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Since their advent in daily clinical practice, continuous subcutaneous insulin infusion (CSII) systems have been increasingly improved, leading to a high percentage of both adult and pediatric patients with diabetes now using insulin pumps. Different types of CSII systems are currently available, which are characterized by different settings and technical features. This longitudinal observational study aims to evaluate real-word glycemic outcomes in children and adolescents with type 1 diabetes using three different CSII devices: hybrid closed-loop (HCL) systems, predictive low glucose (PLGS) systems, and non-automated insulin pumps. The secondary objective was to identify clinical variables that may significantly influence the achievement of therapeutic goals in our study cohort. One-hundred-and-one patients on CSII therapy attending our pediatric diabetes center were enrolled. When compared with the non-automated group, patients using HCL systems showed higher levels of time in target glucose range (p = 0.003) and lower glucose variability (p = 0.008). Similarly, we found significantly better glucose metrics in HCL users in comparison to PLGS patients (time in range p = 0.008; coefficient of variation p = 0.009; time above 250 mg/dL p = 0.007). Multiple linear regression models showed that HCL systems (time in range p < 0.001) and high daily percentage of glycemic sensor use (time in range p = 0.031) are predictors for good glycemic control. The introduction and increasing availability of novel technologies for diabetes represent a promising strategy to improve glycemic control and quality of life in pediatric patients with type 1 diabetes. Our real-world data confirm the superiority of HCL systems in terms of improvement of time spent in the target glucose range, prevention of hypoglycemia, and reduction of glycemic variability.

Background Although type 1 diabetes (T1D) represents one of the most common chronic diseases in pediatric age, few studies on the epidemiology of T1D exist globally and the exact prevalence and incidence rates of the disease are unknown. In many countries, including Italy, national registries are missing. Methods This study aims to assess T1D incidence in the pediatric population of the Calabria region (southern Italy) in the period 2019–2021. The secondary objective was to describe the main demographical, clinical and immunological features of incident cases. Case ascertainment and all clinical data were assessed by retrospectively reviewing the electronic medical records of children and adolescents diagnosed with diabetes at any Pediatric Diabetes Center belonging to the Rete Diabetologica Calabrese (Calabria Region Diabetes Network), from January 2019 to December 2021. The incidence of T1D was estimated for the entire region and was stratified according to age group (0–4 years, 5–9 years, and 10–14 years) and gender. Standardized incidence ratios for each province in the region were also calculated. Results The crude incidence of T1D was 20.6/100,000 person/years. Incidence rates were higher among females and children aged 5–9 years. The crude incidence of T1D was higher in the province of Reggio Calabria (26.5/100,000 person-years). The provinces of Crotone, Catanzaro, and Vibo Valentia showed significantly lower standardized incidence ratios. The annual incidence in the region progressively increased by 43% during the study period. Conclusions Our study revealed a relatively high incidence in the Calabria region. The marked increasing incidence trend over the past two years could be related to the global impact of the COVID-19 pandemic, but further long-scale population-based studies are needed to confirm these findings.

Skin involvement is an overlooked aspect in the management of paediatric patients with type 1 diabetes. A comprehensive search of published literature using the PubMed database was carried out using the following key terms: “children”, “pediatric/paediatric patients”, “skin”, “skin disorders”, “type 1 diabetes”. Dermatological side effects are frequently observed among diabetic children and adolescents. Insulin-induced lipodystrophies and allergic contact dermatitis caused by insulin pumps or glycaemic sensors are the most common skin reactions in these patients. Furthermore, several diabetes-associated skin diseases such as necrobiosis lipoidica, granuloma annulare, vitiligo, and bullosis diabeticorum may already be present in paediatric age. Paediatric diabetes specialists should pay attention to their patients’ skin so as to recognize these disorders, identify the potential causes, and choose the most suitable treatment. Finally, the evaluation of skin concentrations of advanced glycation end-products using non-invasive diagnostic techniques may be used to assess the risk of chronic complications of diabetes as early as adolescence.

Thyroid cancer (TC) in childhood is a rare disease characterized by an excellent prognosis. Thyroid nodules in children, although less common than in adults, have a greater risk of malignancies, particularly in those cases associated with anamnestic, clinical and ultrasonographic risk factors. Among the factors, which have been found to be linked with an increased relative risk of TC in children, an important role seems to be possibly played by an underlying nodular Hashimoto’s thyroiditis (HT) and by the serum levels of TSH. Aim of this Commentary was to specifically address this last point. According to the available pediatric literature on the relationships between these risk factors and phenotypical expression of TC in children, it is possible to conclude that: 1) It is not completely clarified if HT per se predisposes to malignancy or if it represents an incidental histologic finding in cases with TC or if it may be the result of an immune response against tumoral cells. 2) It is unclear whether phenotypic expression of TC is more severe in the cases with associated HT but normal TSH serum levels. 3) Persistently elevated TSH levels play an independent role as predictors of the likelihood of TC, especially in children but also in adults. 4) Patients with nodular HT and subclinical hypothyroidism need to be treated with Levothyroxine in order to prevent the development of both TC and severe thyroid dysfunctions.

Background Hepatic glycogenosis is characterized by excessive glycogen accumulation in hepatocytes and represents a complication of poor controlled type 1 diabetes. It can be caused by excessive insulin doses or recurrent ketoacidosis episodes. Mauriac’s syndrome is a rare disease, which includes short stature, growth maturation delay, dyslipidemia, moon facies, protuberant abdomen, hepatomegaly with transaminase elevation. It has become even less common after the emergence of advances on diabetes treatment, but still exists. Recent reports described glycogenosis without the full spectrum of Mauriac’s syndrome in both adults and children with brittle diabetes. Clinical, laboratory and histological abnormalities are reversible with appropriate glycemic control. Case presentation We hereby report a case of 11-year-old male who presented with hepatic glycogenosis mimicking Mauriac’s syndrome. The patient was admitted at our Pediatric Diabetes Clinic for marked hepatomegaly, short stature and for the poor metabolic control. Blood investigations and liver tests excluded most of major causes of hepatopathy. A liver biopsy allowed us to make diagnosis of hepatic glycogenosis. To control hyperglycaemia, initially we titrated daily insulin dosage, and then intravenous insulin treatment was practiced with the consequent normalization of liver enzymes. Conclusion Mauriac’s syndrome should be considered in subjects with brittle type 1 diabetes and hepatomegaly.

Aim To compare nasal glucagon (NG) with intramuscular glucagon (IMG) for the treatment of insulin‐induced hypoglycaemia in Japanese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). Materials and methods This phase 3, randomized, open‐label, two‐treatment, two‐period crossover non‐inferiority study enrolled Japanese adults with T1DM or T2DM on insulin therapy, with glycated haemoglobin levels ≤86 mmol/mol (≤10%). After ≥8 hours of fasting, hypoglycaemia was induced with human regular insulin (intravenous infusion). Patients received NG 3 mg or IMG 1 mg approximately 5 minutes after insulin termination. The primary endpoint was the proportion of patients achieving treatment success [plasma glucose (PG) increase to ≥3.9 mmol/L (≥70 mg/dL) or ≥1.1 mmol/L (≥20 mg/dL) increase from the PG nadir within 30 minutes of receiving glucagon]. Non‐inferiority was declared if the upper limit of the two‐sided 95% confidence interval (CI) of the mean difference in the percentage of patients achieving treatment success (IMG minus NG) was 2 patients were rhinalgia, increased blood pressure, nausea, ear pain and vomiting in the NG group, and nausea and vomiting in the IMG group. Conclusion Nasal glucagon was non‐inferior to IMG for successful treatment of insulin‐induced hypoglycaemia in Japanese patients with T1DM/T2DM, supporting use of NG as a rescue treatment for severe hypoglycaemia.

Aim: To evaluate the impact of a virtual educational camp (vEC) on glucose control in children and adolescents with type 1 diabetes using a closed-loop control (CLC) system. Materials and Methods: This was a prospective multicentre study of children and adolescents with type 1 diabetes using the Tandem Basal-IQ system. Insulin pumps were upgraded to Control-IQ, and children and their parents participated in a 3-day multidisciplinary vEC. Clinical data, glucose metrics and HbA1c were evaluated over the 12 weeks prior to the Control-IQ update and over the 12 weeks after the vEC. Results: Forty-three children and adolescents (aged 7-16 years) with type 1 diabetes and their families participated in the vEC. The median percentage of time in target range (70-180 mg/dL; TIR) increased from 64% (interquartile range [IQR] 56%-73%) with Basal-IQ to 76% (IQR 71%-81%) with Control-IQ (P&nbsp

Introduction: Despite advances in the management of type 1 diabetes (T1D), there is an increasing incidence of skin reactions related to diabetes devices such as patch pumps and glucose sensors. Aim of the present study was to assess the prevalence of dermatological complications in pediatric patients with T1D using technological devices. Methods: Online survey regarding skin reactions related to the use of patch pumps and/or glucose sensors was administered to families of children and adolescents (0-17 years) with T1D. Data were collected on demographic characteristics, duration of diabetes, and clinical features of dermatological complications if present. Results: Our study population consisted of 139 patients (female 51.8%) aged 11.1 ± 3.3 years. More than half (51.1%) experienced skin reactions due to patch pumps or glucose sensors. Dermatological complications were mainly caused by continuous glucose monitoring (56.3% of total). Timing of appearance of dermatological reactions varied from a few days to several months after the introduction of the device. The application of hypoallergenic barrier bandages was the most frequently adopted measure to solve the issue. Conclusions: Our study confirmed high frequency of dermatological complications among pediatric patients with type 1 diabetes. Well-designed studies are awaited to provide clear recommendations to minimize the burden of skin issues related to technological devices.

Partial clinical remission (PCR) is a transitory period characterized by the residual endogenous insulin secretion following type 1 diabetes (T1D) diagnosis and introducing the insulin therapy. Scientific interest in PCR has been recently increasing, as this phase could be crucial to preserve functional beta cells after T1D onset, also taking advantage of new therapeutic opportunities. The aim of this study was to assess the frequency, duration and associated factors of PCR in children newly diagnosed with T1D. Our cohort study included 167 pediatric patients aged 13.8 &plusmn, 4.1 years. The association of clinical and laboratory factors with the occurrence and duration of PCR was evaluated via logistic regression and multivariable generalized linear model, respectively. PCR occurred in 63.5% of the examined patients. Patients who achieved the remission phase were significantly older, and they had lower daily insulin requirement compared with non-remitters. PCR was positively associated to body mass index (OR = 1.11, p = 0.032), pH value (OR 49.02, p = 0.003) and c-peptide levels (OR 12.8, p = 0.002). The average duration of PCR was 13.4 months, and older age at diagnosis was the only predictor factor. Two years after diagnosis remitter patients had lower HbA1c and daily insulin requirement.

The recent EAACI/GA2 LEN/EDF/WAO guidelines recommend omalizumab (anti-IgE) for the management of patients aged ≥12 years with chronic urticaria unresponsive to high-doses second-generation H1 -antihistamines (antiH1 ). However, there is little published information on the success of omalizumab for such a treatment in children. We reported our experience of six patients with chronic spontaneous urticaria (CSU) treated with omalizumab. Mean age of our case series was 14.7 years (range 11-16 years) with a prevalence of male gender (66.7%). All six patients were treated with at least one 6-months course of omalizumab. The average follow-up period was 13 ± 6 months. Only one patient was no responder to omalizumab therapy. Thus far, two patients have experienced a complete CSU regression over 12 months after the final omalizumab administration. The remaining three patients needed a second course of treatment. Our experience demonstrates that omalizumab is effective and safe as treatment option for CSU unresponsive to antiH1 , even in adolescent age.

Background: Glucose sensors consist of real-time continuous glucose monitoring (rtCGM) and intermittently scanned CGM (isCGM). Their clinical use has been widely increasing during the past 5 years. The aim of this study is to evaluate percentage of time in range (TIR) in a large group of children with type 1 diabetes (T1D) using glucose sensors with nonautomated insulin delivery systems, in a real-world setting. Methods: An 11-center cross-sectional study was conducted during January-May 2019. Children with T1D 1 year, treated with multiple daily injections (MDI) or nonautomated insulin pump (IP), were recruited consecutively. Clinical data, HbA1c measurement, and CGM downloaded data were collected by each center and included in a centralized database for the analysis. Glucose metrics of four treatment strategies were analyzed: isCGM-MDI, rtCGM-MDI, isCGM-IP, and rtCGM-IP. Results: Data from 666 children with T1D (51% male and 49% female), median age 12 years, diabetes duration 5 years, were analyzed. An rtCGM was used by 51% of the participants, and a nonautomated IP by 46%. For isCGM-MDI, rtCGM-MDI, isCGM-IP, and rtCGM-IP, the median TIR 70-180 mg/dL values were 49%, 56%, 56%, and 61% (P < 0.001), respectively; HbA1c 7.6%, 7.5%, 7.3%, and 7.3% (P < 0.001), respectively. Use of rtCGM was associated with significant lower time below target range 180 mg/dL and lower HbA1c. If there are no barriers, an upgrade of the treatment strategy with a higher performing technology should be offered to all children who do not achieve blood glucose metrics within the suggested range.

Aims Aim of our observational study was to assess the prevalence of allergic contact dermatitis among children and adolescents with type 1 diabetes who use technological devices for diabetes treatment and its management. Secondary outcome was to identify possible clinical and/or demographic variables that could be associated to contact dermatitis. Methods Among a total of 215 patients using insulin pumps and/or glucose sensors followed-up at our Pediatric Diabetes Centre between January and September 2018, 64 patients were enrolled and 42 (19 male and 23 female) completed the study. Demographic and clinical features of the study population were statistically analysed. All the patients underwent patch testing with specific allergens belonged to resin and acrylate classes. Results Eighteen patients experienced skin reactions suggestive of allergic contact dermatitis, demonstrating a prevalence of 8.4%. None of the demographic or clinical variables were associated to skin reactions. Colophonium was the most identified sensitizing allergen (87.5% of the cases). Conclusions The rate of sensitization to allergens included into diabetes devices among pediatric patients is higher than commonly assumed. Well-designed studies are needed to better investigate the association between type 1 diabetes and allergic contact dermatitis. Moreover, we suggest that manufactures should supply detailed information about adhesives in order to avoid dermatological complications and consequently a worsening of disease management and patients’ quality of life.

We studied 45 patients with Wolfram syndrome 1 (WS1) to describe their clinical history and to search for possible genotype–phenotype correlations. Clinical criteria contributing to WS1 diagnosis were analyzed. The patients were classified into three genotypic classes according to type of detected mutations. WS1 prevalence in Italy is 0.74/1,000,000. All four manifestations of DIDMOAD were found in 46.7% of patients. Differently combined WS1 clinical features were detected in 53.3% of patients. We found 35 WFS1 different mutations and a novel missense mutation, c.1523A>G. WS1 patients were homozygotes or compound heterozygotes for WFS1 mutations except for 2 heterozygote patients (4.5%). Each genotypic group exhibited a different age onset of DM, D, and DI but not of OA. Genotypic Group 2 patients manifested a lower number of clinical manifestations compared to Groups 1 and 3. Moreover, genotypic Group 1 patients tended to have a shorter survival time than the other groups. No differences were found regarding type of clinical pictures. Our study suggested that molecular WFS1 typing is a useful tool for early assessment of clinical history, follow-up, and prognosis of WS1.

Aims Our observational study aimed to evaluate the impact of the lockdown period due to 2019 Coronavirus disease pandemic on glycaemic control in a cohort of paediatric patients with type 1 diabetes (T1D). Methods Eighty-five patients with T1D aged 5–18 years using continuous glucose monitoring (CGM) systems were enrolled. Demographic and clinical data, including glucose metrics generated by CGM-specific web-based cloud platforms, were collected in three different periods (pre-lockdown phase, lockdown phase, and post-lockdown phase) of 90 days each and were statistically analysed. Results During the lockdown period, a clear improvement in almost all CGM metrics (time in range, time above range, coefficient of variation, and glucose management indicator) was observed in our study population, regardless of age and insulin type treatment. In the months following lockdown, maintaining satisfactory diabetes outcomes was confirmed only in younger patients (aged 5–9 years) and in those individuals on hybrid closed loop therapy. Conclusions The increasing use of innovative technological devices together with data sharing systems and interaction with multidisciplinary diabetes team through telemedicine allowed paediatric patients with T1D to improve glucose metrics during the lockdown period. However, our findings showed that the achievement of better glycaemic control was transient for most patients.

Context An etiologic diagnosis of diabetes can affect the therapeutic strategy and prognosis of chronic complications. Objective The aim of the present study was to establish the relative percentage of different diabetes subtypes in patients attending Italian pediatric diabetes centers and the influence of an etiologic diagnosis on therapy. Design, setting, and patients This was a retrospective study. The clinical records of 3781 consecutive patients (age, 0 to 18 years) referred to 15 pediatric diabetes clinics with a diagnosis of diabetes or impaired fasting glucose from January 1, 2007 to December 31, 2012 were examined. The clinical characteristics of the patients at their first referral to the centers, type 1 diabetes-related autoantibodies, molecular genetics records, and C-peptide measurements, if requested for the etiologic diagnosis, were acquired. Main outcome measures The primary outcome was to assess the percentage of each diabetes subtype in our sample. Results Type 1 diabetes represented the main cause (92.4%) of diabetes in this group of patients, followed by monogenic diabetes, which accounted for 6.3% of cases [maturity onset diabetes of the young (MODY), 5.5%; neonatal diabetes mellitus, 0.6%, genetic syndromes, 0.2%]. A genetic diagnosis prompted the transfer from insulin to sulphonylureas in 12 patients bearing mutations in the HNF1A or KCNJ11 genes. Type 2 diabetes was diagnosed in 1% of the patients. Conclusions Monogenic diabetes is highly prevalent in patients referred to Italian pediatric diabetes centers. A genetic diagnosis guided the therapeutic decisions, allowed the formulation of a prognosis regarding chronic diabetic complications for a relevant number of patients (i.e.,GCK/MODY), and helped to provide genetic counseling.

In the past few years, the increasing use of devices for diabetes treatment, such as continuous subcutaneous insulin infusion pumps, flash glucose monitoring, continuous glucose monitoring systems, sensor-augmented pumps, and automated insulin delivery devices, has resulted in important improvements in disease management. Meanwhile, the longer a patient uses a device, the greater the likelihood of developing a skin reaction. Allergic contact dermatitis is the most frequently described skin side effect caused by adhesive tapes contained in the insulin infusion sets or glucose sensor sets and used to connect these devices to the body. We describe 18 patients, followed up at our Pediatric Diabetes Centre, who experienced dermatological complications due to diabetes device use from January 2018 to December 2018. All the patients were patch tested with allergens from a "standard" series and from a "plastics and glues" series. Patch tests resulted positive in 66.7% of patients. Colophonium was the most frequently isolated sensitizing allergen (41.1% of cases). It is a complex mixture of >100 compounds derived from pine trees. Colophonium is commonly used, in both unmodified and modified forms, as a fast-acting adhesive for industrial, medical, or other commercial uses. Its presence in the adhesive of the insulin sets and glucose sensors was confirmed by the manufacturer of some devices brand. On the basis of our results, we stress the importance of contacting manufacturers for product information. We also highlight that there should be stricter legal restrictions to label medical adhesives, even if only small amounts of colophonium are used.

Background Currently, severe allergic asthma and food allergy in children represent an important public health problem with medical, psychosocial and economic impacts. Omalizumab is a humanized monoclonal anti-IgE antibody, approved for refractory allergic asthma and chronic urticaria. It has been widely used in clinical practice as add-on therapy in patients with severe uncontrolled allergic asthma. In recent years there has seen the emergence of an allergic epidemic with increasing food allergy, which represents the main cause of anaphylaxis in children. The standard of care for food allergy is strictly dietary allergen avoidance and emergency treatment, but recent clinical trials have suggested that omalizumab may have a role to play as an adjuvant to oral immunotherapy (OIT). We present a case series of patients treated at our institution with omalizumab for severe allergic asthma and food allergy. Methods Patients received omalizumab according to a standard reference nomogram after failing standard therapies. In children with comorbid severe food allergy, omalizumab was administered in conjunction with an oral immunotherapy protocol. Results Omalizumab was effective in controlling symptoms of allergic asthma, allergic rhinitis and rhinosinusitis, but not eosinophilic esophagitis, while aiding successful oral desensitization of comorbid severe food allergies. Conclusions Omalizumab appears to be an excellent therapeutic option in children with inadequately controlled severe allergic asthma, allergic rhinitis and rhinosinusitis, with or without food allergy.

Aim of this commentary is to report current knowledges on the main clinical and metabolic abnormalities which might be observed in children with longstanding and untreated subclinical hypothyroidism (SH) and to comment the most recent views about natural evolution of thyroid function in the cases with either idiopathic or Hashimoto’s thyroiditis-related SH. On the basis of these preliminary remarks, the essential guidelines for an appropriate and tailored management of SH children are also proposed.

Aim of this commentary is to analyze the current views about the phenotypic features of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) in Turner syndrome (TS) girls, in terms of epidemiology, clinical and biochemical presentation, long-term course and metamorphic autoimmunity evolution. In TS GD course is not atypical, whereas HT course is characterized by both a mild presenting picture and a severe long-term evolution of thyroid function tests. Furthermore, TS girls seem to have an increased risk of switching over time from HT to GD. On the light of these findings, it may be concluded that TS girls with HT need a careful monitoring of thyroid status over time. Conclusions: 1) In children the association with TS is able to condition a peculiar phenotypic expression of HT in terms of epidemiology, presentation course and long-term metamorphic autoimmunity; 2) by contrast, children with TS do not exhibit an atypical clinical and biochemical course of GD, but only a significantly higher prevalence of this disease.

Aim: To analyze the factors that might allow an early discrimination between permanent (P) and transient (T) congenital hypothyroidism (CH). Methods: Clinical, biochemical and imaging data of 64 children with eutopic gland, who were positively screened and treated for CH during the period 1998-2011, were retrospectively analyzed. Results: During a 3-year treatment period, the mean doses of L-thyroxine (L-T4) per kilogram of body weight at various times were significantly lower in the 46 children with T CH than in the remaining 18 with P CH. No patients with T CH had required any increment of the doses of L-T4 per kilogram of body weight to maintain normal thyroid-stimulating hormone levels over time, whereas 16/18 children with P CH during the same period had needed some dose increments (p < 0.0001). Conclusions: (a) L-T4 requirements >4.9 µg/kg/day at 12 months or >4.27 µg/kg/day at 24 months are highly suggestive of P CH, irrespective of gland ultrasonography; (b) L-T4 requirements

Background Although the autoimmune polyglandular syndrome type 3 (APS-3) is the commonest APS that may be encountered in pediatric age, last year literature includes only few studies aiming to specifically ascertain the clinical spectrum of APS-3 in childhood and adolescence. Aims of these study were: a) to ascertain how many young patients with apparently isolated Hashimoto’s thyroiditis (HT) are at risk of manifesting other autoimmune disorders (ADs) compatible with APS-3; b) to individuate the ADs which most frequently segregate with HT in the context of an APS-3. Methods A selected population of 211 young patients with HT and no risk factors for other APSs was investigated, in order to evaluate the prevalence of other ADs apart from HT and to individuate the ADs which most frequently cluster with HT in the context of APS-3. Results The majority of our patients (70.2%) was found to be affected by no other ADs apart from HT, whereas the remaining 29.8% were classified as affected by an APS-3. The ADs which were found most frequently in aggregation with HT were type 1 diabetes mellitus T1DM (61.9%) and celiac disease CD (22.2%). Conclusions 1) About 30% of young patients with HT may exhibit a clinical picture consistent with APS-3; 2) In the context of APS-3 the ADs that most frequently cluster with HT are T1DM and CD.

Aim of this commentary is to report the most recent views about natural history of subclinical hypothyroidism (SH) according to the different etiologies. In children with idiopathic SH the natural evolution is often favourable, with a high percentage of cases reverting to euthyroidism or remaining SH even after a prolonged follow-up. By contrast, the risk of a significant deterioration of thyroid status is distinctly higher in the SH children with Hashimoto's thyroiditis (HT). This risk is even higher in the cases with both HT-related SH and chromosomal abnormalities, such as Turner or Down's syndrome.

Background: No reviews have specifically addressed, to now, whether autoimmune polyglandular syndromes (APSs) may have a peculiar epidemiology and phenotypical expression in pediatric age. Objectives: To review the most recent literature data about the specific epidemiological and clinical peculiarities of APSs in childhood and adolescence. Design: The main features of the different APSs in pediatric age were compared among them. Conclusions: 1) Among the different APSs, the one that is most typical of pediatric age is APS-1; 2) APS-1 is not characterized only by the classical triad (chronic moniliasis-hyposurrenalism-hypoparathyroidism) and its clinical spectrum is enlarging over time; 3)APS-2 may have a different epidemiological and clinical expression according to two different nosological classifications. (www.actabiomedica.it)

BACKGROUND: Due to the lack of specific pediatric studies, no data are available about natural history of endogenous subclinical hyperthyroidism (SH) in childhood. AIMS: (a) To investigate for the first time the natural history of SH [suppressed thyrotropin (TSH) and normal free thyroxine free thyroxine (FT4) levels] when presenting as initial manifestation of Hashimoto's thyroiditis (HT) in childhood (group A); (b) to compare spontaneous evolution of HT-related SH with that observed in age-matched patients with HT-related frank hyperthyroidism (suppressed TSH and elevated FT4 levels), i.e., Hashitoxicosis Htx (group B). RESULTS: In the 11 patients of group A, TSH normalization spontaneously occurred 1-24 months after diagnosis, while in the 10 patients of group B it occurred 3-9 months after diagnosis, with no differences between the 2 groups in terms of time interval from entry to TSH normalization. In group A, this time interval was related to baseline thyroid peroxidase antibodies (r = 0.78, p = 0.04). During follow-up, eight patients of each group remained euthyroid, whereas two became hypothyroid (in both groups) and one developed Graves' disease (in group A). CONCLUSION: (a) HT should be included among the causes of endogenous SH in pediatric age; (b) in children with HT-related SH, spontaneous normalization of TSH levels occurs within the first 24 months after diagnosis, as well as in age-matched patients with Htx; (c) in both these conditions, a further deterioration of thyroid function might re-present in some patients during follow-up; (d) Ht-related SH and Htx might be possibly seen as different biochemical stages along the same continuum.

Background Cow's milk allergy is common in infancy, and total avoidance of this food is the only effective approach. In alternative, oral immunotherapy has been proposed to achieve tolerance. Once desensitization is achieved, daily intake of milk is recommended to maintain it, but this may be impractical for children/parents. We assessed whether a twice weekly maintenance regimen is effective. Methods Children who were successfully desensitized with oral immunotherapy were randomized to two maintenance regimens for 1 year: group A had to eat 150–200 ml milk daily, group B had to eat 150–200 ml milk twice weekly. Both regimens were associated to a totally free diet. Maintenance of tolerance and adverse events were recorded during 1 year. Specific IgE, IgG4 and prick-by-prick test to milk were carried out before immunotherapy (T0), before maintenance (T1), and after 1 year (T2). Results Recorded episodes included asthma, oral itching, urticaria, rhinitis, abdominal pain variously combined, usually associated with concomitant illness or exercise. The episodes were 8 in group A and 9 in group B, with no difference. None of the children discontinued the feeding maintenance. Specific IgG4 increased at T1 and remained high at T2. Specific IgE and skin reactivity significantly decreased at T2. There was no difference in those parameters between the groups. Conclusion After achieving desensitization to cow milk with oral immunotherapy, a maintenance regimen with milk given twice weekly is as effective as the daily maintenance.

Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE gene mutation. It is characterized by the association of multiple autoimmune diseases, with a classical triad including chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure. Its clinical spectrum has significantly enlarged in the last years with the apparence of new entities. One of these novel manifestations is the chronic inflammatory demyelinating polineuropathy (CIDP), that is characterized by involvement of peripheral nervous system, with nerve demyelination, progressive muscular weakness of both arms and legs and sensory loss. The identification of myelin protein zero as an important autoantigen (Ag) in CIDP may suggest the development of Ag-based therapies, such as Ag-specific DNA vaccination or infusion of Ag-coupled cells.

It is not well known whether the association with Down's syndrome (DS) may be able to affect the phenotypic expression of Hashimoto's thyroiditis (HT).To review the most recent literature data about the specific peculiarities of HT in DS children.The main epidemiological features of DS-related HT were compared with those generally reported in HT children without DS. The prevalence rates of the different thyroid function patterns detected at the time of HT diagnosis and five years later were summarized in Tables 1 and 2.1) the association with DS can condition a peculiar phenotypic expression of HT in pediatric age, as confirmed by the analysis of both epidemiological and biochemical features; 2) in DS children thyroid function status may be severely impaired both at HT presentation and some years later.

BACKGROUND Oral immunotherapy (OIT) for food allergy is gaining interest due to the favorable clinical results reported with cow's milk, hen egg and peanut. The safety of the procedure remains a critical aspect that can limit the introduction of OIT in clinical practice. OBJECTIVE We described herein, in detail, the occurrence and characteristics of adverse events (AE) with OIT in children who participated in controlled trials at our unit. METHODS The clinical records of 68 children who received active treatment (40 for cow's milk and 28 for hen egg) were carefully reviewed. The inclusion and exclusion criteria, and the grading of AEs were the same across the trials. Of the 68 children involved, 6 (9%) had to discontinue the OIT procedure due to severe AEs. Fifty percent of the children underwent the buildup and maintenance phases without AEs. Mild-to-moderate AEs were documented in 28 patients, who could complete the desensitization. The majority of reactions were mild or moderate, occurred during an acute intercurrent illness and required only symptomatic treatment. CONCLUSION A careful review of the patients who received food OIT in controlled trials confirmed that AEs were not rare but that ∼90% of children could achieve an effective desensitization. The procedure remains investigational and should be performed only by trained physicians, especially in the pediatric setting.

Background: Few papers focus on exercise-related blood glucose (BG) in patients on continuous sc insulin infusion (CSII) or multiple daily injections (MDI) with glargine. Aim: The main objective was to evaluate the degree of glycemic control in Type 1 diabetes mellitus adolescents on CSII doing physical activity with pump switched on or off. These findings were also compared with a small group of patients on MDI with glargine. Subjects and methods: Eight patients on CSII (basal rate continued or turned off in alternating sessions) and 5 on MDI joined 4 sessions of moderate-severe exercise. Results: Post-exercise BG significantly increased with the pump off and was unchanged/decreased with the pump on and MDI groups vs baseline. The hypoglycemia rate was not different among the 3 groups at any time. Pump on: hypoglycemias more frequent both at bed-time (p=0.031) and at awakening (p

Aims The long-acting insulin analogue glargine reduces nocturnal hypoglycaemia and stabilizes morning blood glucose levels in patients with Type 1 diabetes (T1DM) on multiple injection therapy. However, young children may not tolerate such intensive insulin regimens. We investigated the effects of glargine in various three-injections-daily insulin combinations on 24-h glucose control in prepubertal children. Methods Seventeen T1DM prepubertal children (10 boys), median age 10.2 years (range 6.0–12.4), glycated haemoglobin (HbA1c) 8.8% (6.8–11.5) were recruited to a randomized, open-label, cross-over study. After a 2-week run-in period (with NPH pre-bed), every child underwent three different 3-week treatment blocks in random order. All treatment blocks included glargine pre-bed, but used different morning insulins: block 1, soluble only; block 2, soluble + NPH; block 3, aspart + NPH. Continuous glucose monitoring was performed for 3 days at the end of the run-in and each treatment block. Results Compared with the run-in period on NPH, the three glargine treatment blocks were associated with lower (P

Primary gonadal failure may occur in most individuals with Turner syndrome (TS). Since ovaries in TS girls undergo premature apoptosis and cryopreservation of ovarian tissue is now feasible, it would be useful to identify a reliable marker of ovarian reserve in these patients. We planned to evaluate ovarian function in a group of TS patients by measuring both traditional markers and inhibin B and to compare these results with those of a control group.We enrolled 23 patients with TS and 17 age-matched healthy girls. The median age of our TS patients was 17.6 years. Three out of the 23 patients (13%) showed spontaneous pubertal development and regular menstrual cycles; the remaining 20 (86.9%) presented with primary amenorrhea.The median level of inhibin B in the TS patients with primary amenorrhea was 42 pg/mL and did not differ significantly among the different subgroups in relation to karyotype. The median inhibin B level in the control group was significantly higher than in the TS girls with primary amenorrhea (83 vs. 42 pg/mL, pTS patients with primary amenorrhea have significantly lower levels of inhibin B than TS girls with spontaneous puberty and healthy controls. Inhibin B does not correlate with follicle-stimulating hormone/luteinizing hormone. If our results are confirmed in further studies, inhibin B could become a first-line screening test for assessing ovarian reserve and a longitudinal marker of the possible decline of ovarian function in TS.

Recent epidemiological studies estimated that more than 30% of European suffer from allergic rhinitis or conjunctivitis, while up to 20% suffer from asthma and 15% from allergic skin conditions, while for many other regions the prevalence is increasing. Allergen immunotherapy represents the only available treatment that can modify the allergic disease process, and thus is worth considering as a treatment in affected individuals. A beneficial effect of allergen immunotherapy has been shown in both adults and children affected by allergic rhinitis, allergic conjunctivitis, allergic asthma and hymenoptera venom allergy. The present study represents an overview on allergen immunotherapy, focusing on the principal aspects of the use of immunotherapy in the past, its recent clinical applications and future outlook.

Type 2 and monogenic diabetes are emerging causes of diabetes in youths. Among 1244 Italian patients

Aim of this commentary is to summarize the salient literature news on the relationships between autoimmune thyroid diseases (ATDs) and either Down syndrome (DS) or Turner syndrome (TS). According to literature reports both Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are more frequent in children with DS or TS than in those without these chromosomopathies. An up-regulation of proinflammatory cytokines might be responsible for the enhanced susceptibility of TS children to ATDs, whereas a dysregulation of immune system may favor the development of ATDs in DS. In TS children biochemical presentation of HT is less severe than in peer controls. In both DS and TS GD picture at the time of diagnosis is not significantly different than in the pediatric general population. The evolution over time of GD in DS and TS does not differ from that observed in the pediatric general population, whereas the evolution of HT in both TS and DS is more severe than in girls without these chromosomopathies. Conclusions: The association with TS or DS is able to affect both epidemiology and course of ATDs by conditioning: a) an increased susceptibility to these disorders; b) a less severe biochemical presentation and a more severe evolutive pattern of HT in TS girls; c) a more severe biochemical presentation and evolution of HT in DS patients.

In this study, which aims to investigate for the first time auditory sensitivity in congenital central hypothyroidism (CH), we concluded that: (1) permanent sensorineural hearing loss may be observed not only in congenital primary disorders of thyroid function, as reported hitherto; (2) it may also be found in patients with congenital CH, at least when substitutive treatment is started many years after thyroid failure presentation; (3) the concept of a ‘critical therapeutic window’ in preventing hearing impairment also holds true for children with congenital CH; (4) the therapeutic window in CH is wider than in primary hypothyroidism; (5) this is probably due to the less severe thyroid impairment in the cases with a central origin of hypothyroidism. These conclusions were suggested by the following data obtained in a cohort of 10 patients with congenital CH who were euthyroid at the time of audiological evaluation thanks to long-standing substitutive therapy: (a) four out of 10 patients exhibited a bilateral sensorineural hearing loss; (b) hearing impaired patients were the oldest of the entire series at diagnosis of hypothyroidism and none of them was aged less than 7 years at the time of the start of replacement therapy; (c) a strong positive relationship was found between age at therapy start and hearing loss.

Background/Aim: Combined growth hormone (GH) and insulin therapy is rarely prescribed by pediatric endocrinologists. We investigated the attitude of Italian physicians to prescribing that therapy in the case of short stature and type-1 diabetes (T1DM). Methods: A questionnaire was sent and if a patient was identified, data on growth and diabetes management were collected. Results: Data from 42 centers (84%) were obtained. Of these, 29 centers reported that the use of combined therapy was usually avoided. A total of 17 patients were treated in 13 centers (GH was started before T1DM onset in 9 patients and after the onset of T1DM in 8). Height SDS patterns during GH therapy in the 11 patients affected by GH deficiency ranged from -0.3 to +3.1 SDS. In the 8 diabetic patients in whom GH was added subsequently, mean insulin dose increased during the first 6 months of therapy from 0.7 ± 0.2 to 1.0 ± 0.2 U/kg (p = 0.004). HbA1c was unchanged during the first 6 months of combined therapy. Conclusions: Most Italian physicians do not consider prescribing the combined GH-insulin therapy in diabetic children with growth problems. However, the results of the 17 patients identified would confirm that the combined therapy was feasible and only caused mild insulin resistance. GH therapy was effective in promoting growth in most patients and did not affect diabetes metabolic control.

Since the original description, there have been only few epidemiological studies of Wolfram syndrome (WS).Aims of the present paper are to ascertain WS prevalence and expression in a district of North-eastern Sicily, i.e. a geographic area where consanguineous unions are not very unusual.Prevalence rates of WS in the Messina district were calculated by taking into consideration both the total population (653,737) and the populations included within the 0-30 year age range (202,681). We estimated the relative prevalence of WS among patients with youth-onset insulin-dependent diabetes mellitus (DM) who are currently aged under 30 years (256).Global WS prevalence in our district is 1:54,478, whereas prevalence among individuals under 30 is 1:16,890 and relative prevalence among patients with juvenile-onset insulin-dependent DM is 1:22.3. When compared with the patients with insulin-dependent DM of Messina district, WS patients did not exhibit significant differences in terms of biochemical features at DM onset, whereas age at DM diagnosis was significantly earlier in WS group.(a) WS prevalence is not so infrequent as generally expected; (b) in our series, DM presented before 10 years in 11/12 patients and ten cases have already developed all the four peculiar manifestations of WS by 26 years; (c) 9/12 patients exhibited a homozygous frameshift/truncation mutation (Y454_L459del_fsX454), which is the one most frequently found also in patients from other Italian regions; (d) age at DM diagnosis was significantly earlier in WS group than in the patients with insulin-dependent DM of Messina district.

The aim of the present paper is to describe a novel missense mutation (G107R) of WFS1 gene that was unexpectedly detected, in two siblings from Southern Italy, outside exon 8; a very unusual finding which has previously been reported only twice in Italian patients with Wolfram syndrome (WS). Although in Spanish pedigrees' WFS1 mutations are frequently located in exon 4, this finding is very infrequent in other pedigrees, particularly in Italian patients. Conclusions: a) our report of two siblings with one novel WSF1 mutation (G107R) expands the molecular spectrum of WS; b) this is the 3rd report of Italian patients harbouring one mutation outside exon 8 and the 2nd with one mutation in exon 4; c) on the basis of the present observations, and literature data we can infer that mutation locations outside exon 8 do not seem to be clearly associated with peculiar phenotype expressions of WFS1 gene.

Aims: To ascertain the prevalence of Graves’ disease (GD) in 1,323 Caucasian children with type 1 diabetes mellitus (T1DM), and to compare the course of GD in T1DM patients with the one observed in 109 Caucasian peer patients with GD but without T1DM (group B). Results: Only 7 patients (0.53%) of the T1DM series also presented with GD (group A)which was diagnosed many years after diabetes presentation. At GD diagnosis, the prevalence of preclinical hyperthyroidism was higher in group A (p = 0.0001), whereas serum TSH receptor antibodies (TRABs) were higher in group B (p = 0.04). The subsequent course with methimazole therapy and after its withdrawal was very similar in both groups. Conclusions: GD prevalence in T1DM patients was 0.53%, i.e. almost identical to the one reported in the general population. GD was diagnosed many years after T1DM presentation. At GD diagnosis, the clinical picture was milder and TRAB serum levels were lower in diabetic patients. Preclinical diagnosis and early treatment of GD were not associated with better responsiveness to therapy. Screening programs based on periodical TRAB assessments are not useful in T1DM.

Previous studies on menarcheal age (MA) in type 1 diabetes mellitus (T1DM) have shown conflicting results about the effects of DM, but most lack a control group. The present study design is peculiar in that it covers a study population of 73 intensively treated menarcheal adolescents with premenarcheal onset of T1DM (Group A), whose MA was compared with that recorded in three control populations: the first one consisting of 280 healthy adolescents, the second one consisting of 20 T1DM adolescents with postmenarcheal DM onset (Group B) and the third one represented by the respective mothers.MA of Group A patients was significantly delayed when compared with the respective mothers, healthy controls and Group B patients. By contrast MA of Group B girls was superimposable to the one of both their respective mothers and healthy controls. In Group A MA was strongly related (p0.0005) to HbA1c at the time of menarche and to average HbA1c concentrations during the last years before menarche. In Group A no relationship between patients' and mothers' MAs was found, whilst such a correlation was significant in Group B.(a) MA is significantly delayed in girls with premenarcheal presentation of T1DM, even if intensively treated; (b) menarcheal retardation is more severe in the patients with suboptimal metabolic control at the time of menarche; and (c) MA in premenarcheal presenting T1DM is irrespective of maternal MA, age and HbA1c concentrations at DM presentation, body mass index and daily insulin dose at menarche.

Background Atopic dermatitis often has an allergic component, and immunotherapy may therefore prove beneficial. Objective To assess the effect of sublingual immunotherapy (SLIT) in children with atopic dermatitis. Methods Children age 5 to 16 years with atopic dermatitis (Scoring Atopic Dermatitis [SCORAD] > 7) and sensitization to dust mites alone, without food allergy or chronic asthma, were enrolled in a randomized, double-blind, placebo-controlled study and stratified according to disease severity. SLIT or placebo was given for 18 months in addition to standard therapy. SCORAD, visual analog scale, and rescue medication consumption were recorded at 3-month intervals. Results Fifty-six children were enrolled, and 28 were allocated to SLIT. Forty-eight completed the study, with 2 dropouts in the active and 6 in the placebo group. The difference from baseline in the SCORAD was significant ( P = .025) between the 2 groups starting from month 9. Similarly, there was a significant reduction in the use of medications only in the active group. A trend toward significance was seen for the visual analog score only in the active group versus baseline ( P = .07). A significant difference in the considered parameters was found only in patients with a mild-moderate disease, whereas severe patients had only a marginal benefit. SLIT had to be discontinued in 2 patients because of exacerbation of dermatitis. Conclusion Sublingual immunotherapy to dust mite improves mild-moderate atopic dermatitis. Clinical implications Sublingual immunotherapy may represent an additional therapeutic tool for the treatment of extrinsic atopic dermatitis in properly selected children.

Turner's syndrome (TS) is a chromosomal disorder that results from the loss of the entire or a part of the X-chromosome and occurs in 1/2,500 female births. According to the majority of specific reports, intelligence in TS is generally found to be normal and the prevalence of mental retardation does not seem to be increased in TS except for those patients with a small ring X-chromosome. We evaluated 33 girls with TS with chronological age from 6-18 years. Intellectual assessment included the WISC III and the WAIS-R scales. Our results showed: 1) mean full scale intelligence quotient (FSIQ) was significantly lower than expected based on normative data (p < 0.0005); 2) no correlation was present between height and general intellectual ability; 3) mean performance intelligence quotient (PIQ) was significantly lower than both mean verbal intelligence quotient (VIQ) and FSIQ (p < 0.0025 and p < 0.01, respectively), and most patients had a VIQ-PIQ discrepancy; 4) the frequency of mental retardation in our study group was significantly higher than that observed in the general population (15.1% vs 2.3%, p < 0.025); 5) a significant association was found between karyotype and VIQ, and the best score was achieved in the subgroup of patients with structural abnormalities of the X-chromosome. In the light of these findings we conclude that the clinical picture in TS may encompass a slightly reduced FSIQ, VIQ and especially an inadequate PIQ, but this neurocognitive profile is not significantly affected by statural impairment. Since these neurocognitive defects can be responsible for misdiagnosed school difficulties, we suggest that girls with TS should receive specialized educational support and multidisciplinary care.

One of the toughest aspects which health-care workers have to face in the management of diabetes is informing the family. Thanks to specialized teams of pediatric diabetologists, specialized diabetes nursing staff, dieticians and psychologists, many of these problems have by now been solved. Over the past ten years, scientific research has made it possible to identify some "critical points" which arise as the child passes through the various developmental phases. Based on this research there has been an increasing tendency to highlight contact points between diabetic patient and family management of the illness, aimed at preventing incorrect behaviour during the different growth phases. The diabetological team should not only intervene when necessary, but also work with an eye to prevention so as to improve the quality of life of the child and its family, making it possible that a diabetic child quality of life is the same of a non-diabetic child. Team work is necessary so as to get to know and, where possible, improve, compliance in every family. This is obtained also through the acquisition and subsequent carrying out of questionnaires, which help in making the family understand that there is no difference between diabetic children and non-diabetic children. Data in literature, fortunately, seems to confirm this. Clear progress has also been made in the methods of administration thanks to the introduction of devices such as pens and microinfusors (CSII). Pen devices have greatly improved compliance of young diabetic patients, making them better able to manage administration on their own. Microinfusors, on the other hand, have not only improved metabolic control, bringing it closer to the physiological model, but have also had a positive effect on the quality of life of young people, and, as a consequence, of their families.

Objective: To assess the prevalence of overweight and obesity in 2- to 6-year-old Italian children and to compare the prevalence between the north and the south of the country. Research Methods and Procedures: This was a cross-sectional study of 2150 subjects (M/F: 1137/1013), 5.36 ± 0.83 years of age. The sampling areas were Verona (north Italy) and Messina (south Italy). We used definitions of overweight and obesity using BMI values, with cut-off values proposed by the International Obesity Task Force. Results: The prevalence of overweight was 16.6% (males: 13.9%, females: 19.6%), and it was higher in the south (males: 17.8%, females: 22.4%) than in the north (males: 11.3%, females: 17.9%). The prevalence of obesity was 8.0% (males: 8.3%, females: 7.7%), and it was higher in the south (males: 12.3%, females: 10.7%) than in the north (males: 5.7%, females: 5.8%). Using the Centers for Disease Control reference charts, the prevalence of overweight and obesity of Italian children was close to that reported in children living in the United States (32% vs. 32.7%, respectively). Discussion: The prevalence of overweight and obesity in young Italian children is very high, and it is rapidly growing. In the south of the country, the prevalence is higher than in the north.

OBJECTIVES: a) To describe a very extended inbred pedigree with Wolfram syndrome (WS) (OMIM #222300); b) to report both the clinical picture and evolution in this large family and a peculiar mutation which has been reported hitherto only in Italian patients. DESIGN: The five-generation pedigree from Sicily was reconstructed through a proband with all the main manifestation of WS, born to a couple of healthy consanguineous parents. DNA examination was performed in both patients and healthy family members. RESULTS: In all seven patients we found a homozygous 16-bp deletion in exon 8 of the WFS1 gene that introduces a stop codon in position 454. CONCLUSIONS: This inbred pedigree is the largest with WS described in the literature. Its analysis definitively confirms the view of autosomal recessive inheritance in WS. The 16-bp deletion appears to be a relatively frequent mutation only in Italian patients. Before examining the entire coding region of the WSF1 gene a preliminary screening for the 16-bp deletion in exon 8 might be suggested when a new Italian case of WS is investigated.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy and hemolytic anemia can be triggered by many drugs, by the ingestion of fava beans, and by metabolic imbalances. Nonetheless, only sporadic reports of hemolytic anemia due to G6PD deficiency in patients with type 1 diabetes mellitus (DM1) have been reported to date. We describe an 8 year-old Sicilian boy who suffered from hemolytic anemia some days after admission for DM1. On admission, acid-base equilibrium was normal but 4 days later he presented hemolytic anemia with G6PD deficiency, confirmed by personal and family history and laboratory evaluation. We suggest that the hemolytic crisis in this patient was triggered by the relative hypoglycemia that followed insulin administration. The interference of acidosis, infections, drugs, food or other triggering agents was excluded. This report demonstrates that hemolysis may represent a possible complication of DM treatment in patients with G6PD deficiency and we recommend careful clinical surveillance in these patients.

Self-control led therapy is vital in the treatment of insulin dependent diabetes mellitus (IDDM), allowing as it does, correct insulin therapy, a reduction in hospitalisation and modification of therapy for individual needs in relation to various factors. Undoubtedly it is the responsibility of the diabetes team (doctors, nurses, dietician, psychologist and social assistant) to instruct the patient and help him/her in this new situation. The patient must learn to live and develop normally, participating to the full in school, at work and in all social situations, by fully understanding how to manage the illness autonomously and how to prevent short and long-term complications. Thus, the team must set objectives: making the patient aware of his condition, giving him the knowledge of what to do and how to do it. In this way, quality of life can be improved for patients affected by this chronic illness and they can understand how to face the future with realistic optimism. Modern technology has brought many novelties into the diabetes field, such as the ever smaller and more accurate glucose meters, or finger-prick devices requiring minimal quantities of blood. They represent another step towards a less invasive or disruptive approach in the management of diabetes. Non-specialist press articles may raise false hopes, above all about new research in the field of diabetes, but at least they also raise awareness on a problem of national interest, i.e. insulin dependent diabetes mellitus.