PCSK9 plasma concentration is associated with epicardial adipose tissue volume and metabolic control in patients with type 1 diabetes.

Patients with type 1 diabetes (T1D) have a greater risk of cardiovascular disease. Proconvertase subtilisin-kexin 9 (PCSK9) is involved in the atherosclerosis process. This study aimed to determine the relationship between PCSK9 levels and epicardial adipose tissue (EAT) volume and cardiometabolic variables in patients with T1D. This was an observational cross-sectional study including 73 patients with T1D. Clinical, biochemical and imaging data were collected. We divided the patients into two groups according to their glycemic control and the EAT index (iEAT) percentile. We performed a correlation analysis between the collected variables and PCSK9 levels; subsequently, we performed a multiple regression analysis with the significant parameters. The mean age was 47.6 ± 8.5 years, 58.9% were men, and the BMI was 26.9 ± 4.6 kg/m2. A total of 31.5%, 49.3% and 34.2% of patients had hypertension, dyslipidemia and smoking habit, respectively. The PCSK9 concentration was 0.37 ± 0.12 mg/L, which was greater in patients with worse glycemic control (HbA1c > 7.5%), dyslipidemia and high EAT volume (iEAT > 75th percentile). The PCSK9 concentration was positively correlated with age (r = 0.259; p = 0.027), HbA1c (r = 0.300; p = 0.011), insulin dose (r = 0.275; p = 0.020), VLDL-C level (r = 0.331; p = 0.004), TG level (r = 0.328; p = 0.005), and iEAT (r = 0.438; p < 0.001). Multiple regression analysis revealed that 25% of the PCSK9 variability was explained by iEAT and HbA1c (p < 0.05). The PCSK9 concentration is associated with metabolic syndrome parameters, poor glycemic control and increased EAT volume in patients with T1D.

Comprehensive Genetic Testing of CYP21A2: A Retrospective Analysis in Patients with Suspected Congenital Adrenal Hyperplasia.

The most common form of congenital adrenal hyperplasia (CAH) results from a deficiency of the 21-hydroxylase enzyme (21-OHD), presenting with a broad spectrum of clinical phenotypes according to the CYP21A2 gene mutations. Of the 59 patients with suspected CAH, 62.7% presented a positive genetic result. Of them, 78.4% and 18.9% presented with non-classical and classical forms, respectively. An overall phenotype-genotype correlation of 88.9% was observed. Biochemically, 17-hydroxiprogesterone concentrations were significantly higher in genetically confirmed patients. Genetically, 36 patients presented with previously reported pathogenic variants, and one presented a new variant in homozygosis. Among the 74 alleles tested, point mutations were found in 89.2% and large rearrangements were found in the rest. The most prevalent pathogenic variant was p.(Val282Leu). The inclusion of relatives revealed one further case. Interestingly, 87.5% of relatives were carriers of a pathogenic variant, including two siblings initially classified as genetically positive. In addition, the study of male partners with gestational desire identified several carriers of mild mutations. Studying the allelic distribution of the variants also allowed for reclassifying one patient. In conclusion, a genetic approach including Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, and allelic distribution of the pathogenic variants represents a beneficial tool for better classifying patients with 21-OHD.

Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection.

Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30-70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M-) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M- patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity.

Insulin Therapy in Hospitalized Patients.

BACKGROUND: Hyperglycemia is prevalent and is associated with an increase in morbidity and mortality in hospitalized patients. Insulin therapy is the most appropriate method for controlling glycemia in hospital, but is associated with increased risk of hypoglycemia, which is a barrier to achieving glycemic goals. AREAS OF UNCERTAINTY: Optimal glycemic targets have not been established in the critical and noncritical hospitalized patients, and there are different modalities of insulin therapy. The primary purpose of this review is to discuss controversy regarding appropriate glycemic targets and summarize the evidence about the safety and efficacy of insulin therapy in critical and noncritical care settings. DATA SOURCES: A literature search was conducted through PubMed with the following key words (inpatient hyperglycemia, inpatient diabetes, glycemic control AND critically or non-critically ill patient, Insulin therapy in hospital). RESULTS: In critically ill patient, blood glucose levels >180 mg/dL may increase the risk of hospital complications, and blood glucose levels <110 mg/dL have been associated with an increased risk of hypoglycemia. Continuous intravenous insulin infusion is the best method for achieving glycemic targets in the critically ill patient. The ideal glucose goals for noncritically ill patients remain undefined and must be individualized according to the characteristics of the patients. A basal-bolus insulin strategy resulted in better glycemic control than sliding scale insulin and lower risk of hypoglycemia than premixed insulin regimen. CONCLUSIONS: Extremes of blood glucose lead to poor outcomes, and target glucose range of 110-180 mg/dL may be appropriate for most critically ill patients and noncritically ill patients. Insulin is the most appropriate pharmacologic agent for effectively controlling glycemia in hospital. A continuous intravenous insulin infusion and scheduled basal-bolus-correction insulin are the preferred modalities for glycemic control in critically and noncritically ill hospitalized patients, respectively.

Measurement Properties of the Online EuroQol-5D-Youth Instrument in Children and Adolescents With Type 1 Diabetes Mellitus: Questionnaire Study.

BACKGROUND: The lack of continuity between health-related quality of life (HRQoL) instruments designed for children and adults hinders change analysis with a life course approach. To resolve this gap, EuroQol (EQ) developed the EQ-5D-Youth (EQ-5D-Y), derived from the EQ-5D for adults. Few studies have assessed the metric properties of EQ-5D-Y in children with specific chronic conditions, and none have done so for children with type I diabetes mellitus (T1DM). OBJECTIVE: This study aimed to evaluate the acceptability, validity, reliability, and responsiveness of the EQ-5D-Y in children and adolescents with T1DM, when administered online. METHODS: Participants with T1DM were consecutively recruited from July to December 2014, from a list of potential candidates aged 8-19 years, who attended outpatient pediatric endocrinology units. Before every quarterly routine visit, participants received an email/telephone reminder to complete the online version of two generic HRQoL questionnaires: EQ-5D-Y and KIDSCREEN-27. The EQ-5D-Y measures five dimensions, from which an equally weighted summary score was constructed (range: 0-100). Completion rate and distribution statistics were calculated. Construct validity was evaluated through known group comparisons based on general health, acute diabetic decompensations, mental health, family function, and a multitrait, multimethod matrix between EQ-5D-Y and KIDSCREEN by using Spearman correlations. Construct validity hypotheses were stated a priori. Reliability was assessed with the intraclass correlation coefficient and responsiveness by testing changes over time and calculating the effect size. Reliability and responsiveness were tested among the stable and improved subsamples defined by a KIDSCREEN-10 index change of <4.5 points or ≥4.5 points, respectively, from the first to the fourth visit. RESULTS: Of the 136 participants, 119 (87.5%) responded to the EQ-5D-Y at the last visit. The dimensions that showed higher percentages of participants with problems were "having pain/discomfort" (34.6%) and "worried/sad/unhappy" (28.7%). The mean (SD) of the EQ-5D-Y summary score was 8.5 (10.9), with ceiling and floor effects of 50.7% and 0%, respectively. Statistically significant HRQoL differences between groups defined by their general health (excellent/very good and good/regular/bad) and mental health (Strengths and Difficulties Questionnaire score ≤15 and >16, respectively) were found in three EQ-5D-Y dimensions ("doing usual activities," "having pain/discomfort," and "feeling worried/sad/unhappy"), summary score (effect size for general health and mental health groups=0.7 and 1.5, respectively), and KIDSCREEN-10 index (effect size for general health and mental health groups=0.6 and 0.9, respectively). Significant differences in the EQ-5D-Y dimensions were also found according to acute diabetic decompensations in "looking after myself" (P=.005) and according to family function in "having pain/discomfort" (P=.03). Results of the multitrait, multimethod matrix confirmed three of the four relationships hypothesized as substantial (0.21, 0.58, 0.50, and 0.46). The EQ-5D-Y summary score presented an intraclass correlation coefficient of 0.83. Statistically significant change between visits was observed in the improved subsample, with an effect size of 0.7 (P<.001). CONCLUSIONS: These results support the use of the EQ-5D-Y administered online as an acceptable, valid, reliable, and responsive instrument for evaluating HRQoL in children and adolescents with T1DM.

Associations between epicardial adipose tissue, subclinical atherosclerosis and high-density lipoprotein composition in type 1 diabetes.

BACKGROUND: The pathophysiology of cardiovascular complications in people with type 1 diabetes (T1DM) remains unclear. An increase in epicardial adipose tissue (EAT) and alterations in the composition of high-density lipoprotein (HDL) are associated with coronary artery disease, but information on its relationship in T1DM is very limited. Our aim was to determine the association between EAT volume, subclinical atherosclerosis, and HDL composition in type 1 diabetes. METHODS: Seventy-two long-term patients with T1DM without clinical atherosclerosis were analyzed. EAT volume and subclinical atherosclerosis were measured using cardiac computed tomography angiography. EAT was adjusted according to body surface to obtain an EAT index (iEAT). HDL composition was determined. RESULTS: The mean iEAT was 40.47 ± 22.18 cc/m2. The bivariate analysis showed positive associations of the iEAT with gender, age, hypertension, dyslipidemia, smoking, body mass index, waist circumference, insulin dose, and triglyceride (P < 0.05). The iEAT correlated positively with small HDL, increased content of apolipoprotein (apo)A-II and apoC-III, and decreased content of apoE and free cholesterol. Multiple linear regression showed that age, apoA-II content in HDL, and waist circumference were independently associated with the iEAT. Fifty percent of the patients presented subclinical atherosclerotic lesions. These patients had a higher iEAT, and their HDL contained less cholesterol and more apoA-II and lipoprotein-associated phospholipase A2 than patients without subclinical atherosclerosis. CONCLUSION: Alterations in the composition of HDL in TIDM are associated with increased iEAT and the presence of subclinical atherosclerosis. We propose that these abnormalities of HDL composition could be useful to identify T1DM patients at highest cardiovascular risk.

Impact of monitoring health-related quality of life in clinical practice in children with type 1 diabetes mellitus.

PURPOSE: To test whether the systematic monitoring of health-related quality of life (HRQOL) in clinical practice in Spanish pediatric patients with T1DM helps improve their daily life in a multicenter longitudinal study. METHODS: One hundred thirty-six patients participated, recruited from five centers in Barcelona, Spain (72 girls, mean age 13.4 years). Complete data were collected for 119 patients (85%). Pediatricians were randomly assigned to the HRQOL intervention (n = 70), or control group (n = 49). The intervention group discussed the results of HRQOL face to face with the physician, quarterly over a year. The control group received care as usual. HRQOL was assessed using KIDSCREEN-27 collected online. Standardized mean differences (effect size, ES) and generalized estimating equation (GEE) were computed to compare group differences between baseline and follow-up, taking into account sociodemographic and clinical variables. RESULTS: Statistically significant higher scores were seen in the intervention group at follow-up for the dimensions of Psychological well-being (ES = 0.56), School environment (ES = 0.56), and the KIDSCREEN-10 index (ES = 0.63). No differences were found in the control group. GEE analysis showed an improvement in HRQOL at follow-up with statistically significant association of the intervention on Psychological well-being (B = 4.32; p 0.03 for the interaction of group by follow-up) and School environment (B = 4.64; p 0.02 for the same interaction term). CONCLUSIONS: Routine assessment and face-to-face patient-physician discussion of HRQOL results improved HRQOL scores after a year of follow-up, especially in Psychological well-being and school environment. The results support the routinary use of HRQOL assessment in clinical practice.

Health-related quality of life (HRQOL) and its associated factors in children with Type 1 Diabetes Mellitus (T1DM).

BACKGROUND: The objective of the study was to describe the baseline health-related quality of life (HRQOL) in a cohort of children and adolescents with type 1 diabetes mellitus (T1DM), and analyze its associated clinical and sociodemographic factors, assessing HRQOL through internet. METHODS: This was a descriptive study of 136 patients with T1DM from 5 hospitals in Catalonia, Spain (72 girls, mean age 13.4 years (range 8-19). Inclusion criteria were more than 6 months from diagnosis, more than 8 years old and without cognitive problems. Sociodemographic (age, sex, family level of education, type of family and origin) and clinical variables (type of insulin therapy, duration of disease, adherence to treatment, body mass index and HbA1c) were collected. HRQOL was assessed using the EuroQol-5D (EQ-5D-Y) and KIDSCREEN, collected via web. Mental health status was assessed using the Strengths and Difficulties Questionnaire. Multiple linear regression models were adjusted. RESULTS: Physical-well-being mean scores were lower (worse) than the European average (<50) and especially in girls, older children (>11 years old), those from single-parent families, and those with low adherence. Older children and patients with poor metabolic control (HbA1c >7,5% [58 mmol/mol]) showed worse scores in the KIDSCREEN-10 index. Similar results were observed with the EQ-5D-Y. Multivariate models showed that age, single-parent families, adherence and mental health were the most influential factors. CONCLUSIONS: Diabetic patients report similar HRQOL than the population of the same age with slightly worse physical well-being. The study shows some factors to be taken into account to improve HRQOL, and also the feasibility of using web to collect information in clinical practice.

Control glucémico y complicaciones crónicas a 20 años del comienzo de la diabetes tipo 1. Resultados de una unidad especializada / Blood glucose control and complications at 20 years from onset of type 1 diabetes. Results from a specialist unit

OBJETIVOS: Conocer en un grupo de pacientes con diabetes tipo 1 (DM1) de larga evolución la prevalencia de complicaciones tardías y su relación con el control glucémico desde el diagnóstico, así como la prevalencia y control de los factores de riesgo cardiovascular (FRCV). MATERIAL Y MÉTODOS: Pacientes con comienzo de DM1 entre 1985 y 1994, seguidos en nuestro centro. Se recogieron datos antropométricos, de control glucémico, complicaciones crónicas y FRCV al comienzo y anualmente, mediante revisión de la historia clínica. Se realizó además una visita con examen físico y extracción de muestra de sangre. RESULTADOS: Participaron 77 pacientes (46 varones, edad 47 ± 8,5 años, tiempo de evolución 22,4 ± 2,2 años). Dieciséis pacientes (20,4%) desarrollaron retinopatía, 8 (10,4%) nefropatía, 12 (15,6%) polineuropatía y 3 (3,9%) macroangiopatía. Presentaban hipertensión arterial, dislipidemia y obesidad un 28,6, un 46,8 y un 20,8%, respectivamente. El 22,1% de ellos eran sedentarios y el 35,1%, fumadores. La hemoglobina glucosilada (HbA1c) media durante todo el período de seguimiento fue 7,2 ± 0,8%, en los primeros 5 años 6,4 ± 1,2% y en la visita del estudio 7,6 ± 1,1%. El 70% de los pacientes se mantuvieron dentro de objetivos en los primeros 5 años, el 45% en los 5 años siguientes y alrededor del 25% a partir de los 10 años de evolución. Los pacientes sin complicaciones tenían mejor control glucémico global (HbA1c7,0 ± 0,7% vs. 7,6 ± 0,9%; p = 0,003) y en los primeros 5 años (HbA1c 6,1 ± 0,9 vs. 7,0 ± 1,4%; p = 0,001). CONCLUSIÓN: La prevalencia de complicaciones a los 20 años en pacientes con DM1 bien controlados desde el diagnóstico es baja y está relacionada con el control glucémico global durante el seguimiento y los primeros años de la enfermedad. La prevalencia de fumadores es elevada. OBJECTIVES: To determine the prevalence of chronic complications in a group of patients with long duration type 1 diabetes (DM1), and their relationship with glycemic control since diagnosis of disease, as well as control and prevalence of cardiovascular risk factors (CVRF)

OBJECTIVES: To determine the prevalence of chronic complications in a group of patients with long duration type 1 diabetes (DM1), and their relationship with glycemic control since diagnosis of disease, as well as control and prevalence of cardiovascular risk factors (CVRF). MATERIAL AND METHODS: The study included patients diagnosed in our center between 1985 and 1994 and followed-up until the present. Anthropometric data, glycemic control, chronic complications, and CVRF were collected from medical records at baseline and annually. A visit was made that included a physical examination and complete blood analysis. RESULTS: A total of 77 patients were studied (46 males, and mean age 47 ± 8.5 years, duration of follow-up, 22.4 ± 2.2 years). Sixteen patients (20.4%) developed retinopathy, 8 (10.4%) nephropathy, 12 (15.6%) polyneuropathy, and 3 (3.9%) macroangiopathy. Hypertension, dyslipidemia and obesity were found in 28.6%, 46.8% and 20.8%, respectively, and 22.1% were sedentary, and 35.1% were smokers. Mean glycosylated hemoglobin (HbA1c) during the entire follow-up was 7.2 ± 0.8%. In the first five years it was 6.4 ± 1.2% and at the study visit, it was 7.6 ± 1.1%. More than two-thirds (70%) of patients remained on target in the first five years, with 45% in the next five years, and about 25% from years 10 to 22. Patients with no complications showed better glycemic control during the entire follow-up (HbA1c 7.0 ± 0.7% vs. 7.6 ± 0.9%; P=.003), and also in the first five years (HbA1c 6.1 ± 0.9 vs. 7.0 ± 1.4%; P=.001). CONCLUSION: Prevalence of complications after 20 years of follow-up in well controlled DM1 since diagnosis is low, and is related to the overall glycemic control during follow-up and in the early years of the disease. The prevalence of smoking is high

High-frequency stimulation of the ventrolateral thalamus regulates gene expression in hippocampus, motor cortex and caudate-putamen.

High-frequency stimulation (HFS) of the ventrolateral (VL) thalamus is effective in treating the resting tremor of Parkinson's disease (PD). PD is a movement disorder that involves neurodegeneration, predominantly of the substantia nigra, but also in other brain areas, such as the motor cortex and hippocampus. The mechanisms of action of HFS on remote brain areas at the molecular level are largely unknown. Here, we investigated gene expression profiles using oligonucleotide microarrays and quantitative real-time PCR in rat hippocampi. We showed that chronic (14days) HFS modulates the expression of 176 hippocampal genes. Our results showed that genes involved in proliferation and neurogenesis-related biological functions were specifically regulated by HFS, including nestin (Nes) and doublecortin (Dcx), which are expressed in neural progenitor cells and immature neurons, respectively, as well as genes encoding proteins that may support neural differentiation or migration, such as Timp1, Ccl2, S100a4 and Angpt2. Next, we used quantitative real-time PCR (RT-PCR) to profile these six genes in the motor cortex and the caudate-putamen, which included the subventricular zone (CPu-SVZ). Interestingly, HFS increased Dcx expression in the motor cortex whereas Nes was upregulated in the CPu-SVZ but not in the motor cortex. In the CPu-SVZ Timp1 and Ccl2 were highly upregulated by HFS. In conclusion, our findings suggest that HFS may enhance neuroplasticity at the molecular level in several remote brain areas such as the CPu-SVZ, motor cortex and hippocampus.

Type 1 diabetes mellitus in Catalonia: chronic complications and metabolic control ten years after onset.

BACKGROUND: The purpose of this article is to describe the prevalence of microvascular (retinopathy, nephropathy and neuropathy) and acute diabetic complications, and the metabolic control status, in Catalonian patients with type 1 diabetes mellitus ten years after diagnosis. MATERIAL/METHODS: We performed a cross-sectional population study evaluating 427 Type 1 diabetic patients diagnosed between 1987 and 1988 in 15 hospitals in Catalonia. 278 subjects were located, and all the study parameters were collected from their hospital medical records. Mean age at onset was 13.8+/-6.9 years, and 56.5% were male. The mean age of the patients was 24.8+/-6.7 years. Albumin excretion rate (AER), plasma creatinine, lipid profile, glycosilated hemoglobin (HbA1c), blood pressure, presence of retinopathy and clinical polyneuropathy, and diabetes control were evaluated. RESULTS: The mean HbA1c was 7.8+/-1.7%. HbA1c was <7.5% in 48% of patients and >10% in 11.5%. The prevalence of retinopathy was 7.6%. An AER higher than 20 Kg/min was found in 10.4%. Neuropathy was present in 4.3%. A significant association between microvascular complications as a whole (retinopathy and/or microalbuminuria and/or clinical polyneuropathy) and HbA1c (p=0.04) and hypertension (p=0.04) was observed. There were no differences in diabetic complications regarding sex or age at presentation. CONCLUSIONS: This is one of the first studies in which the prevalence of diabetic microvascular complications is reported in a South European cohort of subjects registered in EURODIAB. This population-based study confirms that complications are already present ten years after diabetes onset in a non-negligible percentage of patients.

Obesitat en la infància i l’adolescència / No disponible

No disponible