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Biomedical subjects

R C O'Brien

Publications and source records attributed to R C O'Brien.

At least 19 recordsLinked to original sources
PubMed2004

Early vitamin E supplementation attenuates diabetes-associated vascular dysfunction and the rise in protein kinase C-beta in mesenteric artery and ameliorates wall stiffness in femoral artery of Wistar rats.

AIMS/HYPOTHESIS: The impact of early vitamin E supplementation on vascular function in diabetes remains unresolved. Therefore, we examined the effects of vitamin E on functional and structural parameters and on chemical markers that are disturbed in diabetes in mesenteric and femoral arteries. METHODS: Segments of both arteries, taken from control and 8-week-old streptozotocin diabetic Wistar rats that were treated or not with vitamin E, were mounted on wire and pressure myographs, after which endothelium-dependent and -independent vasodilation was assessed. Passive mechanical wall properties and the localisation and levels of protein kinase C (PKC)-beta(2) and AGE were evaluated in these vessels. RESULTS: Vitamin E supplementation was associated with improved endothelium-dependent and -independent vasodilatation in mesenteric arteries from diabetic rats. Impaired endothelium-dependent vasodilatation in diabetic mesenteric vessels was associated with PKC-beta(2) up-regulation and this was prevented by vitamin E supplementation. Increased AGE accumulation and plasma isoprostane levels in diabetic rats were not changed by vitamin E. In the femoral artery, vitamin E supplementation had no effect on endothelium-dependent or -independent vasodilatation, but did prevent the wall stiffening associated with diabetes. CONCLUSIONS/INTERPRETATION: Early vitamin E supplementation has a beneficial effect on diabetes-induced endothelial dysfunction in resistance arteries. This benefit may arise from a direct effect on smooth muscle function, as a result of inhibition of the PKC-beta(2) isoform by vitamin E.

Acetylcholine↗
PubMed2001

Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery.

The hypothesis tested in this study is that diabetes has a different impact on an artery in which endothelium-dependent responses derive from both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) compared with responses in which NO predominates and EDHF is absent. The streptozotocin-treated rat model of diabetes was used, and the arteries were mounted on a wire myograph. In mesenteric arteries depolarized and constricted with phenylephrine, acetylcholine evoked hyperpolarization (31 +/- 2 mV) and complete relaxation; these responses were attributed to EDHF and NO. In femoral arteries, acetylcholine evoked a small, NO-mediated hyperpolarization (5 +/- 1 mV) and incomplete relaxation. Bradykinin evoked NO-dependent responses in mesenteric arteries. Whereas diabetes significantly impaired the EDHF-dependent hyperpolarization and relaxation in mesenteric arteries, NO-dependent responses in femoral and mesenteric arteries were preserved. 1-Ethyl-2-benzimidazolinone evoked hyperpolarization and relaxation in mesenteric arteries, and this was impaired in diabetes. In conclusion, NO-dependent responses are preserved in diabetes, whereas endothelial responses-dependent upon EDHF appear to be impaired. The putative channels responsible for mediating the EDHF response may be altered in diabetes.

Acetylcholine↗
PubMed2000

Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice.

A total of 1028 hypercholesterolaemic men and women aged 18-75 participated in an open label, randomised, parallel group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine in terms of their abilities to achieve a plasma total cholesterol target of<5.0 mmol/l. The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6 week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine. The percentage of patients achieving the target at 10 and 20 mg doses of atorvastatin were comparable to 20 and 40 mg of simvastatin, respectively. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.41 and 7.31 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of<5.0 mmol/l. Treatment with atorvastatin achieved the target in 83% of patients, while simvastatin (or simvastatin plus cholestyramine) achieved the target in 66% of the patients (P<0.005). The target was achieved with 10 mg atorvastatin in 38% of patients and with 10 mg simvastatin in 26% of cases (P<0.005). In patients whose baseline cholesterol levels were between 5.6 and 6.5 mmol/l, 95% of the atorvastatin group and 86% of the simvastatin group reached the target. Even with baseline cholesterol levels between 7.6 and 8.5 mmol/l, the target was reached in 78% of the atorvastatin group and 61% of the simvastatin group. It is thus realistic for general practitioners to expect the majority of their at risk patients to achieve target plasma cholesterol levels that have been shown in population studies to be associated with relatively low rates of coronary heart disease. These targets are achieved in significantly more patients and at lower mg doses with atorvastatin than simvastatin.

Administration, Oral↗
PubMed2000

Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study.

OBJECTIVES: We sought to determine, in a double-blind, placebo-controlled, randomized study, whether vitamin E supplementation (1,000 IU for three months) would improve impaired conduit and resistance vessel endothelial vasodilator function (EVF) and systemic arterial compliance (SAC) in type I diabetes mellitus (DM). BACKGROUND: Oxidative stress is thought to be important in the pathogenesis of impaired EVF. Consistent with this hypothesis, we have recently shown that impaired EVF is related to low density lipoprotein (LDL) vitamin E content (VEC) in young subjects with type 1 DM. METHODS: We assessed EVF in the brachial artery (using noninvasive ultrasound, flow-mediated vasodilation [FMD]; n = 41) and in the forearm resistance vessels (by flow responses to intrabrachial acetylcholine [ACh]; n = 21) and measured SAC (simultaneous aortic blood flow and carotid pressure measurements; n = 41) before and after active or placebo therapy. RESULTS: The LDL VEC was increased by 127% after supplementation, resulting in a significant reduction in the oxidative susceptibility of LDL. There was no time-dependent change in FMD or in the response to ACh or SAC in the placebo group. A significant improvement in FMD (2.6 +/- 0.6% to 7.0 +/- 0.7%, p < 0.005) and the dose response to ACh (p < 0.05) were observed in those randomized to vitamin E therapy. Systemic arterial compliance was not affected by vitamin E (0.41 +/- 0.03 vs. 0.49 +/- 0.06 arbitrary compliance units, p = NS). The change in FMD was related to the change in LDL VEC (r = 0.42, p < 0.05) and the change in the oxidative susceptibility of LDL (r = 0.64, p < 0.0001). CONCLUSIONS: Short-term daily oral supplementation with vitamin E improves EVF in both the conduit and resistance vessels of young subjects with type I DM.

Administration, Oral↗
PubMed2000

Endothelial vasodilator function is related to low-density lipoprotein particle size and low-density lipoprotein vitamin E content in type 1 diabetes.

OBJECTIVES: We sought to determine whether endothelial vasodilator function (EVF) in patients with type 1 diabetes was related to low-density lipoprotein (LDL) particle size (LDLPS), LDL vitamin E content (LDLVE) or the susceptibility of LDL to oxidation (OxLDL). BACKGROUND: Impaired EVF is an early feature of diabetic vascular disease and may be related to oxidant stress. Although small, dense LDL and oxidized LDL are features of type 2 diabetes and predict the development of coronary artery disease, their role in type 1 diabetes is less clear. METHODS: Endothelium-dependent vasodilation was assessed in the brachial artery (flow-mediated vasodilation [FMD]) and in the forearm resistance circulation using venous occlusion plethysmography in response to graded doses of intrabrachial acetylcholine (ACh). Thirty-seven patients with type 1 diabetes mellitus (DM) and 45 matched controls underwent flow-mediated dilation, while a subset of 19 DM and 20 controls underwent plethysmography. RESULTS: Total, LDL and high-density lipoprotein cholesterol or triglycerides were not different in DM compared with controls, but LDLPS was smaller (25.6 +/- 0.06 vs. 26.1 +/- 0.1 nm, p < 0.05) and LDLVE was reduced (2.0 +/- 0.25 vs. 2.6 +/- 0.18 micromol/mmol LDL, p < 0.05). Oxidative susceptibility of LDL was not different. Flow-mediated vasodilation was impaired in DM compared with controls (3.6 +/- 0.6% vs. 7.1 +/- 0.5%, p < 0.005), as was the vasodilator response to ACh (p < 0.05). Flow-mediated vasodilation was directly related to LDLPS and LDLVE in both the entire study cohort and DM alone (p < 0.05), but not to other parameters of the standard lipid profile. Similarly, endothelium-dependent vasodilation in the resistance circulation was directly related to LDLPS and LDLVE, but not to OxLDL. CONCLUSION: These results suggest, but do not prove, that LDL particle size and LDL vitamin E may be determinants of conduit and resistance vessel endothelial vasodilator function in type 1 diabetes. Further work will be required to prove cause and effect.

Acetylcholine↗
PubMed2000

Basal and exercise-induced skeletal muscle blood flow is augmented in type I diabetes mellitus.

Hyperaemia occurs early in the renal and retinal microcirculation of patients with type I (insulin-dependent) diabetes mellitus, and may be critical in the development of nephropathy and retinopathy. We therefore sought to determine whether resting and exercise-induced hyperaemia was also apparent in the skeletal muscle circulation of young subjects with type I diabetes. Blood flow was assessed by venous occlusion plethysmography in 18 diabetic (DM) subjects and 20 matched controls. Exercise entailed 2 min of isotonic exercise against no load. Endothelium-dependent and -independent vasodilator function was assessed following intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. Forearm blood flow (FBF) was higher in DM subjects than in controls (3.3+/-0.3 and 2.2+/-0.2 ml x min(-1) x 100 ml(-1) forearm respectively; P<0.005). This was not due to differences in forearm or body size, blood pressure, heart rate, lipid status or glycaemic control. Peripheral insulin levels were higher in DM subjects than in controls (48.5+/-8 and 15.5+/-1.5 micro-units/ml respectively; P<0.005). Resting FBF was closely correlated with insulin levels (r(2)=0.4; P<0.005). Parameters of exercise-induced hyperaemia [including peak flow (16.4+/-1.4 and 12.0+/-0.7 ml x min(-1) x 100 ml(-1) forearm in DM and control subjects respectively; P<0.01) and the volume repaid to the forearm at 5 min post-exercise (32.1+/-3.1 and 23.1+/-1.4 ml x 100 ml(-1) forearm respectively; P<0.05)] were also significantly greater in DM subjects, even when differences in resting FBF were taken into account. Peak hyperaemic blood flow and the volume repaid at 5 min were also related to insulin levels (r(2)=0.16; P<0.05 and r(2)=0.27; P<0.005 respectively). The vasodilator response to acetylcholine was reduced in DM subjects (P<0.05; analysis of variance), and the slope of this dose-flow relationship was inversely related to insulin levels (r(2)=0.2; P<0.05). These data show that both resting and exercise-induced skeletal muscle blood flow are augmented in young patients with type I diabetes, possibly due to the vasodilatory effect of increased insulin levels. Diminished vasodilator responses to acetylcholine may also, in part, be a consequence of insulin-augmented resting muscle blood flow.

Acetylcholine↗
PubMed2000

Vasodilator prostanoids, but not nitric oxide, may account for skeletal muscle hyperaemia in Type I diabetes mellitus.

We and others have previously documented increased resting and exercise-induced skeletal muscle blood flow in young subjects with Type I (insulin-dependent) diabetes mellitus compared with healthy controls. Both NO and prostanoids are important regulators of vascular tone and may therefore contribute to this hyperaemia. The aim of the present study was to determine the contribution of NO and vasodilator prostanoids to this skeletal muscle hyperaemia in diabetes. We assessed the effects of infusion into the intrabrachial artery of the cyclo-oxygenase inhibitor acetylsalicylic acid (ASA; aspirin) and of the L-arginine analogue N(G)-monomethyl-L-arginine (L-NMMA) on skeLetal muscle blood flow in subjects with Type I diabetes mellitus (DM subjects) and control subjects. Blood flow was measured by venous occlusion plethysmography. Isotonic forearm exercise involved 2 min of wrist flexion and extension. Resting flow (forearm blood flow; FBF) was augmented in DM subjects, as was peak exercise-related blood flow (PFBF) and the volume repaid to the forearm 5 min after exercise (AUC 5, where AUC is area under the flow-time curve) (P<0.05), even when accounting for differences in basal flow. Infusion of L-NMMA reduced resting flow by 48% in controls (P<0.005) and by 12% in DM subjects (not significant). L-NMMA reduced PFBF and AUC 5 by 29% (P<0.05) and 39% (P<0.0005) respectively in controls, but had no significant effect on these parameters in DM subjects. Infusion of ASA reduced FBF, PFBF and AUC 5 in both DM (P<0.05) and control (P<0.05) subjects, but the magnitude of this reduction was greater in DM than in control subjects (ANOVA, P<0.05), even when differences in resting FBF were accounted for. Indeed, ASA eliminated the differences in FBF, PFBF and AUC 5 between DM and control subjects. Thus increased release of vasodilator prostanoids, rather than of NO, appears to account for skeletal muscle hyperaemia in Type I diabetes.

Adult↗
PubMed1999

Systemic arterial compliance is reduced in young patients with IDDM.

Arterial elastic properties are altered with increasing age and in various disease states, including non-insulin-dependent diabetes mellitus (NIDDM). Whether young patients with insulin-dependent diabetes mellitus (IDDM) have reduced arterial compliance before developing endothelial dysfunction or overt micro- and macrovascular disease is unclear. Systemic arterial compliance and endothelium-dependent, flow-mediated vasodilation (FMD) was assessed in 25 individuals with uncomplicated IDDM (23 +/- 4 yr, 14 females and 11 males) and compared with 30 age-matched controls (15 females and 15 males). Arterial compliance was determined via simultaneous measurements of aortic blood flow and carotid arterial pressure. The relationship between arterial compliance and endothelial function (assessed by brachial artery FMD) was also examined. Arterial compliance was 29% lower in IDDM subjects compared with control subjects (0.46 +/- 0.05 vs. 0.65 +/- 0.07 arbitrary compliance units, P < 0.05). Blood pressure, lipid levels, and daily energy expenditure (a measure of physical activity levels) were not different between groups. Compliance in the IDDM group was not related to the integrity of endothelial vasodilator function, disease duration, or degree of glycemic control. Arterial compliance is reduced in young patients with IDDM before the development of overt micro- or macrovascular disease. Early assessment of arterial compliance may be useful in predicting the development of diabetic vascular complications.

Adult↗
PubMed1998

Gemfibrozil treatment increases low-density lipoprotein particle size in Type 2 diabetes mellitus but does not alter in vitro oxidizability.

The aim of this study was to determine the effect of the lipid modifying agent gemfibrozil on lipid and coagulation risk factors in patients with Type 2 diabetes mellitus (Type 2 DM). Twenty-six subjects with Type 2 DM and dyslipidaemia were treated for 24 weeks with either gemfibrozil 600 mg orally twice daily or placebo in a double-blind randomized trial. Lipid profiles, fibrinogen, Factor VII, and plasminogen activator inhibitor-1 (PAI-1) were measured by routine laboratory methods. Low density lipoprotein (LDL) size was determined by gradient gel electrophoresis and the resistance of LDL to copper-induced oxidation was assessed by measuring absorbance at 234 nm. Gemfibrozil significantly reduced total cholesterol (-0.9 (-0.48, -1.32) mmol l(-1); p < 0.05) and triglycerides (-2.7 (-1.55, -1.35) mmol l(-1); p < 0.001) vs placebo. The fall in triglyceride was reflected by a fall in VLDL cholesterol levels in the gemfibrozil treated group vs placebo (-1.31 mmol l(-1); p < 0.001). LDL-cholesterol level did not change but LDL particle size increased by 0.5 nm (0.01, 0.93); P < 0.02. The increase in particle size was inversely correlated with the change of triglyceride level (r = -0.79, p < 0.0001) but did not result in any reduction of susceptibility to copper-induced oxidation. There were no significant changes in the coagulation parameters studied. Because of its ability to correct the lipid abnormalities associated with Type 2 DM particularly hypertriglyceridaemia, gemfibrozil provides a useful therapeutic option in the management of diabetic dyslipidaemia but it does not alter in vitro oxidizability of LDL.

Blood Coagulation↗
PubMed1998

Aminoguanidine has an anti-atherogenic effect in the cholesterol-fed rabbit.

Advanced glycosylation endproducts (AGEs) which result from the non-enzymatic interaction of proteins and glucose are implicated in the vasculopathy of diabetes and aging. Since aminoguanidine (A) inhibits the accumulation of AGEs, we explored its effects on the development of atherosclerosis. Male New Zealand white cross rabbits fed a high cholesterol (1%) diet were randomized to control (C) or increasing doses of A treatment (25, 50 and 100 mg/kg A body weight). The animals were sacrificed after 12 weeks. Sudan IV was used to stain the lipid containing plaques of the aortic arch, thoracic and abdominal aorta and the surface area occupied by atheroma was assessed. Increasing doses of A treatment were associated with reduction in plaque formation in the aorta. At a dose of 100 mg/kg A, there was a 30, 49 and 48% reduction in plaque formation in the aortic arch, thoracic and abdominal aorta, respectively. There was a correlation between AGE levels and the degree of atheroma in these cholesterol fed rabbits (control, r = 0.75, P < 0.01; 100 mg/kg A, r = 0.59, P = 0.02). These data suggest that advanced glycation may participate in atherogenesis and raise the possibility that inhibitors of advanced glycation may retard this process.

Animals↗
PubMed1997

The effects of gliclazide and other sulfonylureas on low-density lipoprotein oxidation in vitro.

Diabetes is associated with increased oxidant stress. This may contribute to the development of diabetic macrovascular complications through increased oxidation of low-density lipoprotein (LDL), which is thought to be a crucial step in the development of atherosclerosis. The sulfonylurea gliclazide has been shown to have free radical-scavenging activity in vitro, but its effects on LDL oxidation, and these effects of other sulfonylureas, are unknown. To investigate this we studied the effects of in vitro supplementation with gliclazide 1 mumol/L on copper-induced oxidation of LDL isolated from 20 control subjects and 22 type II diabetic patients. The effects of 1 mumol/L vitamin C, a known water-soluble antioxidant, were studied simultaneously. The resistance to oxidation, expressed as the lag time between the addition of copper and commencement of oxidation, was significantly increased by both gliclazide and vitamin C, and the effect was similar for LDL from diabetic and control subjects. The baseline oxidation lag time was 63.4 +/- 2.1 minutes, and increased to 108 +/- 4.4 minutes with gliclazide and 88.7 +/- 5.6 minutes with vitamin C (P = .0001, baseline v either treatment). The increase in lag time with gliclazide of 70% +/- 3% was greater than the 30% +/- 5% increase with vitamin C (P < .0005). In a separate experiment, LDL isolated from eight control and 10 diabetic subjects was supplemented with 1 mumol/L gliclazide, glibenclamide, glipizide, and tolbutamide. For each LDL sample, all drugs were studied simultaneously and the oxidation lag time was compared against that of untreated LDL. Gliclazide increased the lag time from 53.7 +/- 2.4 minutes to 108.4 +/- 4.5 minutes (P = .0001). None of the other sulfonylureas had any effect on lag time. These findings demonstrate that gliclazide is an effective inhibitor of in vitro LDL oxidation, and in this respect, it is more potent on a molar basis than vitamin C. This antioxidant property of gliclazide was not shared by the other sulfonylureas studied.

Administration, Oral↗
PubMed1997

Long-term estrogen therapy improves vascular function in male to female transsexuals.

OBJECTIVES: This study sought to examine the effects of long-term estrogen therapy on vascular function in male to female transsexuals and to compare the findings with those observed in men and premenopausal women. BACKGROUND: Gender differences in coronary artery disease have largely been attributed to the beneficial effects of estrogen on vascular function and plasma lipids in women. However, the effects of estrogen on the male vasculature have not been widely studied. METHODS: We compared the effects of estrogen on vascular function in 14 male to female transsexuals, 14 age-matched men and 15 premenopausal women. Flow-mediated vasodilation and response to nitroglycerin were assessed in the brachial artery using noninvasive ultrasound. RESULTS: Flow-mediated vasodilation was similar in transsexuals and women but greater than that in men ([mean +/- SE] 11.5 +/- 1.3% and 9.4 +/- 1.1% vs. 5.2 +/- 1.0% respectively, p < 0.005). Responses to nitroglycerin were also greater in transsexuals and women than in men (21.6 +/- 1.7% and 21.0 +/- 0.9% vs. 14.5 +/- 1.2%, respectively, p = 0.0005). These differences persisted even after adjusting for vessel size. Despite similar total cholesterol levels, transsexuals had high density lipoprotein cholesterol levels similar to those in women and greater than those observed in men (1.76 +/- 0.12 and 1.82 +/- 0.11 mmol/liter vs. 1.35 +/- 0.07 mmol/liter, respectively, p < 0.005). Moreover, triglyceride levels were greater in transsexuals than in men and women, and low density lipoprotein cholesterol (LDL-C) particle size was smaller (25.7 +/- 0.2 nm vs. 26.2 +/- 0.1 and 26.6 +/- 0.1 nm, respectively, p = 0.0001). Serum testosterone (an index of estrogen therapy in transsexuals) was markedly suppressed in transsexuals and similar to that in women. Univariate analysis revealed that there was a strong inverse correlation between serum testosterone and flow-mediated vasodilation (r(s) = -0.48, p < 0.005). Multivariate analysis revealed that the best combination of predictors of flow-mediated vasodilation was serum testosterone, vessel size and LDL-C (R2 = 0.3, p < 0.005). CONCLUSIONS: Long-term estrogen therapy appears to improve vascular function in male to female transsexuals and occurs despite higher triglyceride levels and the presence of small, dense LDL-C. The beneficial effects of estrogen are not gender specific or solely mediated through endothelium-derived nitric oxide.

Adult↗
PubMed1993

Long-term glycemic control and the rate of progression of early diabetic kidney disease.

In this prospective study of 11.9 years duration (range 9 to 14), we examined the progression of albuminuria prior to and after the onset of microalbuminuria [albumin excretion rate (AER): 20 to 200 micrograms/minute]. Glycated hemoglobin (HbA1), AER and blood pressure were measured every six months. Twenty-two (13 type I, 9 type II) patients were identified in whom AER increased progressively (progressors). These patients were compared with 22 others matched for age, duration and type of diabetes in whom AER did not change significantly during the study period (non-progressors). In the progressors, the rate of increase in AER correlated with mean HbA1 for the study period in patients with type I (r = 0.68, P < 0.01) and type II diabetes (r = 0.71, P < 0.05). Furthermore, AER began increasing well before the conventional 20 micrograms/minute threshold of microalbuminuria had been reached and within the first five years of diagnosis of type I diabetes. We conclude that in predisposed diabetic patients, long-term glycemic control is correlated with the rate of development of early renal abnormalities. Repeated measurements of AER from the time of diagnosis may be useful in the early detection of patients who will develop microalbuminuria and ultimately overt diabetic nephropathy.

Adolescent↗
PubMed1993

The effects of perindopril and triple therapy in a normotensive model of diabetic nephropathy.

The effect of the angiotensin-converting enzyme inhibitor, perindopril, on functional and structural parameters of diabetic nephropathy has been compared with triple therapy (hydralazine, reserpine, and hydrochlorothiazide) in normotensive, STZ-induced diabetic Sprague-Dawley rats. Animal groups included control rats, diabetic rats treated with perindopril, diabetic rats receiving triple therapy, and untreated diabetic rats. Treatment was continued for 32 wk. Blood pressure reduction and severity of diabetes, as assessed by body weight and glycemic control were similar with both drug regimens. A similar rise in plasma renin activity occurred in the two groups receiving antihypertensive drugs, whereas the perindopril but not the triple therapy group had suppressed plasma angiotensin-converting enzyme activity. No significant difference was observed in renal function among the four groups. Diabetes was associated with a progressive increase in albuminuria, but this rise was ameliorated by both perindopril and triple therapy. No significant difference was noted in albuminuria between triple therapy and perindopril-treated diabetic rats. Diabetes was associated with glomerular basement membrane thickening, mesangial expansion, and glomerular volume. No glomerular ultrastructural parameter was affected by antihypertensive drugs. No specific benefit of angiotensin-converting enzyme inhibition over triple therapy could be detected in this normotensive model of diabetic nephropathy.

Analysis of Variance↗