TY  - JOUR
A1  - Taal, H. Rob
A1  - St Pourcain, Beate
A1  - Thiering, Elisabeth
A1  - Das, Shikta
A1  - Mook-Kanamori, Dennis O.
A1  - Warrington, Nicole M.
A1  - Kaakinen, Marika
A1  - Kreiner-Moller, Eskil
A1  - Bradfield, Jonathan P.
A1  - Freathy, Rachel M.
A1  - Geller, Frank
A1  - Guxens, Monica
A1  - Cousminer, Diana L.
A1  - Kerkhof, Marjan
A1  - Timpson, Nicholas J.
A1  - Ikram, M. Arfan
A1  - Beilin, Lawrence J.
A1  - Bonnelykke, Klaus
A1  - Buxton, Jessica L.
A1  - Charoen, Pimphen
A1  - Chawes, Bo Lund Krogsgaard
A1  - Eriksson, Johan
A1  - Evans, David M.
A1  - Hofman, Albert
A1  - Kemp, John P.
A1  - Kim, Cecilia E.
A1  - Klopp, Norman
A1  - Lahti, Jari
A1  - Lye, Stephen J.
A1  - McMahon, George
A1  - Mentch, Frank D.
A1  - Mueller-Nurasyid, Martina
A1  - O'Reilly, Paul F.
A1  - Prokopenko, Inga
A1  - Rivadeneira, Fernando
A1  - Steegers, Eric A. P.
A1  - Sunyer, Jordi
A1  - Tiesler, Carla
A1  - Yaghootkar, Hanieh
A1  - Breteler, Monique M. B.
A1  - Debette, Stephanie
A1  - Fornage, Myriam
A1  - Gudnason, Vilmundur
A1  - Launer, Lenore J.
A1  - van der Lugt, Aad
A1  - Mosley, Thomas H.
A1  - Seshadri, Sudha
A1  - Smith, Albert V.
A1  - Vernooij, Meike W.
A1  - Blakemore, Alexandra I. F.
A1  - Chiavacci, Rosetta M.
A1  - Feenstra, Bjarke
A1  - Fernandez-Banet, Julio
A1  - Grant, Struan F. A.
A1  - Hartikainen, Anna-Liisa
A1  - van der Heijden, Albert J.
A1  - Iniguez, Carmen
A1  - Lathrop, Mark
A1  - McArdle, Wendy L.
A1  - Molgaard, Anne
A1  - Newnham, John P.
A1  - Palmer, Lyle J.
A1  - Palotie, Aarno
A1  - Pouta, Annneli
A1  - Ring, Susan M.
A1  - Sovio, Ulla
A1  - Standl, Marie
A1  - Uitterlinden, Andre G.
A1  - Wichmann, H-Erich
A1  - Vissing, Nadja Hawwa
A1  - DeCarli, Charles
A1  - van Duijn, Cornelia M.
A1  - McCarthy, Mark I.
A1  - Koppelman, Gerard H.
A1  - Estivill, Xavier
A1  - Hattersley, Andrew T.
A1  - Melbye, Mads
A1  - Bisgaard, Hans
A1  - Pennell, Craig E.
A1  - Widen, Elisabeth
A1  - Hakonarson, Hakon
A1  - Smith, George Davey
A1  - Heinrich, Joachim
A1  - Jarvelin, Marjo-Riitta
A1  - Jaddoe, Vincent W. V.
A1  - Adair, Linda S.
A1  - Ang, Wei
A1  - Atalay, Mustafa
A1  - van Beijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Bradfield, Jonathan P.
A1  - Charoen, Pimphen
A1  - Coin, Lachlan
A1  - Cousminer, Diana L.
A1  - Das, Shikta
A1  - Davis, Oliver S. P.
A1  - Elliott, Paul
A1  - Evans, David M.
A1  - Feenstra, Bjarke
A1  - Flexeder, Claudia
A1  - Frayling, Tim
A1  - Freathy, Rachel M.
A1  - Gaillard, Romy
A1  - Geller, Frank
A1  - Groen-Blokhuis, Maria
A1  - Goh, Liang-Kee
A1  - Guxens, Monica
A1  - Haworth, Claire M. A.
A1  - Hadley, Dexter
A1  - Hebebrand, Johannes
A1  - Hinney, Anke
A1  - Hirschhorn, Joel N.
A1  - Holloway, John W.
A1  - Holst, Claus
A1  - Hottenga, Jouke Jan
A1  - Horikoshi, Momoko
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Iniguez, Carmen
A1  - Kaakinen, Marika
A1  - Kilpelainen, Tuomas O.
A1  - Kirin, Mirna
A1  - Kowgier, Matthew
A1  - Lakka, Hanna-Maaria
A1  - Lange, Leslie A.
A1  - Lawlor, Debbie A.
A1  - Lehtimaki, Terho
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Lindi, Virpi
A1  - Maggi, Reedik
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Mook-Kanamori, Dennis O.
A1  - Murray, Jeffrey C.
A1  - Nivard, Michel
A1  - Nohr, Ellen Aagaard
A1  - Ntalla, Ioanna
A1  - Oken, Emily
A1  - O'Reilly, Paul F.
A1  - Palmer, Lyle J.
A1  - Panoutsopoulou, Kalliope
A1  - Pararajasingham, Jennifer
A1  - Prokopenko, Inga
A1  - Rodriguez, Alina
A1  - Salem, Rany M.
A1  - Sebert, Sylvain
A1  - Siitonen, Niina
A1  - Sovio, Ulla
A1  - St Pourcain, Beate
A1  - Strachan, David P.
A1  - Sunyer, Jordi
A1  - Taal, H. Rob
A1  - Teo, Yik-Ying
A1  - Thiering, Elisabeth
A1  - Tiesler, Carla
A1  - Uitterlinden, Andre G.
A1  - Valcarcel, Beatriz
A1  - Warrington, Nicole M.
A1  - White, Scott
A1  - Willemsen, Gonneke
A1  - Yaghootkar, Hanieh
A1  - Zeggini, Eleftheria
A1  - Boomsma, Dorret I.
A1  - Cooper, Cyrus
A1  - Estivill, Xavier
A1  - Gillman, Matthew
A1  - Grant, Struan F. A.
A1  - Hakonarson, Hakon
A1  - Hattersley, Andrew T.
A1  - Heinrich, Joachim
A1  - Hocher, Berthold
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - Lakka, Timo A.
A1  - McCarthy, Mark I.
A1  - Melbye, Mads
A1  - Mohlke, Karen L.
A1  - Dedoussis, George V.
A1  - Ong, Ken K.
A1  - Pearson, Ewan R.
A1  - Pennell, Craig E.
A1  - Price, Thomas S.
A1  - Power, Chris
A1  - Raitakari, Olli T.
A1  - Saw, Seang-Mei
A1  - Scherag, Andre
A1  - Simell, Olli
A1  - Sorensen, Thorkild I. A.
A1  - Timpson, Nicholas J.
A1  - Widen, Elisabeth
A1  - Wilson, James F.
A1  - Ang, Wei
A1  - van Beijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Bradfield, Jonathan P.
A1  - Charoen, Pimphen
A1  - Coin, Lachlan
A1  - Cousminer, Diana L.
A1  - Das, Shikta
A1  - Elliott, Paul
A1  - Evans, David M.
A1  - Frayling, Tim
A1  - Freathy, Rachel M.
A1  - Gaillard, Romy
A1  - Groen-Blokhuis, Maria
A1  - Guxens, Monica
A1  - Hadley, Dexter
A1  - Hottenga, Jouke Jan
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Kaakinen, Marika
A1  - Kowgier, Matthew
A1  - Lawlor, Debbie A.
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Mook-Kanamori, Dennis O.
A1  - Nivard, Michel
A1  - O'Reilly, Paul F.
A1  - Palmer, Lyle J.
A1  - Prokopenko, Inga
A1  - Rodriguez, Alina
A1  - Sebert, Sylvain
A1  - Sovio, Ulla
A1  - St Pourcain, Beate
A1  - Standl, Marie
A1  - Strachan, David P.
A1  - Sunyer, Jordi
A1  - Taal, H. Rob
A1  - Thiering, Elisabeth
A1  - Tiesler, Carla
A1  - Uitterlinden, Andre G.
A1  - Valcarcel, Beatriz
A1  - Warrington, Nicole M.
A1  - White, Scott
A1  - Willemsen, Gonneke
A1  - Yaghootkar, Hanieh
A1  - Boomsma, Dorret I.
A1  - Estivill, Xavier
A1  - Grant, Struan F. A.
A1  - Hakonarson, Hakon
A1  - Hattersley, Andrew T.
A1  - Heinrich, Joachim
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - McCarthy, Mark I.
A1  - Pennell, Craig E.
A1  - Power, Chris
A1  - Timpson, Nicholas J.
A1  - Widen, Elisabeth
A1  - Ikram, M. Arfan
A1  - Fornage, Myriam
A1  - Smith, Albert V.
A1  - Seshadri, Sudha
A1  - Schmidt, Reinhold
A1  - Debette, Stephanie
A1  - Vrooman, Henri A.
A1  - Sigurdsson, Sigurdur
A1  - Ropele, Stefan
A1  - Coker, Laura H.
A1  - Longstreth, W. T.
A1  - Niessen, Wiro J.
A1  - DeStefano, Anita L.
A1  - Beiser, Alexa
A1  - Zijdenbos, Alex P.
A1  - Struchalin, Maksim
A1  - Jack, Clifford R.
A1  - Nalls, Mike A.
A1  - Au, Rhoda
A1  - Hofman, Albert
A1  - Gudnason, Haukur
A1  - van der Lugt, Aad
A1  - Harris, Tamara B.
A1  - Meeks, William M.
A1  - Vernooij, Meike W.
A1  - van Buchem, Mark A.
A1  - Catellier, Diane
A1  - Gudnason, Vilmundur
A1  - Windham, B. Gwen
A1  - Wolf, Philip A.
A1  - van Duijn, Cornelia M.
A1  - Mosley, Thomas H.
A1  - Schmidt, Helena
A1  - Launer, Lenore J.
A1  - Breteler, Monique M. B.
A1  - DeCarli, Charles
T1  - Common variants at 12q15 and 12q24 are associated with infant head circumference
JF  - Nature genetics
N2  - To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Y1  - 2012
U6  - https://doi.org/10.1038/ng.2238
SN  - 1061-4036
VL  - 44
IS  - 5
SP  - 532
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Ikram, M. Arfan
A1  - Fornage, Myriam
A1  - Smith, Albert V.
A1  - Seshadri, Sudha
A1  - Schmidt, Reinhold
A1  - Debette, Stephanie
A1  - Vrooman, Henri A.
A1  - Sigurdsson, Sigurdur
A1  - Ropele, Stefan
A1  - Taal, H. Rob
A1  - Mook-Kanamori, Dennis O.
A1  - Coker, Laura H.
A1  - Longstreth, W. T.
A1  - Niessen, Wiro J.
A1  - DeStefano, Anita L.
A1  - Beiser, Alexa
A1  - Zijdenbos, Alex P.
A1  - Struchalin, Maksim
A1  - Jack, Clifford R.
A1  - Rivadeneira, Fernando
A1  - Uitterlinden, Andre G.
A1  - Knopman, David S.
A1  - Hartikainen, Anna-Liisa
A1  - Pennell, Craig E.
A1  - Thiering, Elisabeth
A1  - Steegers, Eric A. P.
A1  - Hakonarson, Hakon
A1  - Heinrich, Joachim
A1  - Palmer, Lyle J.
A1  - Jarvelin, Marjo-Riitta
A1  - McCarthy, Mark I.
A1  - Grant, Struan F. A.
A1  - St Pourcain, Beate
A1  - Timpson, Nicholas J.
A1  - Smith, George Davey
A1  - Sovio, Ulla
A1  - Nalls, Mike A.
A1  - Au, Rhoda
A1  - Hofman, Albert
A1  - Gudnason, Haukur
A1  - van der Lugt, Aad
A1  - Harris, Tamara B.
A1  - Meeks, William M.
A1  - Vernooij, Meike W.
A1  - van Buchem, Mark A.
A1  - Catellier, Diane
A1  - Jaddoe, Vincent W. V.
A1  - Gudnason, Vilmundur
A1  - Windham, B. Gwen
A1  - Wolf, Philip A.
A1  - van Duijn, Cornelia M.
A1  - Mosley, Thomas H.
A1  - Schmidt, Helena
A1  - Launer, Lenore J.
A1  - Breteler, Monique M. B.
A1  - DeCarli, Charles
A1  - Adair, Linda S.
A1  - Ang, Wei
A1  - Atalay, Mustafa
A1  - vanBeijsterveldt, Toos
A1  - Bergen, Nienke
A1  - Benke, Kelly
A1  - Berry, Diane J.
A1  - Coin, Lachlan
A1  - Davis, Oliver S. P.
A1  - Elliott, Paul
A1  - Flexeder, Claudia
A1  - Frayling, Tim
A1  - Gaillard, Romy
A1  - Groen-Blokhuis, Maria
A1  - Goh, Liang-Kee
A1  - Haworth, Claire M. A.
A1  - Hadley, Dexter
A1  - Hebebrand, Johannes
A1  - Hinney, Anke
A1  - Hirschhorn, Joel N.
A1  - Holloway, John W.
A1  - Holst, Claus
A1  - Hottenga, Jouke Jan
A1  - Horikoshi, Momoko
A1  - Huikari, Ville
A1  - Hypponen, Elina
A1  - Kilpelainen, Tuomas O.
A1  - Kirin, Mirna
A1  - Kowgier, Matthew
A1  - Lakka, Hanna-Maaria
A1  - Lange, Leslie A.
A1  - Lawlor, Debbie A.
A1  - Lehtimaki, Terho
A1  - Lewin, Alex
A1  - Lindgren, Cecilia
A1  - Lindi, Virpi
A1  - Maggi, Reedik
A1  - Marsh, Julie
A1  - Middeldorp, Christel
A1  - Millwood, Iona
A1  - Murray, Jeffrey C.
A1  - Nivard, Michel
A1  - Nohr, Ellen Aagaard
A1  - Ntalla, Ioanna
A1  - Oken, Emily
A1  - Panoutsopoulou, Kalliope
A1  - Pararajasingham, Jennifer
A1  - Rodriguez, Alina
A1  - Salem, Rany M.
A1  - Sebert, Sylvain
A1  - Siitonen, Niina
A1  - Strachan, David P.
A1  - Teo, Yik-Ying
A1  - Valcarcel, Beatriz
A1  - Willemsen, Gonneke
A1  - Zeggini, Eleftheria
A1  - Boomsma, Dorret I.
A1  - Cooper, Cyrus
A1  - Gillman, Matthew
A1  - Hocher, Berthold
A1  - Lakka, Timo A.
A1  - Mohlke, Karen L.
A1  - Dedoussis, George V.
A1  - Ong, Ken K.
A1  - Pearson, Ewan R.
A1  - Price, Thomas S.
A1  - Power, Chris
A1  - Raitakari, Olli T.
A1  - Saw, Seang-Mei
A1  - Scherag, Andre
A1  - Simell, Olli
A1  - Sorensen, Thorkild I. A.
A1  - Wilson, James F.
T1  - Common variants at 6q22 and 17q21 are associated with intracranial volume
JF  - Nature genetics
N2  - During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Y1  - 2012
U6  - https://doi.org/10.1038/ng.2245
SN  - 1061-4036
VL  - 44
IS  - 5
SP  - 539
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Wang, Zi-Neng
A1  - Chen, You-Peng
A1  - Dong, Yun-Peng
A1  - Shuai, Han-Lin
A1  - Xiao, Xiao-Min
A1  - Reichetzeder, Christoph
A1  - Hocher, Berthold
T1  - Late gestational maternal serum cortisol is inversely associated with fetal brain growth
JF  - Neuroscience & biobehavioral reviews : official journal of the International Behavioral Neuroscience Society
N2  - To analyze the association between fetal brain growth and late gestational blood serum cortisol in normal pregnancy.Blood total cortisol was quantified at delivery in 432 Chinese mother/child pairs. Key inclusion criteria of the cohort were: no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking no hypertensive disorders and no impairment of glucose tolerance and no use of steroid medication during pregnancy. Differential ultrasound examination of the fetal body was done in early (gestational day 89.95 +/- 7.31), middle (gestational day 160.17 16.12) and late pregnancy (gestational day 268.89 +/- 12.42). Newborn's cortisol was not correlated with any of the ultrasound measurements during pregnancy nor with birth weight. Multivariable regression analysis, considering timing of the ultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight at delivery, the timing of cortisol measurement and maternal uterine contraction states, revealed that maternal serum total cortisol was significantly negative correlated with ultrasound parameters describing the fetal brain: late biparietal diameter (R-2 =0.512, p =0.009), late head circumference (R-2 = 0.498, p= 0.001), middle biparietal diameter (R-2= 0.819, p = 0.013), middle cerebellum transverse diameter R-2 = 0.76, p= 0.014) and early biparietal diameter(R-2 = 0.819, p = 0.013). The same analysis revealed that birth weight as well as ultrasound parameters such as abdominal circumference and femur length were not correlated to maternal cortisol levels.
 In conclusion, our study demonstrates that maternal cortisol secretion within physiological ranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to be demonstrated whether maternal cortisol secretion negatively influencing fetal brain growth translates to adverse neurological outcomes in later life.
KW  - Brain development
KW  - Fetal programming
KW  - Cortisol Maternal cortisol
KW  - Head circumference
KW  - Biparietal diameter
Y1  - 2012
U6  - https://doi.org/10.1016/j.neubiorev.2011.12.006
SN  - 0149-7634
VL  - 36
IS  - 3
SP  - 1085
EP  - 1092
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Chen, You-Peng
A1  - Xiao, Xiao-Min
A1  - Li, Jian
A1  - Reichetzeder, Christoph
A1  - Wang, Zi-Neng
A1  - Hocher, Berthold
T1  - Paternal body mass index (BMI) is associated with offspring intrauterine growth in a gender dependent manner
JF  - PLoS one
N2  - Background: Environmental alternations leading to fetal programming of cardiovascular diseases in later life have been attributed to maternal factors. However, animal studies showed that paternal obesity may program cardio-metabolic diseases in the offspring. In the current study we tested the hypothesis that paternal BMI may be associated with fetal growth.
 Methods and Results: We analyzed the relationship between paternal body mass index (BMI) and birth weight, ultrasound parameters describing the newborn's body shape as well as parameters describing the newborns endocrine system such as cortisol, aldosterone, renin activity and fetal glycated serum protein in a birth cohort of 899 father/mother/child triplets. Since fetal programming is an offspring sex specific process, male and female offspring were analyzed separately. Multivariable regression analyses considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal total glycated serum protein, parity and either gestational age (for birth weight) or time of ultrasound investigation (for ultrasound parameters) as confounding showed that paternal BMI is associated with growth of the male but not female offspring. Paternal BMI correlated with birth parameters of male offspring only: birth weight; biparietal diameter, head circumference; abdominal diameter, abdominal circumference; and pectoral diameter. Cortisol was likewise significantly correlated with paternal BMI in male newborns only.
 Conclusions: Paternal BMI affects growth of the male but not female offspring. Paternal BMI may thus represent a risk factor for cardiovascular diseases of male offspring in later life. It remains to be demonstrated whether this is linked to an offspring sex specific paternal programming of cortisol secretion.
Y1  - 2012
U6  - https://doi.org/10.1371/journal.pone.0036329
SN  - 1932-6203
VL  - 7
IS  - 5
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Nair, Anil V.
A1  - Hocher, Berthold
A1  - Verkaart, Sjoerd
A1  - van Zeeland, Femke
A1  - Pfab, Thiemo
A1  - Slowinski, Torsten
A1  - Chen, You-Peng
A1  - Schlingmann, Karl Peter
A1  - Schaller, Andre
A1  - Gallati, Sabina
A1  - Bindels, Rene J.
A1  - Konrad, Martin
A1  - Hönderop, Joost G.
T1  - Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy
JF  - Proceedings of the National Academy of Sciences of the United States of America
N2  - Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 ((VI)-I-1393, (KE)-E-1584) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 ((VI)-I-1393) and TRPM6((KE)-E-1584), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T-1391) and TRPM6(S-1583). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
KW  - kidney
KW  - distal convoluted tubule
KW  - transient receptor potential
KW  - vesicular trafficking
Y1  - 2012
U6  - https://doi.org/10.1073/pnas.1113811109
SN  - 0027-8424
VL  - 109
IS  - 28
SP  - 11324
EP  - 11329
PB  - National Acad. of Sciences
CY  - Washington
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Armbruster, Franz Paul
A1  - Stöva, Stanka
A1  - Reichetzeder, Christoph
A1  - Groen, Hans Jürgen
A1  - Lieker, Ina
A1  - Khadzhynov, Dmytro
A1  - Slowinski, Torsten
A1  - Roth, Heinz Jürgen
T1  - Measuring Parathyroid Hormone (PTH) in patients with oxidative stress - do we need a fourth generation Parathyroid Hormone assay?
JF  - PLoS one
N2  - Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7% of traditionally measured PTH was free of oxidation, whereas in other patients 34% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis.
Y1  - 2012
U6  - https://doi.org/10.1371/journal.pone.0040242
SN  - 1932-6203
VL  - 7
IS  - 7
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Ott, Ina M.
A1  - Alter, Markus L.
A1  - von Websky, Karoline
A1  - Kretschmer, Axel
A1  - Tsuprykov, Oleg
A1  - Sharkovska, Yuliya
A1  - Krause-Relle, Katharina
A1  - Raila, Jens
A1  - Henze, Andrea
A1  - Stasch, Johannes-Peter
A1  - Hocher, Berthold
T1  - Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic
 Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II
 Receptor Blockade
JF  - PLOS ONE
N2  - The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2 +/- 2.3 mmHg vs. 117.1 +/- 2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2 +/- 2.5 mmHg and 105.0 +/- 3.2 mmHg, respectively, vs. 117.1 +/- 2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3 +/- 9.6 mu g/24 h vs. 170.8 +/- 34.2 mu g/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4 +/- 10.6 mu g/24 h), whereas the reduction by single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or riociguat (97.1 +/- 15.7 mu g/24 h) was not statistically significant. The combination treatment led to a significant (p < 0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.
Y1  - 2012
U6  - https://doi.org/10.1371/journal.pone.0042623
SN  - 1932-6203
VL  - 7
IS  - 8
PB  - PUBLIC LIBRARY SCIENCE
CY  - SAN FRANCISCO
ER  - 
TY  - JOUR
A1  - Schmerbach, K.
A1  - Kalk, Philipp.
A1  - Wengenmayer, Christina
A1  - Lucht, K.
A1  - Unger, T.
A1  - Hocher, Berthold
A1  - Thoene-Reineke, C.
T1  - Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce.
 Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies.
 Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options.
 Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.
KW  - Renal failure
KW  - angiotensin receptor blockers
KW  - ACE inhibitors
KW  - telmisartan
KW  - ramipril
Y1  - 2012
U6  - https://doi.org/10.7754/Clin.Lab.2011.110622
SN  - 1433-6510
VL  - 58
IS  - 7-8
SP  - 625
EP  - 633
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Alter, Markus L.
A1  - Kretschmer, Axel
A1  - Von Websky, Karoline
A1  - Tsuprykov, Oleg
A1  - Reichetzeder, Christoph
A1  - Simon, Alexandra
A1  - Stasch, Johannes-Peter
A1  - Hocher, Berthold
T1  - Early urinary and plasma biomarkers for experimental diabetic Nephropathy
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: As the prevalence of diabetes rises, its complications such as diabetic nephropathy affect an increaseing number of patients. Consequently, the need for biomarkers in rodent models which reflect the stage and course of diabetic nephropathy is high. This article focuses on Heart-type fatty acid binding protein (H-FABP), osteopontin (OPN), nephrin, and Neutrophil gelatinase-associated lipocalin (NGAL) in urine, and kidney injury molecule (KIM)-1, clusterin, and tissue inhibitior of metalloproteinases (TIMP) 1 in plasma in uni-nephrectomized rats with streptocotozin-induced type 1 diabetes mellitus, a common animal model to explore renal impairment in the setting of diabetes mellitus.
 Methods: 23 male Wistar rats were uni-nephrectomized and subsequently divided into two study groups. The diabetic group received streptozotocin (STZ) via tail-vein injection, the non-diabetic group received citrate buffer without STZ. Subsequently, blood glucose, body weight, and blood pressure were checked regularly. After 18 weeks, animals were placed in metabolic cages, blood and urine obtained and subsequently organs were harvested after sacrifice.
 Results: Blood glucose levels were highly increased in diabetic animals throughout the experiment, whereas systolic blood pressure did not differ between the study groups. At study end, classical biomarkers such as urinary albumin and protein and plasma cystatin c were only slightly but not significantly different between groups indicating a very early disease state. In contrast, urinary excretion of H-FABP, OPN, nephrin, and NGAL were highly increased in diabetic animals with a highly significant p-value (p<0.01 each) compared to non-diabetic animals. In plasma, differences were found for calbindin, KIM-1, clusterin, TIMP-1, and OPN. These findings were confirmed by means of the area under the receiver operating characteristic curve (ROC-AUC) analysis.
 Conclusions: In summary, our study revealed elevated levels of new plasma and urinary biomarkers (urinary osteopontin, urinary nephrin, urinary NGAL, urinary H-FABP, plasma KIM-1, plasma TIMP-1) in uni-nephrectomized diabetic rats, an established rat model of diabetic nephropathy. These biomarkers appeared even before the classical biomarkers of diabetic nephropathy such as albuminuria and urinary protein excretion. The new biomarkers might offer advantage to urinary albumin and plasma cystatin c with respect to early detection.
KW  - diabetic nephropathy
KW  - urinary biomarker
KW  - blood biomarker
KW  - heart-type fatty acid binding protein
KW  - osteopontin
KW  - nephrin
KW  - neutrophil gelatinase-associated lipocalin
KW  - kidney injury molecule 1
KW  - clusterin
KW  - tissue inhibitior of metalloproteinases 1
Y1  - 2012
U6  - https://doi.org/10.7754/Clin.Lab.2011.111010
SN  - 1433-6510
VL  - 58
IS  - 7-8
SP  - 659
EP  - 671
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Vignon-Zellweger, Nicolas
A1  - Rahnenführer, Jan
A1  - Theuring, Franz
A1  - Hocher, Berthold
T1  - Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: Endothelin-1 (ET-1) is a multifunctional peptide, which is implicated in the renal and cardiac physicology as well as in many pathologies of these systems. ET-1's actions take place after the activation of two receptors: ETA and ETB. The expression of these receptors may be modulated during the pathologic process. The analysis of the distribution and level of expression of the receptors in animal models is therefore crucial.
 Methods: We developed a protocol for non-radioactive in situ hybridization for the mRNA of the two endothelin receptors on paraffin-embedded tissue using digoxigenin-labeled RNA probes.
 Results: In heart and kidney, the staining was reliable and specific. In a mouse model for endothelin/nitric oxide imbalance, cardiac ETB expression was reduced. The distribution of the receptors was in accordance with the actual knowledge. Differences in cell specific expression are discussed.
 Conclusions: We developed a protocol for the in situ hybridization of the endothelin receptors in mice. Given that the endothelin system is implicated in the development of many diseases, we believe that this protocol may be useful for a number of future preclinical studies.
KW  - Endothelin-1
KW  - endothelin receptors
KW  - in situ hybridization
KW  - mouse
Y1  - 2012
U6  - https://doi.org/10.7754/Clin.Lab.2012.120216
SN  - 1433-6510
VL  - 58
IS  - 9-10
SP  - 939
EP  - 949
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  -