A look through the new therapeutic window: irbesartan

Although an impressive array of efficacious antihypertensive agents are available to treat hypertension, the optimal use of these agents is limited by dose-related side-effect profiles. This is particularly the case for widely used first-line antihypertensive agents such as diuretics, beta-blockers, calcium antagonists, and alpha1-blockers; this represents a major therapeutic dilemma in treating hypertension. With the development of the angiotensin II receptor antagonists (AIIRAs), this dilemma might have been solved. Irbesartan is a long-acting AIIRA that provides dose-related efficacy with placebo-like tolerability at all clinical doses. The results of placebo and active-control trials of irbesartan have demonstrated that the agent is as effective as the leading members of major antihypertensive classes with respect to blood pressure control, while having superior tolerability. Pooled data from nine multicenter, randomized, placebo-controlled trials with irbesartan have documented no adverse events caused by dose-response. This feature could widen the traditionally narrow therapeutic window in the treatment of hypertension and point to the use of AIIRAs such as irbesartan as first-line therapy in the management of hypertension.

The Rapakivi texture of feldspars in a plutonic mixing environment - A dissolution-recrystallization process

A new hypothesis is formulated to explain the development of rapakivi texture in and around the mafic enclaves of porphyritic granitoids, i.e. in environments involving magma mixing and mingling. The formation of a plagioclase mantle around alkali feldspar megacrysts is attributed to the localized presence of a melt resulting from the reaction of these megacrysts, with host hybrid magma with which they are in disequilibrium. This feldspathic melt adheres to the resorbed crystals and is virtually immiscible with the surrounding magma. Its composition is modified in terms of the relative proportions of K2O, Na2O, and CaO through selective diffusion of these elements, thus allowing the specific crystallization of andesine. With decreasing temperature, the K-feldspar, again stable, crystallizes along with the plagioclase, leading to mixed mantle structures.

Lumbar spine texture enhances 10-year fracture probability assessment.

We found that lumbar spine texture analysis using trabecular bone score (TBS) is a risk factor for MOF and a risk factor for death in a retrospective cohort study from a large clinical registry for the province of Manitoba, Canada. INTRODUCTION: FRAX® estimates the 10-year probability of major osteoporotic fracture (MOF) using clinical risk factors and femoral neck bone mineral density (BMD). Trabecular bone score (TBS), derived from texture in the spine dual X-ray absorptiometry (DXA) image, is related to bone microarchitecture and fracture risk independently of BMD. Our objective was to determine whether TBS provides information on MOF probability beyond that provided by the FRAX variables. METHODS: We included 33,352 women aged 40-100 years (mean 63 years) with baseline DXA measurements of lumbar spine TBS and femoral neck BMD. The association between TBS, the FRAX variables, and the risk of MOF or death was examined using an extension of the Poisson regression model. RESULTS: During the mean of 4.7 years, 1,754 women died and 1,872 sustained one or more MOF. For each standard deviation reduction in TBS, there was a 36 % increase in MOF risk (HR 1.36, 95 % CI 1.30-1.42, p < 0.001) and a 32 % increase in death (HR 1.32, 95 % CI 1.26-1.39, p < 0.001). When adjusted for significant clinical risk factors and femoral neck BMD, lumbar spine TBS was still a significant predictor of MOF (HR 1.18, 95 % CI 1.12-1.23) and death (HR 1.20, 95 % CI 1.14-1.26). Models for estimating MOF probability, accounting for competing mortality, showed that low TBS (10th percentile) increased risk by 1.5-1.6-fold compared with high TBS (90th percentile) across a broad range of ages and femoral neck T-scores. CONCLUSIONS: Lumbar spine TBS is able to predict incident MOF independent of FRAX clinical risk factors and femoral neck BMD even after accounting for the increased death hazard.

Assessment of left coronary artery beat-to-beat repositioning in order to propose an optimal acquisition window for coronary MRA

Introduction: Coronary magnetic resonance angiography (MRA) is a medical imaging technique that involves collecting data from consecutive heartbeats, always at the same time in the cardiac cycle, in order to minimize heart motion artifacts. This technique relies on the assumption that coronary arteries always follow the same trajectory from heartbeat to heartbeat. Until now, choosing the acquisition window in the cardiac cycle was based exclusively on the position of minimal coronary motion. The goal of this study was to test the hypothesis that there are time intervals during the cardiac cycle when coronary beat-to-beat repositioning is optimal. The repositioning uncertainty values in these time intervals were then compared with the intervals of low coronary motion in order to propose an optimal acquisition window for coronary MRA. Methods: Cine breath-hold x-ray angiograms with synchronous ECG were collected from 11 patients who underwent elective routine diagnostic coronarography. Twenty-three bifurcations of the left coronary artery were selected as markers to evaluate repositioning uncertainty and velocity during cardiac cycle. Each bifurcation was tracked by two observers, with the help of a user-assisted algorithm implemented in Matlab (The Mathworks, Natick, MA, USA) that compared the trajectories of the markers coming from consecutive heartbeats and computed the coronary repositioning uncertainty with steps of 50ms until 650ms after the R-wave. Repositioning uncertainty was defined as the diameter of the smallest circle encompassing the points to be compared at the same time after the R-wave. Student's t-tests with a false discovery rate (FDR, q=0.1) correction for multiple comparison were applied to see whether coronary repositioning and velocity vary statistically during cardiac cycle. Bland-Altman plots and linear regression were used to assess intra- and inter-observer agreement. Results: The analysis of left coronary artery beat-to-beat repositioning uncertainty shows a tendency to have better repositioning in mid systole (less than 0.84±0.58mm) and mid diastole (less than 0.89±0.6mm) than in the rest of the cardiac cycle (highest value at 50ms=1.35±0.64mm). According to Student's t-tests with FDR correction for multiple comparison (q=0.1), two intervals, in mid systole (150-200ms) and mid diastole (550-600ms), provide statistically better repositioning in comparison with the early systole and the early diastole. Coronary velocity analysis reveals that left coronary artery moves more slowly in end systole (14.35±11.35mm/s at 225ms) and mid diastole (11.78±11.62mm/s at 625ms) than in the rest of the cardiac cycle (highest value at 25ms: 55.96±22.34mm/s). This was confirmed by Student's t-tests with FDR correction for multiple comparison (q=0.1, FDR-corrected p-value=0.054): coronary velocity values at 225, 575 and 625ms are not much different between them but they are statistically inferior to all others. Bland-Altman plots and linear regression show that intra-observer agreement (y=0.97x+0.02 with R²=0.93 at 150ms) is better than inter-observer (y=0.8x+0.11 with R²=0.67 at 150ms). Discussion: The present study has demonstrated that there are two time intervals in the cardiac cycle, one in mid systole and one in mid diastole, where left coronary artery repositioning uncertainty reaches points of local minima. It has also been calculated that the velocity is the lowest in end systole and mid diastole. Since systole is less influenced by heart rate variability than diastole, it was finally proposed to test an acquisition window between 150 and 200ms after the R-wave.

Trabecular bone score (TBS) the new parameter of 2D texture analysis for the evaluation of 3D bone micro architecture status

X-ray is a technology that is used for numerous applications in the medical field. The process of X-ray projection gives a 2-dimension (2D) grey-level texture from a 3- dimension (3D) object. Until now no clear demonstration or correlation has positioned the 2D texture analysis as a valid indirect evaluation of the 3D microarchitecture. TBS is a new texture parameter based on the measure of the experimental variogram. TBS evaluates the variation between 2D image grey-levels. The aim of this study was to evaluate existing correlations between 3D bone microarchitecture parameters - evaluated from μCT reconstructions - and the TBS value, calculated on 2D projected images. 30 dried human cadaveric vertebrae were acquired on a micro-scanner (eXplorer Locus, GE) at isotropic resolution of 93 μm. 3D vertebral body models were used. The following 3D microarchitecture parameters were used: Bone volume fraction (BV/TV), Trabecular thickness (TbTh), trabecular space (TbSp), trabecular number (TbN) and connectivity density (ConnD). 3D/2D projections has been done by taking into account the Beer-Lambert Law at X-ray energy of 50, 100, 150 KeV. TBS was assessed on 2D projected images. Correlations between TBS and the 3D microarchitecture parameters were evaluated using a linear regression analysis. Paired T-test is used to assess the X-ray energy effects on TBS. Multiple linear regressions (backward) were used to evaluate relationships between TBS and 3D microarchitecture parameters using a bootstrap process. BV/TV of the sample ranged from 18.5 to 37.6% with an average value at 28.8%. Correlations' analysis showedthat TBSwere strongly correlatedwith ConnD(0.856≤r≤0.862; p<0.001),with TbN (0.805≤r≤0.810; p<0.001) and negatively with TbSp (−0.714≤r≤−0.726; p<0.001), regardless X-ray energy. Results show that lower TBS values are related to "degraded" microarchitecture, with low ConnD, low TbN and a high TbSp. The opposite is also true. X-ray energy has no effect onTBS neither on the correlations betweenTBS and the 3Dmicroarchitecture parameters. In this study, we demonstrated that TBS was significantly correlated with 3D microarchitecture parameters ConnD and TbN, and negatively with TbSp, no matter what X-ray energy has been used. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.

Fracture Discrimination by Combined Bone Mineral Density (BMD) and Microarchitectural Texture Analysis.

The use of bone mineral density (BMD) for fracture discrimination may be improved by considering bone microarchitecture. Texture parameters such as trabecular bone score (TBS) or mean Hurst parameter (H) could help to find women who are at high risk of fracture in the non-osteoporotic group. The purpose of this study was to combine BMD and microarchitectural texture parameters (spine TBS and calcaneus H) for the detection of osteoporotic fractures. Two hundred and fifty five women had a lumbar spine (LS), total hip (TH), and femoral neck (FN) DXA. Additionally, texture analyses were performed with TBS on spine DXA and with H on calcaneus radiographs. Seventy-nine women had prevalent fragility fractures. The association with fracture was evaluated by multivariate logistic regressions. The diagnostic value of each parameter alone and together was evaluated by odds ratios (OR). The area under curve (AUC) of the receiver operating characteristics (ROC) were assessed in models including BMD, H, and TBS. Women were also classified above and under the lowest tertile of H or TBS according to their BMD status. Women with prevalent fracture were older and had lower TBS, H, LS-BMD, and TH-BMD than women without fracture. Age-adjusted ORs were 1.66, 1.70, and 1.93 for LS, FN, and TH-BMD, respectively. Both TBS and H remained significantly associated with fracture after adjustment for age and TH-BMD: OR 2.07 [1.43; 3.05] and 1.47 [1.04; 2.11], respectively. The addition of texture parameters in the multivariate models didn't show a significant improvement of the ROC-AUC. However, women with normal or osteopenic BMD in the lowest range of TBS or H had significantly more fractures than women above the TBS or the H threshold. We have shown the potential interest of texture parameters such as TBS and H in addition to BMD to discriminate patients with or without osteoporotic fractures. However, their clinical added values should be evaluated relative to other risk factors.

Simple estimation of incident HIV infection rates in notification cohorts based on window periods of algorithms for evaluation of line-immunoassay result patterns.

BACKGROUND: Tests for recent infections (TRIs) are important for HIV surveillance. We have shown that a patient's antibody pattern in a confirmatory line immunoassay (Inno-Lia) also yields information on time since infection. We have published algorithms which, with a certain sensitivity and specificity, distinguish between incident (< = 12 months) and older infection. In order to use these algorithms like other TRIs, i.e., based on their windows, we now determined their window periods. METHODS: We classified Inno-Lia results of 527 treatment-naïve patients with HIV-1 infection < = 12 months according to incidence by 25 algorithms. The time after which all infections were ruled older, i.e. the algorithm's window, was determined by linear regression of the proportion ruled incident in dependence of time since infection. Window-based incident infection rates (IIR) were determined utilizing the relationship 'Prevalence = Incidence x Duration' in four annual cohorts of HIV-1 notifications. Results were compared to performance-based IIR also derived from Inno-Lia results, but utilizing the relationship 'incident = true incident + false incident' and also to the IIR derived from the BED incidence assay. RESULTS: Window periods varied between 45.8 and 130.1 days and correlated well with the algorithms' diagnostic sensitivity (R(2) = 0.962; P<0.0001). Among the 25 algorithms, the mean window-based IIR among the 748 notifications of 2005/06 was 0.457 compared to 0.453 obtained for performance-based IIR with a model not correcting for selection bias. Evaluation of BED results using a window of 153 days yielded an IIR of 0.669. Window-based IIR and performance-based IIR increased by 22.4% and respectively 30.6% in 2008, while 2009 and 2010 showed a return to baseline for both methods. CONCLUSIONS: IIR estimations by window- and performance-based evaluations of Inno-Lia algorithm results were similar and can be used together to assess IIR changes between annual HIV notification cohorts.

Increased therapeutic window for the R91W mutant form of Rpe65 compared to Rpe65 null backgroud

Purpose:Given the advances of gene therapy studies to cure RPE65-derived Leber Congenital Amaurosis (LCA) (clinical trials phase I) and the heterogeneity of the targeted patients both genetically and phenotypically, it is of prime importance to examine the rescue efficiency of gene transfer in different mutant contexts. Indeed, half of these mutations are missense mutations, leading to potential residual RPE65 activity. Consequently, we wanted to evaluate the effect on retinal activity and cone survival of lentivirus-mediated gene therapy in the R91W knock-in mouse model expressing the mutant Rpe65R91W gene (Samardzija et al. 2008), a mutation found in LCA patients. Notably we investigated whether if the therapeutic window is prolonged in comparison to null mutations. Methods:An HIV-1-derived lentiviral vector (LV) expressing either the GFP or the mouse Rpe65 cDNA under the control of a 0.8 kb fragment of the human Rpe65 promoter (R0.8) was produced by transient transfection of 293T cells. LV-R0.8-RPE65 or GFP was injected into 5-days-old (P5) or 1 month-old R91W mice. Functional rescue was assessed by ERG (1 and 4 months post-injection) and pupillary light response (PLR) recordings and cone survival by histological analysis. Results:Increased light sensitivity was detected by scotopic ERG in animals injected with LV-R0.8-RPE65 at both P5 and 1 month compared to GFP-treated animals or untreated mice. PLR was also improved in some eyes and histological analysis of cone markers showed that the density of cones reached the wild type level in the region of wt RPE65 delivery after treatment at P5. However, the rescue effect of the injection at 1 month was limited and attained 60% of the wild type level, but still more cones were observed in the treated area than in 1 month-old untreated Rpe65R91W mice. Conclusions:We were able to show that lentivirus-mediated Rpe65 gene transfer not only increases retinal activity of the Rpe65R91W mouse and survival of cones after treatment at P5 but also after treatment at 1 month. However even if the treatment at 1 month is more limited (60% of the wild type level) than treatment at P5, the amount of cone markers is increased compared to the proportion found at 1 month of age in untreated animals. This results contrast with the lack of cone rescue by treatment at 1 month of age in Rpe65-/- (Bemelmans et al, 2006). Thus patient suffering from R91W mutation might benefit from a prolonged therapeutic window.

Spine Bone Texture Assessed by Trabecular Bone Score (TBS) to Evaluate Bone Health in Thalassemia Major.

Due to the increasing survival of thalassemic patients, osteopathy is a mounting clinical problem. Low bone mass alone cannot account for the high fracture risk described; impaired bone quality has been speculated but so far it cannot be demonstrated noninvasively. We studied bone quality in thalassemia major using trabecular bone score (TBS), a novel texture measurement extracted from spine dual-energy X-ray absorptiometry (DXA), proposed in postmenopausal and secondary osteoporosis as an indirect index of microarchitecture. TBS was evaluated in 124 adult thalassemics (age range 19-56 years), followed-up with optimal transfusional and therapeutical regimens, and in 65 non-thalassemic patients (22-52 years) undergoing DXA for different bone diseases. TBS was lower in thalassemic patients (1.04 ± 0.12 [range 0.80-1.30]) versus controls (1.34 ± 0.11 [1.06-1.52]) (p < 0.001), and correlated with BMD. TBS and BMD values correlated with age, indicating that thalassemia negatively affects both bone quality and quantity, especially as the patient gets older. TBS was 1.02 ± 0.11 [0.80-1.28] in the osteoporotic thalassemic patients, 1.08 ± 0.12 [0.82-1.30] in the osteopenic ones and 1.15 ± 0.10 [0.96-1.26] in those with normal BMD. No gender differences were found (males: 1.02 ± 0.13 [0.80-1.30], females 1.05 ± 0.11 [0.80-1.30]), nor between patients with and without endocrine-metabolic disorders affecting bone metabolism. Our findings from a large population with thalassemia major show that TBS is a valuable tool to assess noninvasively bone quality, and it may be related to fragility fracture risk in thalassemic osteopathy.

Point defects and texture of Pd1-xInx sputtered intermetallic thin films

Pd1-xInx thin films (0.4 < x < 0.56) were prepared by radio frequency sputtering from a multi-zone target. The properties of these Hume-Rothery alloys were studied by X-ray diffractometry, electron probe microanalysis and scanning tunneling microscopy. The diffraction spectra were analyzed to obtain the intensity ratio of the (100) superlattice line to the (200) normal line, together with the variations of the lattice constant. The results ape explained quantitatively by a model based on point defects, i.e. Pd vacancies in In-rich films and Pd antisite atoms in Pd-rich films. In-rich films grow preferentially in the [100] direction while Pd-rich films grow preferentially in the [110] direction. The grains in indium-rich sputtered films appear to be enclosed in an atomically thick, indium-rich layer. The role of texture and the influence of point defects on electrical resistivity is also reported. (C) 1996 Elsevier Science Limited.

Effects of Exemestane and Tamoxifen Treatment on Bone Texture Analysis Assessed by TBS in Comparison With Bone Mineral Density Assessed by DXA in Women With Breast Cancer.

We performed an analysis of a substudy of the randomized Tamoxifen Exemestane Adjuvant Multinational trial to determine the effects of exemestane (EXE) and tamoxifen (TAM) adjuvant treatment on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry compared with the trabecular bone score, a novel grey-level texture measurement that correlates with 3-dimensional parameters of bone texture in postmenopausal women with hormone receptor-positive breast cancer for the first time. In total, 36 women were randomized to receive TAM (n = 17) or EXE (n = 19). Patients receiving TAM showed a mean increase of BMD in lumbar spine from baseline of 1.0%, 1.5%, and 1.9% and in trabecular bone score of 2.2%, 3.5%, and 3.3% at 6-, 12-, and 24-mo treatment, respectively. Conversely, patients receiving EXE showed a mean decrease from baseline in lumbar spine BMD of -2.3%, -3.6%, and -5.3% and in trabecular bone score of -0.9%, -1.7%, and -2.3% at 6-, 12-, and 24-mo treatment, respectively. Changes in trabecular bone score from baseline at spine were also significantly different between EXE and TAM: p = 0.05, 0.007, and 0.006 at 6, 12, and 24mo, respectively. TAM induced an increase in BMD and bone texture analysis, whereas EXE resulted in decreases. The results were independent from each other.

Optimal perfusion computed tomographic thresholds for ischemic core and penumbra are not time dependent in the clinically relevant time window.

BACKGROUND AND PURPOSE: This study aims to determine whether perfusion computed tomographic (PCT) thresholds for delineating the ischemic core and penumbra are time dependent or time independent in patients presenting with symptoms of acute stroke. METHODS: Two hundred seventeen patients were evaluated in a retrospective, multicenter study. Patients were divided into those with either persistent occlusion or recanalization. All patients received admission PCT and follow-up imaging to determine the final ischemic core, which was then retrospectively matched to the PCT images to identify optimal thresholds for the different PCT parameters. These thresholds were assessed for significant variation over time since symptom onset. RESULTS: In the persistent occlusion group, optimal PCT parameters that did not significantly change with time included absolute mean transit time, relative mean transit time, relative cerebral blood flow, and relative cerebral blood volume when time was restricted to 15 hours after symptom onset. Conversely, the recanalization group showed no significant time variation for any PCT parameter at any time interval. In the persistent occlusion group, the optimal threshold to delineate the total ischemic area was the relative mean transit time at a threshold of 180%. In patients with recanalization, the optimal parameter to predict the ischemic core was relative cerebral blood volume at a threshold of 66%. CONCLUSIONS: Time does not influence the optimal PCT thresholds to delineate the ischemic core and penumbra in the first 15 hours after symptom onset for relative mean transit time and relative cerebral blood volume, the optimal parameters to delineate ischemic core and penumbra.