Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3.

Familial dysbetalipoproteinemia has been reported to be associated uniquely with an apolipoprotein E phenotype (E2/2) that occurs in approximately 1% of all persons. We have observed the typical clinical and biochemical characteristics of this disorder in five members of a family, in all of whom the apolipoprotein E phenotype, as determined by isoelectric focusing electrophoresis, is E3/3. The disorder is present in three generations of the family: the proband, her mother, and three of the proband's five children. The proband's husband, father of all five children, also has apolipoprotein E phenotype E3/3, as do his two unaffected children. As in normal persons with phenotype E3/3, the apolipoprotein E of affected members appears to have a single residue of cysteine. When incorporated with egg lecithin into discoidal complexes, the apolipoprotein E from affected members was taken up normally into perfused livers of estradiol-treated rats, in which a high level of LDL receptors is expressed. When isoelectric focusing electrophoresis was carried out over a narrow range of pH (5-7), each of the apolipoprotein E isoforms of affected members was observed as a doublet, even after reduction of dimers of the protein with 2-mercaptoethanol and treatment with neuraminidase to minimize the content of sialylated forms of the protein. Doublets were also observed in the apolipoprotein E-2 of patients with classical dysbetalipoproteinemia, but only in the affected members of the family with atypical dysbetalipoproteinemia were the components of the doublets equally prominent. As in classical dysbetalipoproteinemia, both apolipoprotein B-100 and B-48 were present in the very low density lipoprotein fraction of plasma obtained in the postabsorptive state, indicating that remnantlike lipoproteins of both hepatic and intestinal origin accumulate. This observation, together with available evidence on the structural and functional heterogeneity of human apolipoprotein E, lead us to suggest that the disorder in this family is caused by one or two structurally abnormal forms of apolipoprotein E that contain a single residue of cysteine.

Cholesterol net transport, esterification, and transfer in human hyperlipidemic plasma.

Cholesterol esterification, cholesteryl ester transfer between lipoproteins, and cholesterol transport between lipoproteins and cultured cells have been measured in the plasma of 22 patients with primary hyperlipidemia and 10 normolipidemic subjects. In hyperbetalipoproteinemia, increase in plasma low density lipoprotein levels was associated with a reduction of cholesteryl ester transfer rates, and with a reversal of the normal direction of sterol transport between fibroblasts and their plasma culture medium. Instead of net transport from cells to medium there was a net uptake of sterol from plasma by the cells, despite a level of plasma lecithin/cholesterol acyltransferase activity that was within the normal range. In dysbetalipoproteinemia, esterification rates were increased above normal levels, but cholesteryl ester transfer was reduced and the direction of sterol transport between the cells and plasma medium was reversed, as in the hyperbetalipoproteinemic group. In hypertriglyceridemia, those subjects with cardiovascular disease showed a metabolic pattern similar to the hyperbetalipoproteinemic group. The subjects in this group without symptoms of cardiovascular disease showed a normal direction of sterol transport, normal or raised rates of cholesteryl ester transfer between lipoproteins, and an increased rate of sterol esterification in plasma that decreased towards normal levels as plasma triglyceride levels decreased. Despite their quite distinct metabolic patterns there was no consistent difference between the two hypertriglyceridemic groups in triglyceride or cholesterol levels, very low density lipoprotein composition, or electrophoretic or isoelectric focussing patterns. All hypertriglyceridemic subjects with documented cardiovascular disease showed reversed cell-plasma sterol transport and all subjects without such disease showed a normal direction of cell-plasma sterol transport. The results of this study indicate major and reproducible abnormalities in plasma cholesterol metabolism in several groups of subjects with genetically distinct hyperlipidemias, who are at risk for atherosclerotic vascular disease. The possible predictive value of sterol metabolic measurements in the analysis of cardiovascular disease is discussed.

Radioimmunoassay of human arginine-rich apolipoprotein, apoprotein E. Concentration in blood plasma and lipoproteins as affected by apoprotein E-3 deficiency.

A radioimmunoassay for apolipoprotein E in human blood serum has been developed that measures equally the major polymorphic species of the protein (apolipoproteins E-1, E-2, E-3, and E-4) and the apo E in the dimer of apolipoproteins E and A-II. The assay is specific and yields values for apolipoprotein E in very low density lipoproteins that agree closely with those obtained by a quantitative electrophoretic method. Apolipoprotein E is also present in at least one species of high density lipoprotein, but the content of apolipoprotein E in the lipoprotein fractions of plasma is uncertain owing to dissociation during ultracentrifugation. The concentration of apolipoprotein E is higher in serum of normolipidemic, premenopausal women than in men of comparable age and is a direct function of the serum triglyceride level. Apolipoprotein E levels are increased out of proportion to triglyceride levels in hyperlipidemic patients with familial dysbetalipoproteinemia (homozygotes for lack of apolipoprotein E-3). Heterozygous relatives of homozygotes have significantly higher apolipoprotein E levels in serum than unaffected relatives. The concentration of partially degraded (remnant) triglyceride-rich lipoproteins also appears to be increased in heterozygotes, who comprise about 15% of the population.

Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial.

BACKGROUND: Niacin and lovastatin are both effective drugs for the treatment of hypercholesterolemia and are among the drugs of first choice recommended by the adult treatment panel. To date, however, no studies have directly compared the lipoprotein-modifying effects and safety of lovastatin and niacin across their usual dosage range in patients with primary hypercholesterolemia. METHODS: The efficacy and safety of lovastatin and niacin were compared in a controlled, randomized, open-label study of 26 weeks' duration that was conducted at five lipid clinics. One hundred thirty-six patients with primary hypercholesterolemia participated in the study. Entry criteria were a low-density lipoprotein (LDL) cholesterol level greater than 4.37 mmol/L (160 mg/dL) with coronary heart disease and/or more than two coronary heart disease risk factors or an LDL cholesterol level greater than 5.19 mmol/L (190 mg/dL) in patients without coronary heart disease or less than two coronary heart disease risk factors. The study consisted of a 4-week diet run-in period after which eligible patients were randomly assigned to receive treatment with either lovastatin (20 mg/d) or niacin (1.5 g/d) for 10 weeks. On the basis of the LDL cholesterol response and patient tolerance, the doses were sequentially increased to 40 and 80 mg/d of lovastatin or 3 and 4.5 g/d of niacin after 10 and 18 weeks of treatment, respectively. RESULTS: In the two patient groups, 66% of patients treated with lovastatin and 54% of patients treated with niacin underwent full dosage titration. At all time points, lovastatin was significantly (P < .01) more effective than niacin in reducing LDL cholesterol levels (26% vs 5% at week 10, 28% vs 16% at week 18, and 32% vs 23% at week 26), whereas niacin was more effective (P < .01) in increasing high-density lipoprotein cholesterol levels (6% vs 20% at week 10, 8% vs 29% at week 18, and 7% vs 33% at week 26). Niacin reduced Lp(a) lipoprotein levels by 35% at week 26, whereas lovastatin had no effect. Cutaneous flushing was the most common side effect during treatment with niacin. CONCLUSIONS: Lovastatin and niacin both exerted favorable dose-dependent changes on the concentrations of plasma lipids and lipoproteins. Lovastatin was more effective in reducing LDL cholesterol concentrations, whereas niacin was more effective in increasing high-density lipoprotein cholesterol concentrations and reducing the Lp(a) lipoprotein level. Lovastatin was better tolerated than niacin, in large part because of the common cutaneous side effects of niacin.

Russell's viper venom levels in serum of snake bite victims in Burma.

Serum levels of venom antigen were measured using enzyme-linked immunosorbent assay (ELISA) in 38 Russel's viper bite victims before and after administration of 40 ml of monovalent liquid antivenom. Initial serum levels ranged from one with less than 10.0 ng to 290 ng/ml and in one case a level of 75 ng/ml was detected 27 hours after the bite. Serum venom levels after liquid monospecific antivenom therapy indicated that venom clearance was similar in each case to the natural clearance of venom in the absence of antivenom therapy. In one case a venom level of 11.5 ng/ml was detected 66 hours after liquid antivenom therapy whereas in two fatal cases, serum venom levels of 95 ng/ml and 185 ng/ml were detected after the same interval. Failure of complete neutralization of venom is probably the result of loss of potency of antivenom during improper storage. The amount of venom excreted in the urine was not related to initial serum levels.

Amount of venom injected by Russell's viper (Vipera russelli).

The total yield of venom (desiccated) in 25 adult V. russelli (mean length 111 +/- 1.8 cm (S.E.) ranges from 21-268 mg (127 +/- 13 mg, mean +/- S.E.) and that of 13 juvenile snakes (mean length 79 +/- 2.8 cm) is 8-79 mg (45 +/- 7 mg). The venom yield per milking correlated well with the length of the snake. The average amount of venom injected in the first bite of 31 adults (mean length 107 +/- 1.4 cm) is 63 +/- 7 mg (range 6-147 mg) and by 17 juvenile snakes (mean length 83 +/- 1.1 cm) is 41 +/- 8 mg (range 3-138 mg). Adults inject 45% of the glands' content in the first bite. More than 75 mg of venom (desiccated) was injected by 11 out of 31 adults and 2 out of 17 juvenile snakes. This indicates that in a substantial proportion of cases of envenomation, 40 ml of Burma Pharmaceutical Industry monovalent antivenom, which is commonly used, may not be adequate.

Fast noisy speech: age differences in processing rapid speech with background noise.

In order to investigate the effects of age on the ability to process speech under conditions of background noise, younger and older adults listened to and reported time-compressed spoken sentences presented with varying levels of background babble. Although the two age groups did not differ significantly in terms of either pure tone averages or in the ability to accurately report the sentences when they were presented in quiet, the older participants showed less tolerance for background noise than younger adults. This age difference in performance was further magnified by increased speech rates, suggesting that both age-related slowing of processing and reduced inhibition of distracting sounds may produce age deficits in speech processing.

Speech-processing capacity in young and older adults: a dual-task study.

Adult age differences in processing speech were examined with a dual-task paradigm. Subjects listened to spoken passages for later recall while performing a concurrent reaction time task intended to index cognitive capacity usage on the speech memory task. Age differences in secondary task decision latencies were eliminated when subgroups of young and older subjects were matched on working memory span. These findings are interpreted as showing that an age-related reduction in working memory efficiency contributes to age differences in processing discourse for memory.

Rapid speech processing and divided attention: processing rate versus processing resources as an explanation of age effects.

The authors conducted a dual-task study to examine age differences in speech processing under varying loads. Younger and older adults listened to and immediately recalled spoken passages presented at various speech rates (140-280 words per min). This task was performed alone as well as in a divided-attention condition in which subjects concurrently performed a picture recognition task. Consistent with the slowing hypothesis, older adults' immediate memory performance was differentially depressed when speech rates were very fast. The Age x Speech Rate interaction, however, was not exacerbated in the divided-attention condition. This suggests that aging may reduce the rate at which the processing operations underlying memory for speech are completed, but this is conceptually distinct from an age-related reduction in attentional capacity.

Response latencies for false memories: gist-based processes in normal aging.

Three experiments have demonstrated that age-related increases in both probability and speed of false recognitions for word lists depended on the use of a gist-based memory strategy. When test conditions promoted a gist strategy, both younger and older participants were as likely to falsely recognize a thematically associated lure as to correctly recognize a studied item, and both groups were equally fast in making these decisions. However, when test conditions deemphasized a gist-based strategy, older adults were more likely than younger adults, and faster, to falsely recognize both strong and weakly associated lures. These findings suggest an age-related increase in reliance on gist-based processing that may underlie age differences in false memory.

Regaining lost time: adult aging and the effect of time restoration on recall of time-compressed speech.

Two experiments in which time was restored to artificially accelerated (time-compressed) speech are reported. Experiment 1 showed that although both young and older adults' recall of the speech benefited from the restoration of time, time restoration failed to boost the older adults to their baseline levels for unaltered speech. In Experiment 2, either 100% or 125% of lost time was restored by inserting pauses, either at linguistic boundaries or at random points within the passages. Experiment 2 showed that the beneficial effects of time restoration depended on where processing time was inserted, as well as how much time was restored. Results are interpreted in terms of age-related slowing in speech processing moderated by preserved linguistic knowledge and short-term conceptual memory.

One voice too many: adult age differences in language processing with different types of distracting sounds.

An experiment is reported that investigated factors that might contribute to age differences in the ability to process spoken language under conditions of competition from various types of background noise. Age differences in recall of spoken sentences were shown to depend on the type of background noise as well as its intensity. Increased intensity levels of just one competing speaker produced differentially greater impairment in older adults than in young adults. Analyses showed that listening performance was predicted not only by individual differences in hearing ability but also by speed of processing, which underscores the combined role of age-related auditory and cognitive changes in processing spoken language.

Age differences in veridical and reconstructive recall of syntactically and randomly segmented speech.

Young and elderly adults listened to spoken passages that were segmented for immediate recall either at natural syntactic boundaries (such as after sentences or major clauses), or at random, nonsyntactic intervals. In addition, speech rate was manipulated using time-compression of the speech materials. Results showed that random segmentation was especially detrimental to the elderly subjects' recall, as was the effect of increasing speech rate. An analysis of subjects' recall errors offered evidence for reconstruction in short-term segment recall in a manner similar to that usually associated with long-term memory.

Cognitive and affective disorders in elderly diabetics.

In non-insulin-dependent diabetes mellitus, performance of complex cognitive tasks requiring the storage and retrieval of new information is poorer than in age-matched controls. By contrast, performance of less demanding tasks such as immediate memory and simple reaction time is essentially equivalent for NIDDM patients and controls. This pattern parallels the cognitive change observed with normal aging, in which age differences are minimal on less demanding immediate memory tasks but older adults perform more poorly than young adults on secondary or long-term memory tasks. Age-related changes in cognitive performance have been attributed to a reduction in processing resources or working memory capacity. Although the explanation for NIDDM-related deficits remains to be identified, reduced glucose control and elevated levels of triglycerides appear to play some role in cognitive impairment. Non-insulin-dependent diabetes is associated not only with elevated levels of depression, but with an increased frequency of self-reported memory problems. Moreover, elevated levels of depression are associated with various indicators of neuropathy and with significant reductions in self-regulated control of glucose at the time of medical office visits. Diabetic patients may perceive less control over their lives as a result of the many restrictions associated with the disease. When provided with the opportunity to exercise control, however, performance on many cognitive tasks can be improved in NIDDM as well as in age-matched controls. This suggests that by providing NIDDM patients with opportunities to exercise increased control over their lives it may be possible to enhance motivation and to increase the likelihood of the patient's adopting more effective self-regulatory behaviors.

Heparin therapy in Russell's viper bite victims with disseminated intravascular coagulation: a controlled trial.

A controlled clinical trial of low dose heparin was carried out in confirmed cases of Russell's viper bite. Twenty patients with systemic envenoming were included in the study. They were randomized to receive low dose heparin in an initial dose of 50 units/kg body weight intravenously immediately after antivenom followed by a continuous infusion of 10 unit 3 kg/hour in isotonic saline for 24 hours, or antivenom alone. Response to treatment was assessed clinically as well as by serial measurements of coagulation factors and biochemical values. No significant difference was observed in the outcome among two groups, the recovery rate from the clotting defect being similar in both. The mean serum creatinine values of the two groups were also not statistically different. The results indicated that there is no beneficial effect of adding heparin to the standard treatment by antivenom.

The association of cardiac vagal control and executive functioning--findings from the MIDUS study.

Cardiac vagal control (CVC), an index of parasympathetic contribution to cardiac regulation, has been linked to enhanced executive functioning (EF). However, findings to date have been based on small or unique samples. Additionally, previous studies assessed the CVC-EF link only during rest or recovery period from a cognitive challenge, but not during both states. In the present study, data on 817 socioeconomically diverse participants were obtained from the Midlife Development in the United States (MIDUS) study. As part of this study, participants completed cognitive tests, including EF, along with laboratory-based measures of CVC during rest and following recovery from a cognitive challenge. Regression analyses adjusting for respiratory rate revealed no effect of CVC at rest or during recovery on a global index of EF. However, exploratory post-hoc analyses of the components of the global EF index revealed a significant association between faster vagal recovery and better attention-switching and response inhibition abilities, as indexed by faster reaction time to the mixed SGST. This association remained significant after controlling for demographic, clinical (BMI, diseases and medications altering cardiac autonomic functioning, etc.), and health behavior covariates (Beta = .148, p = .010). Our findings suggest that future studies may need to investigate the links of CVC to specific EF abilities, rather than global measures of EF. Additionally, our results highlight the importance of assessing CVC during both rest and recovery from a cognitive challenge. The authors discuss the putative neurobiological underpinning of this link, as well as suggestions for future basic and clinical research.

Age differences in processing expository and narrative text.

A dual-task procedure was used to examine the effects of text genre on prose processing, comprehension, and recall in 20 young (18-33 years) and 20 old (65-80 years) adults. Response latencies on a secondary task provided an index of cognitive capacity used in reading narrative and expository passages. Both groups recalled more of narratives than of expository passages, although old subjects recalled less than young. Also, the narrative protocols of both age groups showed a greater difference for recall of main ideas as compared to details. Age differences in the pattern of text genre effects were found on measures of comprehension, capacity utilization, and processing efficiency. It appears that the narrative genre facilitated most measures of performance and partially compensated for some limitations in the older group.

Passage difficulty, speech rate, and age differences in memory for spoken text: speech recall and the complexity hypothesis.

Memory for speech in young and elderly adults was studied by varying speech rate and average predictability of prose passages (measured by a "cloze" procedure). Increased speech rate and decreased predictability yielded poorer memory performance on three retention measures (free recall, cued recall, and multiple-choice recognition), confirming passage predictability as a good predictor of empirical difficulty of a speech passage. Older adults recalled less than young adults on all three measures, with increasing speech rates producing special difficulty for the elderly subjects relative to the young. Although there was a suggestion that elderly subjects were less able to take advantage of passage predictability than the young in recall of very rapid speech, neither age group showed an interaction between passage predictability and speech rate. Results are discussed in terms of a simple extension of the complexity hypothesis to speech recall.

Age and diabetes related changes in verbal fluency.

Non-insulin-dependent diabetes mellitus is present in 7-10% of the aged. This disease appears to be associated with an acceleration of the aging process and results in compromised performance on learning and memory tasks. The present study used a verbal fluency test to examine semantic memory performance in two age groups (55-64 and 65-74 years) of diabetic subjects and controls. In addition, immediate and secondary memory were also examined using the digit symbol and digit span tests and a serial learning task. Results showed that digit symbol performance was poorer for older subjects and diabetics while serial learning was poorer only for diabetic subjects. However, the number of words generated on the verbal fluency test was similar for all groups. Qualitative analyses of the verbal output revealed that older subjects and diabetics produced the greatest number of previously recited words (repetitions). Repetitions may signal a failure to adequately monitor behavior which in turn could contribute to cognitive decline.

Complementarity of colestipol, niacin, and lovastatin in treatment of severe familial hypercholesterolemia.

OBJECTIVE: To compare the effectiveness of the ternary-drug combination of colestipol, niacin, and lovastatin with binary combinations of those drugs in treating patients with familial hypercholesterolemia. DESIGN: An open sequential study of serum lipoprotein responses in patients receiving diet alone (mean duration, 4 months); colestipol and niacin with diet (mean duration, 9 months); and colestipol, niacin, and lovastatin with diet (mean duration, 15 months). SETTING: Metabolic ward and lipid clinic of a university medical center. PATIENTS: Twenty-two patients with clinical characteristics of familial hypercholesterolemia (low-density-lipoprotein cholesterol, greater than 8.48 mmol/L; 21 of 22 with tendon xanthomas). INTERVENTIONS: Diet: less than 200 mg/d of cholesterol and less than 8% of total calories from saturated fat; colestipol, 30 g/d; lovastatin, 40 to 60 mg/d; and niacin, 1.5 to 7.5 g/d. MEASUREMENTS AND MAIN RESULTS: Mean total serum cholesterol and low-density-lipoprotein cholesterol levels of 4.86 +/- 0.62 mmol/L (188 +/- 24 mg/dL SD) and 2.89 +/- 0.54 mmol/L (112 +/- 21 mg/dL SD), respectively, were significantly lower during ternary-drug treatment than during colestipol-niacin treatment (p less than 0.003) or during treatment in which other possible binary combinations were given. The cholesterol content of very low-density-lipoproteins was lower and high-density-lipoprotein cholesterol levels higher during this phase than during the colestipol-niacin phase. CONCLUSIONS: Colestipol, lovastatin, and niacin are mutually complementary in treating hypercholesterolemia. This regimen produces reductions in serum cholesterol levels similar to those associated with regression of atheromatous plaques in animal studies.