RESUMO
Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 µM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.
Assuntos
Hemocromatose , Sobrecarga de Ferro , Osteoporose , Animais , Camundongos , Ferro/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Hemocromatose/genética , Fosfatase Alcalina/metabolismo , Proteína da Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Fígado/metabolismo , Osteoporose/genética , Colágeno/metabolismo , Camundongos KnockoutRESUMO
Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells.
Assuntos
Dano ao DNA , Infecções por Escherichia coli/patologia , Peptídeos/metabolismo , Policetídeos/metabolismo , Bexiga Urinária/patologia , Infecções Urinárias/patologia , Escherichia coli Uropatogênica/isolamento & purificação , Idoso , Animais , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Mutagênicos/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/microbiologia , Infecções Urinárias/genética , Infecções Urinárias/microbiologiaRESUMO
Oral clefts (OCs) are frequently co-occurring with other non-OC congenital anomalies. The types and the prevalence of anomalies co-occurring with OCs vary in the reported studies. The aims of this report were to study the types and the prevalence of the anomalies co-occurring with OCs in a well-defined population. The types and the prevalence of anomalies co-occurring in cases with OCs were ascertained in all terminations of pregnancy, stillbirths, and live births in 387,067 births occurring consecutively during the period 1979-2007 in the area covered by our registry of congenital anomalies which is population based, 789 cases of OCs were registered during the study period with a prevalence of 20.4 per 10,000 births, 39.5% of the cases had associated non-OC anomalies. Associated anomalies were more common in cases with cleft palate (52.4%) than in cases with cleft lip and palate (37.3%) and in cases with cleft lip only (16.8%). Chromosomal abnormalities were present in 94 (11.9%) cases including 27 trisomies 13, 15 trisomies 18, 12 22 q11.2 deletion, and 40 other chromosomal abnormalities. Nonchromosomal recognizable conditions were diagnosed in 38 cases (4.8%) including syndromes, associations, spectrums and sequences. Multiple congenital anomalies (MCAs) were present in 180 cases (22.8%). The most frequent MCA were in the musculoskeletal system (16.7%), the central nervous system (15.0%), the urogenital system (13.7%), the cardiovascular system (8.6%), and the digestive system (6.6%). The high prevalence of associated anomalies justifies a thorough screening for other congenital anomalies in cases with OCs.
Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Cardiopatias Congênitas , Doenças Musculoesqueléticas , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Fenda Labial/complicações , Fenda Labial/epidemiologia , Fenda Labial/genética , Fissura Palatina/complicações , Fissura Palatina/epidemiologia , Fissura Palatina/genética , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Gravidez , Prevalência , TrissomiaRESUMO
The pathogenesis of omphalocele and gastroschisis is not obvious. Their etiology is disputed. The prevalence and the types of anomalies co-occurring with omphalocele and gastroschisis are variable in the different series published. The aim of this study was to estimate the frequency and the types of co-occurring anomalies in cases with gastroschisis and omphalocele. This study was performed in a well-described population of 387,067 consecutive births between 1979 and 2007. Hundred-one cases with omphalocele were registered (2.61 per 10,000), 75 (74.3%) had co-occurring anomalies comprising chromosomal anomalies (28 cases, 27.7%, including 18 trisomy 18), non-chromosomal syndromes (16 cases, 15.8%, including 3 cases with Beckwith-Wiedemann syndrome, 2 cases with the OEIS sequence, and one case with the Pentalogy of Cantrell complex), and 31 cases, 30.7% with MCA (multiple congenital anomalies). The most common MCA were musculoskeletal (23.5%), urogenital (20.4%), cardiovascular (15.1%), and central nervous (9.1%). Seventy-one cases of gastroschisis were ascertained (1.83 per 10,000). However, the prevalence increased during the study period. The frequency was highest in the mothers 15-19 years old. Sixteen out of the 71 cases with gastroschisis, (22.5%) had co-occurring anomalies including 11 cases of MCA and 5 cases with syndromes. To conclude, the frequency and the types of anomalies co-occurring with omphalocele and gastroschisis are peculiar. Therefore, cases with gastroschisis and omphalocele need to be screened for co-occurring anomalies.
Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Gastrosquise/diagnóstico , Hérnia Umbilical/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética , Parede Abdominal/patologia , Adolescente , Adulto , Síndrome de Beckwith-Wiedemann/complicações , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Aberrações Cromossômicas , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Anormalidades Congênitas/patologia , Feminino , Gastrosquise/complicações , Gastrosquise/genética , Gastrosquise/patologia , Hérnia Umbilical/complicações , Hérnia Umbilical/genética , Hérnia Umbilical/patologia , Humanos , Recém-Nascido , Idade Materna , Mães , Síndrome da Trissomía do Cromossomo 18/complicações , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/patologia , Adulto JovemRESUMO
Iron excess increases the hepatic expression of hepcidin, the systemic iron metabolism regulator that favors iron sequestration in the spleen. Genetic iron overload related to hepcidin insufficiency decreases the spleen iron concentration and increases hepatic iron concentration, whereas during secondary iron overload, the hepcidin expression increases together with spleen iron concentration in addition to hepatic iron concentrations increase. Links between iron metabolism and other metals being suggested, our aim was to investigate, during iron overload, the relationships between the hepatic hepcidin expression level and the hepatic and splenic concentrations of iron, manganese, copper, zinc, and molybdenum, determined using inductively coupled plasma mass spectrometry. Hepcidin-deficient mice, secondary iron overload mice models, and their respective controls were studied. Spleen molybdenum and manganese concentrations paralleled the modulation of both spleen iron concentrations, increasing in secondary iron overload and decreasing in hepcidin deficiency related iron overload, as well as hepatic hepcidin mRNA expression. Our data suggest that iron, manganese, and molybdenum metabolisms could share mechanisms controlling their distribution that are associated to hepcidin modulation. In diseases with abnormal hepcidin levels, including chronic inflammation, special attention should be paid to those metals that can participate with the phenotype.-Cavey, T., Latour, C., Island, M.-L., Leroyer, P., Guggenbuhl, P., Coppin, H., Roth, M.-P., Bendavid, C., Brissot, P., Ropert, M., Loréal, O. Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin-deficient and secondary iron overload models in mice.
Assuntos
Hepcidinas/genética , Sobrecarga de Ferro/metabolismo , Ferro/metabolismo , Manganês/metabolismo , Molibdênio/metabolismo , Animais , Hepcidinas/deficiência , Hepcidinas/metabolismo , Sobrecarga de Ferro/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/metabolismoRESUMO
Congenital clubfoot CTEV is a common congenital anomaly, its etiology is unclear and its pathogenesis is controversial. Cases with CTEV often have other non-CTEV associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with CTEV were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 504 cases with CTEV, representing a prevalence of 13.02 per 10,000, 107 (21.2%) had associated anomalies. There were 31 (6.1%) cases with chromosomal abnormalities, and 21 (4.2%) non-chromosomal recognized dysmorphic conditions including syndromes: 6 arthrogryposis multiplex congenita, 2 22q11.2 microdeletion, and one fetal alcohol syndrome. Fifty-five (10.9%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the central nervous, the urinary, the orofacial, and the musculoskeletal systems were the most common other anomalies in the cases with MCA. The anomalies associated with CTEV could be classified into a recognizable malformation syndrome in 52 of the 107 cases (48.6%) with associated anomalies. This study included special strengths: it is population-based, each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, one of five cases, emphasizes the need for a screening for other anomalies in cases with CTEV.
Assuntos
Anormalidades Cardiovasculares/genética , Sistema Nervoso Central/anormalidades , Pé Torto Equinovaro/genética , Anormalidades Congênitas/genética , Anormalidades Cardiovasculares/complicações , Anormalidades Cardiovasculares/epidemiologia , Anormalidades Cardiovasculares/patologia , Sistema Nervoso Central/patologia , Aberrações Cromossômicas , Pé Torto Equinovaro/complicações , Pé Torto Equinovaro/epidemiologia , Pé Torto Equinovaro/patologia , Anormalidades Congênitas/patologia , Feminino , Humanos , Nascido Vivo/epidemiologia , Nascido Vivo/genética , Masculino , Gravidez , Natimorto/epidemiologia , Natimorto/genética , Bexiga Urinária/anormalidades , Bexiga Urinária/patologiaRESUMO
Lack of either bone morphogenetic protein 6 (BMP6) or the BMP coreceptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin insufficiency, hepatic iron loading, and extrahepatic iron accumulation in males. This is consistent with the current views that HJV is a coreceptor for BMP6 in hepatocytes. To determine whether BMP6 and HJV may also signal to hepcidin independently of each other, we intercrossed Hjv-/- and Bmp6-/- mice and compared the phenotype of animals of the F2 progeny. Loss of Bmp6 further repressed Smad signaling and hepcidin expression in the liver of Hjv-/- mice of both sexes, and led to iron accumulation in the pancreas and the heart of females. These data suggest that, in Hjv-/- females, Bmp6 can provide a signal adequate to maintain hepcidin to a level sufficient to avoid extrahepatic iron loading. We also examined the impact of Bmp6 and/or Hjv deletion on the regulation of hepcidin by inflammation. Our data show that lack of 1 or both molecules does not prevent induction of hepcidin by lipopolysaccharide (LPS). However, BMP/Smad signaling in unchallenged animals is determinant for the level of hepcidin reached after stimulation, which is consistent with a synergy between interleukin 6/STAT3 and BMP/SMAD signaling in regulating hepcidin during inflammation.
Assuntos
Proteína Morfogenética Óssea 6/deficiência , Deleção de Genes , Hepcidinas/metabolismo , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/deficiência , Animais , Proteína Morfogenética Óssea 6/metabolismo , Feminino , Proteínas Ligadas por GPI , Proteína da Hemocromatose , Masculino , Proteínas de Membrana/metabolismo , Camundongos Knockout , Fenótipo , Transdução de Sinais/efeitos dos fármacosRESUMO
Agenesis of corpus callosum (ACC) is an uncommon congenital anomaly, its etiology is unclear and its pathogenesis is controversial. Cases with ACC often have other non-ACC associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with ACC were collected in all live births, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 99 cases with ACC, representing a prevalence of 2.56 per 10,000, 73 (73.7%) had associated anomalies. There were 16 (16.2%) cases with chromosomal abnormalities, and 13 (13.2%) nonchromosomal recognized dysmorphic conditions including syndromes two each: Aicardi, Dandy-Walker, and fetal alcoholism. Forty-four (44.4%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the musculoskeletal, the urogenital, the central nervous, the cardiovascular, and the digestive systems were the most common other anomalies in the cases with MCA. The anomalies associated with ACC could be classified into a recognizable malformation syndrome in 29 out of the 73 cases (39.7%) with associated anomalies. This study included special strengths: it is population-based, each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, three of four cases, emphasizes the need for a screening for other anomalies in cases with ACC.
Assuntos
Anormalidades Múltiplas/patologia , Agenesia do Corpo Caloso/complicações , Anormalidades Múltiplas/epidemiologia , Agenesia do Corpo Caloso/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Razão de MasculinidadeRESUMO
Hepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested for matriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic downstream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the BMP-SMAD signaling.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Eritropoetina/farmacologia , Hepcidinas/metabolismo , Fígado/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Hepcidinas/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Serina Endopeptidases/genética , Proteínas Smad/genéticaRESUMO
Anorectal anomalies (ARA) are common congenital anomalies. The etiology of ARA is unclear and its pathogenesis is controversial. Cases with ARA often have other non-ARA-associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with ARA were collected in all live births, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 202 cases with ARA, representing a prevalence of 5.21 per 10,000, 100 (49.5%) had associated anomalies. There were 7 (3.3%) cases with chromosomal abnormalities, and 31 (15.3%) nonchromosomal recognized dysmorphic conditions, including 17 cases with Vertebral defects, Anal atresia, Cardiac septal defects, esophageal atresia or TracheoEsophageal fistula, Renal anomalies and radial Limb defects association. Sixty two (30.7%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the urogenital, the musculoskeletal, the cardiovascular, the digestive, and the central nervous systems were the most common other anomalies in the cases with MCA. The anomalies associated with ARA could be classified into a recognizable malformation syndrome or pattern in 38 out of the 100 cases (38%) with associated anomalies. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion, the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a routine screening for other anomalies in cases with ARA.
Assuntos
Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/etiologia , Malformações Anorretais/epidemiologia , Malformações Anorretais/etiologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/cirurgia , Malformações Anorretais/diagnóstico , Malformações Anorretais/cirurgia , Pré-Escolar , Aberrações Cromossômicas , Feminino , Humanos , Lactente , Recém-Nascido , Nascido Vivo , Masculino , Razão de Chances , Fenótipo , Vigilância da População , Prevalência , Sistema de Registros , NatimortoRESUMO
UNLABELLED: Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and ß2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. CONCLUSION: These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice.
Assuntos
Proteína Morfogenética Óssea 6/genética , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Receptores da Transferrina/genética , Animais , Feminino , Proteínas Ligadas por GPI , Deleção de Genes , Regulação da Expressão Gênica , Proteína da Hemocromatose , Ferro , Camundongos , Camundongos Endogâmicos C57BL , FenótipoRESUMO
Malaria, a major global health challenge worldwide, is accompanied by a severe anemia secondary to hemolysis and increased erythrophagocytosis. Iron is an essential functional component of erythrocyte hemoglobin and its availability is controlled by the liver-derived hormone hepcidin. We examined the regulation of hepcidin during malarial infection in mice using the rodent parasite Plasmodium berghei K173. Mice infected with Plasmodium berghei K173 develop a severe anemia and die after 18 to 22 days without cerebral malaria. During the early phase of blood-stage infection (days 1 to 5), a strong inflammatory signature was associated with an increased production of hepcidin. Between days 7 and 18, while infection progressed, red blood cell count, hemoglobin and hematocrit dramatically decreased. In the late phase of malarial infection, hepcidin production was reduced concomitantly to an increase in the messenger RNA expression of the hepcidin suppressor erythroferrone in the bone marrow and the spleen. Compared with wild-type mice, Erfe-/- mice failed to adequately suppress hepcidin expression after infection with Plasmodium berghei K173. Importantly, the sustained production of hepcidin allowed by erythroferrone ablation was associated with decreased parasitemia, providing further evidence that transient iron restriction could be beneficial in the treatment of malaria.
Assuntos
Anemia/sangue , Anemia/etiologia , Citocinas/metabolismo , Hepcidinas/sangue , Malária/complicações , Proteínas Musculares/metabolismo , Anemia/diagnóstico , Animais , Biomarcadores , Citocinas/genética , Modelos Animais de Doenças , Progressão da Doença , Eritropoese , Regulação da Expressão Gênica , Malária/parasitologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Parasitemia , Plasmodium berghei , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Índice de Gravidade de DoençaRESUMO
Esophageal atresia (EA) is a common type of congenital anomaly. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. Infants with esophageal atresia often have other non-EA associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with EA were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 116 cases with esophageal atresia, representing a prevalence of 2.99 per 10,000, 54 (46.6%) had associated anomalies. There were 9 (7.8%) cases with chromosomal abnormalities including 6 trisomies 18, and 20 (17.2%) nonchromosomal recognized dysmorphic conditions including 12 cases with VACTERL association and 2 cases with CHARGE syndrome. Twenty five (21.6%) of the cases had multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the digestive, the urogenital, the musculoskeletal, and the central nervous systems were the most common other anomalies. The anomalies associated with esophageal atresia could be classified into a recognizable malformation syndrome or pattern in 29 out of 54 cases (53.7%). This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a thorough investigation of cases with EA. A routine screening for other anomalies may be considered in infants and in fetuses with EA.
Assuntos
Transtornos Cromossômicos/fisiopatologia , Anormalidades Congênitas/fisiopatologia , Atresia Esofágica/fisiopatologia , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Canal Anal/anormalidades , Canal Anal/fisiopatologia , Aberrações Cromossômicas , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/genética , Atresia Esofágica/complicações , Atresia Esofágica/epidemiologia , Atresia Esofágica/genética , Esôfago/anormalidades , Esôfago/fisiopatologia , Feminino , Feto/fisiopatologia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Rim/anormalidades , Rim/fisiopatologia , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/epidemiologia , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Gravidez , Coluna Vertebral/anormalidades , Coluna Vertebral/fisiopatologia , Natimorto , Traqueia/anormalidades , Traqueia/fisiopatologiaRESUMO
Activins are members of the transforming growth factor-beta (TGF-ß) superfamily of cytokines. They play critical roles in the onset of acute and chronic inflammatory responses. The aim of this study was to investigate how activin inhibition affects acute kidney injury and inflammation after transplantation. The study was carried out in kidney transplantation and renal ischemia-reperfusion models in the rat. Soluble activin type 2 receptor (sActRIIB-Fc) was used to inhibit activin signaling. Transplantation groups were as follows: (i) cyclosporine A (CsA) (ii) CsA + sActRIIB-Fc, (iii) CsA+ inactive protein control Fc-G1. IRI groups were as follows: (i) no treatment, (ii) sActRIIB-Fc. Serum activin B concentration was significantly elevated after transplantation and IRI, whereas activin A was produced locally in renal allografts. Activin inhibition efficiently limited neutrophil, macrophage, and dendritic cell infiltration to the allografts measured 72 h after transplantation. In addition, sActRIIB-Fc treatment modulated serum cytokine response after transplantation and reduced the early accumulation of fibroblasts in the graft interstitium. In conclusion activin inhibition reduces the innate immune response early after renal transplantation in the rat. It also limits the accumulation of fibroblasts in the graft suggesting that activins may be involved in the fibrogenic signaling already early after kidney transplantation.
Assuntos
Ativinas/antagonistas & inibidores , Aloenxertos/imunologia , Imunidade Inata , Transplante de Rim , Rim/imunologia , Ativinas/metabolismo , Animais , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Fibroblastos/metabolismo , Humanos , Inflamação , Masculino , Projetos Piloto , Ratos , Ratos Wistar , Insuficiência Renal/cirurgia , Traumatismo por Reperfusão , Transdução de Sinais , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Transplante HomólogoAssuntos
Estresse do Retículo Endoplasmático , Hepcidinas , Estresse do Retículo Endoplasmático/genética , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Ferro/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação a RNA , Serina Endopeptidases/genéticaRESUMO
BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is the most common form of genetic iron loading disease. It is mainly related to the homozygous C282Y/C282Y mutation in the HFE gene that is, however, a necessary but not a sufficient condition to develop clinical and even biochemical HH. This suggests that modifier genes are likely involved in the expressivity of the disease. Our aim was to identify such modifier genes. METHODS: We performed a genome-wide association study (GWAS) using DNA collected from 474 unrelated C282Y homozygotes. Associations were examined for both quantitative iron burden indices and clinical outcomes with 534,213 single nucleotide polymorphisms (SNP) genotypes, with replication analyses in an independent sample of 748 C282Y homozygotes from four different European centres. RESULTS: One SNP met genome-wide statistical significance for association with transferrin concentration (rs3811647, GWAS p value of 7×10(-9) and replication p value of 5×10(-13)). This SNP, located within intron 11 of the TF gene, had a pleiotropic effect on serum iron (GWAS p value of 4.9×10(-6) and replication p value of 3.2×10(-6)). Both serum transferrin and iron levels were associated with serum ferritin levels, amount of iron removed and global clinical stage (p<0.01). Serum iron levels were also associated with fibrosis stage (p<0.0001). CONCLUSIONS: This GWAS, the largest one performed so far in unselected HFE-associated HH (HFE-HH) patients, identified the rs3811647 polymorphism in the TF gene as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels. Because these two outcomes were clearly associated with the biochemical and clinical expression of the disease, an indirect link between the rs3811647 polymorphism and the phenotypic presentation of HFE-HH is likely.
Assuntos
Genes Modificadores , Hemocromatose/genética , Hemocromatose/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Ferro/metabolismo , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Transferrina/genética , Adulto , Substituição de Aminoácidos , Feminino , França , Estudo de Associação Genômica Ampla , Proteína da Hemocromatose , Homozigoto , Humanos , Ferro/sangue , Itália , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Transferrina/metabolismoRESUMO
UNLABELLED: Gender-related disparities in the regulation of iron metabolism may contribute to the differences exhibited by men and women in the progression of chronic liver diseases associated with reduced hepcidin expression, e.g., chronic hepatitis C, alcoholic liver disease, or hereditary hemochromatosis. However, their mechanisms remain poorly understood. In this study we took advantage of the major differences in hepcidin expression and tissue iron loading observed between Bmp6-deficient male and female mice to investigate the mechanisms underlying this sexual dimorphism. We found that testosterone robustly represses hepcidin transcription by enhancing Egfr signaling in the liver and that selective epidermal growth factor receptor (Egfr) inhibition by gefitinib (Iressa) in males markedly increases hepcidin expression. In males, where the suppressive effects of testosterone and Bmp6-deficiency on hepcidin expression are combined, hepcidin is more strongly repressed than in females and iron accumulates massively not only in the liver but also in the pancreas, heart, and kidneys. CONCLUSION: Testosterone-induced repression of hepcidin expression becomes functionally important during homeostatic stress from disorders that result in iron loading and/or reduced capacity for hepcidin synthesis. These findings suggest that novel therapeutic strategies targeting the testosterone/EGF/EGFR axis may be useful for inducing hepcidin expression in patients with iron overload and/or chronic liver diseases.
Assuntos
Receptores ErbB/metabolismo , Hepcidinas/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Fatores Sexuais , Transdução de Sinais/fisiologia , Testosterona/metabolismo , Animais , Proteína Morfogenética Óssea 6/deficiência , Proteína Morfogenética Óssea 6/genética , Proteína Morfogenética Óssea 6/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Feminino , Homeostase/fisiologia , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Miocárdio/metabolismo , Pâncreas/metabolismo , Proteínas Smad/metabolismoRESUMO
Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BN(m) for "BN mutated." In BN(m) rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4(+) CD25(bright) regulatory T cells (Treg) is defective in BN(m) rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BN(m) rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BN(m) rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BN(m)×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment.