Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy

OBJECTIVE: The objective of the study was to determine the feasibility of detecting fetal brain lactate, a marker of fetal metabolic acidemia, using a noninvasive technique, proton magnetic resonance spectroscopy (1H MRS), in intrauterine growth-restricted (IUGR) fetuses. STUDY DESIGN: In vivo human fetal brain lactate detection was determined by 1H MRS in 5 fetuses with IUGR. Oxygenation and acid-base balance data were obtained at birth. RESULTS: 1H MRS analysis showed the presence of a lactate peak in the brain of the most severely affected IUGR fetus, with abnormal umbilical artery Doppler and fetal heart rate tracing. This finding was consistent with the low oxygen content and high lactic acid concentration observed in umbilical blood obtained at delivery. CONCLUSION: 1H MRS allows the noninvasive detection of cerebral lactate in IUGR fetuses. Lactate detected by 1H MRS may represent a possible marker of in utero cerebral injury or underperfusion

MiR-340 inhibits tumor cell proliferation and induces apoptosis by targeting multiple negative regulators of p27 in non-small cell lung cancer

MicroRNAs (miRNAs) control cell cycle progression by targeting the transcripts encoding for cyclins, CDKs and CDK inhibitors, such as p27(KIP1) (p27). p27 expression is controlled by multiple transcriptional and posttranscriptional mechanisms, including translational inhibition by miR-221/222 and posttranslational regulation by the SCF(SKP2) complex. The oncosuppressor activity of miR-340 has been recently characterized in breast, colorectal and osteosarcoma tumor cells. However, the mechanisms underlying miR-340-induced cell growth arrest have not been elucidated. Here, we describe miR-340 as a novel tumor suppressor in non-small cell lung cancer (NSCLC). Starting from the observation that the growth-inhibitory and proapoptotic effects of miR-340 correlate with the accumulation of p27 in lung adenocarcinoma and glioblastoma cells, we have analyzed the functional relationship between miR-340 and p27 expression. miR-340 targets three key negative regulators of p27. The miR-340-mediated inhibition of both Pumilio family RNA-binding proteins (PUM1 and PUM2), required for the miR-221/222 interaction with the p27 3'-UTR, antagonizes the miRNA-dependent downregulation of p27. At the same time, miR-340 induces the stabilization of p27 by targeting SKP2, the key posttranslational regulator of p27. Therefore, miR-340 controls p27 at both translational and posttranslational levels. Accordingly, the inhibition of either PUM1 or SKP2 partially recapitulates the miR-340 effect on cell proliferation and apoptosis. In addition to the effect on tumor cell proliferation, miR-340 also inhibits intercellular adhesion and motility in lung cancer cells. These changes correlate with the miR-340-mediated inhibition of previously validated (MET and ROCK1) and potentially novel (RHOA and CDH1) miR-340 target transcripts. Finally, we show that in a small cohort of NSCLC patients (n=23), representative of all four stages of lung cancer, miR-340 expression inversely correlates with clinical staging, thus suggesting that miR-340 downregulation contributes to the disease progression

miR-340 inhibits tumor cell proliferation and induces apoptosis by targeting multiple negative regulators of p27 in non-small cell lung cancer

MicroRNAs (miRNAs) control cell cycle progression by targeting the transcripts encoding for cyclins, CDKs and CDK inhibitors, such as p27KIP1 (p27). p27 expression is controlled by multiple transcriptional and posttranscriptional mechanisms, including translational inhibition by miR-221/222 and posttranslational regulation by the SCFSKP2 complex. The oncosuppressor activity of miR-340 has been recently characterized in breast, colorectal and osteosarcoma tumor cells. However, the mechanisms underlying miR-340-induced cell growth arrest have not been elucidated. Here, we describe miR-340 as a novel tumor suppressor in non-small cell lung cancer (NSCLC). Starting from the observation that the growth-inhibitory and proapoptotic effects of miR-340 correlate with the accumulation of p27 in lung adenocarcinoma and glioblastoma cells, we have analyzed the functional relationship between miR-340 and p27 expression. miR-340 targets three key negative regulators of p27. The miR-340-mediated inhibition of both Pumilio family RNA-binding proteins (PUM1 and PUM2), required for the miR-221/222 interaction with the p27 3'-UTR, antagonizes the miRNA-dependent downregulation of p27. At the same time, miR-340 induces the stabilization of p27 by targeting SKP2, the key posttranslational regulator of p27. Therefore, miR-340 controls p27 at both translational and posttranslational levels. Accordingly, the inhibition of either PUM1 or SKP2 partially recapitulates the miR-340 effect on cell proliferation and apoptosis. In addition to the effect on tumor cell proliferation, miR-340 also inhibits intercellular adhesion and motility in lung cancer cells. These changes correlate with the miR-340-mediated inhibition of previously validated (MET and ROCK1) and potentially novel (RHOA and CDH1) miR-340 target transcripts. Finally, we show that in a small cohort of NSCLC patients (n=23), representative of all four stages of lung cancer, miR-340 expression inversely correlates with clinical staging, thus suggesting that miR-340 downregulation contributes to the disease progression

Lack of Association Between Optineurin Gene Variants T34T, E50K, M98K, 691_692insAG and R545Q and Primary Open Angle Glaucoma in Brazilian Patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Purpose: To verify the frequencies of T34T, E50K, M98K, 691_692insAG, and R545Q variants in the optineurin (OPTN) gene in Brazilian subjects with primary open-angle glaucoma (POAG) and controls. Patients and Methods: Ninety-nine patients with POAG and 100 normal controls were enrolled in this study. The frequency of alterations in the OPTN gene was analyzed by direct sequencing and enzymatic digestion of PCR products. Results: None of the five alterations evaluated was significantly associated with POAG when compared to controls. However, the T34T silent change was present in greater frequency in POAG patients (37.37% vs. 23.00% in controls), while the R545Q change was more prevalent in controls (23.00% vs. 10.10% in POAG). The M98K and 691_692insAG presented with low frequencies in POAG patients (1.01% and 2.02%, respectively) and controls (2.00% and 2.00%, respectively). The E50K substitution was not observed. Conclusion: Our data show no association between the five evaluated variants and POAG in the Brazilian population.3011318FAP-SCSPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [02/11575-0

The effect of fetal sex on customized fetal growth charts

Objective: To evaluate the effect of fetal sex on singleton pregnancy growth charts customized for parental characteristics, race, and parity Methods: In a multicentric cross-sectional study, 8070 ultrasonographic examinations from low-risk singleton pregnancies between 16 and 40 weeks of gestation were considered. The fetal measurements obtained were biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). Quantile regression was used to examine the impact of fetal sex across the biometric percentiles of the fetal measurements considered together with parents\u2019 height, weight, parity, and race. Results: Fetal gender resulted to be a significant covariate for BDP, HC, and AC with higher values for male fetuses (p 64 0.0009). Minimal differences were found among sexes for FL. Parity, maternal race, paternal height and maternal height, and weight resulted significantly related to the fetal biometric parameters considered independently from fetal gender. Conclusion: In this study, we constructed customized biometric growth charts for fetal sex, parental, and obstetrical characteristics using quantile regression. The use of gender-specific charts offers the advantage to define individualized normal ranges of fetal biometric parameters at each specific centile. This approach may improve the antenatal identification of abnormal fetal growth

Lack Of Association Between Optineurin Gene Variants T34t, E50k, M98k, 691-692insag And R545q And Primary Open Angle Glaucoma In Brazilian Patients

Purpose: To verify the frequencies of T34T, E50K, M98K, 691-692insAG, and R545Q variants in the optineurin (OPTN) gene in Brazilian subjects with primary open-angle glaucoma (POAG) and controls. Patients and Methods: Ninety-nine patients with POAG and 100 normal controls were enrolled in this study. The frequency of alterations in the OPTN gene was analyzed by direct sequencing and enzymatic digestion of PCR products. Results: None of the five alterations evaluated was significantly associated with POAG when compared to controls. However, the T34T silent change was present in greater frequency in POAG patients (37.37% vs. 23.00% in controls), while the R545Q change was more prevalent in controls (23.00% vs. 10.10% in POAG). The M98K and 691-692insAG presented with low frequencies in POAG patients (1.01% and 2.02%, respectively) and controls (2.00% and 2.00%, respectively). The E50K substitution was not observed. Conclusion: Our data show no association between the five evaluated variants and POAG in the Brazilian population. Copyright © Informa Healthcare USA, Inc.3011318Weinreb, R.N., Glaucoma neuroprotection: What is it? Why is it needed? (2007) Can J Ophthalmol, 42, pp. 396-398Raymond, V., Molecular genetics of the glaucomas: Mapping of the first five "GLC" loci (1997) Am J Hum Genet, 60, pp. 272-277Sarfarazi, M., Recent advances in molecular genetics of glaucomas (1997) Hum Mol Genet, 6, pp. 1667-1677Wilson, M.R., Hertzmark, E., Walker, A.M., Childs-Shaw, K., Epstein, D.L., A case-control study of risk factors in open angle glaucoma (1987) Arch Ophthalmol, 105, pp. 1066-1071Drance, S., Chronic open angle glaucoma: Risk factors in addition to intraocular pressure (2001) Acta Ophthalmol Scand, 79, p. 545Monemi, S., Spaeth, G., DaSilva, A., Popinchalk, S., Ilitchev, E., Liebmann, Ritch, R., Sarfarazi, M., Identification of a novel adult-onset primary open glaucoma (POAG) gene on 5q22.1 (2005) Hum Mol Genet, 14, pp. 725-733Rezaie, T., Child, A., Hitchings, R., Brice, G., Miller, L., Coca-Prados, M., Héon, E., Sarfarazi, M., Adult-onset primary open-angle glaucoma caused by mutations in optineurin (2002) Science, 295, pp. 1077-1079Libby, R.T., Douglas, B., Gould, D.B., Anderson, M.G., John, S.M., Complex Genetic of Glaucoma Susceptibility (2005) Annu Rev Genomics Hum Genet, 6, pp. 15-44Funayama, T., Ishikawa, K., Ohtake, Y., Tanino, T., Kurosaka, D., Kimura, I., Suzuki, K., Mashima, Y., Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma (2004) Invest Ophthalmol Vis Sci, 45, pp. 4359-4367Hodapp, E., Parrish II, R.K., Anderson, D.R., (1993) Clinical decisions in glaucoma, pp. 52-61. , St Louis, The C.V, Mosby CoWilloughby, C.E., Chan, L.L., Herd, S., Billingsley, G., Noordeh, N., Levin, A.V., Buys, Y., Héon, E., Defining the pathogenicity of optineurin in juvenile open-angle glaucoma (2004) Invest Ophthalmol Vis Sci, 45, pp. 3122-3130Fan, B.J., Wang, D.Y., Fan, D.S., Tam, P.O., Lam, D.S., Tham, C.C., Lam, C.Y., Pang, C.P., SNPs and interaction analyses of myocilin, optineurin, and apolipoprotein E in primary open angle glaucoma patients (2005) Mol Vis, 11, pp. 625-631Tang, S., Toda, Y., Kashiwagi, K., Mabuchi, F., Iijima, H., Tsukahara, S., Yamagata, Z., The association between Japanese primary open-angle glaucoma and normal tension glaucoma patients and the optineurin gene (2003) Hum Genet, 113, pp. 276-279Fuse, N., Takahashi, K., Akiyama, H., Nakazawa, T., Seimiya, M., Kuwahara, S., Tamai, M., Molecular genetic analysis of optineurin gene for primary open-angle and normal tension glaucoma in the Japanese population (2004) J Glaucoma, 13, pp. 299-303Jansson, M., Wadelius, C., Rezaie, T., Sarfarazi, M., Analysis of rare variants and common haplotypes in the optineurin gene in Swedish glaucoma cases (2005) Ophthalmic Genet, 26, pp. 85-89Mukhopadhyay, A., Komatireddy, S., Acharya, M., Bhattacharjee, A., Mandal, A.K., Thakur, S.K., Chandrasekhar, G., Ray, K., Evaluation of Optineurin as a candidate gene in Indian patients with primary open angle glaucoma (2005) Mol Vis, 11, pp. 792-797Hauser, M.A., Sena, D.F., Flor, J., Walter, J., Auguste, J., Larocque-Abramson, K., Graham, F., Wiggs, J.L., Distribution of optineurin sequence variations in an ethnically diverse population of low-tension glaucoma patients from the United States (2006) J Glaucoma, 15, pp. 358-363Leung, Y.F., Fan, B.J., Lam, D.S., Lee, W.S., Tam, P.O., Chua, J.K., Tham, C.C., Pang, C.P., Different optineurin mutation pattern in primary open-angle glaucoma (2003) Invest Ophthalmol Vis Sci, 44, pp. 3880-3884Toda, Y., Tang, S., Kashiwagi, K., Mabuchi, F., Iijima, H., Tsukahara, S., Yamagata, Z., Mutations in the optinurin gene in Japanese patients with primary open angle glaucoma and normal tension glaucoma (2004) Am J Med Genet A, 125 A, pp. 1-4Baird PN, Foote SJ, Mackey DA, Craig J, Speed TP, Bureau A. Evidence for a novel glaucoma locus at chromosome 3p21-22. Hum Genet. 2005;117:249-257Alward, W.L., Kwon, Y.H., Kawase, K., Craig, J.E., Hayreh, S.S., Johnson, A.T., Khanna, C.L., Stone, E.M., Evaluation of optineurin sequence variations in 1048 patients with open angle glaucoma (2003) Am J Ophthalmol, 136, pp. 904-910Aung, T., Rezaie, T., Okada, K., Viswanathan, A.C., Child, A.H., Brice, G., Bhattacharya, S.S., Hitchings, R.A., Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene (2005) Invest Ophthalmol Vis Sci, 46, pp. 2816-2822Weisschuh, N., Neumann, D., Wolf, C., Wissinger, B., Gramer, E., Prevalence of myocilin and optineurin sequence variants in German normal tension glaucoma patients (2005) Mol Vis, 11, pp. 284-287Melki, R., Belmouden, A., Akhayat, O., Brézin, A., Garchon, H.J., The M98K variant of the OPTINEURIN (OPTN) gene modifies initial intraocular pressure in patients with primary open angle glaucoma (2003) J Med Genet, 40, pp. 842-844Urbano, A.P., Freitas, T.G., Arcieri, E.S., Urbano, A.P., Costa, V.P., Avaliação dos tipos de glaucoma no Serviço de Oftalmologia da Unicamp. 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Customized Fetal Growth Charts for Parents' Characteristics, Race, and Parity by Quantile Regression Analysis : a Cross-sectional Multicenter Italian Study

Objectives-The purpose of this study was to construct fetal biometric charts between 16 and 40 weeks' gestation that were customized for parental characteristics, race, and parity, using quantile regression analysis. Methods-In a multicenter cross-sectional study, 8070 sonographic examinations from low-risk pregnancies between 16 and 40 weeks' gestation were analyzed. The fetal measurements obtained were biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. Quantile regression was used to examine the impact of parental height and weight, parity, and race across biometric percentiles for the fetal measurements considered. Results-Paternal and maternal height were significant covariates for all of the measurements considered (P < .05). Maternal weight significantly influenced head circumference, abdominal circumference, and femur diaphysis length. Parity was significantly associated with biparietal diameter and head circumference. Central African race was associated with head circumference and femur diaphysis length, whereas North African race was only associated with femur diaphysis length. Conclusions-In this study we constructed customized biometric growth charts using quantile regression in a large cohort of low-risk pregnancies. These charts offer the advantage of defining individualized normal ranges of fetal biometric parameters at each specific percentile corrected for parental height and weight, parity, and race. This study supports the importance of including these variables in routine sonographic screening for fetal growth abnormalities