We performed a systematic review of clinical trials investigating the health benefits of physical activity in pediatric patients with type 1 diabetes.
To perform this systematic review, search ...strategies were created and adapted to four databases. Only randomized controlled trials written in English before 1998 and that answered to the PICOS criteria were included. The PRISMA guidelines were followed to ensure highest scientific rigor within studies.
Seven studies out of 2655 were included in this systematic review according to the inclusion criteria. These studies showed positive gains on global health: blood lipid profile, physical fitness, quality of life and body size and body composition but only one demonstrated a positive effect on glycemic control.
Globally, physical activity exerts a positive impact on metabolic (i.e., decrease in total cholesterol, improvement of physical fitness, etc.) and psychological health in children with type 1 diabetes. Yet variations in study protocols or sample size restrict statistical power to reach the outcome of improving glycemic control in most studies. Here, we address the measured outcomes in individual trials and discuss potential key elements to consider for future clinical trials.
Background
In patients with diabetes, the dynamics in which hypoglycemia recovers impacts cardiovascular disease risk. Our study investigated the extents of “post-hypoglycemic hyperglycemia (PHH)” ...(i.e. hypoglycemia that recover to hyperglycemia in any circumstance) and factors likely to influence PHH characteristics in a pediatric cohort of patients with type 1 diabetes (T1D).
Methods
We collected retrospective continuous glucose monitoring (CGM) data from 142 pediatric patients with T1D to characterize episodes of PHH during a two-month follow-up period. Factors influencing PHH were determined using univariate and multivariate analyses.
Results
In our EPHICA cohort, PHH rate was 0.6 ± 0.3 episode/day and correlated (r=0.33; p<0.0001) with hyperglycemia rate (2.6 ± 0.5 episodes/day). The global proportion of hyperglycemia corresponding to PHH was 0.22 ± 0.1, yet 14.8% of patients had more than 1/3 of hyperglycemia related to PHH. Episodes of PHH lasted 239.6 ± 124.8 minutes with a hyperglycemic peak of 258.8 ± 47.1 mg/dL. Only 12.2% of PHH occurred at night. While a younger age (<12 years) and lower body mass index (BMI) (SDS: -2 to 1.6) were associated with higher daily PHH rates, teenagers (≥12 years) and obese patients experienced longer PHH and higher hyperglycemic peaks. Parameters of glycemic variability (i.e. HbA
1C
, IDAA
1C
and GTAA
1C
) moderately correlated with PHH duration and related hyperglycemic peak. Multivariate analysis confirmed these results, as factors likely to influence PHH rate were phenotype (age and BMI) and glycemic variability parameters (time in range, mean glycemia, HbA
1C
and GTAA
1C
).
Conclusion
Our EPHICA study highlights the importance of PHH as a prominent component of hyperglycemia in some children and adolescents with T1D. Factors associated with PHH features are age, BMI and parameters of glycemic control. Young and lean children are more prone to experience hypoglycemia that recover with hyperglycemia, but adolescents and obese children tend to experience hyperglycemia of longer duration.
To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric ...patients undergoing partial remission or not. In the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual beta-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve PHH.sub.AUC ) and glycemic homeostasis markers were studied using adjusted mixed-effects models. PHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratio<0.02; sensitivity = 86% and specificity = 68%). PHH.sub.AUC moderately correlated with parameters of glucose homeostasis including TIR (R.sup.2 = 0.35, p-value < 0.05), coefficient of variation (R.sup.2 = 0.22, p-value < 0.05) and Insulin-Dose Adjusted A1c (IDAA.sub.1C) (R.sup.2 = 0.32, p-value < 0.05) and with residual beta-cell secretion (R.sup.2 = 0.17, p-value < 0.05). Classification of patients into four previously described glucotypes independently validated PHH parameters as reliable markers of glucose homeostasis and improved the segregation of patients with intermediate values of IDAA.sub.1C and estimated C-peptide (CPEP.sub.EST). Finally, a combination of PHH parameters identified groups of patients with specific patterns of hypoglycemia. PHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims: Umbilical cord matrix stem cells (UCMSCs) are able to differentiate into mesodermal and ectodermal lineages. The present study investigates the differentiation potential of human ...UCMSCs into hepatic lineage. Methods: We isolated human UCMSCs and characterized them in vitro by measuring their expansion potential, by assessing expression of mesenchymal stem cell (MSC) markers, and by evaluating their ability to differentiate into adipocytes and osteocytes. UCMSCs were thereafter subjected to a hepatogenic differentiation protocol. Expression of hepatic and MSC markers in differentiated cells was analyzed by reverse-transcription polymerase chain reaction, flow cytometry, and immunocytochemical assays and compared with undifferentiated UCMSCs and freshly isolated liver cells. UCMSCs were transplanted into livers of hepatectomized-SCID mice, and engraftment capacity was investigated by detection of human nucleus and mitochondria and human hepatic-specific proteins. Results: In vitro expanded UCMSCs constitutively expressed markers of hepatic lineage, including albumin, α-fetoprotein, cytokeratin-19, connexin-32, and dipeptidyl peptidase IV. In vitro-differentiated UCMSCs exhibited hepatocyte-like morphology, up-regulated several hepatic markers, stored glycogen, produced urea, and exhibited an inducible CYP 3A4 activity. However, absence of some hepatic markers in differentiated UCMSCs, as HepPar1 or hepatocyte nuclear factor 4 (HNF-4), implied that their differentiation did not reach the level of mature hepatocytes. We also noticed that differentiated UCMSCs partially preserved MSC markers. Engraftment capacity of UCMSCs was observed, and expression of human albumin and α-fetoprotein was detected 2, 4, and 6 weeks after transplantation in mice livers, while cytokeratin 19 was completely down-regulated. Conclusions: We conclude that UCMSCs, with a newly demonstrated endodermic differentiation potential, might be an alternative source for liver-directed cell therapies.
Liver cell transplantation is an attractive technique to treat liver-based inborn errors of metabolism. The feasibility and efficacy of the procedure has been demonstrated, leading to medium term ...partial metabolic control of various diseases. Crigler-Najjar is the paradigm of such diseases in that the host liver is lacking one function with an otherwise normal parenchyma. The patient is at permanent risk for irreversible brain damage. The goal of liver cell transplantation is to reduce serum bilirubin levels within safe limits and to alleviate phototherapy requirements to improve quality of life. Preliminary data on Gunn rats, the rodent model of the disease, were encouraging and have led to successful clinical trials. Herein we report on two additional patients and describe the current limits of the technique in terms of durability of the response as compared to alternative therapeutic procedures. We discuss the future developments of the technique and new emerging perspectives.
X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary ...tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.
To evaluate whether indexes of glycemic variability may overcome residual β-cell secretion estimates in the longitudinal evaluation of partial remission in a cohort of pediatric patients with ...new-onset type 1 diabetes.
Values of residual β-cell secretion estimates, clinical parameters (e.g., HbA1c or insulin daily dose), and continuous glucose monitoring (CGM) from 78 pediatric patients with new-onset type 1 diabetes were longitudinally collected during 1 year and cross-sectionally compared. Circadian patterns of CGM metrics were characterized and correlated to remission status using an adjusted mixed-effects model. Patients were clustered based on 46 CGM metrics and clinical parameters and compared using nonparametric ANOVA.
Study participants had a mean (± SD) age of 10.4 (± 3.6) years at diabetes onset, and 65% underwent partial remission at 3 months. β-Cell residual secretion estimates demonstrated weak-to-moderate correlations with clinical parameters and CGM metrics (r2 = 0.05-0.25; P < 0.05). However, CGM metrics strongly correlated with clinical parameters (r2 >0.52; P < 0.05) and were sufficient to distinguish remitters from nonremitters. Also, CGM metrics from remitters displayed specific early morning circadian patterns characterized by increased glycemic stability across days (within 63-140 mg/dL range) and decreased rate of grade II hypoglycemia (P < 0.0001) compared with nonremitters. Thorough CGM analysis allowed the identification of four novel glucotypes (P < 0.001) that segregate patients into subgroups and mirror the evolution of remission after diabetes onset.
In our pediatric cohort, combination of CGM metrics and clinical parameters unraveled key clinical milestones of glucose homeostasis and remission status during the first year of type 1 diabetes.
Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the
gene with more than five hundred pathogenic mutations identified. Pheochromocytomas ...and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10.
We diagnosed a 9-year-old girl of normal appearance and severe refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation of
gene (c.414A>G), also present in three members of her family. At age 13, a pelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline
gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the
gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life.
This family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the
mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine.
Adrenal insufficiency is defined as impaired adrenocortical hormone synthesis. According to its source, the deficit is classified as primary (adrenal steroidogenesis impairment), secondary (pituitary ...adrenocorticotropic hormone deficit) or tertiary (hypothalamic corticotropin-releasing hormone deficit). The management of adrenal insufficiency resides primarily in physiological replacement of glucocorticoid secretion. Standard glucocorticoid therapy is shrouded in several controversies. Along the difficulties arising from the inability to accurately replicate the pulsatile circadian cortisol rhythm, come the uncertainties of dose adjustment and treatment monitoring (absence of reliable biomarkers). Furthermore, side effects of inadequate replacement significantly hinder the quality of life of patients. Therefore, transition to circadian hydrocortisone therapy gains prominence. Recent therapeutic advancements consist of oral hydrocortisone modified-release compounds (immediate, delayed and sustained absorption formulations) or continuous subcutaneous hydrocortisone infusion. In addition to illustrating the current knowledge on conventional glucocorticoid regimens, this review outlines the latest research outcomes. We also describe the management of pediatric patients and suggest a novel strategy for glucocorticoid replacement therapy in adults.
Aims. New-onset type 1 diabetes mellitus (T1D) in pediatric patients represents a clinical challenge for initial total daily insulin dosing (TIDD) due to substantial heterogeneity in practice and ...lack of consensus on the optimal starting dose. Our INSENODIAB (INsulin SEnsitivity in New Onset type 1 DIABetes) study is aimed at (1) exploring the influence of patient-specific characteristics on insulin requirements in pediatric patients with new-onset T1D; (2) constructing a predictive model for the recommended TIDD tailored to individual patient profiles; and (3) assessing potential associations between TIDD and patient outcomes at follow-up intervals of 3 and 12 months. Methods. We conducted a comprehensive analysis of medical records for children aged 6 months to 18 years, hospitalized for new-onset T1D from 2013 to 2022. The study initially involved multivariable regression analysis on a retrospective cohort (rINSENODIAB), incorporating baseline variables. Subsequently, we validated the model robustness on a prospective cohort (pINSENODIAB) with a significance threshold of 5%. The model accuracy was assessed by Pearson’s correlation. Results. Our study encompassed 103 patients in the retrospective cohort and 80 in the prospective cohort, with median TIDD at diagnosis of 1.1 IU/kg BW/day (IQR 0.5). The predictive model for optimal TIDD was established using baseline characteristics, resulting in the following formula: TIDD IU/d=0.09×Age2+0.68×%Weight Loss+28.60×Veinous pH−1.03×Veinous bicarbonates+0.81×Weight−194.63. Validation of the model using the pINSENODIAB cohort demonstrated a significant Pearson correlation coefficient of 0.74. Notably, no significant correlation was observed between TIDD at diagnosis and partial remission markers (IDAA1C, C-peptide) at 3- and 12-months postdiagnosis time points. Conclusions. In the context of new-onset T1D in pediatric patients, we identified key influencing factors for determining optimal TIDD, including age, percentage of weight loss, weight, veinous pH, and bicarbonates. These findings have paved the way for the development of a dosing algorithm to potentially expedite glycemic control stabilization and facilitate a more individualized approach to treatment regimens.
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