Effect of D2R, NMDAR and CB1R genetic variants associated with cannabis use and childhood trauma in first-episode psychosis in a Brazilian population [abstract only]

Introduction Gene-environment interactions increase psychosis risk (Gayer-Anderson et al. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657). However, identifying the genetic variants involved and how they interact with environmental risk factors underlying psychosis remains challenging. Objectives To investigate whether there are gene-environment interactions in the relationships of childhood trauma, lifetime cannabis use, and single nucleotide variants (SNVs) of dopamine D2 receptor (D2R: DRD2), N-methyl-d-aspartate receptor (NMDAR: GRIN1, GRIN2A and GRIN2B) and cannabinoid receptor type 1 (CB1R: CNR1) with psychosis. Methods In a population-based case-control study nested in an incident study (STREAM, Brazil) (Del-Ben et al. Br J of Psychiatry 2019; 215(6):726-729), part of the EU-GEI consortium (Gayer-Anderson et al. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657), 143 first-episode psychosis patients and 286 community-based controls of both sexes aged between 16 and 64 years were included over a period of 3 years. Twenty-three SNVs of D2R (rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R genes (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898), were genotyped from peripheral blood DNA using a custom Illumina HumanCoreExome-24 BeadChip. Environmental adversities were evaluated using the Cannabis Experience Questionnaire (Di Forti et al. The Lancet Psychiatry 2009; 6(5):427–436) and the Childhood Trauma Questionnaire (Grassi-Oliveira et al. Rev Saude Publica 2006; 40(2):249-55). Associations between SNVs and environmental risk factors were performed using the nonparametric multifactor dimensionality reduction software (version 3.0.2). Results Single locus analysis showed no association among the 23 SNVs with psychosis; however, gene-environment analysis was significant for the polymorphic loci rs12720071 and rs7766029 in CNR1. The best association models were the two-factor representing by the combination of CNR1 rs12720071 with lifetime cannabis use (p<0.001), and CNR1 rs12720071 with childhood trauma (p<0.05), both suggesting an increased risk of psychosis. Additionally, when considering the interaction of both environmental factors in the same model, we found CNR1 rs7766029 to be associated with psychosis (p<0.001). Conclusions Our study supports the hypothesis of gene-environment interactions for psychosis involving the T allele carriers of CNR1 SNVs (rs12720071 and rs7766029), childhood trauma and lifetime cannabis use in psychosis

Clinical And Molecular Spectrum Of Patients With 17β-hydroxysteroid Dehydrogenase Type 3 (17-β-hsd3) Deficiency [espectro Clínico E Molecular De Pacientes Com Deficiência De 17β-hidroxiesteroide Desidrogenase Tipo 2 (17-β-hsd3)]

The enzyme 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) catalyzes the conversion of androstenedione to testosterone in the testes, and its deficiency is a rare disorder of sex development in 46,XY individuals. It can lead to a wide range of phenotypic features, with variable hormonal profiles. We report four patients with the 46,XY karyotype and 17-β-HSD3 deficiency, showing different degrees of genital ambiguity, increased androstenedione and decreased testosterone levels, and testosterone to androstenedione ratio G novel mutation, and c.277+4A>T mutation, both located within the intron 3 splice donor site of the HSD17B3 gene, were identified in case 3. In addition, homozygosis for the missense p.Ala203Val, p.Gly289Ser, p.Arg80Gln mutations were found upon HSD17B3 gene sequencing in cases 1, 2, and 4, respectively. © ABEM todos os direitos reservados.568533539Andersson, S., Moghrabi, N., Physiology and molecular genetics of 17beta-hydroxysteroid dehydrogenases (1997) Steroids, 62, pp. 143-147Lukacik, P., Kavanagh, K.L., Oppermann, U., Structure and function of human 17beta-hydroxysteroid dehydrogenases (2006) Mol Cell Endocrinol, 248, pp. 61-71Labrie, F., Luu-The, V., Lin, S.X., Labrie, C., Simard, J., Breton, R., The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology (1997) Steroids, 62, pp. 148-158George, M.M., New, M.I., Tem, S., Sultan, C., Bhangoo, A., The clinical and molecular heterogeneity of 17aHSD3 enzyme deficiency (2010) Horm Res Paediatr, 74, pp. 229-240Boehmer, A.L., Brinkmann, A.O., Sandkuijl, L.A., Halley, D.J., Niermeijer, M.F., Andersson, S., 17beta-hydroxysteroid dehydrogenase-3 deficiency: Diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations (1999) J Clin Endocrinol Metab, 84, pp. 4713-4721Mendonça, B.B., Inacio, M., Arnhold, I.J., Costa, E.M., Bloise, W., Martin, R.M., Male pseudohermaphroditism due to 17beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management (2000) Medicine (Baltimore), 79, pp. 299-309Lee, Y.S., Kirk, J.M., Stanhope, R.G., Johnston, D.I., Harland, S., Auchus, R.J., Phenotypic variability in 17beta-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls (2007) Clin Endocrinol (Oxf), 67, pp. 20-28Faienza, M.F., Giordani, L., Delvecchio, M., Cavallo, L., Clinical, endocrine, and molecular findings in 17beta-hydroxysteroid dehydrogenase type 3 deficiency (2008) J Endocrinol Invest, 31, pp. 85-91Andersson, S., Geissler, W.M., Wu, L., Davis, D.L., Grumbach, M.M., New, M.I., Molecular genetics and pathophysiology of 17 betahydroxysteroid dehydrogenase 3 deficiency (1996) J Clin Endocrinol Metab, 81, pp. 130-136Mendonca, B.B., Arnhold, I.J., Bloise, W., Andersson, S., Russell, D.W., Wilson, J.D., 17Beta-hydroxysteroid dehydrogenase 3 deficiency in women (1999) J Clin Endocrinol Metab, 84, pp. 802-804Prehn, C., Möller, G., Adamski, J., Recent advances in 17betahydroxysteroid dehydrogenases (2009) J Steroid Biochem Mol Biol, 114, pp. 72-77Hiort, O., Reinecke, S., Thyen, U., Jurgensen, M., Holterhus, P.M., Schon, D., Puberty in disorders of somatosexual differentiation (2003) J Pediatr Endocrinol Metab, 16 (SUPPL. 2), pp. 297-306Cohen-Kettenis, P.T., Gender change in 46, XY persons with 5alphareductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency (2005) Arch Sex Behav, 34, pp. 399-410Faisal Ahmed, S., Iqbal, A., Hughes, I.A., The testosterone: Androstenedione ratio in male undermasculinization (2000) Clin Endocrinol (Oxf), 53, pp. 697-702Ben Rhouma, B., Belguith, N., Mnif, M.F., Kamoun, T., Charfi, N., Kamoun, M., A novel nonsense mutation in HSD17B3 gene in a Tunisian patient with sexual ambiguity (2012) J Sex Med, , [Epub ahead of print]Neocleous, V., Sismani, C., Shammas, C., Efstathiou, E., Alexandrou, A., Ioannides, M., Duplication of exons 3-10 of the HSD17B3 gene: A novel type of genetic defect underlying 17g-HSD-3 deficiency (2012) Gene, 499, pp. 250-255Sambrook, J., Fritsch, E.F., Maniatis, T.E., (1989) Molecular cloning, a laboratory manual, , New York: Cold Spring HarborSaez, J.M., De Peretti, E., Morera, A.M., David, M., Bertrand, J., Familial male pseudohermaphroditism with gynecomastia due to a testicular 17-ketosteroid reductase defect. I. Studies in vivo (1971) J Clin Endocrinol Metab, 32, pp. 604-610Saez, J.M., Morera, A.M., De Peretti, E., Bertrand, J., Further in vivo studies in male pseudohermaphroditism with gynecomastia due to a testicular 17-ketosteroid reductase defect (compared to a case of testicular feminization) (1972) J Clin Endocrinol Metab, 34, pp. 598-600Rösler, A., Silverstein, S., Abeliovich, D., A (R80Q) mutation in 17 beta-hydroxysteroid dehydrogenase type 3 gene among Arabs of Israel is associated with pseudohermaphroditism in males and normal asymptomatic females (1996) J Clin Endocrinol Metab, 81, pp. 1827-1831Rösler, A., 17 beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population (2006) Pediatr Endocrinol Rev, 3 (SUPPL. 3), pp. 455-461McKeever, B.M., Hawkins, B.K., Geissler, W.M., Wu, L., Sheridan, R.P., Mosley, R.T., Amino acid substitution of arginine 80 in 171-hidroxysteroide dehydrogenase 3 and its effect on NADPH cofator binding and oxidation/reduction kinetics (2002) Biochim Biophys Acta, 1601, pp. 29-37Rosler, A., Belanger, A., Labrie, F., Mechanisms of androgen production in male pseudohermaphroditism due to 17b-hydroxysteroid dehydrogenase deficiency (1992) J Clin Endocrinol Metab, 75, pp. 773-778Culigan, W., Phoenicia and Phoenician colonization (1991) The Cambridge ancienty history, pp. 461-546. , 2nd Ed, In: Boardman J, Edwards IE, Hammond NG, Sollberger E, Walker CB, eds, Cambridge University PressCavalli-Sforza, L.L., Menozzi, P., Piazza, A., (1994) The history and geography of human genes, pp. 217+242-245+260. , Princeton: Princeton University PressGeissler, W.M., Davis, D.L., Wu, L., Bradshaw, K.D., Patel, S., Mendonça, B.B., Male pseudohermaphroditism caused by mutations of testicular 17o-hidroxysteroide dehydrogenase 3 (1994) Nat Genet, 7, pp. 34-39Moghrabi, N., Hughes, I.A., Dunaif, A., Andersson, S., Deleterious missense mutations and silent polymorphism in the human 17b-hydroxysteroid dehydrogenase 3 gene (hsd17b3) (1998) J Clin Endocrinol Metabol, 83 (8), pp. 2855-2860http://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;g=ENSG00000130948;r=9:98997588-99064434;t=ENST00000375263;v=rs2066479;vdb=variation;vf=16374979, Accessed on: Sept 30, 2012Margiotti, K., Kim, E., Pearce, C.L., Spera, E., Novelli, G., Reichardt, J.K., Association of the G289S single nucleotide polymorphism in the HSD17B3 gene with prostate cancer in Italian men (2002) Prostate, 53, pp. 65-68Sata, F., Kurahashi, N., Ban, S., Moriya, K., Tanaka, K.D., Ishizuka, M., Genetic polymorphisms of 17 G-hydroxysteroid dehydrogenase 3 and the risk of hypospadias (2010) J Sex Med, 7 (8), pp. 2729-2738Mains, L.M., Vakili, M.B., Lacassie, Y., Andersson, S., Lindqvistc, A., Rock, J.A., 17beta hydroxysteroid dehydrogenase 3 deficiency in a male Pseudohermaphrodite (2008) Fertil Steril, 89 (1), pp. 228.e13-228.e17Lee, P.A., Houk, C.P., Faisal, A., Hughes, I.A., International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology (2006) Pediatrics, 118, pp. 488-50

46,xx Male - Testicular Disorder Of Sexual Differentiation (dsd): Hormonal, Molecular And Cytogenetic Studies [homem 46,xx (dsd Testicular): Estudos Hormonal, Molecular E Citogenético]

The XX male syndrome - Testicular Disorder of Sexual Differentiation (DSD) is a rare condition characterized by a spectrum of clinical presentations, ranging from ambiguous to normal male genitalia. We report hormonal, molecular and cytogenetic evaluations of a boy presenting with this syndrome. Examination of the genitalia at age of 16 months, showed: penis of 3.5 cm, proximal hypospadia and scrotal testes. Pelvic ultrasound did not demonstrate Mullerian duct structures. Karyotype was 46,XX. Gonadotrophin stimulation test yielded insufficient testosterone production. Gonadal biopsy showed seminiferous tubules without evidence of Leydig cells. Molecular studies revealed that SRY and TSPY genes and also DYZ3 sequences were absent. In addition, the lack of deletions or duplications of SOX9, NR5A1, WNT4 and NROB1 regions was verified. The infant was heterozygous for all microsatellites at the 9p region, including DMRT1 gene, investigated. Only 10% of the patients are SRY-negative and usually they have ambiguous genitalia, as the aforementioned patient. The incomplete masculinization suggests gain of function mutation in one or more genes downstream to SRY gene. © ABE&M todos os direitos reservados.548685689Vorona, E., Zitsmann, M., Gromoll, J., Schüring, N., Nieschlag, E., Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients (2007) J Clin Endocrinol Metab, 92, pp. 3458-3465Rajender, S., Vutukuri, R., Gupta, N.J., Chakravarty, B., Singh, L., Thangaraj, K., SRY-negative 46,XX male with normal genitals, complete masculinization and infertility (2006) Mol Hum Reprod, 5, pp. 341-346Ergun-Longmire, B., Vinci, G., Alonso, L., Matthew, S., Tansi, S., Lin-Su, K., Clinical, hormonal and cytogenetic evaluation of 46,XX male and review of the literature (2005) J Pediatr Endocrinol Metab, 18 (8), pp. 739-748Berta, P., Hawkins, J.R., Sinclair, A.H., Taylor, A., Griffiths, B.L., Goodfellow, P.N., Genetic evidence equating SRY and the testisdetermining factor (1990) Nature, 348 (6300), pp. 448-450Koopman, P., Münsterberg, A., Capel, B., Vivian, N., Lovell-Badge, R., Expression of a candidate sex-determining gene during mouse testis differentiation (1990) Nature, 348 (6300), pp. 450-452Kim, J.W., Bak, C.W., Chin, M.U., Cha, D.H., Yoon, T.K., Shim, S.H., SRY-negative 46,XX infertile male with Leydig cell hyperplasia: Clinical, cytogenetic, and molecular analysis and review of the literature (2010) Fertil Steril, 94 (2), p. 753. , e5-e9Wang, T., Liu, J.H., Yang, J., Chen, J., Ye, Z.Q., 46, XX male sex reversal syndrome: A case report and review of the genetic basis (2009) Andrologia, 41 (1), pp. 59-62de la Chapelle, A., The etiology of maleness in XX men (1981) Hum Genet, 58 (1), pp. 105-116Fechner, P.Y., Marcantonio, S.M., Jaswaney, V., Stetten, G., Goodfellow, P.N., Migeon, C.J., The role of the sex-determining region Y gene in the etiology of 46,XX maleness (1993) J Clin Endocrinol Metab, 76 (3), pp. 690-695Dauwerse, J.G., Hansson, K.B.M., Brouwers, A.A.M., Peters, D.J.M., Breuning, M.H., An XX male with the sex-determining region Y gene inserted in the long arm of cromossome 16 (2006) Fertil Steril, 86 (463), pp. e2-e5Chien, S.C., Li, Y.C., Ho, M., Hsu, P.C., Teng, R.H., Lin, W.D., Rare rearrangements: A "jumping satellite" in one family and autosomal location of the SRY gene in an XX male (2009) Am J Med Genet A, 149 A (12), pp. 2775-2781Queralt, R., Madrigal, I., Vallecillos, M.A., Morales, C., Ballescá, J.L., Oliva, R., Atypical XX male with the SRY gene located at the long arm of chromosome 1 and a 1qter microdeletion (2008) Am J Med Genet A, 146 A (10), pp. 1335-1340Parada-Bustamante, A., Ríos, R., Ebensperger, M., Lardone, M.C., Piottante, A., Castro, A., 46,XX/SRY-negative true hermaphrodite (2010) Fertil Steril, 94 (6), p. 2330. , 13-16Berger-Zaslav, A.L., Mehta, L., Jacob, J., Mercado, T., Gadi, I., Tepperberg, J.H., Ovotesticular disorder of sexual development (true hermaphroditism) (2009) Urology, 73 (2), pp. 293-296Maciel-Guerra, A.T., de Mello, M.P., Coeli, F.B., Ribeiro, M.L., Miranda, M.L., Marques-de-Faria, A.P., XX Maleness and XX true hermaphroditism in SRY-negative monozygotic twins: Additional evidence for a common origin (2008) J Clin Endocrinol Metab, 93 (2), pp. 339-343Ramos, E.S., Moreira-Filho, C.A., Vicente, Y.A., Llorach-Velludo, M.A., Tucci, S., Duarte, M.H., SRY-negative true hermaphrodites and an XX male in two generations of the same family (1996) Hum Genet, 97, pp. 596-598Zenteno, J.C., Lopez, M., Vera, C., Mndez, J.P., Kofman-Alfaro, S., Two SRY-negative XX male brothers without genital ambiguity (1997) Hum Genet, 100, pp. 606-610Kojima, Y., Hayashi, Y., Mizuno, K., Sasaki, S., Fukui, Y., Koopman, P., Up-regulation of SOX9 in human sex-determining region on the Y chromosome (SRY)-negative XX males (2008) Clin Endocrinol, 68 (5), pp. 791-799Refai, O., Friedman, A., Terry, L., Jewett, T., Pearlman, A., Perle, M.A., De novo 12;17 translocation upstream of SOX9 resulting in 46,XX testicular disorder of sex development (2010) Am J Med Genet A, 152 A (2), pp. 422-426Polanco, J.C., Wilhelm, D., Davidson, T.L., Knight, D., Koopman, P., Sox10 gain-of-function causes XX sex reversal in mice: Implications for human 22q-linked disorders of sex development (2010) Hum Mol Genet, 19 (3), pp. 506-516Sambrook, J., Fristsch, E.F., Maniatis, T.E., (1989) Molecular Cloning: A Laboratory Manual, , Cold Spring Harbour Laboratory, Press. New York: Cold Spring HarbourCalvari, V., Bertini, V., De Grandi, A., Peverali, G., Zuffardi, O., A new submicroscopic deletion that refines the 9p region for sex reversal (2000) Genomics, 65 (3), pp. 203-212Guioli, S., Schmitt, K., Critcher, R., Bouzyk, M., Spurr, N.K., Ogata, T., Molecular analysis of 9p deletions associated with XY sex reversal: Refining the localization of a sex-determining gene to the tip of the chromosome (1998) Am J Hum Genet, 63 (3), pp. 905-908Veitia, R.A., Nunes, M., Quintana-Murci, L., Rappaport, R., Thibaud, E., Jaubert, F., Swyer syndrome and 46,XY partial gonadal dysgenesis associated with 9p deletions in the absence of monosomy-9p syndrome (1998) Am J Hum Genet, 63 (3), pp. 901-90

Heterozygosis For Cyp21a2 Mutation Considered As 21-hydroxylase Deficiency In Neonatal Screening

Steroid 21-hydroxylase deficiency (21-OHD) accounts for more than 90% of congenital adrenal hyperplasia. CAH newborn screening, in general, is based on 17-hydroxyprogesterone dosage (17-OHP), however it is complicated by the fact that healthy preterm infants have high levels of 17-OHP resulting in false positive cases. We report on molecular features of a boy born pre-term (GA = 30 weeks; weight = 1,390 g) with elevated levels of 17-OHP (91.2 nmol/L, normal < 40) upon neonatal screening who was treated as having CAH up to the age of 8 months. He was brought to us for molecular diagnosis. Medication was gradually suspended and serum 17-OHP dosages mantained normal. The p.V281 L mutation was found in compound heterozygous status with a group of nucleotide alterations located at the 3′ end intron 4 and 5′ end exon 5 corresponding to the splice site acceptor region. Molecular studies continued in order to exclude the possibility of a nonclassical 21-OHD form. The group of three nucleotide changes was demonstrated to be a normal variant since they failed to interfere with the normal splicing process upon minigene studies.52813881392White, P.C., Speiser, P.W., Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2000) Endocr Rev, 21, pp. 245-291Riepe, F.G., Sippell, W.G., Recent advances in diagnosis, treatment, and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2007) Rev Endocr Metab Disord, 8 (4), pp. 349-363New, M., Lorenzen, F., Lerner, A.J., Kohn, B., Oberfield, S.E., Pollack, M.S., Genotyping steroid 21-hydroxylase deficiency: Hormonal reference data (1983) J Clin Endocrinol Metab, 57, pp. 320-326Azziz, R., Hincapie, L.A., Knochenhauer, E.S., Dewailly, D., Fox, L., Boots, L.R., Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women (1999) Fertil Steril, 72, pp. 915-925Bachega, T.A., Brenlha, E.M., Billerbeck, A.E., Marcondes, J.A., Madureira, G., Arnhold, I.J., Mendonca, B.B., Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations (2002) J Clin Endocrinol Metab, 87 (2), pp. 786-790Pang, S., Hotchkiss, J., Drash, A.L., Levine, L.S., New, M., Microfilter paper method for 17-hydroxyprogesterone radioimmunoassay: Its application for rapid screening for congenital adrenal hyperplasia (1977) J Clin Endocrinol Metab, 45, pp. 1003-1008Valentino, R., Tommaselli, A.P., Rossi, R., Lombardi, G., Varrone, S., A pilot study for neonatal screening of congenital adrenal hyperplasia due to 21-hydroxylase and 11-hydroxylase deficiency in Campania region (1990) J Endocrinol lnvest, 13, pp. 221-225Janzen, N., Peter, M., Sander, S., Steuerwald, U., Terhardt, M., Holtkamp, U., Sander, J., Newborn screening for congenital adrenal hyperplasia: Additional steroid profile using liquid chromatography-tandem mass spectrometry (2007) J Clin Endocrinol Metab, 92 (7), pp. 2581-2589Pang, S., Murphey, W., Levine, L.S., Lorenzen, F., Levy, D., Lerner, A.J., Rondanini, G.F., New, M., A pilot newborn screening for congenital adrenal hyperplasia in Alaska (1982) J Clin Endocrinol Metab, 55, pp. 413-420Nordenström, A., Wedell, A., Hagenfeldt, L., Marcus, C., Larsson, A., Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm infants (2001) Pediatrics, 108 (4), pp. E68Cardoso, C.B., Fonseca, A.A., Oliveira Mde, F., Pereira, B.B., Guimarães, M.M., Congenital adrenal hyperplasia newborn screening: Rio de Janeiro experience. Arq Bras Endocrinol (2005) Metabol, 49 (1), pp. 112-119Silveira, EL, D.S., Bachega, T.A., van der, Linden Nader, I., Gross, J.L., Elnecave, R.H., The actual incidence of congenital adrenal hyperplasia in Brazil may not be as high as inferred-an estimate based on a public neonatal screening program in the state of Goiás (2008) J Pediatr Endocrinol Metab, 21 (5), pp. 455-460Sambrook, J., Fritsch, E.F., Maniatis, T.E., (1989) Molecular Cloning, a Laboratory Manual, , New York: Cold Spring HarborAraujo, M., Sanches, M.R., Suzuki, L.A., Guerra-Jr, G., Farah, S.B., De Mello, M.P., Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency (1996) Braz J Med Biol Res, 29, pp. 1-13Wilson, R.C., Wei, J.Q., Cheng, K.C., Mercado, A.B., New, M., Rapid deoxyribonucleic acid analysis by allele-specific polymerase chain reaction for detection of mutations in the steroid 21-hydroxylase gene (1995) J Clin Endocrinol Metab, 80 (5), pp. 1635-1640Lau, I.F., Soardi, F.C., Lemos-Marini, S.H., Guerra-Jr, G., Baptista, M.T., De Mello, M.P., H28+C insertion in the CYP21 gene: A novel frameshift mutation in Brazilian patient with the classical form of 21-hydroxylase deficiency (2001) J Clin Endocrinol Metab, 86, pp. 5877-5880Higashi, Y., Yoshioka, H., Yamane, M., Gotoh, O., Fujii-Kuriyama, Y., Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: A pseudogene and a genuine gene (1986) Proc Natl Acad Sci USA, 83, pp. 2841-2845Wilson, R.C., Nimkarn, S., Dumic, M., Obeid, J., Azar, M.R., Najmabadi, H., Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency (2007) Mol Genet Metab, 90 (4), pp. 414-421Tusie-Luna, M.T., Traktman, P., White, P.C., Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus (1990) J Biol Chem, 265 (34), pp. 20916-20922Higashi, Y., Hiromasa, T., Tanae, A., Miki, T., Nakura, J., Kondo, T., Effects of individual mutations in the P-450(C21) pseudogene on the P-450(C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency (1991) J Biochem, 109 (4), pp. 638-644Bachega, T.A., Billerbeck, A.E., Madureira, G., Marcondes, J.A., Longui, C.A., Leite, M.V., Molecular genotyping in Brazilian patients with the classical and nonclassical forms of 21-hydroxylase deficiency (1998) J Clin Endocrinol Metab, 83 (12), pp. 4416-441

Mdr-1 C3435t Polymorphism May Affect Blood Pressure In Resistant Hypertensive Patients Independently Of Its Effects On Aldosterone Release

Aldosterone increases plasma volume and may be involved with resistant hypertension. P-glycoprotein is a transporter involved in the distribution and disposition of aldosterone, and is encoded by the MDR-1 gene. MDR-1 has functional polymorphisms that may affect P-glycoprotein expression. We hypothesized that the C3435T polymorphism in MDR-1 could be associated with resistant hypertension and with changes in hypertension-related parameters. We studied 105 healthy volunteers, 137 hypertensive patients responsive to treatment, and 83 resistant hypertensive patients. While we found no association of C3435T genotypes with resistance to treatment (p = 0.31), C allele was associated with hypertension (p = 0.03). Furthermore, the CC genotype was associated with higher systolic blood pressure (p T affects mRNA stability (2005) Pharmacogenet Genomics, 15, pp. 693-704Sissung, T.M., Gardner, E.R., Piekarz, R.L., Impact of ABCB1 allelic variants on QTc interval prolongation (2011) Clin Cancer Res, 17, pp. 937-946Bochud, M., Eap, C.B., Maillard, M., Association of ABCB1 genetic variants with renal function in Africans and in Caucasians (2008) BMC Med Genomics, 1, p. 21Cascorbi, I., Paul, M., Kroemer, H.K., Pharmacogenomics of heart failure - Focus on drug disposition and action (2004) Cardiovasc Res, 64, pp. 32-39Eap, C.B., Bochud, M., Elston, R.C., CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt (2007) Hypertension, 49, pp. 1007-1014VI Brazilian Guidelines on Hypertension [in Portuguese] (2010) Arq Bras Cardiol, 95, pp. 1-51Taylor, D.W., Sackett, D.L., Haynes, R.B., Compliance with antihypertensive drug therapy (1978) Ann N y Acad Sci, 304, pp. 390-403Morisky, D.E., Green, L.W., Levine, D.M., Concurrent and predictive validity of a self-reported measure of medication adherence (1986) Med Care, 24, pp. 67-74De Souza, W.A., Yugar-Toledo, J.C., Bergsten-Mendes, G., Effect of pharmaceutical care on blood pressure control and health-related quality of life in patients with resistant hypertension (2007) Am J Health Syst Pharm, 64, pp. 1955-1961Zolk, O., Jacobi, J., Pahl, A., MDR1 genotype-dependent regulation of the aldosterone system in humans (2007) Pharmacogenet Genomics, 17, pp. 137-144Manunta, P., Ferrandi, M., Bianchi, G., Endogenous ouabain in cardiovascular function and disease (2009) J Hypertens, 27, pp. 9-18Tripodi, G., Citterio, L., Kouznetsova, T., Steroid biosynthesis and renal excretion in human essential hypertension: Association with blood pressure and endogenous ouabain (2009) Am J Hypertens, 22, pp. 357-363Fromm, M.F., Importance of P-glycoprotein at blood-tissue barriers (2004) Trends Pharmacol Sci, 25, pp. 423-42

Novel Dmrt1 3'utr+11inst Mutation Associated To Xy Partial Gonadal Dysgenesis [nova Mutação 3'utr+11inst No Gene Dmrt1 Associada à Disgenesia Gonadal Parcial Xy]

The Y-chromosome-located SRY gene encodes a small testis-specific protein containing a DNA- -binding motif known as the HMG (high mobility group) box. However, mutations in SRY are not frequent especially in cases of 46,XY partial gonadal dysgenesis. Several sex-determining genes direct the fate of the bipotential gonad to either testis or ovary. In addition, heterozygous small deletions in 9p can cause complete and partial XY gonadal dysgenesis without other symptoms. Human DMRT1 gene, which is located at 9p24.3, is expressed in testis and ovary and has been considered, among others, a candidate autosomal gene responsible for gonadal dysgenesis. In this report we describe a nucleotide insertion in DMRT1 3'UTR in a patient of XY partial gonadal dygenesis. The 3'UTR+11insT is located within a conserved motif important for mRNA stabilization. © ABE&M todos os direitos reservados.548749753Hughes, I.A., Disorders of sex development: A new definition and classification (2008) Best Pract Res Clin Endocrinol Metab, 22, pp. 119-134Andrade, J.G., Guerra-Júnior, G., Maciel-Guerra, A.T., 46,XY and 45,X/46,XY testicular dysgenesis: Similar gonadal and genital phenotype, different prognosis (2010) Arq Bras Endocrinol Metabol, 54, pp. 331-334Michala, L., Goswami, D., Creighton, S.M., Conway, G.S., Swyer syndrome: Presentation and outcomes (2008) BJOG, 115, pp. 737-741Ribeiro-Scolfaro, M., Cardinalli, I.A., Stuchi-Perez, E.G., de Mello, M.P., Assumpção, J.G., Baptista, M.T.M., Morphometry and histology of gonads from 13 children with dysgenetic male pseudohermaphroditism (2001) Arch Pathol Lab Med, 125, pp. 652-656Berta, P., Hawkins, J.R., Sinclair, A.H., Taylor, A., Griffiths, B.L., Goodfellow, P.N., Genetic evidence equating SRY and the testis- -determining factor (1990) Nature, 348, pp. 448-450Knower, K.C., Kelly, S., Harley, V.R., Turning on the male-SRY, SOX9 and sex determination in mammals (2003) Cytogenet Genome Res, 101, pp. 185-198Tagliarini, E.B., Assumpção, J.G., Scolfaro, M.R., Mello, M.P., Maciel-Guerra, A.T., Guerra, G., Mutations in SRY and WT1 genes required for gonadal development are not responsible for XY partial gonadal dysgenesis (2005) Braz J Med Biol Res, 38, pp. 17-25Biason-Lauber, A., Control of sex development (2010) Best Pract Res Clin Endocrinol Metab, 24 (2), pp. 163-186Veitia, R.A., Nunes, M., Quintana-Murci, L., Rappaport, R., Thibaud, E., Jaubert, F., Swyer syndrome and 46,XY partial gonadal dysgenesis associated with 9p deletions in the absence of monosomy- 9p syndrome (1998) Am J Hum Genet, 63, pp. 901-905Calvari, V., Bertini, V., de Grandi, A., Peverali, G., Zuffardi, O., Ferguson-Smith, M., A new submicroscopic deletion that refines the 9p region of sex reversal (2000) Genomics, 65, pp. 203-212Raymond, C.S., Shamu, C.E., Shen, M.M., Seifert, K.J., Hisch, B., Hodgkin, J., Evidence for evolutionary conservation of sex-determining genes (1998) Nature, 391, pp. 691-694Pask, A.J., Behringer, R.R., Renfree, M.B., Expression of DMRT1 in the mammalian ovary and testis--from marsupials to mice (2003) Cytogenet Genome Res, 101, pp. 229-236Raymond, C.S., Parker, E.D., Kettlewell, J.R., Brown, L.G., Page, D.C., Kusz, K., A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators (1999) Hum Mol Genet, 8, pp. 989-996Furlong, R.A., Lyall, J.E., Lush, M.J., Affara, N.A., Ferguson-Smith, M.A., Four dinucleotide repeat polymorphisms on chromosome 9 (D9S143-146) (1992) Hum Mol Genet, 1, p. 447Cheng, H.H., Ying, M., Tian, Y.H., Guo, Y., McElreavey, K., Zhou, J.R., Transcriptional diversity of DMRT1 (dsx- and mab3-related transcription factor 1) in human testis (2006) Cell Res, 16, pp. 389-393Lu, H., Xiao, H., Liao, Z., Yiqing, G., Hanhua, C., Rongjia, Z., Multiple alternative splicing of mouse Dmrt1 during gonadal differentiation (2007) Biochem Biophys Res Commun, 352, pp. 630-634Smith, P.J., Zhang, C., Wang, J., Chew, S.L., Zhang, M.Q., Krainer, A.R., An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers (2006) Hum Mol Genet, 15, pp. 2490-2508Cartegni, L., Wang, J., Zhu, Z., Zhang, M.Q., Krainer, A.R., ESEfinder: A web resource to identify exonic splicing enhancers (2003) Nucleic Acid Res, 31, pp. 3568-3571Zhang, X.H., Chasin, L.A., Computational definition of sequence motifs governing constitutive exon splicing (2004) Genes Dev, 18, pp. 1241-1250Zhang, X.H., Kangsamaksin, T., Chao, M.S., Banerjee, J.K., Chasin, L.A., Exon inclusion is dependent on predictable exonic splicing enhancers (2005) Mol Cell Biol, 25, pp. 7323-7332Herpin, A., Nakamura, S., Wagner, T.U., Tanaka, M., Schartl, M., A highly conserved cis-regulatory motif directs differential gonadal synexpression of Dmrt1 transcripts during gonad development (2009) Nucleic Acids Res, 37, pp. 1510-152

Delay From Fracture To Hospital Admission: A New Risk Factor For Hip Fracture Mortality?

Summary: The relationship between surgical timing and hip fracture mortality is unknown in the context of developing countries where large delays to surgery are common. We observed that delay from fracture to hospital admission is associated with decreased survival after a hip fracture. Introduction: To examine the relationship between the time interval from fracture to surgery as well as its subcomponents (time from fracture to hospital admission and time from admission to surgery) and hip fracture survival. Methods: The medical records of all patients aged 60 years and older admitted to a public university hospital in the city of Rio de Janeiro with a primary diagnosis of hip fracture between 1995 and 2000 were reviewed. Survival to hospital discharge and at 1 year were examined. Results: Among 343 patients included in the study, there were 18 (5.3%) in-hospital deaths, and 297 (86.6%) patients remained alive 1 year after surgery. Very long delays from the time of fracture to hospital admission (mean 3 days) and from hospital admission to surgery (mean 13 days) were identified. Increased time from fracture to hospital admission was associated with reduced survival to hospital discharge (hazard ratio [HR] 1.09, 95% CI 1.03-1.15, p00.005) and reduced survival at 1 year after surgery (HR 1.07, 95% CI 1.03-1.10, p< 0.001). The interval of time from hospital admission to surgery was not associated with reduced survival to hospital discharge (HR 1.03, 95% CI 0.96-1.10, p00.379) or at 1 year after surgery (HR 1.03, 95% CI 0.99-1.07, p00.185). Conclusions: If the association estimated in our study is causal, our results provide evidence that some hip fracturerelated deaths could be prevented by improved patient access to appropriate and timely hospital care in the context of a developing country. © International Osteoporosis Foundation and National Osteoporosis Foundation 2012.231228472853Johnell, O., Kanis, J., Epidemiology of osteoporotic fractures (2005) Osteoporosis International, 16 (SUPPL. 2), pp. S3-S7. , DOI 10.1007/s00198-004-1702-6Cummings, S.R., Melton, L.J., Epidemiology and outcomes of osteoporotic fractures (2002) Lancet, 359 (9319), pp. 1761-1767Hiligsmann, M., Bruyere, O., Ethgen, O., Gathon, H.J., Reginster, J.Y., Lifetime absolute risk of hip and other osteoporotic fracture in Belgian women (2008) Bone, 43 (6), pp. 991-994Haentjens, P., Magaziner, J., Colon-Emeric, C.S., Vanderschueren, D., Milisen, K., Velkeniers, B., Boonen, S., Meta-analysis: Excess mortality after hip fracture among older women and men (2010) Ann Intern Med, 152 (6), pp. 380-390Vidan, M.T., Sanchez, E., Gracia, Y., Maranon, E., Vaquero, J., Serra, J.A., Causes and effects of surgical delay in patients with hip fracture: A cohort study (2011) Ann Intern Med, 155 (4), pp. 226-233Majumdar, S.R., Beaupre, L.A., Johnston, D.W.C., Dick, D.A., Cinats, J.G., Jiang, H.X., Lack of association between mortality and timing of surgical fixation in elderly patients with hip fracture: Results of a retrospective population-based cohort study (2006) Medical Care, 44 (6), pp. 552-559. , DOI 10.1097/01.mlr.0000215812.13720.2e, PII 0000565020060600000010Novack, V., Jotkowitz, A., Etzion, O., Porath, A., Does delay in surgery after hip fracture lead to worse outcomes? A multicenter survey (2007) International Journal for Quality in Health Care, 19 (3), pp. 170-176. , DOI 10.1093/intqhc/mzm003Shiga, T., Wajima, Z., Ohe, Y., Is operative delay associated with increased mortality of hip fracture patients? Systematic review, meta-analysis, and meta-regression (2008) Canadian Journal of Anesthesia, 55 (3), pp. 146-154Kahn, S.K., Kalra, S., Khanna, A., Thiruvengada, M.M., Parker, M.J., Timing of surgery for hip fractures: A systematic review of 52 published studies involving 291, 413 patients (2009) Injury, 40 (7), pp. 692-697Leung, F., Lau, T.W., Kwan, K., Chow, S.P., Kung, A.W.C., Does timing of surgery matter in fragility hip fractures? (2010) Osteoporos Int, 21 (SUPPL. 4), pp. S529-S534Vidal, E.I., Moreira-Filho, D.C., Coeli, C.M., Camargo, K.R., Fukushima, F.B., Blais, R., Hip fracture in the elderly: Does counting time from fracture to surgery or from hospital admission to surgery matter when studying in-hospital mortality? (2009) Osteoporos Int, 20 (5), pp. 723-729Gullberg, B., Johnell, O., Kanis, J.A., World-wide projections for hip fracture (1997) Osteoporosis International, 7 (5), pp. 407-413. , DOI 10.1007/PL00004148Computerised record linkage: Compared with traditional patient follow-up methods in clinical trials and illustrated in a prospective epidemiological study. West of Scotland Coronary Prevention Study Group (1995) J Clin Epidemiol., 48 (12), pp. 1441-1452Jaro, M., Probabilistic linkage of large public health data files (1995) Stat Med, 14 (5-7), pp. 491-498Vidal, E.I.O., Coeli, C.M., Pinheiro, R.S., Camargo Jr., K.R., Mortality within 1 year after hip fracture surgical repair in the elderly according to postoperative period: A probabilistic record linkage study in Brazil (2006) Osteoporosis International, 17 (10), pp. 1569-1576. , DOI 10.1007/s00198-006-0173-3Shannon, H.S., Jamieson, E., Walsh, C., Julian, J.A., Fair, M.E., Buffet, A., Comparison of individual follow-up and computerized record linkage using the Canadian Mortality Data Base (1989) Canadian Journal of Public Health, 80 (1), pp. 54-57Coutinho, E.S.F., Coeli, C.M., Accuracy of the probabilistic record linkage methodology to ascertain deaths in survival studies (2006) Cadernos de Saude Publica, 22 (10), pp. 2249-2252. , http://www.scielo.br/pdf/csp/v22n10/24.pdfCamargo Jr., K.R., Coeli, C.M., Reclink: An application for database linkage implementing the probabilistic record linkage method (2000) Cad Saude Publica, 16 (2), pp. 439-447Charlson, M.E., Pompei, P., Ales, K.A., MacKenzie, C.R., A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation (1987) Journal of Chronic Diseases, 40 (5), pp. 373-383. , DOI 10.1016/0021-9681(87)90171-8Grambsch, P., Therneau, T., Proportional hazards tests and diagnostics based on weighted residuals (1994) Biometrika, 81 (3), pp. 515-526R: A language and environment for statistical computing (2009) R Foundation for Statistical Computing, , R Development Core Team, Vienna, AustriaOrosz, G.M., Hannan, E.L., Magaziner, J., Koval, K., Gilbert, M., Aufses, A., Straus, E., Siu, A.L., Hip fracture in the older patient: Reasons for delay in hospitalization and timing of surgical repair (2002) J Am Geriatr Soc, 50 (8), pp. 1336-1340Hefley Jr., W.F., Nelson, C.L., Puskarich-May, C.L., Effect of delayed admission to the hospital on the preoperative prevalence of deep-vein thrombosis associated with fractures about the hip (1996) Journal of Bone and Joint Surgery - Series A, 78 (4), pp. 581-583Grimes, J.P., Gregory, P.M., Noveck, H., Butler, M.S., Carson, J.L., The effects of time-to-surgery on mortality and morbidity in patients following hip fracture (2002) American Journal of Medicine, 112 (9), pp. 702-709. , DOI 10.1016/S0002-9343(02)01119-1, PII S0002934302011191Beaupre, L.A., Jones, C.A., Saunders, L.D., Johnston, D.W.C., Buckingham, J., Majumdar, S.R., Best practices for elderly hip fracture patients: A systematic overview of the evidence (2005) Journal of General Internal Medicine, 20 (11), pp. 1019-1025. , DOI 10.1111/j.1525-1497.2005.00219.xOrosz, G.M., Magaziner, J., Hannan, E.L., Morrison, R.S., Koval, K., Gilbert, M., McLaughlin, M., Siu, A.L., Association of Timing of Surgery for Hip Fracture and Patient Outcomes (2004) Journal of the American Medical Association, 291 (14), pp. 1738-1743. , DOI 10.1001/jama.291.14.1738Bhandari, M., Tornetta III, P., Ellis, T., Audige, L., Sprague, S., Kuo, J.C., Swiontkowski, M.F., Hierarchy of evidence: Differences in results between non-randomized studies and randomized trials in patients with femoral neck fractures (2004) Archives of Orthopaedic and Trauma Surgery, 124 (1), pp. 10-16. , DOI 10.1007/s00402-003-0559-zMcGuire, K., Bernstein, J., Polsky, D., Silber, J., Delays until surgery after hip fracture increases mortality (2004) Clin Orthop Rel Res, 428, pp. 294-301Zuckerman, J.D., Skovron, M.L., Koval, K.J., Aharonoff, G., Frankel, V.H., Postoperative complications and mortality associated with operative delay in older patients who have a fracture of the hip (1995) J Bone Joint Surg Am, 77 (10), pp. 1551-155

Screening For The Gjb2 C.-3170 G>a (ivs 1+1 G>a) Mutation In Brazilian Deaf Individuals Using Multiplex Ligation-dependent Probe Amplification.

Mutations in GJB2 gene are the most common cause of nonsyndromic sensorineural recessive hearing loss. One specific mutation, c.35delG, is the most frequent in the majority of Caucasian populations and may account for up to 70% of all GJB2 mutations. However, 10-40% of the patients carry only one pathogenic mutation in the GJB2 gene. Deletions del(GJB6-D13S1830) and del(GJB6-D13S1854), truncating the GJB6 gene, have been detected in GJB2 heterozygous patients in different populations. The IVS 1+1 G>A splice site mutation in the noncoding region of the GJB2 gene has been found in heterozygous state in addition to c.35delG mutation. This mutation has not been reported in Brazilian deaf patients. In the present study we investigated the presence of the IVS 1+1 G>A mutation by multiplex ligation-dependent probe amplification in 185 unrelated Brazilian patients with autosomal recessive nonsyndromic sensorineural hearing loss (43 heterozygous patients and 142 without any pathogenic mutation in the GJB2-coding region). We have found two patients (4.6%) carrying the IVS 1+1 G>A mutation in compound heterozygous with c.35delG mutation.13570170

T Allele Of -344c/t Polymorphism In Aldosterone Synthase Gene Is Not Associated With Resistant Hypertension

Resistant hypertension (RH) is the maintenance of elevated blood pressure concurrent with the use of three different anti-hypertensive drugs, one of which is a diuretic. The Renin-Angiotensin-Aldosterone System plays a major role in volume-dependent hypertension. Therefore, its components are interesting targets for genetic association studies. This work focused on the -344 C/T polymorphism in the CYP11b2 gene, which encodes aldosterone synthase. This work evaluates the association between T allele and resistance to anti-hypertensive treatment. Genotyping analysis included 88 subjects with RH, 142 who were responsive to anti-hypertensive treatment and 110 subjects as a control group. Plasmatic concentrations of aldosterone, renin and cortisol, carotid intima-media thickness and carotid-femoral pulse wave velocity were assessed in a smaller subset of hypertensive patients. An association was found between T allele and hypertension (P<0.005), but there was no difference in allele frequencies between both hypertensive groups. There was no difference in plasmatic parameters either, in remodeling indicators between the genotypic groups.322159162Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003289: 2560-2572Gaddam, K.K., Nishizaka, M.K., Pratt-Ubunama, M.N., Pimenta, E., Aban, I., Oparif, S., Calhoun, D.A., Characterization of resistant hypertension: Association between resistant hypertension, alcosterone, and persistent intravascular volume expansion (2008) Arch Intern Med, 168, pp. 1159-1164Freel, E.M., Ingram, M., Friel, E.C., Fraser, R., Brown, M., Samani, N.J., Caulfield, M., Connell, J.M., Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: Data from the MRC BRIGHT Study (2007) Clin Endocrinol (Oxf), 67, pp. 832-838White, P.C., Slutsker, L., Haplotype analysis of CYP11B2 (1995) Endocr Res, 21, pp. 437-442Freitas, S.R., Cabello, P.H., Moura-Neto, R.S., Dolinsky, L.C., Lima, A.B., Barros, M., Bittencourt, I., Cordovil, I.L., Analysis of renin-angiotensin-aldosterone system gene polymorphisms in resistant hypertension (2007) Braz J Med Biol Res, 40, pp. 309-316Hilgers, K.F., Schmidt, B.M., Gene variants of aldosterone synthase and hypertension (2005) J Hypertens, 23, pp. 1957-1959Davies, E., Holloway, C.D., Ingram, M.C., Inglis, G.C., Friel, E.C., Morrison, C., Anderson, N.H., Connell, J.M., Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2 (1999) Hypertension, 33, pp. 703-707Iwai, N., Kajimoto, K., Tomoike, H., Takashima, N., Polymorphism of CYP11B2 determines salt sensitivity in Japanese (2007) Hypertension, 49, pp. 825-831Park, S., Kim, J.B., Shim, C.Y., Ko, Y.G., Choi, D., Jang, Y., Chung, N., The influence of serum aldosterone and the aldosterone-renin ratio on pulse wave velocity in hypertensive patients (2007) J Hypertens, 25, pp. 1279-1283Holaj, R., Zelinka, T., Wichterle, D., Petrak, O., Strauch, B., Widimsky Jr, J., Increased intima-media thickness of the common carotid artery in primary aldosteronism in comparison with essential hypertension (2007) J Hypertens, 25, pp. 1451-1457Boutouyrie, P., Tropeano, A.I., Asmar, R., Gautier, I., Benetos, A., Lacolley, P., Laurent, S., Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: A longitudinal study (2002) Hypertension, 39, pp. 10-15Laurent, S., Cockcroft, J., Van Bortel, L., Boutouyrie, P., Giannattasio, C., Hayoz, D., Pannier, B., Struijker-Boudier, H., Expert consensus document on arterial stiffness: Methodological issues and clinical applications (2006) Eur Heart J, 27, pp. 2588-2605Pitt, B., Zannad, F., Remme, W.J., Cody, R., Castaigne, A., Perez, A., Palensky, J., Wittes, J., The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators (1999) N Engl J Med, 341, pp. 709-717Pitt, B., Remme, W., Zannad, F., Neaton, J., Martinez, F., Roniker, B., Bittman, R., Gatlin, M., Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction (2003) N Engl J Med, 348, pp. 1309-1321Schiffrin, E.L., Effects of aldosterone on the vasculature (2006) Hypertension, 47, pp. 312-318Taylor, D.W., Sackett, D.L., Haynes, R.B., Johnson, A.L., Gibson, E.S., Roberts, R.S., Compliance with antihypertensive drug therapy (1978) Ann NY Acad Sci, 304, pp. 390-403Cittadino, M., Goncalves de Sousa, M., Ugar-Toledo, J.C., Rocha, J.C., Tanus-Santos, J.E., Moreno Jr, H., Biochemical endothelial markers and cardiovascular remodeling in refractory arterial hypertension (2003) Clin Exp Hypertens, 25, pp. 25-3