Biallelic splicing variants in the nucleolar 60S assembly factor RBM28 cause the ribosomopathy ANE syndrome.

Alopecia, neurologic defects, and endocrinopathy (ANE) syndrome is a rare ribosomopathy known to be caused by a p.(Leu351Pro) variant in the essential, conserved, nucleolar large ribosomal subunit (60S) assembly factor RBM28. We report the second family of ANE syndrome to date and a female pediatric ANE syndrome patient. The patient presented with alopecia, craniofacial malformations, hypoplastic pituitary, and hair and skin abnormalities. Unlike the previously reported patients with the p.(Leu351Pro) RBM28 variant, this ANE syndrome patient possesses biallelic precursor messenger RNA (pre-mRNA) splicing variants at the 5' splice sites of exon 5 (ΔE5) and exon 8 (ΔE8) of RBM28 (NM_018077.2:c.[541+1_541+2delinsA]; [946G > T]). In silico analyses and minigene splicing experiments in cells indicate that each splice variant specifically causes skipping of its respective mutant exon. Because the ΔE5 variant results in an in-frame 31 amino acid deletion (p.(Asp150_Lys180del)) in RBM28 while the ΔE8 variant leads to a premature stop codon in exon 9, we predicted that the ΔE5 variant would produce partially functional RBM28 but the ΔE8 variant would not produce functional protein. Using a yeast model, we demonstrate that the ΔE5 variant does indeed lead to reduced overall growth and large subunit ribosomal RNA (rRNA) production and pre-rRNA processing. In contrast, the ΔE8 variant is comparably null, implying that the partially functional ΔE5 RBM28 protein enables survival but precludes correct development. This discovery further defines the underlying molecular pathology of ANE syndrome to include genetic variants that cause aberrant splicing in RBM28 pre-mRNA and highlights the centrality of nucleolar processes in human genetic disease.

Maternal-fetal impact of vitamin D deficiency: a critical review.

Research into the extra-skeletal functions of vitamin D has been expanding in recent years. During pregnancy, maternal vitamin D status may be of concern because of the key role of this vitamin in fetal skeletal development and due to the association between hypovitaminosis D and adverse maternal-fetal outcomes. Therefore, the objective of this manuscript was to review the maternal-fetal impact of gestational vitamin D deficiency and the benefits of vitamin D supplementation during pregnancy. A literature search was performed in PubMed and Embase employing the following keywords: vitamin D deficiency, pregnancy, 25-hydroxyvitamin D, and hypovitaminosis D. All relevant articles in English language published since 1980 were analysed by the two authors. Neonatal complications derived from vitamin D deficiency include low birth weight, growth restriction, and respiratory tract infection. In the mother, vitamin D deficiency has been associated with altered glucose homeostasis and increased incidence of gestational diabetes mellitus, pre-eclampsia, and bacterial vaginosis. However, the current state of the evidence is controversial for some other endpoints and the actual benefit of vitamin D supplementation in pregnancy remains unclear. Additional longitudinal studies may clarify the actual impact of vitamin D deficiency during pregnancy, and randomised trials are required to define the benefits of vitamin D supplementation in reducing the incidence of adverse outcomes in the mother and infant.

Reference values for glomerular filtration rate in healthy Brazilian adults.

BACKGROUND: Glomerular filtration rate (GFR) is the best index of renal function, but age, gender and ethnicity can putatively affect its values. The aim of this study was to establish reference values for GFR in healthy Brazilian subjects while taking these factors into account. METHODS: In this cross-sectional study, GFR was measured by the 51Cr-EDTA single-injection method. GFR reference values were developed according to CLSI Guidelines for Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory (CLSI C28 protocol). RESULTS: The age range of the 285 healthy individuals was 19 to 70 years, 57% were females, and GFR was 106 ± 18 mL/min/1.73 m(2). There was no difference between male and female GFRs (108 ± 18 vs. 104 ± 18 mL/min/1.73 m(2) respectively, P = 0.134), and reference values were therefore developed from the pooled sample. GFR values were lower in subjects aged ≥45 years as compared with those younger than 45 years (98 ± 15 vs.112 ± 18 mL/min/1.73 m(2), P < 0.001). Based on mean ± 2 SD, GFR reference values were 76 to 148 mL/min/1.73 m(2) for subjects younger than 45 years and 68 to 128 mL/min/1.73 m(2) for individuals older than 45 years, irrespective of gender. CONCLUSION: The age-adjusted reference intervals reported may be reliably adopted to evaluate kidney function, since they are based on recommended standards.

Efficacy of empagliflozin for weight and glycemic control of a patient with Prader-Willi syndrome, systemic lymphedema and extreme obesity: a case report.

A patient with Prader-Willi syndrome (PWS), extreme obesity and hyperglycemia had her body weight increased considerably for 6 months, even with exercise and diet programs. Treatment with metformin and empagliflozin (12.5 mg/day) induced a weight loss of 14 kg (-10.3%) for 6 months and the reduction of glycated hemoglobin A1c.

Glomerular filtration rate estimation: performance of serum cystatin C-based prediction equations.

Serum creatinine measurement is a mainstay in the routine laboratory evaluation of renal function, despite of having several disadvantages. Cystatin C, on the other hand, suffers less influence of gender and muscle mass and has been proposed as a more sensitive marker for glomerular filtration rate. However, serum endogenous markers should not be used alone to assess glomerular filtration rate. Creatinine-based equations such as the modification of diet in renal disease (MDRD) and Cockcroft-Gault are widely used despite their limitations. A large number of cystatin C-based prediction equations were developed in recent years, in diverse populations, with different laboratory assays and methods. Several studies demonstrated that cystatin C-based equations are reliable markers of glomerular filtration rate and can be used for diagnosis, evaluation and follow-up of kidney disease. They are simpler than creatinine-based equations and have at least the same accuracy and precision for glomerular filtration rate estimation. In conclusion, diabetes mellitus, cystic fibrosis, kidney transplantation, HIV-infection, and cirrhosis are clinical situations where cystatin C-based equations can be useful. Extremes of age such as childhood and advanced age have also been evaluated with favorable results.

New insights into the management of differentiated thyroid carcinoma in children and adolescents (Review).

Differentiated thyroid carcinoma (DTC) is the most common malignant neoplasm of the endocrine system. In children and adolescents, DTC usually presents as a more aggressive disease than in the adult population, but patients often have a favourable prognosis, even in cases of advanced disease. Nevertheless, certain patients have persistent or recurrent disease leading to increased morbidity. A significant challenge in the management of DTC is identifying the subgroup of patients with a high risk of unfavourable outcomes. Prognostic factors related to the patient, tumour, and stratification systems (Tumor­Node­Metastasis/American Joint Committee on Cancer, American Thyroid Association risk classification and dynamic risk stratification) are used in an attempt to identify the individuals at increased risk. In the present review, the current risk classification systems applied for paediatric thyroid cancer are discussed, highlighting the major differences between paediatric and adult DTC in pathophysiology, clinical presentation and long­term outcomes. In recent years, genetic markers have also been proposed as prognostic factors for children and adolescents with DTC. Advances in the understanding of the molecular profile of paediatric DTC may aid individualized management, potentially improving diagnosis and treatment. This review article aims to critically review and update the current concepts on DTC management in children and adolescents, with an emphasis on clinical presentation, treatment, risk assessment, follow­up and future perspectives.

Psychiatric illness, emotional distress, glycemic control and chronic complications in type 1 diabetes subjects.

OBJECTIVE: To assess the prevalence of psychiatric disorders in patients with type 1 diabetes mellitus (T1D) and to compare patients with and without psychiatric disorder. METHODS: We made a cross-sectional study including patients with T1D assisted in the outpatient clinics of the Brazilian National Health System. To assess depression and anxiety, we used the PHQ-9 questionnaire and the DSM-5th edition criteria, respectively. B-PAID evaluated the level of emotional distress associated with diabetes; EAT-26, eating disorders; SCI-R, adherence to the proposed clinical treatment. RESULTS: We analyzed 166 patients aged 33 (22-45.2) years, 53.6% female. The prevalence of depression and anxiety was 20.5% and 40.4%, respectively. HbA1c was worse in the depressed (9.0% vs. 8.4%, p = 0.008), in the anxious ones (9.0% vs. 8.3%, p = 0.012) and in the patients with high levels of B-PAID (8.8 % vs. 8.3 %, p = 0.009). There was no difference in the prevalence of complications related to diabetes. CONCLUSION: The prevalence of psychiatric disorders and emotional distress related to diabetes was high in our population of T1D patients, and depression and high levels of B-PAID were associated with the worse glycemic control.

Gender does not influence cystatin C concentrations in healthy volunteers.

BACKGROUND: Current data are conflicting about the influence of gender on cystatin C concentrations. The goal of this study was to determine the reference interval for serum cystatin C in normal Brazilian subjects, taking into account the influence of gender. METHODS: Ninety-seven healthy volunteers, aged 18-70 years, 44% male, had glomerular filtration rate (GFR) measured using a (51)Cr-EDTA method and estimated with the Modification of Diet in Renal Disease (MDRD) study equation. Serum cystatin C was measured using a turbidimetric method, and creatinine by the Jaffe method. RESULTS: Mean serum cystatin C was not significantly different between males and females, 0.62 +/- 0.12 vs. 0.65 +/- 0.12 mg/L, respectively (p = 0.26). However, median serum creatinine was significantly higher in men [97 (80-115) vs. 80 (53-88) micromol/L; p = 0.0001]. There were also no significant differences between genders with respect to GFR measured using (51)Cr-EDTA (103 +/- 14 for males and 106 +/- 19 mL/min/1.73 m(2) for females, p = 0.47), and estimated with the MDRD equation (86 +/- 12 vs. 83 +/- 16 mL/min/1.73 m(2), respectively, p = 0.24). CONCLUSIONS: There was no effect of gender on serum cystatin C, as well as on measured and estimated GFR.

Medical education on hospital hyperglycemia improving knowledge and outcomes

ABSTRACT Objective: To evaluate the effects of medical education on hospital hyperglycemia on physician's technical knowledge and the quality of medical prescriptions, patient care, and clinical outcomes. Subjects and methods: The intervention included online classes and practical consultations provided by an endocrinologist to medical preceptors and residents of the Department of Internal Medicine. A pretest and a post-test (0 to 10 points) were applied before and after the intervention and patients medical records were reviewed before and after the intervention. The outcomes were improvement in medical knowledge, in the quality of prescriptions for patients in the clinical area, and clinical outcomes. Results: The global mean of correct answers improved with the intervention [before: 6.9 points (±1.7) versus after the intervention: 8.8 points (±1.5) (p < 0.001)]. The number of patients who did not have at least one blood glucose assessment during the entire hospitalization for acute illness decreased from 12.6% before to 2.6% (p < 0.001) after the intervention. There was also a significant reduction in hospital hypoglycemia rates (p < 0.026). The use of sliding-scale insulin as the main treatment was quite low before and after the intervention (2.2% and 0%). After 6 months, medical knowledge did not show significant reduction. Conclusion: Medical education on hospital hyperglycemia can improve medical knowledge and clinical outcomes for patients. The improvement in medical knowledge was maintained after 6 months.

Targeted sequencing identifies novel variants in common and rare MODY genes.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). METHODS: We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. RESULTS: After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. CONCLUSION: A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes.

Cerebral syphilitic gumma in HIV-infected patients: case report and review.

Neurosyphilis presenting as a cerebral gumma is an uncommon event. To date there are seven cases of cerebral gumma reported in human immunodeficiency virus (HIV)-infected patients. We describe a HIV-infected patient with neurosyphilis presenting as an expanding central nervous system lesion and unremarkable cerebrospinal fluid analysis. This case report illustrates the clinical and therapeutic aspects of syphilitic gumma in HIV-infected patients.

Influence of maternal weight gain on birth weight: a gestational diabetes cohort.

Objective Our objective was to evaluate gestational weight gain (GWG) patterns and their relation to birth weight. Subjects and methods We prospectively enrolled 474 women with gestational diabetes mellitus (GDM) at a university hospital (Porto Alegre, Brazil, November 2009-May 2015). GWG was categorized according to the 2009 Institute of Medicine guidelines; birth weight was classified as large (LGA) or small (SGA) for gestational age. Adjusted relative risks (aRRs) and 95% confidence intervals (95% CIs) were determined. Results Adequate GWG occurred in 121 women [25.5%, 95% CI: 22, 30%]; excessive, in 180 [38.0%, 95% CI: 34, 43%]; and insufficient, in 173 [36.5%, 95% CI: 32, 41%]. In women with normal body mass index (BMI), the prevalence of SGA was higher in those with insufficient compared to adequate GWG (30% vs. 0%, p < 0.001). In women with BMI ≥ 25 kg/m2, excessive GWG increased the prevalence of LGA [aRR 2.58, 95% CI: 1.06, 6.29] and protected from SGA [aRR 0.25, 95% CI: 0.10, 0.64]. Insufficient vs. adequate GWG did not influence the prevalence of SGA [aRR 0.61, 95% CI: 0.31, 1.22]; insufficient vs. excessive GWG protected from LGA [aRR 0.46, 95% CI: 0.23, 0.91]. Conclusions One quarter of this cohort achieved adequate GWG, indicating that specific ranges have to be tailored for GDM. To prevent inadequate birth weight, excessive GWG in women with higher BMI and less than recommended GWG in normal BMI women should be avoided; less than recommended GWG may be suitable for overweight and obese women.

[Low-dose aspirin in patients with diabete melitus: risks and benefits regarding macro and microvascular complications]. / Aspirina em baixa dosagem em pacientes com diabete melito: riscos e benefícios em relação às complicações macro e microvasculares.

Aspirin is recommended as cardiovascular disease prevention in patients with diabetes mellitus. Due to the increased risk of bleeding and because of the hypothesis that there could be a worsening of microvascular complications related to aspirin, there has been observed an important underutilization of the drug. However, it is now known that aspirin is not associated with a deleterious effect on diabetic retinopathy and there is evidence indicating that it also does not affect renal function with usual doses (150 mg/d). On the other hand, higher doses may prove necessary, since recent data suggest that diabetic patients present the so called "aspirin resistance". The mechanisms of this resistance are not yet fully understood, being probably related to an abnormal intrinsic platelet activity. The employment of alternative antiplatelet strategies or the administration of higher aspirin doses (150-300 mg/d) should be better evaluated regarding effective cardiovascular disease prevention in diabetes as well as the possible effects on microvascular complications.

Clinical characteristics of women with gestational diabetes - comparison of two cohorts enrolled 20 years apart in southern Brazil.

CONTEXT AND OBJECTIVE:: The prevalence and characteristics of gestational diabetes mellitus (GDM) have changed over time, reflecting the nutritional transition and changes in diagnostic criteria. We aimed to evaluate characteristics of women with GDM over a 20-year interval. DESIGN AND SETTING:: Comparison of two pregnancy cohorts enrolled in different periods, in university hospitals in Porto Alegre, Brazil: 1991 to 1993 (n = 216); and 2009 to 2013 (n = 375). METHODS:: We applied two diagnostic criteria to the cohorts: International Association of Diabetes and Pregnancy Study Groups (IADPSG)/World Health Organization (WHO); and National Institute for Health and Care Excellence (NICE). We compared maternal-fetal characteristics and outcomes between the cohorts and within each cohort. RESULTS:: The women in the 2010s cohort were older (31 ± 7 versus 30 ± 6 years), more frequently obese (29.4% versus 15.2%), with more hypertensive disorders (14.1% versus 5.6%) and at increased risk of cesarean section (adjusted relative risk 1.8; 95% confidence interval: 1.4 - 2.3), compared with those in the 1990s cohort. Neonatal outcomes such as birth weight category and hypoglycemia were similar. In the 1990s cohort, women only fulfilling IADPSG/WHO or only fulfilling NICE criteria had similar characteristics and outcomes; in the 2010s cohort, women only diagnosed through IADPSG/WHO were more frequently obese than those diagnosed only through NICE (33 ± 8 kg/m2 versus 28 ± 6 kg/m2; P < 0.001). CONCLUSION:: The epidemic of obesity seems to have modified the profile of women with GDM. Despite similar neonatal outcomes, there were differences in the intensity of treatment over time. The IADPSG/WHO criteria seemed to identify a profile more associated with obesity.

Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data.

AIMS: Maturity-Onset Diabetes of the Young (MODY) comprises a heterogeneous group of monogenic forms of diabetes caused by mutations in at least 14 genes, but mostly by mutations in Glucokinase (GCK) and hepatocyte nuclear factor-1 homeobox A (HNF1A). This study aims to establish a national registry of MODY cases in Brazilian patients, assessing published and unpublished data. METHODS: 311 patients with clinical characteristics of MODY were analyzed, with unpublished data on 298 individuals described in 12 previous publications and 13 newly described cases in this report. RESULTS: 72 individuals had GCK mutations, 9 described in Brazilian individuals for the first time. One previously unpublished novel GCK mutation, Gly178Ala, was found in one family. 31 individuals had HNF1A mutations, 2 described for the first time in Brazilian individuals. Comparisons of GCK probands vs HNF1A: age 16±11 vs 35±20years; age at diagnosis 11±8 vs 21±7years; BMI 19±6 vs 25±6kg/m2; sulfonylurea users 5 vs 83%; insulin users 5 vs 17%; presence of arterial hypertension 0 vs. 33%, all p<0.05. No differences were observed in lipids and C-peptide. CONCLUSIONS: Most MODY cases in Brazil are due to GCK mutations. In agreement with other studied populations, novel mutations are common. Only 14% of patients with familial diabetes carry a HNF1A mutation. Diagnosis of other rare forms of MODY is still a challenge in Brazilian population, as well as adequate strategies to screen individuals for molecular diagnosis.

Vitamin D Deficiency Increases the Risk of Adverse Neonatal Outcomes in Gestational Diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) and vitamin D deficiency have been associated with increased risk of adverse perinatal outcomes but the consequences of both conditions simultaneously present in pregnancy have not yet been evaluated. Our objective was to study the influence of vitamin D deficiency in neonatal outcomes of pregnancies with GDM. METHODS: 184 pregnant women with GDM referred to specialized prenatal monitoring were included in this cohort and had blood sampled for 25-hydroxyvitamin D measurement. Vitamin D was measured by chemiluminescence and deficiency was defined as < 20 ng/mL. Participants were followed until puerperium and adverse neonatal outcomes were evaluated. RESULTS: Newborns of women with vitamin D deficiency had higher incidences of hospitalization in intensive care units (ICU) (32 vs 19%, P = 0.048), of hypoglycemia (any, 17.3 vs 7.1%, P = 0.039requiring ICU, 15.3 vs 3.6%, P = 0.008), and were more frequently small for gestational age (SGA) (17.3 vs 5.9%, P = 0.017). After adjustment, relative risk (RR) for hypoglycemia requiring ICU was 3.63 (95%CI 1.09-12.11) and for SGA was 4.32 (95%CI 1.75-10.66). The incidence of prematurity, jaundice and shoulder dystocia was no statistically different between groups. CONCLUSIONS: In this cohort of pregnant women with GDM, vitamin D deficiency was associated with a major increase in the incidence of adverse neonatal outcomes such as SGA newborns and neonatal hypoglycemia.

Psychiatric illness, emotional distress, glycemic control and chronic complications in type 1 diabetes subjects

ABSTRACT Objectives: To assess the prevalence of psychiatric disorders in patients with type 1 diabetes mellitus (T1D) and to compare patients with and without psychiatric disorder. Materials and methods: We made a cross-sectional study including patients with T1D assisted in the outpatient clinics of the Brazilian National Health System. To assess depression and anxiety, we used the PHQ-9 questionnaire and the DSM-5th edition criteria, respectively. B-PAID evaluated the level of emotional distress associated with diabetes; EAT-26, eating disorders; SCI-R, adherence to the proposed clinical treatment. Results: We analyzed 166 patients aged 33 (22-45.2) years, 53.6% female. The prevalence of depression and anxiety was 20.5% and 40.4%, respectively. HbA1c was worse in the depressed (9.0% vs. 8.4%, p = 0.008), in the anxious ones (9.0% vs. 8.3%, p = 0.012) and in the patients with high levels of B-PAID (8.8 % vs. 8.3 %, p = 0.009). There was no difference in the prevalence of complications related to diabetes. Conclusions: The prevalence of psychiatric disorders and emotional distress related to diabetes was high in our population of T1D patients, and depression and high levels of B-PAID were associated with the worse glycemic control.

Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations.

Thirty-two patients with diabetes negative for point mutations in GCK and HNF1A underwent further molecular screening of GCK, HNF1A, HNF4A, and HNF1B by MLPA analysis. We described the first Brazilian case of MODY5 due to a heterozygous whole-gene deletion in HNF1B, who developed rapidly progressive renal failure and death.