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Biomedical subjects

D Bedford

Publications and source records attributed to D Bedford.

At least 19 recordsLinked to original sources
PubMed2001

The coffee diterpene cafestol increases plasma triacylglycerol by increasing the production rate of large VLDL apolipoprotein B in healthy normolipidemic subjects.

BACKGROUND: Cafestol is a diterpene in unfiltered coffee that raises plasma triacylglycerol in humans. OBJECTIVE: We studied whether cafestol increases plasma triacylglycerol by increasing the production rate or by decreasing the fractional catabolic rate of VLDL(1) [Svedberg flotation unit (S(f)) 60-400] apolipoprotein (apo) B. In addition, we studied the effect of cafestol on the composition of VLDL(1) and VLDL(2) (S(f) 20-60). DESIGN: Eight healthy normolipidemic men were administered a daily dose of 75 mg cafestol for 2 wk. A bolus injection of 7 mg L-[5,5,5-(2)H(3)]leucine/kg body wt was given after a baseline period with no cafestol and again after treatment with cafestol. We derived kinetic constants to describe the metabolism of VLDL(1) apo B by using a multicompartmental model. RESULTS: Cafestol significantly increased plasma triacylglycerol by 31% or 0.32 mmol/L (95% CI: 0.03, 0.61); the increase was due mainly to a nonsignificant rise in VLDL(1) triacylglycerol of 57% or 0.23 mmol/L (95% CI: -0.02, 0.48). Cafestol significantly increased the mean rate of VLDL(1) apo B production by 80% or 755 mg/d (95% CI: 0.2, 5353), whereas it did not significantly change the mean fractional catabolic rate of VLDL(1) apo B (mean increase of 3 pools/d; 95% CI: -4, 10]). Cafestol did not change the composition of VLDL(1). A significant increase in the ratio of VLDL(2) cholesteryl ester to triacylglycerol indicates that VLDL(2) became enriched with cholesteryl esters at the cost of triacylglycerol. CONCLUSION: Cafestol increases plasma triacylglycerol by increasing the production rate of VLDL(1) apo B, probably via increased assembly of VLDL(1) in the liver.

Adult↗
PubMed2000

Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions.

Apolipoprotein B (apoB) metabolism was investigated in 20 men with plasma triglyceride 0.66-2.40 mmol/l and plasma cholesterol 3.95-6. 95 mmol/l. Kinetics of VLDL(1) (S(f) 60-400), VLDL(2) (S(f) 20-60), IDL (S(f) 12-20), and LDL (S(f) 0;-12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which allowed input into each fraction. VLDL(1) apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL(2) apoB production (from 0.18 to 8.4 mg/kg/d) but the two were not correlated. IDL plus LDL apoB direct production accounted for up to half of total apoB production and was inversely related to plasma triglyceride (r = -0.54, P = 0.009). Percent of direct apoB production into the IDL/LDL density range (r = 0.50, P < 0.02) was positively related to the LDL apoB fractional catabolic rate (FCR). Plasma triglyceride in these subjects was determined principally by VLDL(1) and VLDL(2) apoB fractional transfer rates (FTR), i.e., lipolysis. IDL apoB concentration was regulated mainly by the IDL to LDL FTR (r = -0.71, P < 0.0001). LDL apoB concentration correlated with VLDL(2) apoB production (r = 0.48, P = 0.018) and the LDL FCR (r = -0.77, P < 0. 001) but not with VLDL(1), IDL, or LDL apoB production. Subjects with predominantly small, dense LDL (pattern B) had lower VLDL(1) and VLDL(2) apoB FTRs, higher VLDL(2) apoB production, and a lower LDL apoB FCR than those with large LDL (pattern A). Thus, the metabolic conditions that favored appearance of small, dense LDL were diminished lipolysis of VLDL, resulting in a raised plasma triglyceride above the putative threshold of 1.5 mmol/l, and a prolonged residence time for LDL. This latter condition presumably permitted sufficient time for the processes of lipid exchange and lipolysis to generate small LDL particles.

Adult↗
PubMed1999

Effect of heparin-stimulated plasma lipolytic activity on VLDL APO B subclass metabolism in normal subjects.

Heparin given intravenously enhances lipolysis, although fasting lipids are not markedly altered in long-term administration. In the present study we investigated heparin-induced acute perturbation of VLDL subclass metabolism. Eight men were examined during a control study and during an 8.5 h infusion of heparin. 2H3-leucine was used as tracer and kinetic constants derived using a non-steady-state model. Heparin infusion increased both plasma lipoprotein and hepatic lipase activity and raised plasma FFAs two-fold (P < 0.001). The fractional catabolic rate (FCR) of VLDL1 apo B increased on heparin (25.7 +/- 4.2 and 10.8 +/- 1.7 pools/d, heparin vs. control, P < 0.02). The FCR of VLDL2 apo B increased to 12.6 +/- 1.9 pools/d on heparin vs. 8.8 +/- 1.1 pools/d during the control (NS). Total VLDL apo B production was not significantly changed (824 +/- 45 and 692 +/- 91 mg/d, heparin vs. control, NS). We conclude that during heparin infusion, the catabolism of especially large triglyceride-rich VLDL1 apo B is greatly increased. However, although the FFA levels were high during the heparin study, the production of total VLDL apo B did not rise. These findings are consistent with the known action of heparin on lipoprotein lipase but indicate that acute increase in plasma FFA levels does not lead to a rise in VLDL apo B production.

Adult↗
PubMed1999

Cases of meningococcal infection and bacterial meningitis occur every day and require an 'out of hours' public health response.

Analysis of hospital admissions data over three years in Ireland showed that the 1478 cases of meningococcal disease and meningitis were admitted at the same frequency every day of the week. The need for and the cost effectiveness of an 'out of hours' service in order to manage the community aspects of meningococcal disease/meningitis requires further attention.

Humans↗
PubMed1998

Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects.

The objective of the study was to examine the potential differential effect of insulin and acipimox (both of which reduce free fatty acid [FFA] availability) on VLDL apolipoprotein (apo) B metabolism. We studied eight healthy men (age 40 +/- 4 years, BMI 25.8 +/- 0.9 kg/m2, plasma triglycerides 1.30 +/- 0.12 mmol/l) after an overnight fast (control study, n = 8), during inhibition of lipolysis with an antilipolytic agent, acipimox (n = 8), and under 8.5-h euglycemic-hyperinsulinemic conditions (n = 5). Plasma FFAs were similarly suppressed in the acipimox and insulin studies (approximately 70% suppression). 2H3-leucine was used to trace apo B kinetics in VLDL1 and VLDL2 subclasses (Svedberg flotation rates: 60-400 and 20-60), and a non-steady-state multicompartmental model was used to derive the kinetic constants. The mean rate of VLDL1 apo B production was 708 +/- 106 mg/day at the beginning and 602 +/- 140 mg/day at the end of the control study. Production of the lipoprotein decreased to 248 +/- 93 mg/day during the insulin study (P < 0.05 vs. control study) and to 375 +/- 92 mg/day (NS) during the acipimox study. Mean VLDL2 apo B production was significantly increased during the acipimox study (399 +/- 42 vs. 236 +/- 27 mg/day, acipimox vs. control, P < 0.05) but not during the insulin study (332 +/- 51 mg/day, NS). The fractional catabolic rates of VLDL1 and VLDL2 apo B were similar in all three studies. We conclude that acute lowering of FFAs does not change the overall production rate of VLDL particles, but there is a shift toward production of smaller and denser VLDL2 particles, and, thus, the amount of total VLDL particles secreted remained constant. Insulin acutely suppresses the total production rate of VLDL apo B by decreasing the production of large triglyceride-rich VLDL1 particles. Based on these findings, we postulate that insulin has a direct suppressive effect on the production of VLDL apo B in the liver, independent of the availability of FFAs.

Adult↗
PubMed1997

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM.

Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60-400) without affecting that of VLDL2 (Sf 20-60) sub-class. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 +/- 3 years, body mass index 27.0 +/- 1.0 kg/m2, plasma triglycerides 1.89 +/- 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin approximately 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper- and normoglycaemic conditions. [3-2H]-leucine was used as tracer and kinetic constants derived using a non-steady-state multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 +/- 8% after 8.5 h of hyperinsulinaemia (701 +/- 102 vs 672 +/- 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 +/- 21% under normoglycaemic conditions (603 +/- 145 mg/day). In contrast, in normal subjects insulin induced a 50 +/- 15% decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum nonesterfied fatty acids.

Apolipoproteins B↗
PubMed1997

Metabolic basis of hypotriglyceridemic effects of insulin in normal men.

The mechanism by which acute insulin administration alters VLDL apolipoprotein (apo) B subclass metabolism and thus plasma triglyceride concentration was evaluated in 7 normolipidemic healthy men on two occasions, during a saline infusion and during an 8.5-hour euglycemic hyperinsulinemic clamp (serum insulin, 490 +/- 30 pmol/L). During the insulin infusion, plasma triglycerides decreased by 22% (P < .05), and serum free fatty acid decreased by 85% (P < .05). The plasma concentration of VLDL1 apo B fell 32% during the insulin infusion, while that of VLDL2 apo B remained constant. A bolus injection of [3-(2)H]leucine was given on both occasions to trace apo B kinetics in the VLDL1 and VLDL2 subclasses (Svedberg flotation rate, 60-400 and 20-60, respectively), and the kinetic basis for the change in VLDL levels caused by insulin was examined using a non-steady-state multicompartmental model. The mean rate of VLDL1 apo B synthesis decreased significantly by 35% (P < .05) after 0.5 hour of the insulin infusion (523 +/- 87 mg/d) compared with the saline infusion (808 +/- 91 mg/d). This parameter was allowed to vary with time to explain the fall in VLDL1 concentration. After 8.5 hours of hyperinsulinemia, the rate of VLDL1 apo B synthesis was 51% lower (321 +/- 105 mg/d) than during the saline infusion (651 +/- 81 mg/d, P < .05). VLDL2 apo B production was similar during the saline (269 +/- 35 mg/d) and insulin (265 +/- 37 mg/d) infusions. No significant changes were observed in the fractional catabolic rates of either VLDL1 or VLDL2 apo B. We conclude that acute hyperinsulinemia lowers plasma triglyceride and VLDL levels principally by suppressing VLDL1 apo B production but has no effect on VLDL2 apo B production. These findings indicate that the rates of VLDL1 and VLDL2 apo B production in the liver are independently regulated.

Adult↗
PubMed1997

Lessons to be learned: a case study approach. Hyperactivity and confusion in the presentation of hyoscine overdose.

The case report is presented of a ten-and-a-half year old boy with acute onset of confusion and visual hallucinations, subsequently confirmed to be due to hyoscine toxicity following ingestion of over-the-counter (OTC) travel sickness tablets. It is suggested that packs of such pills should carry a prominent cautionary label. A clear clinical history is very important--not only in aiding the differentiation of acute viral infections involving the central nervous system (such as acute encephalitis) from drug toxicity, but also in rationalizing any further diagnostic investigations. The possible underlying reasons for drug ingestion in this case are discussed.

Antiemetics↗
PubMed1997

The provision of influenza vaccine to patients over 65 years by general practitioners.

Influenza vaccination for all elderly persons is cost effective. Guidelines in Ireland recommend the vaccine for those with chronic illness and to the elderly in care. The aims of this study are to identify how influenza vaccine is provided to elderly patients and to get GPs opinions on what barriers there are to providing the vaccine to persons 65+ years. Of the 143 GPs contacted 117 (81.8%) replied, of whom 116 (99.1%) provide the vaccine to their patients. Ninety nine (85.3%) believe it to be effective in preventing influenza, and only 8 (6.9%) have reservations about the vaccine. Eighteen (15.5%) GPs had a difficulty in identifying those to be vaccinated and only 11 (9.5%) had a computerised system to assist them. Twenty two (19.0%) GPs had difficulty in getting sufficient vaccine for their patients. Ninety six (82.8%) GPs make the vaccine available to those for whom it is recommended and of these 61 make it available to all patients over 65 years. The main patient barriers to an influenza vaccination programme are the patients fear of getting influenza from the vaccine and that many patients do not consider the vaccine to be of value. Barriers identified for GPs are the low level of reimbursement to GPs for vaccinating eligible patients and the lack of proper systems that help identify and contact those who should be getting the vaccine. All of the barriers identified should be easy to overcome so that those who require influenza vaccine can reap the health and social gains that our health services advocate.

Adult↗
PubMed1996

A functional chimeric modular polyketide synthase generated via domain replacement.

BACKGROUND: Modular polyketide synthases (PKSs), such as 6-deoxyerythronolide B synthase (DEBS), are large multifunctional enzymes that catalyze the biosynthesis of structurally complex and medically important natural products. Active sites within these assemblies are organized into 'modules', such that each module catalyzes the stereospecific addition of a new monomer onto a growing polyketide chain and also sets the reduction level of the beta-carbon atom of the resulting intermediate. The core of each module is made up of a 'reductive segment', which includes all, some, or none of a set of ketoreductase (KR), dehydratase, and enoylreductase domains, in addition to a large interdomain region which lacks overt function but may contribute to structural stability and inter-domain dynamics within modules. The highly conserved organization of reductive segments within modules suggests that they might be able to function in unnatural contexts to generate novel organic molecules. RESULTS: To investigate domain substitution as a method for altering PKS function, a chimeric enzyme was engineered. Using a bimodular derivative of DEBS (DEBS1+TE), the reductive segment of module 2, which includes a functional KR, was replaced with its homolog from module 3 of DEBS, which contains a (naturally occurring) nonfunctional KR. A recombinant strain expressing the chimeric gene produced the predicted ketolactone with a yield (35 %) comparable to that of a control strain in which the KR2 domain was retained but mutationally inactivated. CONCLUSIONS: These results demonstrate considerable structural tolerance within an important segment found in virtually every PKS module. The domain boundaries defined here could be exploited for the construction of numerous loss-of-function and possibly even gain-of-function mutants within this remarkable family of multifunctional enzymes.

Multienzyme Complexes↗
PubMed1996

A comparison of the effects of strength and aerobic exercise training on exercise capacity and lipids after coronary artery bypass surgery.

BACKGROUND: Coronary artery surgery improves symptoms and prognosis in patients with angina. Aerobic exercise rehabilitation improves exercise capacity and prognosis in cardiac patients. Strength exercise training has not been extensively studied. DESIGN: We studied the effects of 6 months aerobic and strength exercise training after coronary artery surgery in 81 men, mean age 57 years. RESULTS: Treadmill time(s) increased by 130.3 (95% confidence interval 46.4 to 214.2) in the aerobic group; by 83.1 (0.9 to 165.3) in the strength group, and by 34.3 (-1 to 69.6) in the control group (P = 0.04, control versus aerobic) after 3 months; and by 196.4 (112.2 to 280.7) in the aerobic group, by 122.7 (37.7 to 207.6) in the strength group and by 27 (-40.4 to 94.4) in the control group (P = 0.002, control versus aerobic, and P = 0.03 control versus strength) after 6 months. The level of fitness improved more in the strength-trained group, and there was a minor reduction in body weight and degree of fatness. There were no changes in lipoprotein levels. Aerobic exercise training causes early and sustained benefit in treadmill exercise capacity, while the effects of strength exercise training are later in onset. Exercise training alone did not influence lipid levels. CONCLUSION: Cardiac rehabilitation programmes should be comprehensive, including advice on diet and other risk factor modifications in addition to exercise sessions involving aerobic and strength training elements.

Aged↗
PubMed1996

Sensitive methods to study human apolipoprotein B metabolism using stable isotope-labeled amino acids.

The objective of the study was to develop a sensitive method using stable isotope-labeled tracers that would permit the determination of apolipoprotein B (apoB) metabolism in very low-density lipoprotein subfractions (VLDL1, Sf 60-400; VLDL2, Sf 20-60), intermediate-density lipoprotein (IDL, Sf 12-20), and low-density lipoprotein (LDL, Sf 0-12). Six normolipidemic subjects were given trideuterated leucine, and its clearance from plasma and appearance in the four apoB-containing lipoprotein fractions were followed by use of a highly sensitive gas chromatography-mass spectrometry technique in which the m + 3-to-m + 2 ion ratio was selectively monitored. This analytic approach permitted the precise measurement of low enrichments in IDL and LDL and extension of the turnover out to 250-300 h. A compartmental model was developed to derive rate constants from the plasma and apoB enrichment curves. The model was uniquely identifiable once parameter dependencies had been introduced to reduce the number of unknowns. Values were obtained for apoB input into all lipoprotein density intervals, together with rates of interconversion and catabolism; these agreed well with results from radioiodinated tracer experiments. An alternative model structure was also explored in which input occurred only into VLDL1. Altering the protocol of tracer administration (bolus vs. primed constant infusion) and dose (over a 10-fold range) had no influence on the results obtained. The analytic and modeling approach described will permit stable isotopes to be used to elucidate key features of apoB metabolism in normal and pathological states.

Adult↗
PubMed1996

Accumulation of large very low density lipoprotein in plasma during intravenous infusion of a chylomicron-like triglyceride emulsion reflects competition for a common lipolytic pathway.

Very low density lipoproteins (VLDL) are produced in the liver and contain apolipoprotein (apo) B-100 and endogenous lipids. By contrast, ingestion of fat leads to formation of chylomicrons containing apoB-48 secreted from the intestine. In this study, a 60-min intravenous infusion of a chylomicron-like triglyceride emulsion was given to healthy young men to examine whether competition between chylomicrons and VLDL for the same lipolytic pathway explains the increase in VLDL seen after meals. The responses of two major VLDL subfractions were determined by measuring the concentrations of apoB-100 in fractions of triglyceride-rich lipoproteins with Svedberg flotation rates of 60-400 (large VLDL) and 20-60 (small VLDL) that were separated from plasma by density gradient ultracentrifugation. A threefold elevation in plasma triglycerides was observed during the infusion together with a consistent linear increase of large VLDL. The rate at which large VLDL accumulated in plasma differed markedly among individuals and was not enhanced by doubling of the infusion rate. The response of small VLDL was more heterogeneous; however, a decrease was seen in most subjects. The combined pattern for the two VLDL species is what would be expected if large VLDL particles are the precursors of smaller VLDL species and if lipolysis of large VLDL is inhibited through competition from the triglyceride emulsion. The extent to which the triglyceride emulsion inhibited the lipolysis of VLDL and/or influenced the synthesis rate of large VLDL was estimated from simultaneous stable isotope studies. The emulsion caused a 75-90% block of the conversion of large VLDL apoB to small VLDL apoB and there was no sign of enhanced synthesis of large VLDL after infusion of the triglyceride emulsion. The corollary of these findings is that chylomicrons and their remnants impede the normal lipolytic degradation of VLDL and could thereby be indirectly implicated in the generation of atherogenic remnant lipoproteins.

Adult↗
PubMed1995

The provision of family planning services by family doctors in a health board region.

A survey was carried out to ascertain the extent of family planning services provided by family doctors. Of the 134 doctors surveyed, 119 (88.8%) replied. Of these 97 (81.5%) were male, 30 (25.2%) were aged less than 40 and 22 (18.5%) were greater than 60. Sixty-four (53.8%) worked in single-handed practices, 52(43.7%) were vocationally trained, 101 (84.9%) had the MICGP or equivalent and 42 (35.3%) had a family planning certificate. Of the 119 respondents, 99 (83.2%) give instruction in natural family planning methods, 114 (95.8%) prescribe oral contraceptives, 102 (85.7%) prescribe the "morning after pill", 40 (33.6%) fit diaphragms and 17 (14.3%) fit intrauterine devices. Only 3 (2.5%) perform male sterilisations. Doctors aged less than 60 years were 1.3 times more likely to prescribe oral contraceptives (p < 0.0001), and were four times more likely to fit diaphragms (p < 0.01). Doctors who hold a family planning certificate were 2.4 times more likely to fit diaphragms (p < 0.001) and were 2.5 times more likely to fit intrauterine devices. As to who should provide these services, the family doctor was the preferred option for 95 (79.8%) with regard to natural family planning, 107 (89.9%) for the contraceptive pill, 76 (63.9%) for the diaphragm, 58 (48.7%) for the intrauterine device, 45 (37.8%) for male sterilisations and 4 (3.4%) for female sterilisations. Younger doctors and those with a family planning certificate were more likely to say that family doctors should provide these services.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Relations between plasma lipids and postheparin plasma lipases and VLDL and LDL subfraction patterns in normolipemic men and women.

VLDL1, VLDL2, IDL, and LDL and its subfractions (LDL-I, LDL-II, and LDL-III) were quantified in 304 normolipemic subjects together with postheparin plasma lipase activities, waist/hip ratio, fasting insulin, and glucose. Concentrations of VLDL1 and VLDL2 rose as plasma triglycerides (TGs) increased across the normal range, but the association of plasma TGs with VLDL1 showed a steeper slope than that of VLDL2 (P < .001). Plasma TG level was the most important determination of LDL subfraction distribution. The least dense species, LDL-I, decreased as the level of this plasma lipid rose in the population. LDL-II in both men and women exhibited a positive association with plasma TG level in the range 0.5 to 1.3 mmol/L, increasing from about 100 to 200 mg/dL. In contrast, within this TG range the LDL-III concentration was low (approximately equal to 30 mg/dL) and changed little. As plasma TGs rose from 1.3 to 3.0 mmol/L there was a significant fall in LDL-II concentration in men (r = .45, P < .001) but not in women (r = .1, NS). Conversely, above the TG threshold of 1.3 mmol/L there was a steeper rise in LDL-III concentrations in men than in women (P < .001); 42% of the men had and LDL-III in the range associated with high risk of heart disease ( > 100 mg lipoprotein/dL plasma) compared with only 17% of the women. Other influences on the LDL subfraction profile were the activities of lipases and parameters indicative of the presence of insulin resistance. Men on average had twice the hepatic lipase activity of women. This enzyme was not strongly associated with variation in the LDL subfraction profile in men, but in women it was correlated with LDL-III (r = 39, P = .001) and remained a significant predictor in multivariate analysis. Increased waist/hip ratio, fasting insulin, and glucose were correlated negatively with LDL-I and positively with LDL-III, primarily, at least in the case of LDL-III, through raising plasma TGs. On the basis of these cross-sectional observations we postulate the following model for the generation of LDL-III. Subjects develop elevated levels of large TG-rich VLDL1 for a number of reasons, including failure of insulin action. The increase in the concentration of VLDL1 expands the plasma TG pool, and this, via the action of cholesteryl ester transfer protein (which facilitates neutral lipid exchange between lipoprotein particles), promotes the net transfer of TGs into LDL-II, the major LDL species.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1993

An increased incidence of apolipoprotein E2/E2 and E4/E4 in retinitis pigmentosa.

Previous studies from our laboratory have shown that retinitis pigmentosa (RP), a family of hereditary retinal degenerations, is often accompanied by abnormal levels of cholesterol or polyunsaturated fatty acids. The requirement of the retina for n-3 fatty acids is well known, and a defect in the supply of these lipids (e.g., by apolipoproteins) could affect the course of the disease. The present study confirms and extends a report on apolipoprotein E (apo E) isoforms in German RP patients [Jahn, Oette, Esser, Bergmann, and Leiss, (1987) Ophthalmic Res. 19, 285-288] which showed a tenfold increased frequency of the E2/E2 phenotype compared to the average German population. In our study, apo E phenotypes were determined in the probands of 100 Scottish RP families. The findings revealed a 4-fold increase in the incidence of E2/E2 and an 8-fold increase in E4/E4 compared to a Scottish control population. These increases were statistically significant at the P < 0.05 and P < 0.01 levels, respectively. To investigate the possibility that some of these apparent E2/E2 or E4/E4 phenotypes might actually be new apo E mutations, we examined the behavior of the apo E on sodium dodecyl sulfate-polyacrylamide gels (E2 migrates anomalously) and on isoelectric focusing gels following cysteamine modification of cysteines. These studies showed that two RP patients possibly had new apo E mutations, though amino-terminal sequence analysis revealed no changes in the sequence of the first 19 residues; further sequence analysis is obviously warranted.

Apolipoproteins E↗