RESUMO
Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice1,2. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity3-5. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression.
Assuntos
Neoplasias , Humanos , Camundongos , Animais , Microambiente TumoralRESUMO
BACKGROUND: Despite a glaring need and proven efficacy, prospective surgical registries are lacking in low- and middle-income countries. The objective of this study was to design and implement a comprehensive prospective perioperative registry in a low-income country. METHODS: This study was conducted at Hawassa University Comprehensive Specialized Hospital in Hawassa, Ethiopia. Design of the registry occurred from June 2021 to May 2022 and pilot implementation from May 2022 to May 2023. All patients undergoing elective or emergent general surgery were included. Following one year, operability and fidelity of the registry were analyzed by assessing capture rate, incidence of missing data, and accuracy. RESULTS: A total of 67 variables were included in the registry including demographics, preoperative, operative, post-operative, and 30-day data. Of 440 eligible patients, 226 (51.4%) were successfully captured. Overall incidence of missing data and accuracy was 5.4% and 90.2% respectively. Post pilot modifications enhanced capture rate to 70.5% and further optimized data collection processes. CONCLUSION: The establishment of a low-cost electronic prospective perioperative registry in a low-income country represents a significant step forward in enhancing surgical care in under-resourced settings. The initial success of this registry highlights the feasibility of such endeavors when strong partnerships and local context are at the center of implementation. Continuous efforts to refine this registry are ongoing, which will ultimately lead to enhanced surgical quality, research output, and expansion to other sites.
Assuntos
Melhoria de Qualidade , Sistema de Registros , Etiópia , Humanos , Estudos Prospectivos , Feminino , Masculino , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/normas , Adulto , Pessoa de Meia-Idade , Países em Desenvolvimento , Projetos Piloto , Assistência Perioperatória/normasRESUMO
AIMS: To describe the baseline clinical and laboratory findings and treatment modalities of 367 children and adolescents diagnosed with Type 2 diabetes in various paediatric endocrinology centres in Turkey. METHODS: A standard questionnaire regarding clinical and laboratory characteristics at onset was uploaded to an online national database system. Data for 367 children (aged 6-18 years) newly diagnosed with Type 2 diabetes at 37 different paediatric endocrinology centres were analysed. RESULTS: After exclusion of the children with a BMI Z-score < 1 SD, those with genetic syndromes associated with Type 2 diabetes, and those whose C-peptide and/or insulin levels were not available, 227 cases were included in the study. Mean age was 13.8 ± 2.2 (range 6.5-17.8) years, with female preponderance (68%). Family history of Type 2 diabetes was positive in 86% of the children. The mean BMI was 31.3 ± 6.5 kg/m2 (range 18.7-61) and BMI Z-score was 2.4 ± 0.8 (range 1-5). More than half (57%) of the children were identified by an opportunistic diabetes screening due to existing risk markers without typical symptoms of diabetes. Only 13% (n = 29) were treated solely by lifestyle modification, while 40.5% (n = 92) were treated with metformin, 13% (n = 30) were treated with insulin, and 33.5% (n = 76) were treated with a combination of insulin and metformin initially. Mean HbA1C levels of the insulin and combination of insulin and metformin groups were 98 (11.1%) and 102 mmol/mol (11.5%), respectively, and also were significantly higher than the lifestyle modification only and metformin groups mean HbA1C levels (70(8.6%) and 67 mmol/mol (8.3%), respectively). CONCLUSIONS: An opportunistic screening of children who are at high risk of Type 2 diabetes is essential, as our data showed that > 50% of the children were asymptomatic at diagnosis. The other important result of our study was the high rate of exclusion from the initial registration (38%), suggesting that accurate diagnosis of Type 2 diabetes in youth is still problematic, even for paediatric endocrinologists.
Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Adolescente , Glicemia/análise , Índice de Massa Corporal , Peptídeo C/sangue , Criança , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Jejum , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Insulina/uso terapêutico , Estilo de Vida , Masculino , Programas de Rastreamento/métodos , Metformina/uso terapêutico , Puberdade , Fatores de Risco , TurquiaRESUMO
AIMS: This 52-week, randomized, multinational, open-label, parallel-group, non-inferiority trial investigated the efficacy and safety of basal-bolus treatment with insulin detemir vs. NPH (neutral protamine Hagedorn) insulin, in combination with insulin aspart, in subjects aged 2-16 years with Type 1 diabetes mellitus. METHODS: Of the 347 randomized and exposed subjects, 177 received insulin detemir and 170 NPH insulin, both administered once or twice daily in combination with mealtime insulin aspart. Glycaemic measurements and weight were followed over 52 weeks. RESULTS: After 52 weeks, insulin detemir was shown to be non-inferior to NPH insulin with regard to HbA(1c) [mean difference insulin detemir-NPH: 1.30 mmol/mol, 95% CI -1.32 to 3.92 (0.12%, 95% CI -0.12 to 0.36) in the full analysis set and 1.41 mmol/mol, 95% CI -1.26 to 4.08 (0.13%, 95% CI -0.12 to 0.37) in the per protocol analysis set]. Hypoglycaemic events per subject-year of exposure of 24-h and nocturnal hypoglycaemia were significantly lower with insulin detemir than with NPH insulin (rate ratio 0.76, 95% CI 0.60-0.97, P = 0.028 and 0.62, 95% CI 0.47-0.84, P = 0.002, respectively). Weight standard deviation (sd) scores (body weight standardized by age and gender) decreased with insulin detemir, but increased slightly with NPH insulin (change: -0.12 vs. 0.04, P < 0.001). At end of the trial, median insulin doses were similar in both treatment groups. CONCLUSIONS: Insulin detemir was non-inferior to NPH insulin after 52 weeks' treatment of children and adolescents aged 2-16 years, and was associated with a significantly lower risk of hypoglycaemia, together with significantly lower weight sd score when compared with NPH insulin.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Insulina Aspart/administração & dosagem , Insulina Isófana/administração & dosagem , Insulina de Ação Prolongada/administração & dosagem , Adolescente , Glicemia/metabolismo , Índice de Massa Corporal , Peso Corporal , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Esquema de Medicação , Europa (Continente)/epidemiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina Detemir , Masculino , Resultado do TratamentoRESUMO
This retrospective study evaluated the clinical and laboratory characteristics at presentation and treatment results of patients with Graves' disease (GD) with respect to pubertal status. Records of 143 patients (108 F, 35 M) were reviewed in a multicenter study. At diagnosis, 38% of patients were prepubertal. Anti-thyroid drugs (ATD) were used as initial therapy. There was no significant difference in clinical and laboratory characteristics at diagnosis, during treatment and adverse reaction to ATD with respect to pubertal status. Twenty patients (7 prepubertal, 13 pubertal) reached remission on ATD. Surgery was performed in seven and radioiodine (RAI) in four patients. Duration of treatment needed to achieve remission was longer in prepubertal (4.2 +/- 1.0 yr) than in pubertal patients (3.1 +/- 1.3 yr) (p = 0.02). The rate of remission was not different between prepubertal (25.9%) and pubertal patients (33.3%) (p = 0.59). ATD were associated with low remission rate in pediatric GD and required longer duration of therapy in prepubertal patients. For definitive treatment in older children, RAI could be evaluated as the initial therapy.
Assuntos
Doença de Graves/diagnóstico , Doença de Graves/terapia , Puberdade/fisiologia , Adolescente , Algoritmos , Antitireóideos/uso terapêutico , Pesos e Medidas Corporais , Criança , Pré-Escolar , Feminino , Seguimentos , Doença de Graves/fisiopatologia , Humanos , Lactente , Masculino , Indução de Remissão , Estudos RetrospectivosRESUMO
OBJECTIVES: The effect of economic status (ES) on growth, insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 in healthy children is not well characterized. We aimed to study the interrelationship between height, weight, IGF-I, IGFBP-3, mid-parental height (MPH) and ES. DESIGN/SUBJECTS: Eight hundred and fourteen healthy children (428 boys, 386 girls; age 3-18 years) were classified according to income of the families as low, middle and high. Standard deviation scores (SDSs) of height, weight, MPH, IGF-I and IGFBP-3 were compared between the groups. The combined effect of these parameters and ES on height SDS was investigated with complex statistical models. RESULTS: There was a significant trend for height and weight SDSs to increase with higher income levels in boys, but not in girls. Body mass index (BMI) SDSs were similar in three groups. There was a general trend for MPH SDS to increase with income levels in both sexes. In boys, IGF-I SDS was significantly higher in high ES group than low ES. In girls, IGFBP-3 SDSs were significantly higher in high ES group than in middle ES group. For both genders, height SDS was highly correlated with weight SDS and moderately correlated with BMI SDS, MPH SDS and IGF-1 SDS. All correlations were significant and positive. Complex models showed that MPH (19%), IGF-I (13%) and ES (3%) in boys, and MPH (16%) and IGF-I (7%) in girls have significant contribution to height SDSs. CONCLUSIONS: ES per se, independent of overt malnutrition, affects height, weight, IGF-I and IGFBP-3 with some gender differences in healthy children. Influence of income on height and weight show sexual dimorphism, a slight but significant effect is observed only in boys. MPH is the most prominent variable effecting height in healthy children. Higher height and MPH SDSs observed in higher income groups suggest that secular trend in growth still exists, at least in boys, in a country of favorable economic development.
Assuntos
Estatura/fisiologia , Renda , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Adolescente , Peso Corporal/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Distribuição por Sexo , Fatores Socioeconômicos , TurquiaRESUMO
PURPOSE: To determine the relationship between maternal serum zinc (Zn) levels and birth weight of the offspring and their correlation with cord blood Zn, insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels. METHOD: 22 term small-for-gestational-age (SGA) and 34 term appropriate-for-gestational-age (AGA) infants and their mothers were included. Maternal and cord blood Zn levels and cord blood IGF-1 and IGFBP-3 levels were measured. RESULTS: Eighteen percent of mothers had Zn deficiency (< 75 mcg/dl). No significant difference between IGF-1 and IGFBP-3 levels and birth weight of infants of the mothers with and without Zn deficiency was found. Maternal and neonatal Zn levels correlated (r = 0.38, p < 0.01). Mean IGF-1 and IGFBP-3 levels were significantly lower in the SGA group compared to the AGA group (42.3 +/- 16.8 ng/ml, 1.2 +/- 0.2 mcg/ml, and 62.4 +/- 22.7 ng/ml, 1.5 +/- 0.4 mcg/ml, p < 0.001). A correlation was found between birth weight, IGF-1 and IGFBP-3 levels, and weight gain of the mother during pregnancy (p < 0.01). CONCLUSIONS: Zn deficiency was not observed to be a risk factor for low birth weight. The significant difference between the SGA and AGA babies' IGF-1 and IGFBP-3 levels emphasizes function of the IGF system in intrauterine growth.
Assuntos
Recém-Nascido Pequeno para a Idade Gestacional/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Zinco/sangue , Adulto , Estudos de Casos e Controles , Feminino , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Troca Materno-Fetal/fisiologia , Gravidez , Zinco/deficiênciaRESUMO
BACKGROUND: Hypothalamic obesity (HyOb) is a common complication of childhood hypothalamic tumours. Patients with HyOb probably have a higher mortality rate than those with other types of obesity due in many cases to obstructive sleep apnoea/hypoventilation. OBJECTIVES: To identify predictive factors for mortality caused by HyOb in children. METHODS: Twenty children with HyOb secondary to hypothalamic tumours that were followed-up for ≥3 years and aged <15 years at diagnosis, and received supraphysiological glucocorticoid treatment for ≤1 month. RESULTS: Mean age at diagnosis was 6.36 ± 3.60 years. Mean body mass index (BMI) Standard deviation of the samples (SDS) increased from 0.77 ± 1.26 to 2.66 ± 1.45 during the first 6 months, but slowed from month 6-12 (2.73 ± 1.35). ΔBMI SDS at 0-6 months was significantly higher in patients aged <6 years at diagnosis than in those aged >6 years at diagnosis (3.71 ± 1.96 vs. 0.83 ± 0.73, P < 0.001). Maximum BMI SDS was also significantly higher in the younger group (3.88 ± 1.39 vs. 2.79 ± 0.64, P < 0.05). In all, four patients died and the mortality rate was significantly higher in the patients with a further increase in BMI SDS > 1 SDS after 6 months of therapy (RR: 8.4, P < 0.05). Both overall mortality and obesity-related mortality rates were higher in the patients aged <6 years at diagnosis (4.5-fold, 7.2-fold higher, respectively, P > 0.05). The mortality rate was also 3.7-fold higher in the patients with a maximum BMI SDS ≥ 3 at any time during the first 3 years after therapy(P > 0.05). CONCLUSIONS: An increase in BMI SDS after 6 months of therapy was observed to be a risk factor for mortality caused by HyOb. In addition, age <6 years at diagnosis and a maximum BMI SDS ≥ 3 were associated with a higher mortality rate, indicating that earlier and more aggressive treatment of obesity is required.
Assuntos
Neoplasias Hipotalâmicas/complicações , Hipotálamo/fisiopatologia , Obesidade/etiologia , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Neoplasias Hipotalâmicas/mortalidade , Lactente , Masculino , Obesidade/diagnóstico , Obesidade/mortalidade , Estudos Retrospectivos , Fatores de RiscoRESUMO
Many catabolic conditions are characterized by disturbances in acid-base balance and concomitant alterations in the insulin-like growth factor (IGF) system. However, the influence of acidosis per se on the various components of the IGF system has not been extensively examined. The purpose of the present study was to determine the effect of acute metabolic acidosis on the plasma and tissue concentrations of IGF-I and the various IGF-binding proteins (IGFBPs). Conscious unrestrained fasted rats were infused iv with either 0.2 N HCl or an equal volume of saline for 4 h. The arterial blood pH decreased within 60 min after starting the HCl infusion and remained lower than time-matched control values for the entire experimental protocol. Although the plasma IGF-I concentration fell gradually and was reduced by 30%, compared to time-matched control values, GH levels were unaltered. The IGF-I content of tissues collected at the conclusion of the experiment was increased in liver (35%) and kidney (63%), and unchanged in skeletal muscle. However, whereas acidosis moderately increased IGF-I messenger RNA abundance in liver, no significant alteration in IGF-I expression was detected in kidney. Acidosis also increased the plasma levels of IGFBP-1 and -2 as well as the IGFBP-1 content of liver and kidney. In contrast, the concentration of intact IGFBP-3 was decreased in acid-infused rats, and this reduction was associated with an increased rate of IGFBP-3 protease activity. Acidotic rats demonstrated unremarkable changes in the plasma concentrations of glucose and insulin, but corticosterone levels were elevated throughout the experiment. The results of the present study demonstrate that in the absence of underlying pathology, acute metabolic acidosis decreases circulating levels of IGF-I, probably by increasing renal clearance of the peptide, not by decreasing hepatic IGF-I synthesis.
Assuntos
Acidose/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Animais , Dióxido de Carbono/sangue , Hormônio do Crescimento/sangue , Concentração de Íons de Hidrogênio , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Insulin-Like I/genética , Rim/metabolismo , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Oxigênio/sangue , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The regulation of circulating insulin-like growth factor-binding protein-2 (IGFBP-2) in humans is not well understood. In vitro and animal data have identified the role of insulin in the regulation of IGFBP-2, but such a relationship has not been established clearly in humans. In the present study, serum IGFBP-2 concentrations were assessed by Western ligand blot and immunoblot analysis in children with newly diagnosed and untreated insulin-dependent diabetes mellitus (IDDM) and maturity-onset diabetes of the young before and at various times after insulin therapy. For comparison, IGFBP-2 levels were also determined in lean and obese age-matched controls. Children with IDDM were grouped according to their serum bicarbonate levels at the time of presentation (group A, > 20; group B, 13-20; group C, < 13 milliequivalents/L). Densitometric analysis demonstrated that before insulin therapy, group A patients had serum IGFBP-2 levels comparable to those in lean controls, and no significant change in IGFBP-2 was observed during insulin therapy. However, group B patients had a 2-fold elevation in IGFBP-2 levels before insulin therapy compared to lean controls. In these patients, IGFBP-2 tended to decrease at 1 week, but was not significantly reduced until 1 month after the initiation of insulin therapy. Group C patients had a 2.5-fold elevation of IGFBP-2 before treatment, which normalized by 1 month after treatment. Children with maturity-onset diabetes of the young, who had insulin levels and body mass indexes greater than IDDM patients and lean controls, had significantly lower IGFBP-2 levels than both lean and obese controls. IGFBP-2 levels tended to decrease further during insulin therapy. These results indicate that long standing alterations in serum insulin concentrations beyond the physiological range have significant influence on serum IGFBP-2 levels in children and confirm earlier findings that serum IGFBP-2 levels are not acutely regulated by insulin.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Insulina/sangue , Glicemia/análise , Western Blotting , Criança , Hemoglobinas Glicadas/análise , Humanos , Hidrocortisona/sangue , Immunoblotting , Fator de Crescimento Insulin-Like I/análiseRESUMO
Steatorrhea is seen in 18-24% of patients with autoimmune polyglandular disease (APD) type 1. The etiology and pathophysiology of the steatorrhea in this disease are unknown. We present a patient with APD type 1 and steatorrhea in whom biopsies revealed intestinal lymphangiectasia. This association has not been previously described. Intestinal lymphangiectasia may explain the steatorrhea in some patients with ADP type 1. As blind intestinal biopsies may miss areas of intestinal lymphangiectasia, endoscopically directed intestinal biopsies should be included in the evaluation of steatorrhea in APD type 1.
Assuntos
Doença Celíaca/etiologia , Linfangiectasia Intestinal/complicações , Poliendocrinopatias Autoimunes/complicações , Pré-Escolar , Feminino , HumanosRESUMO
Limited proteolysis of serum insulin-like growth factor (IGF) binding protein (IGFBP)-3 has been described in various conditions and may increase the bioavailability of IGFs. The physiological regulators of serum IGFBP-3 protease activity are unknown. To characterize the relationship between insulin and IGFBP-3 protease activity, we have examined serum IGFBP-3 proteolysis in children with untreated insulin-dependent diabetes mellitus (IDDM) and have followed the effect of insulin therapy on serum IGFBP-3 proteolysis at 1 day, 1 week, and 1 month after the initiation of insulin therapy. Ligand blot analysis of sera from untreated children with IDDM showed that intact IGFBP-3 was 50 +/- 9% of the age-matched control pool. After the initiation of insulin treatment, IGFBP-3 did not change significantly at 1 day after treatment but increased dramatically at 1 week (90 +/- 13%) and 1 month after treatment (102 +/- 13%). In contrast, when measured by immunoradiometric assay (which detects both intact and fragments of IGFBP-3), IGFBP-3 levels were 70% of the control pool before insulin therapy and did not increase significantly until 1 month after treatment. Immunoblot analysis demonstrated that intact IGFBP-3 doublet was diminished to 41 +/- 7% of controls, whereas the major IGFBP-3 fragment (30 kDa) was increased in IDDM sera before insulin therapy. After insulin, intact IGFBP-3 increased and the 30-kDa fragment decreased to values comparable to those observed in controls. In vivo IGFBP-3 proteolysis, which implies preassay exposure of serum IGFBP-3 to proteases, was estimated by immunoblot analysis. IGFBP-3 proteolysis was increased before insulin therapy (160 +/- 9%) and decreased to 81 +/- 9% at 1 week and to 71 +/- 11% at 1 month after insulin treatment. Residual serum IGFBP-3 protease activity was estimated by a 125I-IGFBP-3 degradation assay. Serum IGFBP-3 protease activity increased significantly in untreated diabetics, compared with activity in controls (128 +/- 5% vs. 99 +/- 11%). During insulin therapy, serum IGFBP-3 protease activity decreased gradually to 91 +/- 5% of control values at 1 month. Molecular sizes of the IGFBP-3 proteolytic fragments (30 kDa, 24 kDa, and 19 kDa) and inhibition profile of IGFBP-3 protease were similar in IDDM and pregnancy sera, indicating that similar proteases (cation-dependent serine proteases) were active in both conditions. These results suggest an important role of insulin in the regulation of IGFBP-3 protease activity. Increased IGFBP-3 proteolysis in the sera of children with IDDM may serve to counteract the catabolic state induced by insulin deficiency.
Assuntos
Proteínas de Transporte/sangue , Diabetes Mellitus Tipo 1/sangue , Endopeptidases/metabolismo , Insulina/fisiologia , Fragmentos de Peptídeos/sangue , Adolescente , Análise de Variância , Glicemia/metabolismo , Western Blotting , Criança , Pré-Escolar , Estudos de Coortes , Cetoacidose Diabética/sangue , Feminino , Homeostase , Humanos , Hidrocortisona/sangue , Ensaio Imunorradiométrico , Lactente , Insulina/sangue , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Masculino , Inibidores de Proteases/farmacologia , Puberdade , Proteínas Recombinantes/metabolismo , Valores de ReferênciaRESUMO
We have determined the level of phosphorylated insulin-like growth factor binding protein-1 (pIGFBP-1) in serum during two catabolic states: diabetes mellitus and trauma. Human sera were incubated with [125I]IGF-I for 2 h followed by non-denaturing PAGE. [125I]IGF-I/IGFBP-1 complexes from serum co-migrated with a pure p4IGFBP-1 standard. Complex formation was specifically inhibited by unlabeled IGF-I. The migration of IGF-I/pIGFBP-1 complexes was retarded by IGFBP-1 antibodies, but not by antibodies against IGFBP-2 or IGFBP-3. Sera from three severely traumatized patients had up to 12-fold more pIGFBP-1 than sera from age-matched controls. The level of pIGFBP-1 was reduced in all three patients upon hospital discharge. Sera from three patients with insulin dependent diabetes mellitus (IDDM) and severe ketoacidosis (DKA) had more pIGFBP-1 than controls. Administration of insulin to DKA patients lowered the level of pIGFBP-1. The present study shows that IGFBP-1 exists as a free, high affinity, phosphorylated form in vivo during two catabolic states.
Assuntos
Proteínas de Transporte/sangue , Diabetes Mellitus Tipo 1/sangue , Ferimentos e Lesões/sangue , Acidentes de Trânsito , Adolescente , Adulto , Glicemia/análise , Proteínas de Transporte/isolamento & purificação , Cetoacidose Diabética/sangue , Eletroforese em Gel de Poliacrilamida , Humanos , Hidrocortisona/sangue , Insulina/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Corpos Cetônicos/sangue , Fosforilação , Ligação ProteicaRESUMO
To further characterize the mechanism of impaired growth in children with insulin-dependent diabetes mellitus, we examined the serum components of the insulin-like growth factor (IGF) system in 11 children with new-onset insulin-dependent diabetes mellitus and followed the effect of insulinization on the IGF system longitudinally 1 day, 1 week, and 1 month after starting insulin treatment. Before insulin therapy, serum IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), and GH-binding protein (GHBP) levels were significantly decreased, whereas IGFBP-1 and cortisol were significantly increased in diabetic children compared to those in an age-, sex-, and stage of puberty-matched control group. Random serum GH concentrations did not differ significantly. The alterations in the IGF system reversed with insulin therapy in a sequential manner. IGFBP-1 fell rapidly and was comparable to control values within 24 h after insulin treatment. IGF-I rose 1 week after treatment, reaching levels comparable to those in controls and continued to rise through 1 month of treatment. IGF-II, IGFBP-3, and GHBP showed a slower pattern of change, with their levels reaching control values only 1 month after the start of insulin treatment. Improvement in glycemic control, as determined by a change in hemoglobin-A1c, correlated positively with improvement in IGF-I, IGF-II, IGFBP-3, GHBP, and weight gain after 1 month of insulin therapy. These data are consistent with the hypothesis that changes in the IGF system in the insulinopenic state are similar to those during nutritional deprivation and may serve to minimize IGF's anabolic actions. The decreases in IGF-I, IGF-II, and IGFBP-3 may in part be due to a decrease in the GHBP/receptor. However, the observation that an increase in serum IGF-I was observed earlier than an increase in GHBP and without a significant change in serum GH suggests a direct stimulatory effect of insulin on liver IGF-I production or reversal by insulin of some postreceptor defect in GH action independent of GHBP.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/uso terapêutico , Adolescente , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Proteínas de Transporte/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/patologia , Feminino , Hormônio do Crescimento/sangue , Humanos , Hidrocortisona/sangue , Lactente , Insulina/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , MasculinoRESUMO
A small portion of circulating insulin-like growth factor I (IGF-I) is detected in the free or readily dissociable state, which is thought to be the metabolically active form. The amount of free/dissociable IGF-I in serum is dependent on a complex interplay between the production rate and the concentrations of IGF-I and IGF-binding proteins (IGFBPs). IGF availability is also influenced by posttranslational changes in IGFBPs that affect the affinity of IGFBPs for IGF-I. In the present study, we examined whether a short term fast (approximately 12 h) alters the serum concentration of free/dissociable IGF-I, and whether these changes are associated with alterations in IGFBP-1 and the proteolysis status of IGFBP-3. Circulating free/dissociable IGF-I concentrations, as assessed by a two-site immunoradiometric assay, did not differ between fasting and 4 h after a morning meal (1.48 +/- 0.07 vs. 1.50 +/- 0.07 microgram/L, respectively). Likewise, free/dissociable IGF-I levels measured by RIA after separation by centrifugal ultrafiltration were not different between the two groups (1.43 +/- 0.14 vs. 1.38 +/- 0.18 microgram/L, respectively). IGF-I bioactivity, as measured by thymidine incorporation by fibroblasts, did not differ in fasting and 4-h postprandial sera. There was no difference in IGFBP-3 and total acid-ethanol-extractable IGF-I concentrations in serum from fasted and fed subjects. In contrast, the concentration of IGFBP-1 in the serum was increased approximately 5-fold in the fasted state compared to fed values. IGFBP-1 existed in a highly phosphorylated form under fasting conditions. There was no change in IGFBP-3 proteolysis assessed either in vivo or in vitro between the fasting and fed states. The results indicate that a physiologically relevant short term overnight fast does not alter the circulating levels of free/dissociable IGF-I despite a marked elevation in IGFBP-1.
Assuntos
Jejum , Fator de Crescimento Insulin-Like I/análise , Adulto , Glicemia/análise , Feminino , Humanos , Hidrocortisona/sangue , Insulina/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Masculino , FosforilaçãoRESUMO
Thyroid dysfunction is rare in tuberous sclerosis, although papillary adenomas (hamartomas) of the thyroid gland have been reported in a few autopsy cases. We describe a child with tuberous sclerosis and primary congenital hypothyroidism secondary to a dysgenetic thyroid gland. To our knowledge, this association has not been reported previously. Although the association of these two disorders in one patient may be merely coincidence, we speculate that the dysgenetic thyroid gland in this patient may represent a "hamartia" as a consequence of the tuberous sclerosis gene.
Assuntos
Hipotireoidismo Congênito , Glândula Tireoide/anormalidades , Esclerose Tuberosa/complicações , Feminino , Humanos , Hipotireoidismo/complicações , Recém-Nascido , Modelos Biológicos , Glândula Tireoide/embriologia , Esclerose Tuberosa/patologiaRESUMO
A 24 month-old female with Weaver syndrome who has the most severe overgrowth among reported cases is presented. Prenatal history was remarkable for maternal hydantoin use throughout pregnancy. In addition to all major features of the syndrome, she displayed some novel features, including patent ductus arteriosus, atrial septal defect and diffuse thinning of the corpus callosum. Initially, carpal bone age was more advanced compared to phalangeal bone age, as expected in Weaver syndrome. However, phalangeal bone age caught up with carpal bone age during the follow-up period, suggesting that dysharmonic bone age advancement is an early feature of Weaver syndrome. The apparent male predominance in Weaver syndrome is generally ascribed to milder expression of the syndrome in females. The present patient, showing the most severe expression of the syndrome, refutes the notion that females with Weaver syndrome may have a milder form of the syndrome.
Assuntos
Desenvolvimento Infantil , Anormalidades Craniofaciais/complicações , Transtornos do Crescimento/complicações , Transtornos do Crescimento/fisiopatologia , Deformidades Congênitas da Mão/complicações , Deficiência Intelectual/complicações , Peso Corporal , Feminino , Transtornos do Crescimento/patologia , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Radiografia , SíndromeRESUMO
Chronic idiopathic hyperphosphatasia (CIH), also known as juvenile Paget's disease, is characterized by increased bone turnover, persistently elevated serum alkaline phosphatase concentrations and progressive bone deformities. The pathogenesis of the disease is unknown. Currently, there is no specific treatment and agents that reduce bone turnover have been tried in some cases with limited success. In this report, we present our experience with alendronate treatment in a 17 year-old boy with CIH. Ten weeks of treatment with alendronate resulted in marked clinical improvement and normalization of serum alkaline phosphatase activity. Serum osteocalcin and urinary deoxypyridinoline levels were decreased approximately 50% compared to pretreatment values, indicating decreased bone turnover rate. Alendronate seems to be a promising and safe agent for treatment of CIH.
Assuntos
Alendronato/uso terapêutico , Biomarcadores , Remodelação Óssea , Osteíte Deformante/tratamento farmacológico , Adolescente , Doença Crônica , Humanos , Masculino , Osteíte Deformante/diagnóstico por imagem , RadiografiaRESUMO
A 17 year-old female with septo-optic dysplasia (SOD) and hypopituitarism who has grown normally despite GH deficiency is presented. Her serum was examined to test current hypotheses to explain the phenomenon of growth without GH. The patient's serum possessed potent in vitro growth-promoting activity (GPA) in an erythroid progenitor-cell clonal proliferation assay consistent with the patient's normal growth performance. In contrast to previously reported cases of growth without GH, total IGF-I concentrations were very low in this patient, precluding IGF-I being responsible for the observed GPA and normal growth pattern. Furthermore, circulating free IGF-I was also low which is reported for the first time in such a case. A detailed picture of IGF-binding proteins is also presented. To test the hypothesis that hyperinsulinemia might be responsible for the observed GPA, in vitro GPA experiments were performed before and after removal of insulin by immunodepletion. Neither partial nor complete removal of insulin abolished the in vitro cell proliferation response. These data demonstrate that neither IGF-I nor insulin is the factor responsible for GPA in at least this patient with SOD and growth without GH.