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1.
Calcif Tissue Int ; 114(2): 157-170, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38043102

RESUMO

Childhood-onset osteoporosis is a rare but clinically significant condition. Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal PLS3, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with PLS3-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13 years old. Three of the identified PLS3 variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10 months to 2 years of treatment. Our findings expand the genetic spectrum of PLS3-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.


Assuntos
Fraturas Ósseas , Osteoporose , Fraturas da Coluna Vertebral , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Densidade Óssea/genética , Difosfonatos/uso terapêutico , Fraturas Ósseas/tratamento farmacológico , Vértebras Lombares/patologia , Mutação , Osteoporose/tratamento farmacológico , Fraturas da Coluna Vertebral/genética , Fraturas da Coluna Vertebral/tratamento farmacológico
2.
Eur J Appl Physiol ; 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39259397

RESUMO

PURPOSE: Examine the acute hormonal and cytokine responses to free-weight resistance training in trained prepubertal and pubertal male children. METHODS: Prepubertal (n = 21; age 11.4 ± 1.1 years; Tanner I-II) and pubertal male children (n = 20; age 15.8 ± 0.7 years; Tanner III-V) conducted a moderate-intensity free-weight resistance training program to failure with venous blood sampling before (pre), immediately after (post) and during the recovery phase of the program (post-15,-30 min). Growth hormone (GH), insulin-like growth factor-I (IGF-I), cortisol, testosterone, IL-6, and TNF-α were analyzed in serum samples. Biological maturation was assessed according to the stages of the Tanner scale. RESULTS: There was a significant time-by-group interaction in IGF-I response (p = 0.044; η2 = 0.209) and testosterone (p < 0.001; η2 = 0.508), indicating a greater change in the pubertal group compared to the prepubertal group. Both groups significantly increased post-exercise GH levels (p < 0.05). Only the prepuberal group significantly increased levels of IL-6 at all post-exercise time points (p < 0.05). Both groups showed a significant (p < 0.05) increase in TNF-α levels compared to resting levels. CONCLUSION: These data suggest that acute testosterone and IGF-I response following resistance training differ between trained prepubertal and pubertal male children. Moderate-intensity resistance training performed to failure may thus have different effects in trained prepubertal and pubertal male children, which should be considered when giving training advice. TRIAL REGISTRATION: Clinical trials number: NCT05022992.

3.
J Adv Nurs ; 79(12): 4621-4634, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37357405

RESUMO

AIM: To explore young adults' experiences of living with type 1 diabetes in the transition to adulthood, including experiences of the transfer from paediatric to adult care. DESIGN: A qualitative approach was used. METHOD: Ten young adults, six women and four men, aged 19-29 years, participated. Participants were recruited at their regular diabetes clinic from spring 2021 to spring 2022. Semi-structured interviews were transcribed and analysed using qualitative content analysis. FINDINGS: Dreaming of being nurtured towards self-reliance was the overarching theme. Personal experiences of the transition to adulthood, including the transfer from paediatric to adult care, were described in terms of struggling to find balance in daily life, dealing with feelings of being different, being gradually supported to achieve independence, and wishing to be approached as a unique person in healthcare. CONCLUSION: In healthcare, it is important to emphasize not only diabetes-related factors but also emotional and psychosocial aspects of life connected to the transition to adulthood, including the transfer to adult care. The young adults wished to be seen as unique persons in healthcare during their emerging adulthood and should therefore be supported to achieve self-reliance through personal preparations for new challenges and for the consequences of transitioning to adulthood. Specialist nurses can provide appropriate knowledge and leadership. IMPLICATIONS FOR THE PROFESSION: These findings can guide nurse specialists in support for emerging adults to achieve self-reliance and indicate the importance of person-centred care when experiencing transition and transfer. REPORTING METHOD: The study adhered to EQUATOR guidelines, and the COREQ checklist for qualitative studies was used as the reporting method.


Assuntos
Diabetes Mellitus Tipo 1 , Transição para Assistência do Adulto , Masculino , Humanos , Feminino , Adulto Jovem , Criança , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/psicologia , Atenção à Saúde , Pesquisa Qualitativa , Emoções
4.
BMC Endocr Disord ; 20(1): 55, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349731

RESUMO

BACKGROUND: In 2007, Omnitrope® was the first biosimilar recombinant human growth hormone (rhGH) to be approved in Sweden for treatment in adults and children. Over 10 years' safety and effectiveness data for biosimilar rhGH can now be presented. METHODS: PATRO Children and PATRO Adults are multicenter, longitudinal, observational, post-marketing surveillance studies. Eligible patients include children 0-18 years and adults receiving biosimilar rhGH treatment. Adverse events (AEs) are monitored for safety evaluation. Growth variables in children and metabolic data in adults are recorded for effectiveness evaluation. RESULTS: As of January 2019, data from 136 children (48% male) were reported from Swedish centers. Mean age in rhGH treatment-naïve patients at study entry (n = 114) was 7.5 years, with mean 3.6 years treatment duration. No severe AEs of diabetes, impaired glucose tolerance, or malignancy were reported. The most frequently reported AE was nasopharyngitis (n = 16 patients). No clinically relevant anti-hGH or neutralizing antibodies were observed. The mean change from baseline in height standard deviation score (SDS) in naïve prepubertal GH deficiency patients was + 0.79 at 1 year, + 1.27 at 2 years, and + 1.55 at 3 years. Data from 293 adults (44% rhGH-naïve, 51% male) were included. Fatigue was the most frequently reported AE (n = 26 patients). The incidence of new neoplasms or existing neoplasm progression was 23.8 patients per 1000 patient-years. Type 2 diabetes mellitus was reported in four patients. At baseline in rhGH-naïve adults, mean (SD) body mass index (BMI) was 29.1 (5.6) kg/m2 and mean (SD) insulin-like growth factor (IGF)-I SDS was - 3.0 (1.4). Mean daily dose increased from 0.1 mg at baseline to 0.3 mg after 4 years. IGF-I SDS normalized during the first year of treatment. Mean BMI and glucose were unchanged over 4 years, while low-/high-density lipoprotein cholesterol ratio decreased. CONCLUSIONS: For the first time, Swedish data from the PATRO Children and Adults studies are presented. The 10-year data suggest that biosimilar rhGH is well tolerated across pediatric and adult indications. Safety and effectiveness were similar to previous reports for other rhGH preparations. These results need to be confirmed in larger cohorts, highlighting the importance of long-term post-marketing studies.


Assuntos
Medicamentos Biossimilares/uso terapêutico , Nanismo Hipofisário/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Adulto , Idoso , Anticorpos Neutralizantes , Estatura , Criança , Pré-Escolar , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Duração da Terapia , Feminino , Intolerância à Glucose/epidemiologia , Terapia de Reposição Hormonal , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Nasofaringite/induzido quimicamente , Neoplasias/epidemiologia , Síndrome de Prader-Willi/tratamento farmacológico , Vigilância de Produtos Comercializados , Proteínas Recombinantes , Suécia , Síndrome de Turner/tratamento farmacológico , Adulto Jovem
5.
BMC Endocr Disord ; 15: 84, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26682747

RESUMO

BACKGROUND: Responsiveness to GH treatment can be estimated by both growth and ∆IGF-I. The primary aim of the present study was to investigate if mimicking the physiological increase during puberty in GH secretion, by using a higher GH dose could lead to pubertal IGFs in short children with low GH secretion. The secondary aim was to explore the relationship between IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio and gain in height. METHODS: A multicentre, randomized, clinical trial (TRN88-177) in 104 children (90 boys), who had received GH 33 µg/kg/day during at least 1 prepubertal year. They were followed from GH start to adult height (mean, 7.5 years; range, 4.6-10.7). At onset of puberty, children were randomized into three groups, to receive 67 µg/kg/day (GH(67)) given once (GH(67x1); n = 30) or divided into two daily injection (GH(33x2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33x1); n = 38). The outcome measures were change and obtained mean on-treatment IGF-I(SDS), IGFBP3(SDS) and IGF-I/IGFBP3 ratio(SDS) during prepuberty and puberty. These variables were assessed in relation to prepubertal, pubertal and total gain in heightSDS. RESULTS: Mean prepubertal increases 1 year after GH start were: 2.1 IGF-I(SDS), 0.6 IGFBP3(SDS) and 1.5 IGF-I/IGFBP3ratio(SDS). A significant positive correlation was found between prepubertal ∆IGFs and both prepubertal and total gain in height(SDS). During puberty changes in IGFs were GH dose-dependent: mean pubertal level of IGF-I(SDS) was higher in GH(67) vs GH(33) (p = 0.031). First year pubertal ∆IGF-I(SDS) was significantly higher in the GH(67)vs GH(33) group (0.5 vs -0.1, respectively, p = 0.007), as well as ∆IGF-I(SDS) to the pubertal mean level (0.2 vs -0.2, p = 0.028). In multivariate analyses, the prepubertal increase in '∆IGF-I(SDS) from GH start' and the 'GH dose-dependent pubertal ∆IGF-I(SDS)' were the most important variables for explaining variation in prepubertal (21 %), pubertal (26 %) and total (28 %) gain in height(SDS). TRIAL REGISTRATION: TRN 88-177, not applicable 1988. CONCLUSION: The dose-dependent change in IGFs was related to a dose-dependent pubertal gain in height(SDS). The attempt to mimic normal physiology by giving a higher GH dose during puberty was associated with both an increase in IGF-I and a dose-dependent gain in height(SDS).


Assuntos
Estatura/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/administração & dosagem , Fator de Crescimento Insulin-Like I/metabolismo , Puberdade/metabolismo , Adolescente , Relação Dose-Resposta a Droga , Feminino , Transtornos do Crescimento/fisiopatologia , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Suécia/epidemiologia , Resultado do Tratamento
6.
Artigo em Inglês | MEDLINE | ID: mdl-38344969

RESUMO

Sotos syndrome belongs to the group of diseases characterised by features such as facial dysmorphism, intellectual disability, hypotonia and overgrowth. Usually, Sotos syndrome is caused by heterozygous mutations in the NSD1 gene at chromosome 5q35 or by large genomic deletions of the same region. Genotype-phenotype correlations have mainly been reported as an association of significant or major abnormalities and presence of 5q35 deletions rather than intragenic deletions or point mutations in NSD1. The congenital hyperinsulinaemic hypoglycaemia (CHI) has been described as an uncommon feature in the presentation of Sotos syndrome. Most of the patients with Sotos syndrome and transient CHI were carriers of 5q35 deletions while persistent CHI has been recently reported in individuals with point mutations or small NSD1 deletions. We report the clinical features and medical treatment in a new-born child with Sotos syndrome and CHI that was present for almost two years. Genetic cause of Sotos syndrome in this case was a novel, large genomic deletion encompassing 24 OMIM genes including the entire NSD1 gene and 6 other Morbid genes. Our report shows challenges in diagnostics and management of this rare genetic condition. We propose, that in neonatal diagnostics, the phenotypic spectrum of Sotos syndrome should include CHI as a characteristic feature and molecular genetic testing should be done by whole genome analysis.

7.
Ther Adv Endocrinol Metab ; 15: 20420188241264343, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39371577

RESUMO

Background: Recombinant human growth hormone (rhGH, somatropin) therapy is approved in children with Prader-Willi syndrome (PWS). Objectives: To report safety and effectiveness data for children with PWS treated with biosimilar rhGH (Omnitrope®, Sandoz) in the PAtients TReated with Omnitrope (PATRO) Children study. Design: PATRO Children was a multicenter, non-interventional, postmarketing surveillance study. Methods: Children with PWS received Omnitrope according to standard clinical practice. Adverse events (AEs) were monitored for the duration of Omnitrope treatment. Effectiveness outcomes were also assessed, including height standard deviation (SD) scores (HSDS). Results: As of July 2020 (study completion), 235 patients with PWS had been enrolled. At baseline, 95.7% (n = 225) of patients were prepubertal and 86.4% (n = 203) were rhGH treatment-naïve. At analysis, the median (range) treatment duration in the study was 56.8 (2.9-155.8) months. AEs were reported in 192 patients (81.7%) and were suspected as treatment-related in 39 patients (16.6%). Serious AEs (SAEs) were reported in 96 patients (40.9%) and were suspected as treatment-related in 22 patients (9.4%). The most frequent treatment-related SAEs were sleep apnea syndrome (n = 11; 4.7%), tonsillar hypertrophy (n = 4; 1.7%), and adenoidal hypertrophy (n = 4; 1.7%). Development of scoliosis was considered treatment-related in two patients; development of impaired glucose tolerance in one patient and type 2 diabetes mellitus in another patient were considered treatment-related. Effectiveness outcomes were primarily assessed in 153 patients who completed 3 years of treatment. Among the 151 prepubertal patients (135 treatment-naïve), mean (SD) change from baseline in HSDS after 3 years was +1.50 (1.07) across all patients and +1.57 (1.07) for treatment-naïve patients. Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in patients with PWS managed in real-life clinical practice. Patients with PWS should continue to be closely monitored for well-known safety issues (including respiratory, sleep, and glucose metabolism disorders, and scoliosis) during rhGH treatment.

8.
Sports Med Open ; 8(1): 81, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35727479

RESUMO

BACKGROUND: No previous systematic review has quantitatively compared the effects of resistance training, endurance training, or concurrent training on hormonal adaptations in children and adolescents. Objective was to examine the effects of exercise training and training type on hormonal adaptations in children and adolescents. METHODS: A systematic literature search was conducted in the following databases: PubMed, Web of Science, and EBSCO. Eligibility criteria were: population: healthy youth population sample (mean age < 18 years); intervention: resistance training, endurance training, or concurrent training (> 4 weeks duration); comparison: control group; outcome: pre- and post-levels of hormones and cytokines; and study design: randomized and non-randomized controlled trials. We used a random-effect model for the meta-analysis. The raw mean difference in hormones from baseline to post-intervention was presented alongside 95% confidence intervals (CI). Further, the certainty of evidence quality and the risk of bias were assessed. RESULTS: A total of 3689 records were identified, of which 14 studies were eligible for inclusion. Most studies examined adolescents with fewer studies on children (age < 12 years, N = 5 studies) and females (N = 2 studies). Nine exercise training programs used endurance training, five studies used resistance training, and no eligible study used concurrent training. The meta-analysis showed no significant effect of exercise training on testosterone (MD = 0.84 nmol/L), cortisol (MD = - 17.4 nmol/L), or SHBG (MD = - 5.58 nmol/L). Subgroup analysis showed that resistance training significantly increased testosterone levels after training (MD = 3.42 nmol/L) which was not observed after endurance training (MD = - 0.01 nmol/L). No other outcome differed between training types. Exercise training resulted in small and non-significant changes in GH (MD = 0.48 ng/mL, p = 0.06) and IGF-I (MD = - 22.90 ng/mL, p = 0.07). GH response to endurance training may be age-dependent and evident in adolescents (MD = 0.59 ng/mL, p = 0.04) but not when children and adolescents are pooled (MD = 0.48 ng/mL, p = 0.06). Limited evidence exists to conclude on IL-6 and TNF-α effects of exercise training. Assessments of GRADE domains (risk of bias, consistency, directness, or precision of the findings) revealed serious weaknesses with most of the included outcomes (hormones and cytokines). CONCLUSIONS: This systematic review suggests that exercise training has small effects on hormonal concentrations in children and adolescents. Changes in testosterone concentrations with training are evident after resistance training but not endurance training. GH's response to training may be affected by maturation and evident in adolescents but not children. Further high-quality, robust training studies on the effect of resistance training, endurance training, and concurrent training are warranted to compare their training-specific effects. REGISTRATION: PROSPERO: CRD42021241130.

9.
J Clin Endocrinol Metab ; 107(9): 2644-2651, 2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-35665810

RESUMO

AIMS: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). METHODS: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 µg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. RESULTS: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. CONCLUSIONS: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.


Assuntos
Diabetes Mellitus Tipo 1 , Adolescente , Compostos de Alúmen , Glicemia , Automonitorização da Glicemia , Peptídeo C , Criança , Glutamato Descarboxilase , Controle Glicêmico , Antígeno HLA-DR3 , Humanos , Vitamina D/uso terapêutico , Adulto Jovem
10.
Front Endocrinol (Lausanne) ; 12: 657873, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177802

RESUMO

Aim: Despite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI. Patient: A 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative. Methods: A trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR. Results: Hyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7, ADCY7 gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m(-/-Adcy7) cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis Adcy7 loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes Ins1 and Ins2 (p ≤ 0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of Scl2a2 and Gck via upregulation of Pdx1, and Foxa2 leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway. Conclusion: This study identified a novel candidate gene, ADCY7, to cause CHI via activation of the GSIS pathway.


Assuntos
Adenilil Ciclases/genética , Hiperinsulinismo Congênito/enzimologia , Hiperinsulinismo Congênito/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adenilil Ciclases/deficiência , Sequência de Aminoácidos , Animais , Sistemas CRISPR-Cas , Linhagem Celular , Pré-Escolar , Hiperinsulinismo Congênito/genética , Técnicas de Inativação de Genes , Glucose/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/genética , Secreção de Insulina , Masculino , Ratos , Alinhamento de Sequência , Transativadores/genética , Transativadores/metabolismo
11.
Horm Res Paediatr ; 94(3-4): 133-143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350858

RESUMO

INTRODUCTION: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). METHODS: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. RESULTS: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7-18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was -2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of -2.02 (0.9). CONCLUSION: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.


Assuntos
Hormônio do Crescimento Humano/administração & dosagem , Síndrome de Turner/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Estudos Longitudinais , Resultado do Tratamento , Síndrome de Turner/fisiopatologia
12.
Diabetes Care ; 44(7): 1604-1612, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34021020

RESUMO

OBJECTIVE: To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12-24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7-193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 µg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS: Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845-1.408]; P = 0.5009). However, GAD-alum-treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126-2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose-adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION: Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.


Assuntos
Diabetes Mellitus Tipo 1 , Glutamato Descarboxilase , Peptídeo C , Diabetes Mellitus Tipo 1/tratamento farmacológico , Suplementos Nutricionais , Método Duplo-Cego , Humanos , Vitamina D
13.
Growth Horm IGF Res ; 40: 61-68, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29422321

RESUMO

OBJECTIVE: Daily subcutaneous self-injection of GH is used worldwide to treat short stature in childhood; longitudinal data on the impact of this regimen on GH-uptake are lacking. DESIGN: Children with/without GH-deficiency participating in clinical trials were followed prospectively (≤8 times). Blood was sampled pre-GH-injection (dose GH33/GH67 µg/kg) and either every 30 min thereafter for 24 h (Experimental-setting; 59 GH-curves/15 children); or every 2 h thereafter for 16 h (Clinical-setting; 429 GH-curves/117 children). Pharmacokinetics were estimated by time Tmax (h) of maximal GH-concentration (Cmax, mU/L) and area under the curve for 16 h (AUC, mU/L ∗ h). RESULTS: In the Clinical-setting, median Cmax was 71 mU/L and AUC was 534 mU/L ∗ h, with coefficients of variation for intra-individual variation of 39% and 36%, respectively, and inter-individual variation of 44% and 42%, respectively. 43% of Cmax and AUC variability was explained by GH-dose and proxies for injection depth (baseline GH-level, GHpeakwidth, BMISDS). In the Experimental- versus Clinical-setting, 85% and 40% of GH-curves, respectively, reached zero-levels within 24 h. A longer duration was found following a more superficial GH-injection. Spontaneous GH-peaks were identified already 6 h after the GH-injection in about half of the curves of both GHD and non-GHD patients. CONCLUSION: Very broad intra-individual and inter-individual variability was found. A high GH-peak will optimize growth effects; the highest Cmax was found after a deep injection of GH at the higher dose and concentration. In as many as 60% of the children, GH remained detectable in serum after 24 h; a constant GH-level will promote IGF-I and metabolic effects.


Assuntos
Transtornos do Crescimento/sangue , Transtornos do Crescimento/patologia , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/sangue , Proteínas Recombinantes/administração & dosagem , Biomarcadores/sangue , Criança , Feminino , Seguimentos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/farmacocinética , Humanos , Injeções Subcutâneas , Masculino , Prognóstico , Estudos Prospectivos , Distribuição Tecidual
14.
J Clin Endocrinol Metab ; 99(8): 2917-24, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24823461

RESUMO

CONTEXT: GH treatment significantly increased adult height (AH) in a dose-dependent manner in short non-GH-deficient children in a randomized, controlled, clinical trial; the mean gain in height SD score (heightSDS) was 1.3 (range 0-3), compared with 0.2 in the untreated group. OBJECTIVE: The objective of the study was to analyze the relationship between IGF-1SDS, IGF binding protein-3 SDS (IGFBP3SDS), and their ratioSDS with a gain in the heightSDS until AH in non-GH-deficient short children. DESIGN AND SETTING: This was a randomized, controlled, multicenter clinical trial. INTERVENTION: The intervention included GH treatment: 33 or 67 µg/kg · d plus untreated controls. SUBJECTS: One hundred fifty-one non-GH-deficient short children were included in the intent-to-treat (ITT) population and 108 in the per-protocol (PP) population; 112 children in the ITT and 68 children in the PP populations had idiopathic short stature (ISS). MAIN OUTCOME MEASURES: Increments from baseline to on-treatment study mean IGF-1SDS (ΔIGF-1SDS), IGFBP3SDS, and IGF-1 to IGFBP3 ratioSDS were assessed in relationship to the gain in heightSDS. RESULTS: Sixty-two percent of the variance in the gain in heightSDS in children on GH treatment could be explained by four variables: ΔIGF-1SDS (explaining 28%), bone age delay, birth length (the taller the better), and GH dose (the higher the better). The lower IGF-1SDS was at baseline, the higher was its increment during treatment. For both the AllPP- and the ISSPP-treated groups, the attained IGF-1SDS study level did not correlate with height gain. CONCLUSION: In short non-GH-deficient children, the GH dose-related increment in IGF-1SDS from baseline to mean study level was the most important explanatory variable for long-term growth response from the peripubertal period until AH, when IGF-1SDS, IGFBP3SDS, and their ratioSDS were compared concurrently.


Assuntos
Estatura/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Nanismo/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Adolescente , Adulto , Criança , Nanismo/sangue , Feminino , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Masculino , Resultado do Tratamento
15.
Horm Res Paediatr ; 82(3): 158-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25170833

RESUMO

BACKGROUND/AIMS: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency. METHODS: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH(67)) given as one (GH(67×1); n = 35) or two daily injections (GH(33×2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33×1); n = 40). Growth was assessed as heightSDSgain for prepubertal, pubertal and total periods, as well as AHSDS versus the population and the midparental height. RESULTS: Pubertal heightSDSgain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33×1), 0.41, p < 0.05). AHSDS was greater on GH(67) (GH(67×1), -0.84; GH(33×2), -0.83) than GH(33) (-1.25, p < 0.05), and heightSDSgain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target heightSDS. CONCLUSION: Pubertal heightSDSgain and AHSDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once- and twice-daily GH(67) regimens. © 2014 S. Karger AG, Basel.


Assuntos
Estatura , Transtornos do Crescimento/metabolismo , Hormônio do Crescimento/uso terapêutico , Crescimento , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Puberdade , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Hormônio do Crescimento/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Caracteres Sexuais
16.
Diabetes Technol Ther ; 15(9): 738-43, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23931739

RESUMO

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) patients experience switches of pump systems on a regular basis. We investigated the impact of transition from older pumps to the Accu-Chek(®) Combo system (Roche Diagnostics Deutschland GmbH, Mannheim, Germany) on a patient's glycemic control and diabetes management. PATIENTS AND METHODS: In total, 299 patients (172 female, 127 male; mean±SD age, 39.4±15.2 years; CSII duration, 7.0±5.2 years) were enrolled by 61 European sites into this uncontrolled prospective trial. Glycemic control, safety, and diabetes management parameters were measured at baseline and after 3 and 6 months. Changes from baseline were analyzed. RESULTS: After transition to the new insulin pump, mean±SD hemoglobin A1c (HbA1c) values decreased from 7.8±1.1% (baseline) to 7.7±1.1% (end point). The proportion of patients with HbA1c <7.0% was slightly higher at the end of the study (29.6%) than at baseline (25.2%), whereas the proportion of patients with HbA1c >8.0% decreased (baseline, 36.2%; end point, 32.7%; P<0.05). The number of hypoglycemic episodes (blood glucose<70 mg/dL) improved slightly during the study (baseline, 40.4±34.0 events/quarter; end point, 39.2±33.9 events/quarter). Glycemic control improved significantly in the group with an initial HbA1c >8.0% (-0.46%; P<0.001) and remained solidly stable in the group with an initial HbA1c <7% (+0.04%; not significant). Short-term (<3 years) pump users (n=48) had a larger HbA1c decrease (-0.40%) than long-term (≥3 years) users (n=251) (-0.07%; P<0.05). The number of blood glucose measurements increased (3.7±1.9/day vs. 4.4±1.8/day; P<0.05), whereas the number of insulin boluses decreased (5.1±1.9/day vs. 4.6±1.5/day; P<0.05) during the study. CONCLUSIONS: Transition from older pump systems to the Accu-Chek Combo system in a large patient population resulted in stable glycemic control with significant improvements in HbA1c in patients with unsatisfactory baseline HbA1c and shorter pump use. Increased frequency of self-monitoring of blood glucose and decrease of bolus frequency could suggest a more confident diabetes management and a reduced need for correction boluses.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Insulina/uso terapêutico , Adulto , Idoso , Glicemia/análise , Europa (Continente) , Feminino , Hemoglobinas Glicadas/análise , Humanos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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