Major Protective Effect Research Articles

Population analysis of protection by HLA-DR and DQ genes from insulin-dependent diabetes mellitus in Swedish children with insulin-dependent diabetes and controls.

A negative association between insulin-dependent diabetes mellitus (IDDM) and HLA-DR, DQA1 or DQB1 was found in a large population-based investigation of childhood-onset patients (more than 420 patients) and controls (more than 340 controls) from Sweden. The relative risk was decreased for several haplotypes that were negatively associated with IDDM: DR15-DQA1*0102-DQB1*0602, DR7-DQA1*0201-DQB1*0303, DR14-DQA1*0101-DQB1*0503, DR11-DQA1*0501-DQB1*0301, DR13-DQA1*0103-DQB1*0603 and DR4-DQA1*0301-DQB1*0301. In a relative predispositional effect (RPE) analysis, however, only the DR15-DQA1*0102-DQB1*0602 haplotype was significantly decreased, which suggests that the major protective effect for IDDM is carried by this haplotype. This was supported by the observation that all genotypes which were negatively associated with IDDM, except DR7/13, included at least one allele from the DR15-DQA1*0102-DQB1*0602 haplotype. Relative predispositional effect (RPE) analysis of genotypes showed further that the DR15-DQA1*0102-DQB1*0602 haplotype was also negatively associated with IDDM when combined with any other haplotype, whether negatively or positively associated with IDDM. This supports previous suggestions that DR15-DQA1*0102-DQB1*0602 acts dominantly. However, both the stratification and the predispositional allele test failed to distinguish the negative association between IDDM and DR15 from that of DQB1*0602. On the other hand, these tests indicated that DQA1*0102 was not likely to explain the negative association between IDDM and the DR15-DQA1*0102-DQB1*0602 haplotype. We conclude that the major protective effect for IDDM in the population of Swedish children is conferred by the DR15-DQA1*0102-DQB1*0602 haplotype in a dominant fashion, the DQB1*0602 allele being the allele most likely to be responsible for the protective effect of this haplotype, although an effect of the DR15 allele could not be excluded.

Are low-dose oral contraceptives safer and better?

It is widely believed that the use of low-dose oral contraceptives decreases thrombotic risks, compared with higher-dose oral contraceptives. Two recent epidemiologic studies infer a lower risk with 30 to 35 mcg than with 50 mcg estrogen oral contraceptives. However, as with prior studies from which similar conclusions were drawn, these studies have major flaws, the worst being that all 50 mcg oral contraceptives are lumped together, whereas 50 mcg mestranol oral contraceptives are actually bioequivalent to 35 mcg ethinyl estradiol oral contraceptives, thus confounding all such studies. Moreover, while rare thrombotic events have received inordinate attention, the major protective effect against endometrial and ovarian cancer that has been shown in older studies among users of oral contraceptives containing > or = 50 mcg ethinyl estradiol or > or = 80 mcg mestranol are almost totally ignored. The theoretical benefits of using lower-dose oral contraceptives have not been demonstrated, whereas the protection against these types of reproductive cancer have been shown repeatedly with high-dose oral contraceptives but not, to date, with lower-dose oral contraceptives. Such protection may be diminished by lowering the oral contraceptive dosage. Should every woman of reproductive age use high-dose oral contraceptives for 2 years? Are we throwing out the baby with the bath water?

Fish oil protects mice against acetaminophen hepatotoxicity in vivo

Recent observations suggest that products of non-parenchymal liver cells such as eicosanoids and cytokines might play a role in the expression of liver injury after administration of acetaminophen and other noxious agents. We therefore investigated the effect of a fish oil diet, which results in the generation of eicosanoids with altered biological properties and suppresses the production of certain cytokines on acetaminophen hepatotoxicity. Mice were fed a diet with either 20% fish oil containing n-3 fatty acids or 20% olive oil containing n-6 fatty acids for 2 wk. Cytochrome P-450 activity and the concentration of glutathione were similar in the two groups before acetaminophen administration. Nevertheless, 24 hr after the administration of 375 mg/kg acetaminophen intraperitoneally, the extent of centrilobular necrosis and the activity of ALT in plasma were significantly lower in the n-3 fatty acid group (median = 277 vs. 3,367 IU/L; p less than 0.001). In the n-3 fatty acid group covalent binding of the drug to liver proteins (0.19 +/- 0.03 vs. 0.67 +/- 0.07 nmol/mg protein; p less than 0.01) and the median plasma concentration of acetaminophen (0.1 vs. 0.6 mmol/L) were significantly lower 3 hr after dosing. Mice fed the n-3 fatty acid diet excreted less acetaminophen sulfate but significantly more acetaminophen glucuronide in 24 hr. Thus the major protective effect of the fish oil diet appears to be an increased clearance of acetaminophen resulting from a stimulation of the glucuronidation of acetaminophen, which may be due to the fluidization of microsomal membranes by fish oil.

Fish oil protects mice against acetaminophen hepatotoxicity in vivo

Recent observations suggest that products of nonparenchymal liver cells such as eicosanoids and cytokines might play a role in the expression of liver injury after administration of acetaminophen and other noxious agents. We therefore investigated the effect of a fish oil diet, which results in the generation of eicosanoids with altered biological properties and suppresses the production of certain cytokines on acetaminophen hepatotoxicity. Mice were fed a diet with either 20% fish oil containing n-3 fatty acids or 20% olive oil containing n-6 fatty acids for 2 wk. Cytochrome P-450 activity and the concentration of glutathione were similar in the two groups before acetaminophen administration. Nevertheless, 24 hr after the administration of 375 mg/kg acetaminophen intraperitoneally, the extent of centrilobular necrosis and the activity of ALT in plasma were significantly lower in the n-3 fatty acid group (median = 277 vs. 3,367 IU/L; p < 0.001). In the n-3 fatty acid group covalent binding of the drug to liver proteins (0.19 ± 0.03 vs. 0.67 ± 0.07 nmol/mg protein; p < 0.01) and the median plasma concentration of acetaminophen (0.1 vs. 0.6 mmol/L) were significantly lower 3 hr after dosing. Mice fed the n-3 fatty acid diet excreted less acetaminophen sulfate but significantly more acetaminophen glucuronide in 24 hr. Thus the major protective effect of the fish oil diet appears to be an increased clearance of acetaminophen resulting from a stimulation of the glucuronidation of acetaminophen, which may be due to the fluidization of microsomal membranes by fish oil. (Hepatology 1991;13:557-561.)

Protective effect of ouabain on adriamycin-induced cardiovascular anomalies in chick embryos.

Adriamycin (2.5-10.0 micrograms) was administered to 4 1/2 and 5 day embryonic chicks (Hamburger-Hamilton developmental stages 24-26) to investigate the effect of the drug on cardiovascular morphogenesis. The drug produced dose-related increases in both mortality rate and malformation frequency with a maximum incidence of 82% cardiovascular anomalies following a dose of 10.0 micrograms/egg (P less than .001 relative to saline controls). Frequencies of embryos with ventricular septal defect (P less than .005), dextroposition of the aorta (P less than .005), or aortic arch anomalies (P less than .05) were significantly higher than among controls. In a second study, embryos were pretreated with ouabain (12.2 micrograms), verapamil (0.5 micrograms), coenzyme Q10 (100 micrograms, 200 micrograms), or vitamin E (1.0 mg, 5.0 mg)--agents previously shown to protect against adriamycin-induced cardiotoxicity. Pretreatment of embryos with ouabain significantly reduced the incidence of cardiovascular malformations induced by adriamycin from 55 to 21% (P less than .05). A major protective effect was observed relative to the induction of ventricular septal defect, the frequency of which was reduced from 45 to 14% (P less than .05). However, administration of verapamil, coenzyme Q10, or vitamin E did not have an appreciable effect on adriamycin-induced frequencies of cardiovascular malformations. Negative inotropism is suggested as a mechanism for adriamycin-induced cardiac anomalies but warrants further study.

Immunologic Properties of Enzymatically Degraded Human Keratin Intermediate Filaments

In order to gain insight into the metabolism of keratin intermediate filaments (KIF) as well as the ability of KIF degradation products to interact with the immune system, we performed enzymatic degradation of purified KIF and examined their interaction with anti-KIF autoantibodies and their ability to act as immunogens. Aliquots of KIF aggregates were exposed to 3 different enzymes, that is, alpha-chymotrypsin, plasmin, and trypsin, in dose- and time-dependent experiments. The effect of the digestion was monitored sequentially by polyacrylamide gel electrophoresis and simultaneously by transmission electron microscopy. Furthermore, the KIF degradation proteins were then examined for their ability to bind anti-KIF autoantibodies by immunoblot and for their immunogenicity. In addition, preincubation of KIF with anti-KIF autoantibodies prior to the digestion procedure was performed to investigate a possible protective effect of this treatment against proteolytic degradation. The experiments demonstrated that: (1) KIF are degraded by serine proteinases, (2) with prolonged incubation time intact KIF are progressively replaced by more granular-amorphous material in transmission electron microscopy, (3) anti-KIF autoantibodies bind to KIF degradation proteins, (4) preincubation of KIF with anti-KIF autoantibodies does not exert any major protective effect for KIF against proteolytic degradation, and (5) the enzymatic degradation products of KIF can function as effective immunogens causing the formation of high-titer anti-KIF antibodies.

Overcoming factor VIII inhibitors: a possible new approach.

Treatment of haemophiliacs with antibodies to Factor viii is still a major clinical problem, neither high‐dose Factor viii nor Factor ix concentrates being completely effective. An alternative approach was suggested by the finding that Factor viii, when complexed with phospholipid and Factor IXa, was protected from antibody attack, and that the major protective effect was provided by the phospholipid.The protective effects of various phospholipids were assessed by addition to Factor viii concentrates, incubation with human antibodies to VIII:C and measurement of residual clotting activity in three different assay systems. The most active material was a home‐made extract of bovine brain, prepared by a modified Folch method. Of three commercial lipid preparations manufactured for intravenous injection, one was inactive and the other two were only active at high concentration.Studies with purified phospholipids showed that phosphatidyl serine (PS) was the most active fraction. Phospholipid analyses showed that the three intravenous lipid preparations all contained less than 10% PS, whereas the bovine brain extract contained 20–25%.These studies show that Factor viii can be protected from antibody attack by addition of phospholipid extracts which are rich in PS, and suggest that a Factor viii product containing a suitable phospholipid could be of benefit to haemophiliacs with inhibitors.

Left stellectomy in the prevention of ventricular fibrillation caused by acute myocardial ischemia in conscious dogs with anterior myocardial infarction.

The potential of left stellectomy in reducing the incidence of ventricular fibrillation associated with acute myocardial ischemia was investigated in a new animal model for sudden death. Thirty-two dogs had an anterior myocardial infarction produced by ligation of the left descending coronary artery. One week later they were randomly allocated to a control or to an experimental group that underwent left stellectomy. One month after ligation while the dogs were conscious, a balloon occluder previously positioned around the circumflex coronary artery was inflated and the ensuing coronary occlusion was maintained for 10 minutes. Ventricular fibrillation occurred in 11 of 17 (65%) control dogs, compared with five of 15 (33%) (p < 0.05) in the experimental group. Among the survivors the incidence of arrhythmias was less in the experimental group compared with the control group. Infarct size (21 +/- 2% vs 20 +/- 2%), resting heart rate (143 beats/min vs 127 beats/min) and QTc (347 +/- 11 msec vs 349 +/- 13 msec) were similar between control and experimental groups. The dogs that died had a greater increase in heart rate at 1 minute postocclusion than survivors and also had significantly longer QT intervals. Our study indicates that left stellectomy exerts a major protective effect in reducing the incidence of ventricular fibrillation when conscious dogs with a previous anterior myocardial infarction undergo acute myocardial ischemia. This simple and safe surgical procedure may be considered for a clinical trial in subgroups of patients with ischemic heart disease at very high risk for sudden death.