 100 g in control animals to 5.7±0.8 nmol/min per 100 g. Animals treated with acetaminophen and N-acetylcysteine excreted 2.7±0.8 nmol/min per 100 g of N-acetylcysteine disulfides (measured by high performance liquid chromatography) compared to 0.4±0.1 nmol/min per 100 g in rats treated with N-acetylcysteine alone. In conclusion, exogenous N-acetylcysteine does not form significant amounts of conjugate with the reactive metabolite of acetaminophen in the rat in vivo but increases glutathione synthesis, thus providing more substrate for the detoxification of the reactive metabolite in the early phase of an acetaminophen intoxication when the critical reaction with vital macromolecules occurs.