Effect of omega-3 fatty acid supplementation on arterial elasticity in patients with familial hypercholesterolaemia on statin therapy.

BACKGROUND AND AIMS: Increased arterial stiffness is closely linked with raised blood pressure that contributes substantially to enhanced risk of coronary heart disease in high risk individuals with familial hypercholesterolaemia (FH). Omega-3 fatty acid (ω3-FA) supplementation has been demonstrated to lower blood pressure in subjects with a high cardiovascular disease risk. Whether ω3-FA supplementation improves arterial stiffness in FH subjects, on background statin therapy, has yet to be investigated. METHOD AND RESULTS: We carried out an 8-week randomized, crossover intervention trial to test the effect of 4 g/d ω3-FA supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) on arterial elasticity in 20 adults with FH on optimal cholesterol-lowering therapy. Large and small artery elasticity were measured by pulse contour analysis of the radial artery. ω3-FA supplementation significantly (P < 0.05 in all) increased large artery elasticity (+9%) and reduced systolic blood pressure (-6%) and diastolic blood pressure (-6%), plasma triglycerides (-20%), apoB concentration (-8%). In contrast, ω3-FAs had no significant effect on small artery elasticity. The change in large artery elasticity was not significantly associated with changes in systolic blood pressure or plasma triglyceride concentration. CONCLUSIONS: ω3-FA supplementation improves large arterial elasticity and arterial blood pressure independent of statin therapy in adults with FH. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.com/NCT01577056.

Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: the health in men study.

High total plasma homocysteine (tHcy) has been associated with cognitive impairment in later life, but it is unclear if this association is causal or is due to confounding. The C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase gene (MTHFR) increases basal tHcy, but its contribution to cognitive impairment has not been established. We designed this study to determine if tHcy is causally related to cognitive impairment in later life by investigating its association with high tHcy and the MTHFR-C677T polymorphism. We recruited 1778 older men from the Health in Men Study cohort and established caseness on the basis of the participants' scores on a Telephone Interview for Cognitive Status score 27 in 2008. Exposure to tHcy, gene status and other variables of interest were obtained from assessments 4-7 years earlier. Multivariate logistic regression showed that the odds of cognitive impairment increased with a doubling of tHcy (adjusted odds ratio, OR 1.36; 95% confidence interval, 95% CI 1.02-1.82). Compared with the wild CC genotype, participants with the MTHFR-TT genotype had 46% greater odds of cognitive impairment (OR 1.46, 95% CI 1.01-2.11, P=0.043). The results of this study are consistent with, but do not prove the hypothesis that high tHcy causes cognitive impairment in later life.

Familial lipoprotein lipase deficiency caused by known (G188E) and novel (W394X) LPL gene mutations.

Lipoprotein lipase (LPL) is the key enzyme in the catabolism of triglyceride-rich lipoproteins in the circulation. Familial LPL deficiency is characterized by hypertriglyceridaemia and absence of LPL activity. We report a case of LPL deficiency in a 43-year-old woman, who initially presented in childhood with chylomicronaemia syndrome. At that time, her plasma triglyceride concentration was approximately 30 mmol/L and post-heparin lipolytic activity was very low. In addition to having the known missense mutation LPL G188E, the patient was also found to have a novel nonsense mutation in exon 8, namely LPL W394X. The novel substitution in exon 8 (c.1262G > A) predicts a truncated protein product of 393 amino acids that lacks the carboxylterminal 12% of the mature LPL. Trp(394) is part of a cluster of exposed tryptophan residues in the carboxyl-terminal domain of LPL important for binding lipid substrate. Of 11 members from her three-generation family, three were heterozygotes for G188E (mean plasma triglyceride, 3.5 +/- 2.0 mmol/L), whereas six were heterozygotes for W394X (triglyceride, 4.3 +/- 1.8 mmol/L). In summary, we describe a case of familial LPL deficiency caused by compound heterozygosity for known (G188E) and novel (W394X) LPL gene mutations.

Transferrin receptors on the human placental microvillous membrane.

A preparation of microvillous membrane vesicles from human placental syncytiotrophoblast binds transferrin to specific transferrin receptors. Transferrin binding to placental receptors is rapid, saturable, reversible, and specific. Approximately 2.5 X 10(13) receptors are present per milligram of membrane protein; the apparent association constant of transferrin for the placental receptor is 2.2 X 10(7) X M-1. No evidence for removal of iron from transferrin bound to intact membrane receptors was observed in these studies. Nonionic detergent solubilization and partial purification of the microvillous membrane transferrin receptor were carried out with preservation of the functional properties of the receptor.

Transferrin receptors during rabbit reticulocyte maturation.

Experiments were performed to examine the fate of transferrin receptors in reticulocytes as these cells mature in vivo to erythrocytes. Reticulocytosis, synchronized by administration of actinomycin D, was induced in adult rabbits. Simultaneous measurements were made of haematological parameters and the interaction between transferrin and reticulocytes while the cells matured in vivo to erythrocytes. As the reticulocytes matured there was a parallel decline in their ability to take up transferrin and transferrin iron. At the same time, there was a proportionate decrease in the density of receptors for transferrin on the reticulocyte surface. The affinity of the receptors for transferrin remained unaltered during the maturation process. It was concluded that the inability of erythrocytes to take up transferrin or its iron is due primarily to the loss of transferrin receptors from the maturing reticulocyte surface.

Identification of transferrin receptors in reticulocytes.

Experiments were performed to obtain definitive evidence for the presence of membrane receptors for transferrin on reticulocytes. Rabbit reticulocytes were incubated with 125I-labelled rabbit transferrin. The transferrin taken up by the cells was solubilized using the non-ionic detergent, Teric 12A9 (polyoxyethylene (n=9) dodecyl alcohol). The soluble extracts of the cells were examined by gel filtration and a transferrin-binding moiety of approximate molecular weight 275 000 was identified. This binding moiety was found only in reticulocytes, not in mature erythrocytes. The membrane component could bind only transferrin and not the other plasma proteins studied. Only transferrin could displace bound transferrin from the complex. Rabbit transferrin was bound more strongly than human transferrin. The binding of transferrin to the component was shown to be reversible and saturable. It is concluded from these studies that the transferrin binding component identified in the reticulocyte stroma is a true physiological receptor for transferrin.

Iron-binding proteins in vitreous humour.

The soluble protein composition of Macaque monkey vitreous humour was studied in order to understand its iron-binding properties. The protein content of vitreous humour was 217 micrograms/ml +/- 4.6%, 40% of which was serum albumin and 30% an iron-binding protein of hydrodynamic properties identical to that of transferrin or lactoferrin. Relative to serum, the vitreous humour contained a 13-fold excess of this protein(s). Isoelectric focusing, iron-binding and immunoelectrophoretic studies indicated that both vitreous humour and aqueous humour contained lactoferrin as well as serum transferrin. The iron-binding capacity of these proteins in vitreous humour was equivalent to the mass of haemoglobin iron contained in at least 570000 monkey erythrocytes. It was concluded that the intraocular lactoferrin originated from within the eye. These iron-binding proteins may play a protective role in ocular disturbances such as vitreous haemorrhage, iron foreign body toxicity and infection.

The effect of vitreous humour on prostaglandin production by cultured rabbit chorioretinal fibroblasts.

Factors in vitreous humour which regulate prostaglandin production were investigated using cultured rabbit chorioretinal fibroblasts. These cells produced predominantly prostaglandin E2, 6-ketoprostaglandin F1 alpha, a compound likely to be a metabolite of prostaglandin E2 and 5-hydroxyeicosatetraenoic acid. The synthesis of 6-ketoprostaglandin F1 alpha was nearly completely inhibited by the cyclooxygenase inhibitor aspirin and partially inhibited by 10(-6) M dexamethasone (49%) and 10(-5) M forskolin (68%). Addition of 10% rabbit vitreous humour to subconfluent cells maintained in Dulbecco's modified Eagle's medium plus 1% fetal bovine serum resulted in stimulation of 6-ketoprostaglandin F1 alpha production by as much as 246% as measured by radioimmunoassay. Chorioretinal fibroblasts labelled by [3H]arachidonic acid incorporation into cellular phospholipids synthesised greater amounts of all labelled arachidonic acid metabolites in response to vitreous humour. It was concluded, therefore, that there are factors present in vitreous humour of molecular weight above 10 kDa which are capable of stimulating cellular cyclooxygenase activity. Confluent cells also responded to a factor(s) present in vitreous humour. The fraction of less than 10 kDa inhibited 6-ketoprostaglandin F1 alpha production by 50% when used at a concentration of 10%. Furthermore, 6-ketoprostaglandin F1 alpha production in confluent cells (but not subconfluent cells) was inhibited to 40% of control levels by vitamin C at a concentration of 1 mg/100 ml. The latter result points to an inhibitory role for vitamin C in vitreous humour. We conclude, therefore, that vitreous humour contains factors important for the regulation of prostaglandin metabolism in the eye.

Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial.

BACKGROUND AND PURPOSE: Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine (total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. METHODS: We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B12 0.5 mg, and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. RESULTS: At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [P=0.32]; soluble CD40L [P=0.33]; IL-6 [P=0.77]), endothelial dysfunction (vascular cell adhesion molecule-1 [P=0.27]; intercellular adhesion molecule-1 [P=0.08]; von Willebrand factor [P=0.92]), and hypercoagulability (P-selectin [P=0.33]; prothrombin fragment 1 and 2 [P=0.81]; D-dimer [P=0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-micromol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). CONCLUSIONS: Lowering tHcy by 3.7 micromol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: (1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); (2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or (3) elevated tHcy is a noncausal marker of increased vascular risk.

ATP-binding cassette transporter G8 gene as a determinant of apolipoprotein B-100 kinetics in overweight men.

OBJECTIVE: We examined the influence of genetic variation of the ATP-binding cassette (ABC) transporter G8 on apolipoprotein B (apoB) kinetics in overweight/obese men. METHODS AND RESULTS: Very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) apoB kinetics were determined in 47 men (body mass index 32+/-3 kg/m2) using stable isotope and multicompartmental modeling to estimate production rate (PR), fractional catabolic rate (FCR), and VLDL to LDL-apoB conversion. Relative to the wild-type (400TT), subjects carrying the ABCG8 400K allele had significantly decreased plasma concentrations of triglycerides, sitosterol, and campesterol, lower PR of VLDL-apoB, and higher VLDL to LDL-apoB conversion (P<0.05). The PR and FCR of LDL-apoB were also significantly higher with 400K allele (P<0.05). No association was found with ABCG8 D19H. Compared with APOE2 or APOE3, APOE4 carriers had significantly higher plasma LDL-cholesterol concentrations and lower LDL-apoB FCR. During multiple regression analysis including age, homeostasis model assessment score, plasma concentrations of sitosterol, and lathosterol, ABCG8 and apoE genotypes were independent determinants of VLDL-apoB PR and LDL-apoB FCR, respectively (P<0.05). CONCLUSIONS: Variation in the ABC transporter G8 appears to independently influence the metabolism of apoB-containing lipoproteins in overweight/obese subjects. This may have therapeutic implications for the management of dyslipidemia in these subjects.

Four novel mutations in APOB causing heterozygous and homozygous familial hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is a rare codominant disorder of lipoprotein metabolism characterized by low levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B. Heterozygotes for FHBL have less-than-half normal LDL-cholesterol and apoB concentrations, whereas homozygotes have extremely low or undetectable LDL-cholesterol and apoB levels. These reductions in LDL-cholesterol and apoB have been suggested to provide FHBL subjects with resistance to atherosclerosis. FHBL can be caused by mutations in the APOB gene on chromosome 2. We present four novel mutations and one previously described mutation in APOB causing FHBL in five families. Immunoblotting and DNA sequencing were used to characterize the novel mutation apoB-40.3 (c.5564_5565insC) and the previously reported mutation apoB-80.5 (c.11040T>G). The apoB-6.9 (c.1018_1025del) and apoB-25.8 (c.3600T>A) mutations were identified by DNA sequence analysis, as variants shorter than apoB-31 are not detectable in plasma. A fifth mutation, the splice variant c.82+1G>A, was identified by sequencing and was found in a homozygous subject. In approximately 50% of the FHBL subjects, plasma alanine aminotransferase concentrations were mildly increased, suggestive of fatty liver. All affected FHBL subjects had low to low-normal serum vitamin E concentrations, highlighting the important and recognized relationship between lipid and vitamin E concentrations.

Inherited thrombophilia in ischemic stroke and its pathogenic subtypes.

BACKGROUND AND PURPOSE: One or more of the inherited thrombophilias may be causal risk factor for a proportion of ischemic strokes, but few studies have addressed this association or the association between thrombophilia and pathogenic subtypes of stroke. METHODS: We conducted a case-control study of 219 hospital cases with a first-ever ischemic stroke and 205 randomly selected community control subjects stratified by age, sex, and postal code. With the use of established criteria, cases of stroke were classified by pathogenic subtype in a blinded fashion. The prevalence of conventional vascular risk factors; fasting plasma levels of protein C, protein S, antithrombin III; and genetic tests for the factor V Leiden and the prothrombin 20210A mutation were determined in cases and control subjects. RESULTS: The prevalence of any thrombophilia was 14.7% (95% CI, 9.9% to 19.5%) among cases and 11.7% (95% CI, 7.4% to 17.0%) among control subjects (OR, 1.3; 95% CI, 0.7% to 2.3%). The prevalence of individual thrombophilias among cases ranged from 0.9% (95% CI, 0.1% to 3.4%) for protein S deficiency to 5.2% (95% CI, 0.3% to 9.1%) for antithrombin III deficiency; among control subjects, the prevalence ranged from 1.0% (95% CI, 0.1% to 3.6%) for protein S deficiency to 4.1% (95% CI, 0.2% to 7.8%) for antithrombin III deficiency. There were no significant differences in the prevalence of thrombophilia between cases and control subjects or between pathogenic subtypes of ischemic stroke. CONCLUSIONS: One in 7 patients with first-ever acute ischemic stroke will test positive for one of the inherited thrombophilias, but the relation is likely to be coincidental rather than causal in almost all cases, irrespective of the pathogenic subtype of the ischemic stroke. These results suggest that routine testing for thrombophilia in most patients with acute ischemic stroke may be unnecessary. Whether the thrombophilias may still be important in younger patients with ischemic stroke or in predicting complications (eg, venous thrombosis) and stroke outcome remains uncertain.

Apolipoprotein epsilon 4 homozygosity--a determinant of restenosis after coronary angioplasty.

Conventional coronary risk factors have not consistently been found to be related to restenosis after coronary angioplasty. Apolipoprotein E (apo E) gene polymorphism and/or plasma apo(a) levels were determined in 195 subjects undergoing prospective follow up and angiographic study 6 months after elective balloon angioplasty of a previously untreated coronary obstruction. Restenosis (stenosis > or = 50% plus loss of > or = 50% of initial gain) had occurred in 59 of 150 subjects for whom E genotypes were available. The apo epsilon 4 allele frequency in those with restenosis was higher than those without (0.20 vs. 0.10, P < 0.01), attributable to an excess of epsilon 4 homozygotes in the restenosis group (5 of 59 vs. 1 of 91, P < 0.04). Restenosis was not related to plasma apo(a) and the apo epsilon 4 allele was not associated with elevated levels of apo(a) as has been reported elsewhere. No relationship was found between E genotype and serum lipid and lipoprotein levels; paradoxically, LDL cholesterol was significantly lower and HDL cholesterol higher in those with restenosis. In conclusion, homozygosity for apolipoprotein epsilon 4 appears to be an important determinant of restenosis after coronary angioplasty.

Familial defective apolipoprotein B-100 (FDB): effect of simvastatin therapy on LDL-receptor binding.

Heterozygotes for familial defective apolipoprotein B-100 (FDB) have two populations of low density lipoprotein (LDL), one bearing normal apolipoprotein B-100 (apo B) and the other bearing defective apo B which exhibits a much lower affinity for the LDL-receptor. If HMGCoA reductase inhibitors such as simvastatin lowered LDL mainly by up-regulating LDL-receptor mediated clearance, they should decrease the overall binding affinity of LDL from an FDB heterozygote by selectively decreasing LDL bearing normal apo B. We compared how LDL from FDB heterozygotes competed with normal 125I-labelled LDL for binding to LDL-receptors while on and off therapy with simvastatin. The LDL of FDB heterozygotes had 40% (n = 10) the affinity of normal LDL (n = 12) for the LDL receptor on cultured fibroblasts, and 55% (n = 6) of normal LDL (n = 6) for that on HepG2 cells. Treatment of FDB subjects with simvastatin (n = 10) decreased serum LDL by 22% but had no effect on its binding affinity for LDL receptors, indicative of lowering of LDL containing both normal and defective apo B. This is consistent with the major LDL lowering effect being associated with decreased synthesis of LDL, rather than enhanced LDL-receptor clearance.

The effect of homocysteine on DNA synthesis in cultured human vascular smooth muscle.

Elevated plasma homocysteine is an established risk factor for vascular disease although the mechanisms are unclear. Homocysteine has been reported to stimulate DNA synthesis and proliferation in rat aortic smooth muscle cells. Human vascular smooth muscle cells (HVSMC) from saphenous veins (n = 8), internal mammary arteries (n = 6) and umbilical arteries (n = 2) were studied. To reflect DNA synthesis, 3H-thymidine incorporation, during 24 h exposure to homocysteine in concentrations from 0.0625 to 10 mM, was studied. Incorporation was significantly increased up to 0.5 or 1 mM and thence was progressively depressed, the maximum stimulation being 24 +/- 5(S.E.)% in vein (P < 0.005) and 34 +/- 4% in mammary artery (P < 0.001) while incorporation fell to approximately 25% of the control values at 10 mM (P < 0.001). Qualitatively similar results were obtained in umbilical arteries. Homocysteine had a biphasic effect on DNA synthesis in cultured HVSMC but the higher inhibitory concentrations are well above those commonly found in vivo. While the conditions of exposure to homocysteine render close analogy to the clinical situation impossible, homocysteine can stimulate HVSMC, offering one possible mechanism for the involvement of homocysteine in the pathogenesis of atherosclerosis.

Lipoprotein lipase D9N, N291S and S447X polymorphisms: their influence on premature coronary heart disease and plasma lipids.

Lipoprotein lipase (LPL) plays a pivotal role in lipoprotein metabolism. Three recently described exonic polymorphisms of the gene, D9N, N291S and S447X, have been variably found to influence plasma lipids while effects on coronary heart disease (CHD) are less well documented. Two predominantly Caucasian groups were studied: CHD patients <50 years of age, with angiographically documented CHD; and a randomly recruited community control group without a history of heart disease. The 9N allele of the D9N polymorphism was present in 25 of 428 (5.8%) of Caucasian males with CHD and in seven of 291 (2.4%) of corresponding community subjects (odds ratio, 2.5; 95% confidence interval (CI), 1.1-5.9; P=0.03) and was also significantly over-represented in the Caucasian males with myocardial infarction (MI) (21 of 308 or 6.8%; odds ratio, 2.6; 95% CI, 1.1-5.9; P=0.01). The distributions of the other two polymorphisms were similar in the CHD and community groups. In multivariate models adjusted for age, sex, diabetes, body mass index, smoking, lipid levels and race, the D9N polymorphism remained significantly related to both CHD and MI, with an odds ratio >2. There were, generally, trends to more adverse fasting plasma high-density lipoprotein (HDL) cholesterol and triglycerides in carriers of the 291S and 9N alleles, and the opposite trends for triglycerides in 447X carriers. In the community group, male carriers of 291S (n=13) had significantly (20%) lower HDL cholesterol than corresponding non-carriers (n=323), 0.98+/-0.07 mmol/l (mean+/-S.E.) versus 1.22+/-0.02 mmol/l (P<0.005), while HDL cholesterol was not different in male carriers (n=8) and non-carriers (n=296) of 9N (1.23+/-0.13 mmol/l versus 1.22+/-0.02 mmol/l). Multivariate analysis confirmed that the 291S allele carrier status conferred a significantly lower HDL cholesterol (P=0.001) and the 447X allele lower triglyceride (P<0.01) in the community group. In conclusion, LPL 9N carrier status was unequivocally related to premature CHD and to MI in males, strongly supporting recent results in older aged males. The somewhat different effects of the D9N and N291S polymorphisms on plasma lipids, and the absence of a clear effect of the N291S on CHD, raise the possibility that the effect of 9N carrier status might be mediated through effects on LPL function in addition to those influencing fasting plasma lipids.

Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy.

OBJECTIVE: This study examined the frequency of the Lys198Asn polymorphism in the endothelin-1 (ET-1) gene in women with pre-eclampsia and normal pregnancy; and its contribution to levels of plasma ET-1 and blood pressure. DESIGN AND METHODS: This was a retrospective study examining the frequency of the ET-1 Lys198Asn polymorphism in 72 proteinuric pre-eclamptics and 81 normal pregnant women. Height, weight, blood pressure and plasma ET-1 were measured antenatally and at 6 weeks post-partum. Using specific mutagenic primers, the frequency of the G/G (normal), G/T heterozygote and T/T (mutant) genotypes of the Lys198Asn polymorphism were examined. RESULTS: The polymorphism was not associated with pre-eclampsia. However, in the combined pregnant groups after correction for BMI and group, a significant effect of the T-allele (T/T,G/T) on systolic blood pressure was found (121 +/- 1.5 mmHg compared with 116 +/- 1.3 mmHg in the G/G homozygotes). A significant interaction was found between the T-allele and pregnancy in determining systolic blood pressure, so that the effect was no longer seen post-partum. Pregnant women with the T/T genotype had significantly elevated plasma ET-1 levels 5.8 pg/ml [confidence interval (CI) 3.7-9.1] compared with 3.1 pg/ml (CI 2.6-3.8) in the G/T heterozygotes and 3.6 pg/ml (CI 3.0-4.1) in the normal G/G homozygotes. CONCLUSION: The Lys198Asn polymorphism does not directly contribute to the incidence of pre-eclampsia. However, the association of the T-allele with raised blood pressure and the T/T genotype with increased plasma ET-1 levels suggest that this polymorphism may interact with other genes or environmental factors to sensitize pregnant women to develop pre-eclampsia.

Taxol for the treatment of proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) results in retinal detachment and visual impairment due to fibroblastic proliferation in the vitreous and subsequent cellular contraction. The authors have used an in vitro model for PVR to evaluate the action of the antineoplastic drug, taxol, on chorioretinal fibroblast proliferation and contractility. Dose response curves obtained show taxol to be a potent inhibitor of both cellular events. Fifty percent inhibition of contraction and proliferation occurred at 2 X 10(-8)M and 3 X 10(-9)M, respectively. On the basis of this pharmacodynamic data, three dosage regimes were chosen to evaluate possible prevention of PVR in an animal model based on the intravitreal injection of cultured fibroblasts. These animals trials show that a single intravitreal dose of either 35 micrograms or 0.5 microgram taxol significantly reduces incidence and extent of PVR. The average grade of vitreoretinal traction at 28 days for 35 micrograms taxol and 250,000 cells was 0.4 (control 1.8); for 35 micrograms taxol and 700,000 cells, 1.0 (control 2.2); and for 0.5 microgram taxol and 250,000 cells, 1.0 (control 2.3). Delayed optic nerve damage was noted with the highest dose used, but a good therapeutic margin may exist. Long-term clinical histopathologic and electrophysiologic studies will be required. The authors conclude from these preliminary studies that taxol holds definite promise for the relief of traction retinal detachment and PVR.