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Gas-filled microbubbles are well-established contrast agents for ultrasound imaging and widely studied as delivery systems for theranostics. Herein, we have demonstrated the promising potential of the hydrophobin HFBII—a fungal amphiphilic protein—in stabilizing microbubbles with various fluorinated core gases. A thorough screening of several experimental parameters was performed to find the optimized conditions regarding the preparation technique, type of core gas, HFBII initial concentration, and protein dissolution procedure. The best results were obtained by combining perfluorobutane (C4F10) gas with 1 mg/mL of aqueous HFBII, which afforded a total bubble concentration higher than 109 bubbles/mL, with long-term stability in solution (at least 3 h). Acoustic characterization of such microbubbles in the typical ultrasound frequency range used for diagnostic imaging showed the lower pressure resistance of HFBII microbubbles, if compared to conventional ones stabilized by phospholipid shells, but, at the same time, revealed strong non-linear behavior, with a significant harmonic response already at low acoustic pressures. These findings suggest the possibility of further improving the performance of HFBII-coated perfluorinated gas microbubbles, for instance by mixing the protein with other stabilizing agents, e.g., phospholipids, in order to tune the viscoelastic properties of the outer shell.

Gastroparesis is a long-term complication of diabetes related to autonomic neuropathy. It is characterized clinically by delayed gastric emptying and upper gastrointestinal symptoms, including early satiety, postprandial fullness, nausea, vomiting, and abdominal pain. Gastric emptying scintigraphy is the gold standard for diagnosis as it reveals delayed gastric emptying. Therapeutic strategies include dietary modifications, improvement of glycemic control, and prokinetic drugs. Case descriptions of diabetic gastroparesis in pediatric ages are very scarce. We report the case of a 16-year-old adolescent with severe presentation of diabetic gastroparesis. She presented with recurrent episodes of nausea, vomiting and abdominal pain which led progressively to reduced oral intake and weight loss. Her past glycemic control had been quite brittle, as demonstrated by several hospitalizations due to diabetic ketoacidosis and recurrent episodes of severe hypoglycemia. After the exclusion of infectious, mechanical, metabolic, and neurological causes of vomiting, a gastric emptying scintigraphy was performed, leading to the diagnosis of gastroparesis. Treatment with metoclopramide was started with progressive relief of symptoms. To improve glycemic control, insulin therapy with an advanced hybrid, closed loop system was successfully started. Pediatricians should consider diabetic gastroparesis in children and adolescents with long-standing, poorly controlled diabetes and appropriate symptomology.

There has been continuous progress in diabetes management over the last few decades, not least due to the widespread dissemination of continuous glucose monitoring (CGM) and automated insulin delivery systems. These technological advances have radically changed the daily lives of people living with diabetes, improving the quality of life of both children and their families. Despite this, hypoglycemia remains the primary side-effect of insulin therapy. Based on a systematic review of the available scientific evidence, this paper aims to provide evidence-based recommendations for recognizing, risk stratifying, treating, and managing patients with hypoglycemia. The objective of these recommendations is to unify the behavior of pediatric diabetologists with respect to the timely recognition and prevention of hypoglycemic episodes and the correct treatment of hypoglycemia, especially in patients using CGM or advanced hybrid closed-loop systems. All authors have long experience in the specialty and are members of the Italian Society of Pediatric Endocrinology and Diabetology. The goal of treating hypoglycemia is to raise blood glucose above 70 mg/dL (3.9 mmol/L) and to prevent further decreases. Oral glucose at a dose of 0.3 g/kg (0.1 g/kg for children using “smart pumps” or hybrid closed loop systems in automated mode) is the preferred treatment for the conscious individual with blood glucose

Adolescence, a critical period of physical and psychological development, presents unique challenges in type 1 diabetes (T1D) management due to endocrinological changes, reduced therapeutic adherence, and elevated susceptibility to psychological issues such as depression, anxiety, and eating disorders. This narrative review explores the impact of psychological and behavioral factors on glycemic control in adolescents with T1D. We examine the prevalence and influence of mental health disorders, lifestyle factors, harmful behaviors, and social dynamics on diabetes management and glycemic outcomes. Strategies for improving metabolic control are also reviewed, including cognitive behavioral therapy, technological devices, and educational interventions. The importance of tailored psychological support, family involvement, and targeted interventions to improve adherence to treatment and glycemic control in adolescents with T1D should be emphasized.

Abstract Background Endocan is a soluble dermatan sulfate proteoglycan (50 kDa) secreted by endothelial cells and expressed by dermal, coronary, pulmonary and adipose tissue microvasculature. It plays an important role in the pathogenesis of vascular disorders, inflammatory state, endothelium dysfunction and neoangiogenesis. Aims of the study were to compare fasting serum endocan levels between children with obesity and healthy controls and to investigate the relationships between endocan, body mass index (BMI) and other indices of cardiometabolic risk. Methods This single-center, observational, retrospective study included 19 pediatric patients with obesity aged 11.94 ± 0.52 years and 19 lean matched controls. Each patient underwent clinical and auxological examination and laboratory investigations including routine organs function tests and lipid profile. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Fasting endocan serum levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results Compared to healthy subjects, serum endocan levels were found to be significantly upraised in children with obesity. Endocan resulted significantly correlated with insulin levels (rho 0.47; p = 0.04); in addition, an association with HOMA-IR values with a trend toward the statistical significance (rho 0.43; p = 0.07) was found. No significant correlation with fasting blood glucose values and lipid serum levels was demonstrated. Although not statistically significant, a correlation between endocan and the presence and grading of liver steatosis on ultrasound (rho 0.51; p = 0.08 and rho 0.51; p = 0.08, respectively) was found. Conclusions These findings confirm the association between endothelial damage and insulin resistance in children with obesity. Endocan could be used as a biomarker of early endothelial dysfunction in children with obesity and could be a valid predictor of future cardiovascular risk in adulthood.

Abstract Background Diabetic ketoacidosis (DKA) is one of the most alarming concerns in the management of type 1 diabetes (T1D) in pediatric age. Prevalence of DKA at the onset of diabetes ranges from 30 to 40%. In selected cases of severe DKA, admission to pediatric intensive care unit (PICU) should be considered. Methods This study aims to assess the prevalence of severe DKA treated in PICU in our 5-year monocentric experience. Secondary outcome of the study was to describe the main demographical and clinical features of individuals who required admission to PICU. All clinical data were collected by retrospectively reviewing the electronic medical records of children and adolescents with diabetes hospitalized in our University Hospital from January 2017 to December 2022. Results During the study period, 103 children and adolescents were newly diagnosed with T1D. Among these, 51.5% presented clinical criteria for DKA and almost 10% needed to be treated in PICU. A higher rate of new T1D diagnoses was observed in 2021, as well as episodes of severe DKA being more frequent than in previous years. Due to severe clinical manifestations of DKA, 10 subjects (9.7%) with T1D onset needed to be treated in PICU. Of these, four children were younger than 5. The great majority came from a low household income and some of them had also immigrant background. The most common complication of DKA was acute kidney injury presented by four children. Other complications were cerebral edema, papilledema and acute esophageal necrosis. A 15-year-old girl had deep vein thrombosis (DVT) that evolved into multiple organ failure leading to death. Conclusions Our findings demonstrated that severe DKA is still quite common in children and adolescents at T1D onset, especially in some areas such as Southern Italy. Public awareness campaigns should be increasingly promoted to facilitate the recognition of early symptoms of diabetes and to reduce morbidity and mortality related to DKA.

Background: Fever is one of the most frequent symptoms highlighted during medical assistance. Due to this great impact, our study has the purpose of analyzing the demographic and laboratory characteristics of patients hospitalized in our center and identifying predictive markers to make the differential diagnosis between infectious and non-infectious fever. Methods: Our population included 220 children, collected from January 2017 to August 2022, hospitalized for continuous fever (4 days or more in duration with at least one temperature peak ≥37.5 °C) and excluded cases of discharge against medical advice and/or transfer to other operating units. Demographic (mean age at the time of admission, frequency of hospitalization, and mean days of hospitalization), laboratory, and instrumental variables were analyzed in order to find correlation with fever etiology. Results: Older age at the time of hospitalization, family history of periodic fever, fever lasting more than 8 days, and longer hospitalization are strongly associated with non-infectious fever, together with anemia, high platelet count, high CRP and ferritin, and hyponatremia at the time of admission. Paracetamol is the preferred antipyretic treatment. Echocardiogram has shown anomalies in patients with infectious fever, while ECG anomalies were detected in non-infectious fever. Conclusions: Our data underline the importance of predictive markers, such as clinical and laboratory parameters, to differentiate infectious from non-infectious fevers, but further studies are necessary.

The introduction of continuous glucose monitoring (CGM) systems in clinical practice has allowed a more detailed picture of the intra- and interdaily glycemic fluctuations of individuals with type 1 diabetes (T1D). However, CGM-measured glucose control indicators may be occasionally inaccurate. This study aims to assess the discrepancy between the glucose management indicator (GMI) and glycated hemoglobin (HbA1c) (ΔGMI-HbA1c) within a cohort of children and adolescents with T1D, exploring its correlation with other CGM metrics and blood count parameters. In this single-center, cross-sectional study, we gathered demographic and clinical data, including blood count parameters, HbA1c values, and CGM metrics, from 128 pediatric subjects with T1D (43% female; mean age, 13.4 ± 3.6 years). Our findings revealed higher levels of the coefficient of variation (CV) (p < 0.001) and time above range > 250 mg/dL (p = 0.033) among subjects with ΔGMI-HbA1c > 0.3%. No association was observed between blood count parameters and ΔGMI-HbA1c. In conclusion, despite the advancements and the widespread adoption of CGM systems, HbA1c remains an essential parameter for the assessment of glycemic control, especially in individuals with suboptimal metabolic control and extreme glycemic variability.

Abstract 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.

Abstract Background A retrospective observational study was conducted to assess the prevalence of maturity onset diabetes of the young (MODY) in a large paediatric population of Southern Italy newly diagnosed with diabetes. Clinical and genetic features of the identified MODY patients were also described. Methods Genetic testing was performed in children and adolescents newly diagnosed with diabetes who presented autoantibody negativity and fasting C-peptide levels ≥ 0.8 ng/mL. Patients with a low insulin daily dose and optimal glycaemic control after two years from diabetes onset were also investigated for monogenic diabetes, regardless of their autoimmunity status and/or C-peptide levels. Results A prevalence of 6.5% of MODY was found. In particular, glucokinase-MODY was the most common type of MODY. The mean age at diagnosis was 9.1 years. Clinical presentation and biochemical data were heterogeneous also among patients belonging to the same MODY group. Conclusions We found a relatively high prevalence of MODY among paediatric patients with a new diagnosis of diabetes in comparison to literature data. Our findings highlight that a more detailed clinical evaluation along with easier and less expensive approachability to genetic testing may allow diagnosing an increasing number of MODY cases. A correct, prompt diagnosis is crucial to choose the most appropriate treatment and offer adequate genetic counselling.

Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), caused by mutations in the Autoimmune Regulator (AIRE) gene, is an autosomal recessive multi-organ autoimmunity syndrome usually defined by high serum titers of type I Interferon Autoantibodies (Type 1 IFN-Abs). These antibodies have recently been found in individuals in the general population who develop life-threatening Coronavirus Disease 2019 (COVID-19), but the significance of pre-existing Type 1 IFN-Abs in APECED patients with COVID-19 remains unclear. Previous reports of COVID-19 outcomes in APECED patients have been divergent, and protective roles have been proposed for female sex, age

Abstract Background The year 2020 will be remembered as the “year of the COVID-19 pandemic”. The world population had to familiarize themselves with words as swabs, personal protective equipment, pandemic. To curb the wave of the pandemic, almost all the countries imposed self-isolation and social distancing. We conducted a web-based survey to investigate the behavioural responses during the quarantine due to the COVID-19 pandemic. Methods Participants were 1860 youth aged 12–18 years attending lower secondary schools and upper secondary schools. Data were collected on demographic characteristics, lifestyle changes during the quarantine period, and the psychological impact of the lock-down on adolescents’ life. Results Most adolescents experienced feelings of fear, discouragement, and anxiety which strongly affected the approach to their daily lifestyles. Most of the surveyed subjects reported having used this period to acquire new skills and to practice physical activities at home. The use of technology was predominant both for recreational activities and educational purposes. Conclusions Despite the strong psychological impact of the quarantine, adolescents showed good levels of resilience. Technology played a crucial role during the quarantine for young subjects who have increased the daily use of technological devices to stay connected with the rest of the world.

The increasing use of technological devices for the management of diabetes is related to the prolonged exposure of patients’ skin to chemical and mechanical agents and, consequently, to the increased risk of developing dermatological complications. Among these, contact dermatitis is the most insidious skin disorder. Despite the magnitude of the issue, no universally accepted recommendations on the management of this common complication are currently available. Our observational study aimed to describe all the solutions adopted by patients and their caregivers to treat and prevent the appearance of contact dermatitis and to describe the clinical impact of this cutaneous complication. Twenty-one pediatric patients (mean age 12.1 ± 3.7 years) with type 1 diabetes were recruited in the study. The most common treatment used to treat acute skin lesions was the application of topical corticosteroids, sometimes associated with topical antibiotics (9.5%). In order to prevent the further appearance of dermatitis, the most frequently adopted measure was the use of hydrocolloid and/or silicone-based adhesives, followed by the application of protective barrier films. One patient reported benefit from the off-label use of fluticasone propionate nasal spray. However, only 52.4% of the study participants achieved a definitive resolution of the skin issue, and 38.1% of patients were forced to discontinue insulin pump therapy and/or continuous glucose monitoring. No differences were observed in glycated hemoglobin values between the period before and after the onset of contact dermatitis. Our study confirms the severity of this dermatological complication that may hinder the spread of new technologies for the management of diabetes. Finally, our findings highlight the importance of establishing close collaboration both with pediatric allergy specialists to prescribe the most suitable treatment and with manufacturing companies to ensure that adhesives of technological devices are free of harmful well-known sensitizers.

Abstract 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.

Abstract 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.

Abstract 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.

Lipodystrophy is the most common dermatological complication in patients with diabetes on insulin therapy. Despite the high frequency of lipodystrophy, there are still several difficulties in giving advice about avoidance into practice among children and adolescents with type 1 diabetes and their caregivers. This cross-sectional study aims to evaluate the prevalence of insulin-induced lipodystrophy in a cohort of pediatric patients with type 1 diabetes, to identify associated clinical factors and to assess its influence on glycemic control. Two hundred and twelve patients attending our Diabetes Center during a three-month period were enrolled. The presence of lipodystrophy was assessed by inspection and palpation procedures. Demographic and clinical data including type of treatment, frequency of rotation of insulin administration sites, and glucose metrics of the previous 30 days were assessed and statistically analyzed. Prevalence of lipohypertrophy was 44.3%. Two patients were affected by lipoatrophy (0.9%). Improper rotation of insulin administration sites and low awareness on lipodystrophy were associated to the occurrence of this skin condition (p = 0.050 and p = 0.005, respectively). When comparing patients with and without lipodystrophy, a significant difference in glycemic variability parameters was detected (p = 0.036 for coefficient of variation, p = 0.029 for standard deviation score of glucose levels). Lipodystrophy still represents a common complication in patients on insulin therapy. The present study reveals its negative impact on glycemic variability. This finding emphasizes the importance of prevention strategies to minimize the occurrence of this dermatological complication that may interfere with clinical history of the disease.

Hybrid porous nanoscale metal organic frameworks (nanoMOFs) made of iron trimesate are attracting increasing interest as drug carriers, due to their high drug loading capacity, biodegradability, and biocompatibility. NanoMOF surface modification to prevent clearance by the innate immune system remains still challenging in reason of their high porosity and biodegradable character. Herein, FDA-approved lipids and poly(ethylene glycol) (PEG)-lipid conjugates were used to engineer the surface of nanoMOFs by a rapid and convenient solvent-exchange deposition method. The resulting lipid-coated nanoMOFs were extensively characterized. For the first time, we show that nanoMOF surface modification with lipids affords a better control over drug release and their degradation in biological media. Moreover, when loaded with the anticancer drug Gem-MP (Gemcitabine-monophosphate), iron trimesate nanoMOFs acted as “Trojan horses” carrying the drug inside cancer cells to eradicate them. Most interestingly, the PEG-coated nanoMOFs escaped the capture by macrophages. In a nutshell, versatile PEG-based lipid shells control cell interactions and open perspectives for drug targeting.

Background: A crucial aspect of the 2019 coronavirus disease (COVID-19) pandemic was the psychological impact on the population. Most countries issued restrictive laws to reduce community-based viral spread. Children and adolescents were forced to experience physical and social distancing. Subjects with chronic diseases, such as type 1 diabetes, were more vulnerable and at higher risk of developing psychological disorders.Methods: We conducted a web-based survey to investigate the behavioral responses during quarantine due to the COVID-19 outbreak in a cohort of pediatric patients with type 1 diabetes. Data were collected on demographic and clinical characteristics, lifestyle changes, and the impact of COVID-19 on the management of diabetes.Results: Two hundred four pediatric patients (aged 5–18 years) with type 1 diabetes completed the questionnaire. Interestingly, patients ≤12 years were significantly more influenced by the quarantine period in their approach to the disease than older patients.Conclusion: Although quarantine was a stressful psychological condition, our results showed that most children and adolescents with type 1 diabetes developed high levels of resilience and excellent coping skills by using technology in a proper way.

Abstract ᅟ Aim of this commentary is to summarize the salient literature views on the relationships between presentation and evolution patterns of thyroid function in children with Hashimoto’s thyroiditis (HT). According to the most recent reports, children with HT and subclinical hypothyroidism (SH) are more prone to the risk of developing severe thyroid dysfunctions over time, if compared to those presenting with euthyroidism. In contrast, children presenting with HT and either overt or subclinical hyperthyroidism are incline to exhibit a definitive resolution of the hyperthyroid phase within some months, although there is a wide variability between the different individuals. The natural history of frank hypothyroidism in the children with HT has never been investigated so far, since in these cases an immediate onset of replacement treatment is mandatory. Conclusions 1) a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2) a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism.

Abstract 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.

Vancomycin (VCM) is a last resort antibiotic in the treatment of severe Gram-positive infections. However, its administration is limited by several drawbacks such as: strong pH-dependent charge, tendency to aggregate, low bioavailability, and poor cellular uptake. These drawbacks were circumvented by engineering pH-responsive nanoparticles (NPs) capable to incorporate high VCM payload and deliver it specifically at slightly acidic pH corresponding to infection sites. Taking advantage of peculiar physicochemical properties of VCM, here we show how to incorporate VCM efficiently in biodegradable NPs made of poly(lactic-co-glycolic acid) and polylactic acid (co)polymers. The NPs were prepared by a simple and reproducible method, establishing strong electrostatic interactions between VCM and the (co)polymers’ end groups. VCM payloads reached up to 25 wt%. The drug loading mechanism was investigated by solid state nuclear magnetic resonance spectroscopy. The engineered NPs were characterized by a set of advanced physicochemical methods, which allowed examining their morphology, internal structures, and chemical composition on an individual NP basis. The compartmentalized structure of NPs was evidenced by cryogenic transmission electronic microscopy, whereas the chemical composition of the NPs’ top layers and core was obtained by electron microscopies associated with energy-dispersive X-ray spectroscopy. Noteworthy, atomic force microscopy coupled to infrared spectroscopy allowed mapping the drug location and gave semiquantitative information about the loadings of individual NPs. In addition, the NPs were stable upon storage and did not release the incorporated drug at neutral pH. Interestingly, a slight acidification of the medium induced a rapid VCM release. The compartmentalized NPs could find potential applications for controlled VCM release at an infected site with local acidic pH.

Abstract Positively charged cyclodextrins (PCCDs) are molecular carriers of particular interest for their ability to readily enter into cancer cells. Of main interest, guanidino- and aminoalkyl- PCCDs can be conveniently synthesized and form stable and strong inclusion complexes with various active molecules bearing phosphate groups. We have addressed here the challenge to deliver into cancer cells phosphorylated gemcitabine drugs well known for their instability and inability to permeate cell membranes. NMR data corroborated by semiempirical theoretical calculations have shown that aminoalkyl-CDs form sufficiently stable complexes with both mono- and tri-phosphate forms of gemcitabine by simple mixing of the compounds in aqueous solution at physiological pH. Confocal microscopy and radioactivity counting experiments revealed that the developed systems enabled phosphorylated gemcitabine to penetrate efficiently into aggressive human breast cancer cells (MCF7), eventually leading to a substantial reduction of IC50 values. Moreover, compared to free drugs, phosphorylated metabolites of gemcitabine encapsulated in PCCDs displayed improved in vitro activities also on the aggressive human cancer cells CCRF-CEM Ara-C/8 C, a nucleoside transport-deficient T leukemia cell line. The current study offers the proof-of-principle that phosphorylated nucleoside drugs could be efficiently transported by PCCDs into cancer cells.

Abstract 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.

Abstract Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered “booster” molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, “green” β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.

Autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), tend to aggregate with other non-thyroidal autoimmune diseases (NTADs). Aim of this Mini-review is to report the most recent insights concerning the clustering of NTADs in pediatric patients with either HT or GD, the pathophysiology of AITDs and the metamorphic thyroid autoimmunity. A systematic literature research of the last 15 years, according to EQUATOR statement, was carried out through MEDLINE via PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) Embase, CINAHL, Cochrane Library, based on the following keywords: (autoimmune thyroid disease OR Hashimoto thyroiditis OR Grave's disease) AND (autoimmune comorbidities OR extra-thyroidal autoimmune disorders) AND (children OR adolescents OR pediatrics) AND (celiac disease OR type 1 diabetes mellitus OR arthropathies OR cutaneous diseases) AND (Turner syndrome OR Down syndrome). One-hundred and twenty-eight manuscripts were extrapolated but only seventeen were eligible. On the basis of the available reports it may be inferred that clustering of NTADs can be significantly modified by both patients' age at AITDs presentation and association with Down's syndrome (DS). Particularly, the association of AITDs with celiac disease and type 1 diabetes was most commonly reported in children than in adults. A sequential shifting from HT to GD has been described in children with AITDs, and it seems to be more frequent in children with DS than in those without DS. Coexistence of autoimmune diseases might be the result of a complex interaction among genetics, environment and epigenetic modifications that are able to affect gene expression, immune system response and, finally, the pathogenesis of autoimmune diseases.

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The growing knowledge on the mechanisms of gene silencing and gene regulation by non-coding RNAs (ncRNA), mainly small interfering RNA (siRNA) and microRNA (miRNA), is providing a significant boost to the development of new therapeutic strategies for the treatment of cancer. However, the design of RNA-based therapeutics is hampered by biopharmaceutical issues, thus requiring the use of suitable delivery strategies. In this regards, lipid nanovectors have been successfully investigated to deliver RNA in different forms of cancer. Compared to other biomaterials, lipids offer advantages such as biocompatibility, biodegradability, easy production, low cost, limited toxicity and immunogenicity. The possibility to formulate these materials in the form of nanovectors allows overcoming biopharmaceutical issues associated to the therapeutic use of RNA, with the possibility to target tumors. This review takes stock of the main lipid nanovectors proposed to deliver ncRNA. For each considered delivery strategy, the rational design and the most meaningful in vitro and in vivo results are reported and discussed.