The Journal of Clinical Endocrinology and Metabolism, May 1, 2012
Context: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported ... more Context: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. Patient: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [Ϫ5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, Ϫ3.7 SDS, and IGF-binding protein-3, Ϫ4.5 SDS) were consistent with GHI and IGFD. Results: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the DЈ strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-␥. The phosphorylated p.Phe646Ser, however, could not drive transcription. Conclusion: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 DЈ strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.
Aims/hypothesis Microvascular complications are a common feature of diabetes but additional resea... more Aims/hypothesis Microvascular complications are a common feature of diabetes but additional research is needed regarding diabetic nephropathy endpoints in type 1 and type 2 diabetes. Methods We compared 277 type 1 diabetes patients with 942 type 2 diabetes patients, with clinical proteinuria and no endstage renal disease (ESRD) at baseline, prospectively followed for death, ESRD and decline in estimated glomerular filtration rate (eGFR, all available measures). Results The incidence rate of death was 67.0 (95% CI 59.2, 74.8) vs 24.6 (95% CI, 19.0, 30.2) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for death was greater for type 2 diabetes patients (HR 3.423; 95% CI, 2.501, 4.683; p<0.0001), but the difference The complete list of participating centres is available as electronic supplementary material (ESM).
Archives Des Maladies Professionnelles Et De L Environnement, Oct 1, 2020
Objectif Examiner les effets d’une exposition professionnelle au DiisoNonyl Phtalate (DINP) sur l... more Objectif Examiner les effets d’une exposition professionnelle au DiisoNonyl Phtalate (DINP) sur les niveaux de testosterone seriques chez des salaries de sexe masculin. Methode De 2015 a 2018, 97 salaries ont ete recrutes dans 6 usines francaises de l’industrie des plastiques. Dans une etude courte longitudinale, les changements sur 3 jours dans les niveaux seriques de testosterone total ou libre et les expositions au DINP ont ete mesures. L’exposition au DINP etait evaluee par la mesure de 3 metabolites urinaires oxydes : OXO-MINP, OH-MINP, CX-MINP. Il a ete egalement analyse les changements seriques de FSH, de LH, du ratio TT/E2 et de deux biomarqueurs du remodelage osseux (P1NP, CTX) et mesure la survenue de problemes erectiles via des questionnaires standardises (IIEF-5, ADAM). Des modeles lineaires mixtes ont ete utilises pour estimer des coefficients de regression entre les variables hormonales et l’exposition au DINP, ajustes sur l’âge et le perimetre abdominal. Resultats L’augmentation de l’OXO-MINP urinaire etait associee a une diminution significative des concentrations seriques totales de testosterone, mais uniquement chez les salaries presentant les variations et les expositions les plus faibles (p = 0,002). La meme tendance etait observee pour le CX-MINP sans atteindre la significativite ; aucune association avec le OH-MINP. Ces resultats etaient robustes aux analyses de sensibilite. Davantage de problemes erectiles auto-declarees etaient observes parmi les plus expose (p = 0,01) ; aucune modification etait observee pour les autres parametres biologiques. Conclusion L’exposition a court terme au DINP est associee a une diminution des taux serique de testosterone totale chez des salaries de sexe masculin. Ces resultats confirment que le DINP pourrait presenter des proprietes anti-androgenes chez l’homme. La question d’un classement europeen comme toxique pour la reproduction peut etre posee.
To the Editor: Maturity-onset diabetes of the young (MODY; MIM# 606391) is a genetically and clin... more To the Editor: Maturity-onset diabetes of the young (MODY; MIM# 606391) is a genetically and clinically heterogeneous form of diabetes mellitus, characterized by an autosomal dominant inheritance, early-onset non-insulin-dependent diabetes mellitus and by a primary defect in the pancreatic beta-cell function (1). Until now, six types of MODY diabetes have been identified, depending on the gene causing the disease (2). Screening for glucokinase (GCK) mutations in subjects with clinical characteristics of MODY allows distinguishing between patients with a benign metabolic condition (GCK mutation positive, clinical diagnosis MODY2) and those with a higher risk of progressive hyperglycemia associated with more prevalent and severe diabetic complications (GCK mutation negative). The first mutation in the GCK gene was reported in 1992 (3). Up to now, 195 mutations in GCK have been described, in 285 families (4). Diabetic complications are rare in GCK–MODY, thus GCK–MODY patients only need to be followed by annual HbA1c examination. Also, screening of GCK for heterozygous inactivating mutations allows to determine the subtype of MODY diabetes and to predict the lifelong prognosis. All 12 exons (exons 1a, 1b, 1c and 2–10), the intron–exon boundaries and promotor region of GCK (GenBank accession number, AF04101222) were screened; in 92 Czech probands fulfilling classical MODY criteria, using denaturing highperformance liquid chromatography as previously described (5). The nature of identified mutations was established by direct nucleotide sequencing using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, USA) according to manufacture’s instructions. Mutations were confirmed using a second, independent amplification of the affected part of GCK and re-sequenced the following day. The probands were recruited from pediatricians and endocrinologists from the entire Czech Republic. Fifteen different missense mutations were identified in 27 patients. Of these, six were novel missense mutations R250C (exon 7, c.748C.T), L315H (exon 8, c.944T.A), F316V (exon 8, c.946T.G), F419L (exon 10, c.1255T.C), I436N (exon 10, c.1307T.A) and A454E (exon 10, c.1361C.A). Some of the identified GCK missense mutations are located near putative functional domains: R250C was found in the close vicinity of a putative glucose binding site, while F419L was detected near a putative MgATP binding site and could thus affect binding kinetics (6). Five of these mutations co-segregated with hyperglycemia in the family, suggesting that the variants are new diseasecausing mutations. For the novel R250C variant, family members were not available for cosegregation studies. All codons, which are changed by the six novel mutations, are conserved in the human, mouse, rat and chimpanzee genomes and we found none of these mutations in 50 unrelated healthy Czech Caucasian subjects. Therefore, we assume that the mutations are probably novel disease-causing mutations. We also compared the clinical characteristics of patients with GCK mutations and those without mutation in GCK (data not shown in details). In short – the treatment of hyperglycemia with diet was more frequent (p , 0.001) in the group of probands with mutations in GCK and they had a significantly lower frequency of diabetic complications (p 1⁄4 0.02). None of the patients with mutations in GCK was treated with insulin (p , 0.001). Moreover, GCK mutation carriers had a lower level of glycosylated hemoglobin (p1⁄4 0.02). ThemeanHbA1c (%) inGCK-positive probands vs negative was 5.7 0.2 vs 6.5 0.2. In conclusion, we identified 29% of GCK mutation carriers among Czech MODY probands, confirming that mutations in GCK are a common cause of MODY in the Czech population. The present high relative prevalence of GCK–MODY, compared with some other European studies, might reflect not only a specific genetic background, but also the mode of recruitment, because most of the probands in the present investigation were recruited by
Pflügers Archiv: European Journal of Physiology, Sep 3, 2013
Barker's concept of 'foetal programming' proposes that intrauterine growth restriction (IUGR) pre... more Barker's concept of 'foetal programming' proposes that intrauterine growth restriction (IUGR) predicts complex metabolic diseases through relationships that may be further modified by the postnatal environment. Dietary restriction and deficit in methyl donors, folate, vitamin B 12 , and choline are used as experimental conditions of foetal programming as they lead to IUGR and decreased birth weight. Overfeeding and deficit in methyl donors increase central fat mass and lead to a dramatic increase of plasma free fatty acids (FFA) in offspring. Conversely, supplementing the mothers under protein restriction with folic acid reverses metabolic and epigenomic phenotypes of offspring. High-fat diet or methyl donor deficiency (MDD) during pregnancy and lactation produce liver steatosis and myocardium hypertrophy that result from increased import of FFA and impaired fatty acid β-oxidation, respectively. The underlying molecular mechanisms show dysregulations related with similar decreased expression and activity of sirtuin 1 (SIRT1) and hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). High-fat diet and overfeeding impair AMPK-dependent phosphorylation of PGC-1α, while MDD decreases PGC-1α methylation through decreased expression of PRMT1 and cellular level of S-adenosyl methionine. The visceral manifestations of metabolic syndrome are under the influence of endoplasmic reticulum (ER) stress in overnourished animal models. These mechanisms should also deserve attention in the foetal programming effects of MDD since vitamin B 12 influences ER stress through impaired SIRT1 deacetylation of HSF1. Taken together, similarities and synergies of high-fat diet and MDD suggest, therefore, considering their consecutive or contemporary influence in the mechanisms of complex metabolic diseases.
Background Standardized participants (SPs) methodology is widely used in the context of the Objec... more Background Standardized participants (SPs) methodology is widely used in the context of the Objective Structured Examination (OSCE). Training of SPs fornational licensure OSCE has to ensure the standardization and the reliability of SPs. The aims of the present study were to describe a single center experience in the process of the development of the SPs' training framework for high-stakes OSCEs with the SPs as partners. Methods : An exploratory single center observational study conducted between 2019 and 2021 describing a work ow during the development of the training framework of the SPs for high-stakes OSCEs and evaluating its perceived effectiveness during a formative OSCE. Data were obtained through selfassessment questionnaires. Descriptive statistics were used to analyze items of the questionnaires. Freetext answers were analyzed thematically. Results In total, 17 out of 20 members (85%) of our SPs bank participated in the development of the training framework comporting three two-hour sessions and its evaluation during three formative OSCE session. Sixteen examiners evaluated a mean of 27.7 +/-3.6 SD patient-student encounters. In total, 93.5% of the SPs out of 16, considered the contact with students as easy and 87.5%, as comfortable. Four SPs (31%) reported the experience as stressful due to fears of making mistakes. Two themes emerged from the freetext comments of the SPs trainees: " SPs gaining experience as SP" and " Concerns for the evaluated students." Free-text comments of the examiners revealed their interest to debrief the OSCE case in collaboration with the student and SP trainees. Conclusions The here proposed approach is feasible and might be useful for other medical schools initiating SPbased assessment programs. We plan to study the impact of the training framework on the students' outcomes in summative OSCEs. Future research could explore the utility of self-e cacy as an assessment tool of the readiness of SPs. It would also be interesting to follow individual learning trajectories of the SPs.
Monoclonal gammopathies (MG) are classically associated with lytic bone lesions, hypercalcemia, a... more Monoclonal gammopathies (MG) are classically associated with lytic bone lesions, hypercalcemia, anemia, and renal insufficiency. However, in some cases, symptoms of endocrine dysfunction are more prominent than these classical signs and misdiagnosis can thus be possible. This concerns especially the situation where the presence of M-protein is limited and the serum protein electrophoresis (sPEP) appears normal. To understand the origin of the endocrine symptoms associated with MG, we overview here the current knowledge on the complexity of interactions between cytokines and the endocrine system in MG and discuss the perspectives for both the diagnosis and treatments for this class of diseases. We also illustrate the role of major cytokines and growth factors such as IL-6, IL-1β, TNF-α, and VEGF in the endocrine system, as these tumor-relevant signaling molecules not only help the clonal expansion and invasion of the tumor cells but also influence cellular metabolism through autocrine, paracrine, and endocrine mechanisms. We further discuss the broader impact of these tumor environment-derived molecules and proinflammatory state on systemic hormone signaling. The diagnostic challenges and clinical work-up are illustrated from the point of view of an endocrinologist.
Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a... more Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a major public health problem. Deficiency in methyl donors (folate and vitamin B12) during gestation and lactation is frequent in humans and produces foetal programming effects of metabolic syndrome, with small birth weight and liver steatosis at day 21 (d21), in rat pups. We investigated the effects of fetal programming on liver of rats born from deficient mothers (iMDD) and subsequently subjected to normal diet after d21 and high fat diet (HF) after d50. We observed increased abdominal fat, ASAT/ALAT ratio and angiotensin blood level, but no histological liver abnormality in d50 iMDD rats. In contrast, d185 iMDD/HF animals had hallmarks of steato-hepatitis, with increased markers of inflammation and fibrosis (caspase1, cleaved IL-1β, α1(I) and α2(I) collagens and α-SMA), insulin resistance (HOMA-IR and Glut 2) and expression of genes involved in stellate cell stimulation and remodelling and key genes triggering NASH pathomechanisms (transforming growth factor beta super family, angiotensin and angiotensin receptor type 1). Our data showed a foetal programming effect of MDD on liver inflammation and fibrosis, which suggests investigating whether MDD during pregnancy is a risk factor of NASH in populations subsequently exposed to HF diet. Non-alcoholic fatty liver disease (NAFLD) is a major consequence of central obesity and metabolic syndrome, with a spectrum that ranges from simple steatosis to steatohepatitis (NASH). The metabolic syndrome is a cluster of components, which includes abdominal obesity, high triglycerides and insulin resistance. NASH is considered as a visceral manifestation of metabolic syndrome, which emerges as one of the major public health problem, in the context of the epidemic of severe obesity in Western countries 1. It results from complex mechanisms, which trigger steatosis, inflammation, cellular stress and remodelling of liver tissue 2. The concept of developmental origins of health and disease (DOHaD) considers that the foetal programming during pregnancy and early post-natal life has a long-term impact on the risk of central obesity and other components of metabolic syndrome. This concept is now evidenced by many experimental and epidemiological studies 2. However, little is known on the influence of nutritional conditions during pregnancy and the subsequent post-natal risk of NAFLD and more specifically of NASH. Over the past decade, epidemiological and experimental studies have clearly demonstrated an association between nutritional metabolites of the one carbon metabolism (1-CM) and manifestations of foetal programming 3. Cellular methionine originates from the remethylation pathway of homocysteine by methionine synthase, which uses vitamin B12 (methyl-cobalamin) as a cofactor. The deficit in methyl donors, in particular folate and vitamin B12 leads to decreased synthesis of S-adenosylmethionine (SAM), the methyl donor involved in methylation of DNA and proteins, which regulate gene expression, including histones, nuclear receptors and their co-regulators 3 .
Chronic kidney disease (CKD) represents an important public health problem. Its progression to en... more Chronic kidney disease (CKD) represents an important public health problem. Its progression to endstage renal disease is associated with increased morbidity and mortality. The determinants of renal function decline are not fully understood. Recent progress in the understanding of post-transcriptional regulation of mRNA stability has helped the identification of both the transand cis-acting elements of mRNA as potential markers and therapeutic targets for difficult-to-diagnose and-treat diseases, including CKDs such as diabetic nephropathy. Human antigen R (HuR), a transacting element of mRNA, is an RNA binding factor (RBF) best known for its ability to stabilize AU-rich-element-containing mRNAs. Deregulated HuR subcellular localization or expression occurs in a wide range of renal diseases, such as metabolic acidosis, ischemia, and fibrosis. Besides RBFs, recent evidence revealed that noncoding RNA, such as microRNA and long noncoding RNA, participates in regulating mRNA stability and that aberrant noncoding RNA expression accounts for many pathologic renal conditions. The goal of this review is to provide an overview of our current understanding of the posttranscriptional regulation of mRNA stability in renal pathophysiology and to offer perspectives for this class of diseases. We use examples of diverse renal diseases to illustrate different mRNA stability pathways in specific cellular compartments and discuss the roles and impacts of both the cisand trans-activating factors on the regulation of mRNA stability in these diseases.-Feigerlová, E., Battaglia-Hsu, S.-F. Role of post-transcriptional regulation of mRNA stability in renal pathophysiology: focus on chronic kidney disease.
The Journal of Clinical Endocrinology and Metabolism, May 1, 2012
Context: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported ... more Context: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. Patient: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [Ϫ5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, Ϫ3.7 SDS, and IGF-binding protein-3, Ϫ4.5 SDS) were consistent with GHI and IGFD. Results: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the DЈ strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-␥. The phosphorylated p.Phe646Ser, however, could not drive transcription. Conclusion: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 DЈ strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.
Aims/hypothesis Microvascular complications are a common feature of diabetes but additional resea... more Aims/hypothesis Microvascular complications are a common feature of diabetes but additional research is needed regarding diabetic nephropathy endpoints in type 1 and type 2 diabetes. Methods We compared 277 type 1 diabetes patients with 942 type 2 diabetes patients, with clinical proteinuria and no endstage renal disease (ESRD) at baseline, prospectively followed for death, ESRD and decline in estimated glomerular filtration rate (eGFR, all available measures). Results The incidence rate of death was 67.0 (95% CI 59.2, 74.8) vs 24.6 (95% CI, 19.0, 30.2) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for death was greater for type 2 diabetes patients (HR 3.423; 95% CI, 2.501, 4.683; p<0.0001), but the difference The complete list of participating centres is available as electronic supplementary material (ESM).
Archives Des Maladies Professionnelles Et De L Environnement, Oct 1, 2020
Objectif Examiner les effets d’une exposition professionnelle au DiisoNonyl Phtalate (DINP) sur l... more Objectif Examiner les effets d’une exposition professionnelle au DiisoNonyl Phtalate (DINP) sur les niveaux de testosterone seriques chez des salaries de sexe masculin. Methode De 2015 a 2018, 97 salaries ont ete recrutes dans 6 usines francaises de l’industrie des plastiques. Dans une etude courte longitudinale, les changements sur 3 jours dans les niveaux seriques de testosterone total ou libre et les expositions au DINP ont ete mesures. L’exposition au DINP etait evaluee par la mesure de 3 metabolites urinaires oxydes : OXO-MINP, OH-MINP, CX-MINP. Il a ete egalement analyse les changements seriques de FSH, de LH, du ratio TT/E2 et de deux biomarqueurs du remodelage osseux (P1NP, CTX) et mesure la survenue de problemes erectiles via des questionnaires standardises (IIEF-5, ADAM). Des modeles lineaires mixtes ont ete utilises pour estimer des coefficients de regression entre les variables hormonales et l’exposition au DINP, ajustes sur l’âge et le perimetre abdominal. Resultats L’augmentation de l’OXO-MINP urinaire etait associee a une diminution significative des concentrations seriques totales de testosterone, mais uniquement chez les salaries presentant les variations et les expositions les plus faibles (p = 0,002). La meme tendance etait observee pour le CX-MINP sans atteindre la significativite ; aucune association avec le OH-MINP. Ces resultats etaient robustes aux analyses de sensibilite. Davantage de problemes erectiles auto-declarees etaient observes parmi les plus expose (p = 0,01) ; aucune modification etait observee pour les autres parametres biologiques. Conclusion L’exposition a court terme au DINP est associee a une diminution des taux serique de testosterone totale chez des salaries de sexe masculin. Ces resultats confirment que le DINP pourrait presenter des proprietes anti-androgenes chez l’homme. La question d’un classement europeen comme toxique pour la reproduction peut etre posee.
To the Editor: Maturity-onset diabetes of the young (MODY; MIM# 606391) is a genetically and clin... more To the Editor: Maturity-onset diabetes of the young (MODY; MIM# 606391) is a genetically and clinically heterogeneous form of diabetes mellitus, characterized by an autosomal dominant inheritance, early-onset non-insulin-dependent diabetes mellitus and by a primary defect in the pancreatic beta-cell function (1). Until now, six types of MODY diabetes have been identified, depending on the gene causing the disease (2). Screening for glucokinase (GCK) mutations in subjects with clinical characteristics of MODY allows distinguishing between patients with a benign metabolic condition (GCK mutation positive, clinical diagnosis MODY2) and those with a higher risk of progressive hyperglycemia associated with more prevalent and severe diabetic complications (GCK mutation negative). The first mutation in the GCK gene was reported in 1992 (3). Up to now, 195 mutations in GCK have been described, in 285 families (4). Diabetic complications are rare in GCK–MODY, thus GCK–MODY patients only need to be followed by annual HbA1c examination. Also, screening of GCK for heterozygous inactivating mutations allows to determine the subtype of MODY diabetes and to predict the lifelong prognosis. All 12 exons (exons 1a, 1b, 1c and 2–10), the intron–exon boundaries and promotor region of GCK (GenBank accession number, AF04101222) were screened; in 92 Czech probands fulfilling classical MODY criteria, using denaturing highperformance liquid chromatography as previously described (5). The nature of identified mutations was established by direct nucleotide sequencing using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, USA) according to manufacture’s instructions. Mutations were confirmed using a second, independent amplification of the affected part of GCK and re-sequenced the following day. The probands were recruited from pediatricians and endocrinologists from the entire Czech Republic. Fifteen different missense mutations were identified in 27 patients. Of these, six were novel missense mutations R250C (exon 7, c.748C.T), L315H (exon 8, c.944T.A), F316V (exon 8, c.946T.G), F419L (exon 10, c.1255T.C), I436N (exon 10, c.1307T.A) and A454E (exon 10, c.1361C.A). Some of the identified GCK missense mutations are located near putative functional domains: R250C was found in the close vicinity of a putative glucose binding site, while F419L was detected near a putative MgATP binding site and could thus affect binding kinetics (6). Five of these mutations co-segregated with hyperglycemia in the family, suggesting that the variants are new diseasecausing mutations. For the novel R250C variant, family members were not available for cosegregation studies. All codons, which are changed by the six novel mutations, are conserved in the human, mouse, rat and chimpanzee genomes and we found none of these mutations in 50 unrelated healthy Czech Caucasian subjects. Therefore, we assume that the mutations are probably novel disease-causing mutations. We also compared the clinical characteristics of patients with GCK mutations and those without mutation in GCK (data not shown in details). In short – the treatment of hyperglycemia with diet was more frequent (p , 0.001) in the group of probands with mutations in GCK and they had a significantly lower frequency of diabetic complications (p 1⁄4 0.02). None of the patients with mutations in GCK was treated with insulin (p , 0.001). Moreover, GCK mutation carriers had a lower level of glycosylated hemoglobin (p1⁄4 0.02). ThemeanHbA1c (%) inGCK-positive probands vs negative was 5.7 0.2 vs 6.5 0.2. In conclusion, we identified 29% of GCK mutation carriers among Czech MODY probands, confirming that mutations in GCK are a common cause of MODY in the Czech population. The present high relative prevalence of GCK–MODY, compared with some other European studies, might reflect not only a specific genetic background, but also the mode of recruitment, because most of the probands in the present investigation were recruited by
Pflügers Archiv: European Journal of Physiology, Sep 3, 2013
Barker's concept of 'foetal programming' proposes that intrauterine growth restriction (IUGR) pre... more Barker's concept of 'foetal programming' proposes that intrauterine growth restriction (IUGR) predicts complex metabolic diseases through relationships that may be further modified by the postnatal environment. Dietary restriction and deficit in methyl donors, folate, vitamin B 12 , and choline are used as experimental conditions of foetal programming as they lead to IUGR and decreased birth weight. Overfeeding and deficit in methyl donors increase central fat mass and lead to a dramatic increase of plasma free fatty acids (FFA) in offspring. Conversely, supplementing the mothers under protein restriction with folic acid reverses metabolic and epigenomic phenotypes of offspring. High-fat diet or methyl donor deficiency (MDD) during pregnancy and lactation produce liver steatosis and myocardium hypertrophy that result from increased import of FFA and impaired fatty acid β-oxidation, respectively. The underlying molecular mechanisms show dysregulations related with similar decreased expression and activity of sirtuin 1 (SIRT1) and hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). High-fat diet and overfeeding impair AMPK-dependent phosphorylation of PGC-1α, while MDD decreases PGC-1α methylation through decreased expression of PRMT1 and cellular level of S-adenosyl methionine. The visceral manifestations of metabolic syndrome are under the influence of endoplasmic reticulum (ER) stress in overnourished animal models. These mechanisms should also deserve attention in the foetal programming effects of MDD since vitamin B 12 influences ER stress through impaired SIRT1 deacetylation of HSF1. Taken together, similarities and synergies of high-fat diet and MDD suggest, therefore, considering their consecutive or contemporary influence in the mechanisms of complex metabolic diseases.
Background Standardized participants (SPs) methodology is widely used in the context of the Objec... more Background Standardized participants (SPs) methodology is widely used in the context of the Objective Structured Examination (OSCE). Training of SPs fornational licensure OSCE has to ensure the standardization and the reliability of SPs. The aims of the present study were to describe a single center experience in the process of the development of the SPs' training framework for high-stakes OSCEs with the SPs as partners. Methods : An exploratory single center observational study conducted between 2019 and 2021 describing a work ow during the development of the training framework of the SPs for high-stakes OSCEs and evaluating its perceived effectiveness during a formative OSCE. Data were obtained through selfassessment questionnaires. Descriptive statistics were used to analyze items of the questionnaires. Freetext answers were analyzed thematically. Results In total, 17 out of 20 members (85%) of our SPs bank participated in the development of the training framework comporting three two-hour sessions and its evaluation during three formative OSCE session. Sixteen examiners evaluated a mean of 27.7 +/-3.6 SD patient-student encounters. In total, 93.5% of the SPs out of 16, considered the contact with students as easy and 87.5%, as comfortable. Four SPs (31%) reported the experience as stressful due to fears of making mistakes. Two themes emerged from the freetext comments of the SPs trainees: " SPs gaining experience as SP" and " Concerns for the evaluated students." Free-text comments of the examiners revealed their interest to debrief the OSCE case in collaboration with the student and SP trainees. Conclusions The here proposed approach is feasible and might be useful for other medical schools initiating SPbased assessment programs. We plan to study the impact of the training framework on the students' outcomes in summative OSCEs. Future research could explore the utility of self-e cacy as an assessment tool of the readiness of SPs. It would also be interesting to follow individual learning trajectories of the SPs.
Monoclonal gammopathies (MG) are classically associated with lytic bone lesions, hypercalcemia, a... more Monoclonal gammopathies (MG) are classically associated with lytic bone lesions, hypercalcemia, anemia, and renal insufficiency. However, in some cases, symptoms of endocrine dysfunction are more prominent than these classical signs and misdiagnosis can thus be possible. This concerns especially the situation where the presence of M-protein is limited and the serum protein electrophoresis (sPEP) appears normal. To understand the origin of the endocrine symptoms associated with MG, we overview here the current knowledge on the complexity of interactions between cytokines and the endocrine system in MG and discuss the perspectives for both the diagnosis and treatments for this class of diseases. We also illustrate the role of major cytokines and growth factors such as IL-6, IL-1β, TNF-α, and VEGF in the endocrine system, as these tumor-relevant signaling molecules not only help the clonal expansion and invasion of the tumor cells but also influence cellular metabolism through autocrine, paracrine, and endocrine mechanisms. We further discuss the broader impact of these tumor environment-derived molecules and proinflammatory state on systemic hormone signaling. The diagnostic challenges and clinical work-up are illustrated from the point of view of an endocrinologist.
Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a... more Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a major public health problem. Deficiency in methyl donors (folate and vitamin B12) during gestation and lactation is frequent in humans and produces foetal programming effects of metabolic syndrome, with small birth weight and liver steatosis at day 21 (d21), in rat pups. We investigated the effects of fetal programming on liver of rats born from deficient mothers (iMDD) and subsequently subjected to normal diet after d21 and high fat diet (HF) after d50. We observed increased abdominal fat, ASAT/ALAT ratio and angiotensin blood level, but no histological liver abnormality in d50 iMDD rats. In contrast, d185 iMDD/HF animals had hallmarks of steato-hepatitis, with increased markers of inflammation and fibrosis (caspase1, cleaved IL-1β, α1(I) and α2(I) collagens and α-SMA), insulin resistance (HOMA-IR and Glut 2) and expression of genes involved in stellate cell stimulation and remodelling and key genes triggering NASH pathomechanisms (transforming growth factor beta super family, angiotensin and angiotensin receptor type 1). Our data showed a foetal programming effect of MDD on liver inflammation and fibrosis, which suggests investigating whether MDD during pregnancy is a risk factor of NASH in populations subsequently exposed to HF diet. Non-alcoholic fatty liver disease (NAFLD) is a major consequence of central obesity and metabolic syndrome, with a spectrum that ranges from simple steatosis to steatohepatitis (NASH). The metabolic syndrome is a cluster of components, which includes abdominal obesity, high triglycerides and insulin resistance. NASH is considered as a visceral manifestation of metabolic syndrome, which emerges as one of the major public health problem, in the context of the epidemic of severe obesity in Western countries 1. It results from complex mechanisms, which trigger steatosis, inflammation, cellular stress and remodelling of liver tissue 2. The concept of developmental origins of health and disease (DOHaD) considers that the foetal programming during pregnancy and early post-natal life has a long-term impact on the risk of central obesity and other components of metabolic syndrome. This concept is now evidenced by many experimental and epidemiological studies 2. However, little is known on the influence of nutritional conditions during pregnancy and the subsequent post-natal risk of NAFLD and more specifically of NASH. Over the past decade, epidemiological and experimental studies have clearly demonstrated an association between nutritional metabolites of the one carbon metabolism (1-CM) and manifestations of foetal programming 3. Cellular methionine originates from the remethylation pathway of homocysteine by methionine synthase, which uses vitamin B12 (methyl-cobalamin) as a cofactor. The deficit in methyl donors, in particular folate and vitamin B12 leads to decreased synthesis of S-adenosylmethionine (SAM), the methyl donor involved in methylation of DNA and proteins, which regulate gene expression, including histones, nuclear receptors and their co-regulators 3 .
Chronic kidney disease (CKD) represents an important public health problem. Its progression to en... more Chronic kidney disease (CKD) represents an important public health problem. Its progression to endstage renal disease is associated with increased morbidity and mortality. The determinants of renal function decline are not fully understood. Recent progress in the understanding of post-transcriptional regulation of mRNA stability has helped the identification of both the transand cis-acting elements of mRNA as potential markers and therapeutic targets for difficult-to-diagnose and-treat diseases, including CKDs such as diabetic nephropathy. Human antigen R (HuR), a transacting element of mRNA, is an RNA binding factor (RBF) best known for its ability to stabilize AU-rich-element-containing mRNAs. Deregulated HuR subcellular localization or expression occurs in a wide range of renal diseases, such as metabolic acidosis, ischemia, and fibrosis. Besides RBFs, recent evidence revealed that noncoding RNA, such as microRNA and long noncoding RNA, participates in regulating mRNA stability and that aberrant noncoding RNA expression accounts for many pathologic renal conditions. The goal of this review is to provide an overview of our current understanding of the posttranscriptional regulation of mRNA stability in renal pathophysiology and to offer perspectives for this class of diseases. We use examples of diverse renal diseases to illustrate different mRNA stability pathways in specific cellular compartments and discuss the roles and impacts of both the cisand trans-activating factors on the regulation of mRNA stability in these diseases.-Feigerlová, E., Battaglia-Hsu, S.-F. Role of post-transcriptional regulation of mRNA stability in renal pathophysiology: focus on chronic kidney disease.
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Papers by Eva Feigerlova