Determinants of the effect of estrogen on the progression of subclinical atherosclerosis: Estrogen in the Prevention of Atherosclerosis Trial

OBJECTIVE: To determine the extent to which the estrogen-induced changes in lipids and markers of carbohydrate metabolism explain the beneficial effect of estrogen therapy on the progression of carotid artery intima-media thickness (IMT) in postmenopausal women. DESIGN: A randomized, double-blind, placebo-controlled, single-center trial enrolling 222 postmenopausal women 45 years and older without cardiovascular disease and with low-density lipoprotein (LDL) cholesterol levels of 3.37 mmol/L or greater (> or = 130 mg/dL). Intervention was unopposed micronized 17beta-estradiol versus placebo. Measurements were made using high-resolution B-mode ultrasonography to measure carotid artery IMT at baseline and every 6 months on-trial. RESULTS: Progression of carotid IMT was inversely related to on-trial high-density lipoprotein (HDL) cholesterol (P = 0.04) and was directly related to on-trial LDL-cholesterol (P = 0.005). Compared with placebo, women randomized to estradiol showed a higher mean on-trial HDL-cholesterol level and a lower mean on-trial LDL-cholesterol level. In contrast, fasting glucose, insulin, and hemoglobin A1C were lowered and insulin sensitivity increased with estradiol therapy, but the changes were not related to carotid IMT progression. On-trial HDL-cholesterol and LDL-cholesterol were significant independent determinants of carotid IMT progression, jointly explaining 30% of the treatment effect of unopposed estrogen on the progression of carotid IMT. CONCLUSION: Unopposed 17beta-estradiol reduced carotid IMT progression in postmenopausal women in part by increasing HDL-cholesterol and decreasing LDL-cholesterol. Although women randomized to estradiol showed improvement in all the markers of carbohydrate metabolism, these factors did not play a significant role in carotid IMT progression.     

Postmenopausal oral estrogen therapy and blood pressure in normotensive and hypertensive subjects: the Estrogen in the Prevention of Atherosclerosis Trial

OBJECTIVE: To determine if 17beta-estradiol increases blood pressure in postmenopausal women. DESIGN: A total of 222 healthy postmenopausal women were randomly assigned to either 1 mg micronized 17beta-estradiol daily or placebo for 2 years. Blood pressure measurements were obtained every other month and common carotid artery intima-media thickness measured every 6 months. Statistical analyses comparing longitudinal changes in systolic and diastolic blood pressure between treatment groups used a mixed general linear model including interaction terms to evaluate variations by age or estradiol level. RESULTS: Both placebo and estradiol groups showed small declines in systolic and diastolic blood pressure during the trial among the normotensive subjects and subjects on antihypertensive medications. However, the decline did not differ significantly between the groups. Treatment effects on systolic blood pressure differed significantly by the age of the subject (interaction P value = 0.04) with younger women on estradiol showing on average a rise in systolic blood pressure, and older women a decline. The association between serum estradiol level and systolic blood pressure showed a similar modification with age (P = 0.03). Changes in systolic blood pressure in women on estradiol were positively correlated with intima-media thickness progression (P = 0.03). CONCLUSIONS: Overall, 17beta-estradiol did not influence changes in blood pressure in normotensive or hypertensive women. The effect of 17beta-estradiol treatment on systolic blood pressure may be influenced by a woman's age. Estradiol may increase systolic blood pressure in younger postmenopausal women, while having the opposite effect in older postmenopausal women.     

Artery Length Sensitivity in Patient-Specific Cerebral Aneurysm Simulations

BACKGROUND AND PURPOSE:The reconstruction of aneurysm geometry is a main factor affecting the accuracy of hemodynamics simulations in patient-specific aneurysms. We analyzed the effects of the inlet artery length on intra-aneurysmal flow estimations by using 10 ophthalmic aneurysm models.MATERIALS AND METHODS:We successively truncated the inlet artery of each model, first at the cavernous segment and second at the clinoid segment. For each aneurysm, we obtained 3 models with different artery lengths: the originally segmented geometry with the longest available inlet from scans and 2 others with successively shorter artery lengths. We analyzed the velocity, wall shear stress, and the oscillatory shear index inside the aneurysm and compared the 2 truncations with the original model.RESULTS:We found that eliminating 1 arterial turn resulted in root mean square errors of <18% with no visual differences for the contours of the flow parameters in 8 of the 10 models. In contrast, truncating at the second turn led to root mean square errors between 18% and 32%, with consistently large errors for wall shear stress and the oscillatory shear index in 5 of the 10 models and visual differences for the contours of the flow parameters. For 3 other models, the largest errors were between 43% and 55%, with large visual differences in the contour plots.CONCLUSIONS:Excluding 2 arterial turns from the inlet artery length of the ophthalmic aneurysm resulted in large quantitative differences in the calculated velocity, wall shear stress, and oscillatory shear index distributions, which could lead to erroneous conclusions if used clinically.

Computational fluid dynamics (CFD) simulations of patient-specific cerebral aneurysms provides a valuable tool for understanding the hemodynamic environment. The geometry of the aneurysm needs to be accurately represented, and the computational model needs to account for the main properties of blood flow physics to obtain realistic and accurate flow solutions. When one reconstructs the computational geometry from imaging data, such as CT angiography or MR angiography, the extent of the surrounding vasculature that must be included to obtain rigorous flow solutions is not a priori known. Inclusion of small-diameter surrounding vessels usually does not affect the flow solution results but could add significant computational effort.¹ On the other hand, exclusion or severe truncation of larger vessels might change the flow estimations, usually resulting in nonrealistic flow patterns. The operator-dependent segmentation of radiologic images of aneurysms leads to model geometries that showed errors as large as 60% in the estimated hemodynamic parameters.^2–5 However, there is no published sensitivity study designed to analyze the effect of the arterial inlet length on the intra-aneurysmal flow estimates, to our knowledge. Due to the lack of accurate, clinically measured velocity profiles and cross-sectional geometries, many current studies use generic, mathematically generated blood flow boundary conditions and short arterial lengths.As a rule of thumb, an inlet length of at least 10 artery diameters upstream of the aneurysm must be used in hemodynamic CFD simulations. In addition, the inlet boundary conditions used in the literature, usually velocity profiles, are taken as fully developed and axisymmetric.^1,4,6–8 These assumptions are valid only for flow in straight tubes, which is very different from flow in patient arteries, where the flow is not fully developed even in the common carotid artery, the location where measurements are more readily available. Therefore, using the fully developed axisymmetric velocity profile on a short artery inlet may result in unrealistic flow estimates in the aneurysm. In the absence of physiologic measurements of arterial cross-sectional velocity distributions, it is generally safer to include a longer anatomic inlet artery to let the flow solution develop realistically on the basis of the tortuosity of the arterial geometry.⁹ Thus, we hypothesized that including a longer inlet artery will minimize the effect of the inlet boundary conditions.The aim of this study was to assess the effect of truncating the arterial inlet length proximal to the aneurysm on the local intra-aneurysmal hemodynamics of ophthalmic aneurysms. The goal was to find a sufficient artery length such that the values of velocity, wall shear stress (WSS), and oscillatory shear index (OSI) in the aneurysm are less affected by the arterial length when using the same boundary conditions and fluid properties.     

Biological evaluation of intervertebral disc cells in different formulations of gellan gum‐based hydrogels

Gellan gum (GG)‐based hydrogels are advantageous in tissue engineering not only due to their ability to retain large quantities of water and provide a similar environment to that of natural extracellular matrix (ECM), but also because they can gelify in situ in seconds. Their mechanical properties can be fine‐tuned to mimic natural tissues such as the nucleus pulposus (NP). This study produced different formulations of GG hydrogels by mixing varying amounts of methacrylated (GG‐MA) and high‐acyl gellan gums (HA‐GG) for applications as acellular and cellular NP substitutes. The hydrogels were physicochemically characterized by dynamic mechanical analysis. Degradation and swelling abilities were assessed by soaking in a phosphate buffered saline solution for up to 170 h. Results showed that as HA‐GG content increased, the modulus of the hydrogels decreased. Moreover, increases in HA‐GG content induced greater weight loss in the GG‐MA/HA‐GG formulation compared to GG‐MA hydrogel. Potential cytotoxicity of the hydrogel was assessed by culturing rabbit NP cells up to 7 days. An MTS assay was performed by seeding rabbit NP cells onto the surface of 3D hydrogel disc formulations. Viability of rabbit NP cells encapsulated within the different hydrogel formulations was also evaluated by Calcein‐AM and ATP assays. Results showed that tunable GG‐MA/HA‐GG hydrogels were non‐cytotoxic and supported viability of rabbit NP cells. Copyright © 2012 John Wiley & Sons, Ltd.     

Diabetes and orthopaedic surgery: a review

Diabetes mellitus (DM) is common, estimated to affect 425 million people worldwide in 2017. It is a condition that is continually growing in prevalence and is often associated with multiple co-morbidities. Its multi-system effects on the body mean that its management can pose a challenge, even to more experienced clinicians. In orthopaedic practice, diabetic patients are commonly encountered owing to their increased fracture risk and complications of the disease such as diabetic foot. An appropriate knowledge of diabetes, its pathophysiology, immunology and the pharmacology of medications used in its treatment is essential, as the consequences of mismanagement can be grave. Optimal treatment of diabetics can often require the involvement of a wider multidisciplinary team. Complications that can be encountered in the perioperative and postoperative periods include, diabetic ketoacidosis, hyperosmolar hyperglycaemic state, surgical site infection and venous thromboembolism. This review outlines current concepts in the perioperative management of diabetes and its manifestations within orthopaedic surgery, with a focus on outcomes and complications. A review of the available literature reveals conflicting conclusions between studies, with no clear effect or consensus yet established for many issues. There is a need for a greater number of well-designed, high-quality, appropriately powered trials to establish the true effect of diabetes on outcomes in orthopaedic surgery.     

Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS)

ObjectiveTo examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women.MethodsWomen screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n = 650).ResultsHigher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r = 0.21 and 0.19, respectively; P < 0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides = ?0.16, 0.11, and 0.11, respectively, P < 0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4–1.6], 1.5 [0.8–2.9], and 1.8 [1.0–3.4]; p for linear trend = 0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat.ConclusionWhile hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.     

Importance of catalase in the disposal of hydrogen peroxide within human erythrocytes

The catalase within normal, intact human erythrocytes was completely inactivated with amino triazole. The rate of 14CO2 evolution, when the cells were subsequently incubated with 14C-labeled glucose, provided a measure of the rate at which NADPH was being oxidized by the glutathione peroxidase/reductase system for the disposal of H2O2. This rate was determined in control cells and in catalase-inactivated cells while the cells were exposed to H2O2, which was generated at various constant and predetermined rates by glucose oxidase. The results indicated that catalase handles approximately half of the generated H2O2. The glutathione peroxidase/reductase mechanism accounted for the other half. These results are in agreement with our earlier findings on erythrocytes of a subject with a genetic deficiency of catalase. However, an unexpected result with the present approach was the finding that the increased dependence on the glutathione peroxidase/reductase mechanism did not occur until greater than 98% of the catalase had been inactivated. The latter observation indicates that catalase and the glutathione peroxidase/reductase system function intracellularly in a manner very different from that previously ascribed to them. An explanation of the findings requires that the two methods of H2O2 disposal function in a coordinated way, such as a sequential action in which the glutathione peroxidase/reductase system is the rate-limiting step.     

Antimicrobial Activities of Skincare Preparations from Plant Extracts

In this study, Tithonia diversifolia Helms. (A Gray), Aloe secundiflora (Miller) and Azadirachta indica (A. Juss) plant extracts were used to make herbal soaps while Thevetia peruviana (Schum) seed oil was used to make a herbal lotion for skincare. The soaps were tested for the growth inhibition of Escherichia coli, and Candida albicans. The lotion was evaluated against Staphylococcus aureus and E.coli. Although Tithonia diversifolia soap exhibited the highest inhibitory effect on the test bacterial strains, it had the least inhibition against C. albicans. Results from this study indicated that the ‘Tithonia diversifolia’ soap would have superior skin protection against the tested bacteria but would offer the least skin protection against C. albicans. The herbal lotion inhibited S. aureus and E. coli in a concentration dependent manner, however, the inhibitory effect was more pronounced on S. aureus.     

Probucol reduces oxysterol formation in hypertensive rabbits

The role of lipid peroxidation during the pathogenesis of atherosclerosis has been described through numerous studies and has provided compelling evidence for free radical-mediated processes that link hypertension with atherosclerosis. However, there remains only limited information concerning peroxidative processes in hypertension and their modulation by antioxidants. In the present study, the formation of cholesterol oxidation products was used as a measure of in vivo lipid peroxidation after hypertension induced by coarctation of the aorta in New Zealand White rabbits. The rabbits were fed a standard chow diet devoid of cholesterol or cholesterol oxidation products such that the measured cholesterol oxides in the plasma and aortic tissues would most plausibly arise from endogenous oxidation of cholesterol. After 12 weeks of hypertension, all of the measured cholesterol oxides increased significantly over baseline levels in the surgically coarctated animals; however, this increase was significantly less in hypertensive probucol-treated animals. Similarly, the cholesterol oxide content of aortic tissue from the surgically coarctated animals was significantly greater than that found in normotensive control aortas, and probucol treatment significantly reduced the increase in cholesterol oxide content of aortic tissue relative to that of hypertensive animals not receiving the antioxidant. These findings in hypertensive animals suggest that cholesterol oxidation products measured in plasma and aortic tissue can be derived from endogenous free radical activity and that this activity is enhanced under specific pathological conditions.