HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.

C ardiovascular disease is the leading cause of mortality in patients with chronic kidney disease. 1,2 Aortic stiffness, which results in increased pulse pressure (PP), cardiac overload, and left ventricular hypertrophy, is an established predictor for cardiovascular morbidity and mortality in chronic kidney disease. [3][4][5] Physiologically, the aorta is much more elastic than peripheral muscular arteries providing a physiological stiffness gradient. This physiological gradient of stiffness generates reflecting sites, which dampens the transmission of forward travelling pressure into the microcirculation. In normal aging, aortic stiffness increases to a greater extent than peripheral muscular arteries, resulting in equalization or even reversal of stiffness gradient (aortic stiffness>muscular artery stiffness), referred to as stiffness mismatch. 6-9 Attenuation or reversal of physiological stiffness gradient has been proposed to cause vascular damage through enhanced transmission of forward travelling wave energy into the microcirculation. 9,10In a longitudinal study with repeated measures of aortic and brachial stiffness in hemodialysis patients, we observed an accelerated progression of aortic stiffness and a significant reduction in brachial stiffness. 11 The regression of brachial stiffness was associated to higher degree of aortic stiffness, therefore, leading to an enhanced aortic-brachial stiffness mismatch. In the context of this study, we hypothesized that aortic-brachial stiffness mismatch, as evaluated by the ratio of aortic and brachial pulse wave velocity (PWV) ratio, may prove to be a better prognostic predictor of mortality in dialysis population than aortic PWV. Therefore, the objectives of this study were to examine the nonadjusted and adjusted effect of the PWV ratio on overall mortality and to study its relative predictive value as compared with well-known central and peripheral hemodynamic parameters.Abstract-We hypothesized that increased aortic stiffness (central elastic artery) combined with a decrease in brachial stiffness (peripheral muscular artery) leads to the reversal of the physiological stiffness gradient (ie, mismatch), promoting end-organ damages through increased forward pressure wave transmission into the microcirculation. We, therefore, examined the effect of aortic-brachial stiffness mismatch on mortality in patients in need of dialysis. In a prospective observational study, aortic-brachial arterial stiffness mismatch (pulse wave velocity ratio) was assessed using carotid-femoral pulse wave velocity divided by carotid-radial pulse wave velocity in 310 adult patients on dialysis. After a median follow-up of 29 months, 146 (47%) deaths occurred. The hazard ratio (HR) for mortality related to PWV ratio in a Cox regression analysis was 1.43 (95% confidence interval [CI], 1.24-1.64; P<0.001 per 1 SD) and was still significant after adjustments for confounding factors, such as age, dialysis vintage, sex, cardiovascular disease, diabetes mellitus, smoking status, and weight (HR...

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Despite prophylactic measures, susceptibility to severe infections in patients who had undergone bone marrow transplantation (BMT) is quite variable. To evaluate the potential role of human leukocyte antigen (HLA)-E polymorphism on the incidence of early infections, we analyzed 77 unrelated-donor (UD) BMT pairs identically matched for classical HLA class I and class II alleles. Multivariate analysis taking into account the patient-, donor- and transplant-related factors showed that bacterial infections and transplant-related mortality (TRM) at day 180 were high when the donor genotype was HLA-E*0101/E*0101 (hazard ratio [HR]=2.20; P=0.03 and HR=2.12, P=0.048, respectively), suggesting that homozygous state for HLA-E*0101 allele is a risk factor for early severe bacterial infections and TRM in UD-BMT.

Background: Aortic stiffness is a strong predictor of cardiovascular mortality in various clinical conditions. The aim of this review is to focus on the arterial stiffness gradient, to discuss the integrated role of medium-sized muscular conduit arteries in the regulation of pulsatile pressure and organ perfusion and to provide a rationale for integrating their mechanical properties into risk prediction. Summary: The physiological arterial stiffness gradient results from a higher degree of vascular stiffness as the distance from the heart increases, creating multiple reflective sites and attenuating the pulsatile nature of the forward pressure wave along the arterial tree down to the microcirculation. The stiffness gradient hypothesis simultaneously explains its physiological beneficial effects from both cardiac and peripheral microcirculatory points of view. The loss or reversal of stiffness gradient leads to the transmission of a highly pulsatile pressure wave into the microcirculation. This suggests that a higher degree of stiffness of medium-sized conduit arteries may play a role in protecting the microcirculation from a highly pulsatile forward pressure wave. Using the ratio of carotid-femoral pulse wave velocity (PWV) to carotid-radial PWV, referred to as PWV ratio, a recent study in a dialysis cohort has shown that the PWV ratio is a better predictor of mortality than the classical carotid-femoral PWV. Key Messages: Theoretically, the use of the PWV ratio seems more logical for risk determination than aortic stiffness as it provides a better estimation of the loss of stiffness gradient, which is the unifying hypothesis that explains the impact of aortic stiffness both on the myocardium and on peripheral organs.

These data suggest that the homozygous state for HLA-E*0103 allele behaves as a protective genetic factor against aGVHD and TRM and likely contributes to improved survival in HLA-genoidentical bone marrow transplantation.

We have mapped the DNase I-and micrococcal nuclease-hypersensitive sites present in the 5' end of the human apolipoprotein B (apo-B) gene in nuclei from cells expressing or not expressing the gene. Four DNase I-hypersensitive sites were found in nuclei from liver-derived HepG2 cells and intestine-derived CaCo-2 cells, which express the apo-B gene, but not in HeLa cells, which do not. These sites are located near positions -120, -440, -700, and +760 Apolipoprotein B (apo-B) is the major protein component of low-density lipoproteins, which play a central role in the metabolism and transport of cholesterol. Apo-B is the ligand responsible for the uptake and clearance of low-density lipoproteins from the circulation via the apo-B,E(LDL) receptor pathway (13,20,29,30). We and others have recently determined the primary structure of apo-B by sequencing its cDNA (5, 7, 24, 26), and we have elucidated the complete structure of the 43-kilobase (kb) human apo-B gene (3). The gene comprises 29 exons and 28 introns, with most introns appearing in the 5'-terminal one-third of the gene. Apo-B mRNA has been detected only in the liver and intestines of several mammals, including humans (23), demonstrating that transcription of the apo-B gene is regulated in a tissue-specific manner.To understand the molecular mechanisms involved in the tissue-specific expression of the human apo-B gene, we have begun to map cis-acting regulatory sequences in the 5' flanking region of the gene. We also have examined this region for the presence of DNase I-hypersensitive (DH) sites in cells expressing or not expressing the gene. These sites are located near the 5' ends of the genes that are active or inducible in the cell under study, and their presence often correlates with binding sites for regulatory proteins (for a review, see reference 9). We have also examined the susceptibility of the 5' end of the apo-B gene to another nuclease, micrococcal nuclease (MNase). This enzyme differs from DNase I in its mode of nucleolytic cleavage (22) and thus provides complementary structural information.In the experiments in this study, we show that a 1-kb PvuII fragment from the 5' end of the gene exhibits cellspecific promoter activity. Furthermore, several DH and MNase-hypersensitive (MH) sites were detected in the 5' proximal region of the human apo-B gene in human hepatoma HepG2 cells and colon carcinoma CaCo-2 cells. These sites are absent from cell types that do not express the gene, * Corresponding author.such as HeLa cells. Most of these sites map to regions in which highly conserved base sequence motifs occur. MATERIALS AND METHODSTissue culture. HepG2 cells were grown in monolayer in T150 flasks (Coming) in a CO2 incubator at 37°C in minimum essential medium supplemented with 10% fetal bovine serum. HeLa cells were grown in Dulbecco modified Eagle medium in the presence of 10% fetal calf serum. All cultures were supplemented with 1% penicillin-streptomycin.Undifferentiated CaCo-2 cells were grown as described above, but with 15% serum, and wer...

The sequence of the human apolipoprotein B gene comprises 43 kb divided into 29 exons, one of which is unusually long and contains 7572 bp. Comparison of the gene sequence with four complete and three partial cDNA sequences published elsewhere reveals a total of 60 nucleotide substitutions and 39 amino acid substitutions and one small deletion in the signal peptide.