Worldwide differences in childhood type 1 diabetes: The SWEET experience.

OBJECTIVE: To study worldwide differences in childhood diabetes, comparing relevant indicators among five regions within the SWEET initiative. SUBJECTS: We investigated 26 726 individuals with type 1 diabetes (T1D) from 54 centers in the European region; 7768 individuals from 30 centers in the Asia/Middle East/Africa region; 2642 people from five centers in Australia/New Zealand; 10 839 individuals from seven centers in North America, and 1114 patients from five centers in South America. METHODS: The SWEET database was analyzed based on the following inclusion criteria: T1D, time period 2015-2019, and age < 21 years, with analysis of the most recent documented year of therapy. For the statistical analysis, we used multivariable linear and logistic regression models to adjust for age (<6 years, 6- < 12 years, 12- < 18 years, 18- < 21 years), gender, and duration of diabetes (<2 years, 2- < 5 years, 5- < 10 years, ≥10 years). RESULTS: Adjusted HbA1c means ranged from 7.8% (95%-confidence interval: 7.6-8.1) in Europe to 9.5% (9.2-9.8) in Asia/Middle East/Africa. Mean daily insulin dose ranged from 0.8 units/kg in Europe (0.7-0.8) and Australia/New Zealand (0.6-0.9) to 1.0 unit/kg 0.9-1.1) in Asia/Middle East/Africa. Percentage of pump use was highest in North America (80.7% [79.8-81.6]) and lowest in South America (4.2% [3.2-5.6]). Significant differences between the five regions were also observed with regards to body mass index SD scores, frequency of blood glucose monitoring and presence of severe hypoglycaemia. CONCLUSIONS: We found significant heterogeneity in diabetes care and outcomes across the five regions. The aim of optimal care for each child remains a challenge.

Isolated Fetal Sinus Bradycardia as a First Sign of Congenital Hypopituitarism.

We present a case of marked fetal sinus bradycardia as the sole presenting sign of congenital combined pituitary hormone deficiencies. Fetal sinus bradycardia < 120 beats/min was detected at 36 weeks of gestation during an otherwise uncomplicated pregnancy. Sinus bradycardia persisted after birth, and congenital hypothyroidism and growth hormone deficiencies were subsequently identified. Normal sinus rhythm was rapidly restored with hormone supplementation. Hypothyroidism and growth hormone deficiency should be considered in the differential diagnosis of unexplained perinatal sinus bradycardia because early diagnosis may help to avoid potential complications (ie, mental retardation, severe hypoglycemia, and growth anomaly).

Nous présentons un cas de bradycardie sinusale fœtale significative constituant l'unique signe de déficit hypophysaire combiné d'origine congénitale. Une bradycardie sinusale fœtale avec un rythme cardiaque inférieur à 120 battements par minute a été détectée au cours de la 36e semaine d'une grossesse par ailleurs sans complications. La bradycardie sinusale a persisté après la naissance. Une hypothyroïdie ainsi qu'un déficit en hormone de croissance d'origine congénitale ont été constatés ultérieurement. Une supplémentation hormonale a permis de normaliser rapidement le rythme sinusal. L'hypothyroïdie et le déficit en hormone de croissance doivent être pris en compte dans le diagnostic différentiel d'une bradycardie sinusale périnatale inexpliquée, car un diagnostic précoce peut aider à éviter des complications potentielles (retard mental, hypoglycémie sévère et anomalie de croissance).

Inflammatory Cytokine Profiles in Visceral and Subcutaneous Adipose Tissues of Obese Patients Undergoing Bariatric Surgery Reveal Lack of Correlation With Obesity or Diabetes.

Population studies have linked insulin resistance to systemic low-grade chronic inflammation and have reported elevated levels of inflammatory cytokines such as TNFα, IL-1ß and IL-6, individually or in certain combinations, in adipose tissues or in the serum. We undertook this comprehensive study to simultaneously evaluate the expression of several pro-inflammatory and anti-inflammatory cytokines in serum and in the visceral and subcutaneous adipose tissues from obese patients undergoing bariatric surgery. We observed that several inflammatory cytokines implicated in obesity-associated inflammation showed no significant difference in protein or gene expression between obese patients with or without diabetes and control groups. IL1B gene expression was significantly elevated in the visceral adipose tissues of obese patients, but did not correlate with their diabetes status. Despite the significant increase in IL1B expression in the obese group, a significant proportion of obese patients did not express TNFA, IL1B or IL6 in visceral adipose tissues. Certain inflammatory cytokines showed correlation with the chemokine CCL2 and VEGF-A in visceral adipose tissues. Our findings suggest that the inflammatory cytokine profile in metabolic syndrome is more complex than what is currently perceived and that chronic inflammation in obese patients likely results from incremental contribution from different cytokines and possibly other inflammatory mediators from within and outside the adipose tissues. It is possible that this obesity associated chronic inflammation is not predicted by a single mediator, but rather includes a large spectrum of possible profiles.

Recurrent hypoglycaemia in a toddler on ß-blocker therapy.

Hypoglycaemia is a well-known side effect of Propranolol. We described the case of a child presenting severe and recurrent Propranolol-induced hypoglycaemia. Those episodes were not related to prolonged fasting and were associated with only mild ketosis. Thus, therapy with ß blockers may not only aggravate classical ketotic hypoglycaemia but also interfere with glucose metabolism.

Impaired immune regulation after radioiodine therapy for Graves' disease and the protective effect of Methimazole.

Both therapies for Graves' disease (GD), radioactive iodine (RAI) and antithyroid drugs (ATD), were reported to have specific immune effects. We aimed at investigating the effects of RAI therapy on cellular subsets involved in immune regulation. We conducted a thirty day follow-up prospective cohort study of adult patients. Patients eligible for RAI therapy at our centre were approached. Twenty seven patients with GD were recruited, among whom 11 were treated with ATD. Twenty-two healthy subjects (HS) were also studied. Over time, frequency of regulatory T cells (Treg) and of invariant natural killer T cells (iNKT), along with Treg cell-mediated suppression and underlying mechanisms, were monitored in the peripheral blood. Variance in frequency of Treg and iNKT after RAI therapy was higher in GD patients than in HS over time (p < 0.0001). Reduced Treg suppressive function was observed after RAI therapy in GD patients (p = 0.002). ATD medication prior to RAI dampened these outcomes: less variation of Treg frequency (p = 0.0394), a trend toward less impaired Treg function, and prevention of reduced levels of suppressive cytokines (p < 0.05). Shortly after RAI therapy, alterations in immunoregulatory cells in patients with GD were observed and partially prevented by an ATD pretreatment. Worsening of autoimmunity after RAI was explained in previous studies by enhanced immune activity. This study adds new highlights on immune regulation deficiencies after therapeutic interventions in thyroid autoimmunity.

Interferon-gamma ELISPOT detecting reactivity of T cells to TSH receptor peptides in Graves' disease.

OBJECTIVE: While thyrotrophin receptor (TSHR) is recognized as the main autoantigen in Graves' disease (GD), the actual antigen specificity of T cells that infiltrate the thyroid and the orbit is unknown. Identifying T cell responses to TSHR peptides has been difficult in the past due to the low frequency of autoreactive T cells and to the diversity of the putative epitopes identified by proliferation assays. METHODS: We used the interferon-gamma ELISPOT assay to identify T cell reactivity to TSHR peptides in patients with GD. Peripheral blood T cells were exposed in vitro to four pools of 10 overlapping TSHR peptides. RESULTS: T cells from 11 of 31 (35%) patients with GD and 1 of 22 (4%) healthy controls reacted to at least one peptide pool (P = 0·009). Mean time since diagnosis was 3·2 years in responder patients and 5·6 years in nonresponders (P = 0·07). In two patients, T cell reactivity was observed shortly after radioiodine treatment and not thereafter. CONCLUSIONS: Our findings demonstrate that the ELISPOT assay is effective to test T cell reactivity in patients with GD and that patients with GD have significantly more interferon-gamma responses towards TSHR peptides than controls. The data suggest that screening for T cell responses in patients with GD might be more efficient in recent-onset disease or after radioiodine treatment.

Clinical review: Bariatric surgery following treatment for craniopharyngioma: a systematic review and individual-level data meta-analysis.

OBJECTIVES: Craniopharyngiomas are rare low-grade tumors located in the hypothalamic and/or pituitary region. Hypothalamic involvement and treatment resulting in hypothalamic damage are known to lead to development of "hypothalamic obesity" (HyOb) in 50% of cases. The management of HyOb, associated with eating disorders and rapid comorbidities, is an important issue. Bariatric surgery is the most effective therapy for weight loss in patients with severe exogenous obesity. The aim of this systematic review and meta-analysis was to determine the 12-month outcome of bariatric surgery for HyOb due to craniopharyngioma treatment. METHODS AND RESULTS: Relevant studies were identified by searches of the MEDLINE and EMBASE databases until January 2013. A total of 21 cases were included: 6 with adjustable gastric banding, 8 with sleeve gastrectomy, 6 with Roux-en-Y gastric bypass, and 1 with biliopancreatic diversion. After data pooling, mean weight difference was -20.9 kg after 6 months (95% confidence interval [CI], -35.4, -6.3) and -15.1 kg after 12 months (95% CI, -31.7, +1.4). The maximal mean weight loss was achieved by the gastric bypass group: -31.0 kg (95% CI, -77.5, +15.5) and -33.7 kg (95% CI, -80.7, +13.3) after 6 and 12 months, respectively. CONCLUSIONS: In this largest ever published study on the effect of bariatric surgery on obesity after craniopharyngioma treatment, we observed an important weight loss after 1 year of follow-up. Larger studies are warranted to establish appropriate selection criteria and the best surgical technique to perform bariatric surgery.

Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed?

OBJECTIVES: To search for evidence of acute adrenal failure linked to inappropriate use of stress management protocols. STUDY DESIGN: Patients followed up for primary adrenal insufficiency (n = 102) or secondary adrenal insufficiency (n = 34) between 1973 and 2007 were included. All hospitalizations, both urgent (n = 157) and elective (n = 90), were examined. We recorded clinical evidence of acute adrenal failure, parental management before admission, and details of glucocorticoid prescription and administration in the hospital setting. RESULTS: For urgent hospitalizations, subgroup and time period did not influence the percentage of patients hospitalized (primary adrenal insufficiency 45%; secondary adrenal insufficiency 38%; P = .55). The use of stress glucocorticoid doses by parents increased significantly after 1997 (P < .05), although still only 47% increased glucocorticoids before hospitalization. Stress doses were more frequently administered on arrival in our emergency department after 1990 (P < .05); patients with signs or symptoms of acute adrenal failure decreased to 27% after 1997 (P < .01). Twenty-four percent of all hospitalizations were marked by suboptimal adherence to glucocorticoid stress protocols, with rare but significant clinical consequences. CONCLUSIONS: In spite of an increased use of glucocorticoid stress dose protocols by parents and physicians, patients remain at risk of morbidity and death from acute adrenal failure. This risk may be minimized with conscientious application of stress protocols, but other patient-specific risk factors may also be implicated.

21-Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addison's disease.

In autoimmune adrenal deficiency, autoantibodies target the 21-hydroxylase (21OH) protein. However, it is presumed that autoreactive T cells, rather than antibodies, are the main effectors of adrenal gland destruction, but their identification is still lacking. We performed a T-cell epitope mapping study using 49 overlapping 20mer peptides covering the 21OH sequence in patients with isolated Addison's disease, Autoimmune Polyendocrine Syndrome 1 and 2. IFNγ ELISPOT responses against these peptides were stronger, broader and more prevalent among patients than in controls, whatever the disease presentation. Five peptides elicited T-cell responses in patients only (68% sensitivity, 100% specificity). Blocking experiments identified IFNγ-producing cells as CD8 T lymphocytes, with two peptides frequently recognized in HLA-B8+ patients and a third one targeted in HLA-B35+ subjects. In particular, the 21OH(431-450) peptide was highly immunodominant, as it was recognized in more than 30% of patients, all carrying the HLA-B8 restriction element. This 21OH(431-450) region contained an EPLARLEL octamer (21OH(431-438)) predicted to bind to HLA-B8 with high affinity. Indeed, circulating EPLARLEL-specific CD8 T cells were detected at significant frequencies in HLA-B8+ patients but not in controls by HLA tetramer staining. This report enlightens disease-specific T-cell biomarkers and epitopes targeted in autoimmune adrenal deficiency.

Essential role for TLR9 in prime but not prime-boost plasmid DNA vaccination to activate dendritic cells and protect from lethal viral infection.

One of the requirements for efficient vaccination against infection is to achieve the best combination of an adequate adjuvant with the antigenic information to deliver. Although plasmid DNA is a promising tool bearing the unique potential to activate humoral and cellular immunity, an actual challenge is to increase plasmid immunogenicity in human vaccination protocols in which efficacy has proven rather limited. Previous work showed that the bacterial DNA backbone of the plasmid has potent adjuvant properties because it contains CpG motifs that are particular activating nucleotidic sequences. Among TLRs, which are key sensors of microbial products, TLR9 can detect CpG motifs and confer activation of APCs, such as dendritic cells. However, whether the immunogenic properties of plasmid DNA involve TLR9 signaling has not been clearly established. In the current study, we demonstrate that TLR9 determines the effectiveness of vaccination against lethal lymphocytic choriomeningitis virus infection using plasmid DNA in a prime, but not prime-boost, vaccination regimen. Furthermore, we provide evidence that the presence of TLR9 in dendritic cells is necessary for effective and functional priming of virus-specific CD8+ T cells upon plasmid exposure in vitro or single-dose vaccination in vivo. Therefore, at single or low vaccine doses that are often used in human-vaccination protocols, CpG/TLR9 interactions participate in the immunogenicity of plasmid DNA. These results suggest that the TLR9 signaling pathway is involved in the efficacy of plasmid vaccination; therefore, it should remain a focus in the development or amelioration of vaccines to treat infections in humans.

Genetic-induced variations in the GAD65 T-cell repertoire governs efficacy of anti-CD3/GAD65 combination therapy in new-onset type 1 diabetes.

To enhance efficacy of forthcoming type 1 diabetes (T1D) clinical trials, combination therapies (CTs) are envisaged. In this study, we showed that efficacy of a CT, using anti-CD3 antibody and glutamic acid decarboxylase of 65 kd (GAD65)-expressing plasmid, to reverse new-onset T1D was dependent upon the genetic background. Synergism between both treatments was only observed in the RIP-LCMV-GP but not in the nonobese diabetic (NOD) or RIP-LCMV-NOD models. Efficacy was associated with an expansion of bystander suppressor regulatory T cells (Tregs) recognizing the C-terminal region of GAD65 and secreting interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and interferon-gamma (IFN-gamma). In addition, we found that frequency and epitope specificity of GAD65-reactive CD4(+) T cells during antigen priming at diabetes onset and Tregs detected after CT correlated. Consequently, NOD mice harbored significantly lower levels of GAD65-reactive CD4(+) T cells than RIP-LCMV-GP before and after treatment. Our results demonstrate that antigen-specific T cells available at treatment may differ between various major histocompatibility complex (MHC) and genetic backgrounds. These cells play a major role in shaping T-cell responses following antigen-specific immune intervention and determine whether a beneficial Tregs response is generated. Our findings hold important implications to understand and predict the success of antigen-based clinical trials, where responsiveness to immunotherapy might vary from patient to patient.

Outcome after bariatric surgery in two adolescents with hypothalamic obesity following treatment of craniopharyngioma.

Treatment of craniopharyngioma (CP) in childhood can lead to severe, debilitating obesity with devastating medical and psychological outcomes. Despite sustained nutritional and exercise-oriented interventions, no efficacious medical option is available for hypothalamic obesity. We describe two adolescents who developed morbid obesity and significant comorbidities following diagnosis and treatment of CP, in whom bariatric surgery was achieved, illustrating a novel approach for symptomatic hypothalamic obesity, as well as positive and negative outcomes.

Gonadotrophic status in adolescents with pituitary stalk interruption syndrome.

OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a frequent cause of GH deficiency (GHD) and is commonly associated with other PH deficiencies (PHDs). Although previous reports have correlated multiple PHDs with severe anatomical lesions, the status of the gonadotrophic axis has not yet been thoroughly analysed. METHODS: We retrospectively reviewed the medical records of 27 patients (15 males, 12 females) with GHD and PSIS defined by MRI findings. The status of the gonadotrophic axis was evaluated in children who were at least 14.5 years (boys) or 13 years (girls). RESULTS: Out of 27 patients, five displayed spontaneous full pubertal development with normal hormonal values at the final evaluation, whereas 22 of 27 patients (81%) had complete (n = 18) or partial pubertal deficiency. Three girls had primary amenorrhoea with normal gonadotrophin values, raising the possibility of subtle disturbances of gonadotrophin pulsatility. Of the 21 patients with TSH or ACTH deficiency, 17 (81%) had complete gonadotrophin deficiency. Two of our six patients with apparently isolated GHD during childhood had gonadotrophin deficiency. Cryptorchidism was present at birth in six boys (40%). Of these six boys, one had normal pubertal development. Ten of 11 boys with micropenis at birth had gonadotrophin deficiency. CONCLUSIONS: Gonadotrophin deficiency is a common finding in adolescents with PSIS and is frequently associated with other PHDs. However its severity is variable, ranging from complete gonadotrophin deficiency to normogonadotrophic amenorrhoea. The occurrence of gonadotrophin deficiency in 33% of children with apparently isolated GHD and PSIS has important implications for the counselling and follow-up of these patients.

Progress in the development of immune-based therapies for type 1 diabetes mellitus.

Between ten and twenty million people worldwide have type 1 diabetes mellitus (T1DM), which has previously been called juvenile diabetes, childhood diabetes, and insulin-dependent diabetes mellitus. T1DM is undoubtedly a multifactorial disease affecting predisposed individuals with genetic susceptibilities; it is also associated with environmental factors leading to unbalanced immune responses. This chronic disorder is caused by auto-aggressive T lymphocytes entering the pancreatic islets of Langerhans where they destroy the insulin-producing beta-cells. A wide variety of immuno-interventions cure T1DM effectively in different animal models when given early in disease development. However, few of these interventions are efficacious in humans at a later stage of the disease. Indeed, only three immunotherapeutic compounds have demonstrated both safety and efficacy in phase II/III clinical trials. Although much time and resources have been spent on generating potent immune therapies, none of the patients enrolled in these trials have achieved normoglycemia in the absence of insulin injections. Many reasons can account for such a disappointing conclusion. Firstly, the dynamics of disease pathogenesis differs significantly from patient to patient, which directly impacts the therapeutic efficacy. Also, at trial entry, the percentage of remaining pancreatic beta-cells in T1DM patients often reflects the odds of responding positively to treatment. Based on the knowledge we have gained from preclinical studies and clinical trials, several steps have been made in the development of safer and more efficient immune-based therapies. There are, however, a number of concerns that should be addressed in order to improve future therapeutic strategies.