Monitoraggio glicemico continuo (CGM) nei pazienti acromegalici: impatto delle strategie terapeutiche e correlazione con le apnee ostruttive notturne

Le differenti strategie terapeutiche utilizzate nella gestione dell’acromegalia, possono avere un diverso impatto sull’assetto glicometabolico. Abbiamo pertanto studiato, utilizzando il monitoraggio glicemico continuo (CGM), 41 pazienti acromegalici (20 M/21 F), (56±13.9 anni), a target per la patologia di base da almeno due anni, omogenei per BMI, durata media di malattia, latenza diagnostica media. I pazienti sono stati suddivisi in base al tipo di terapia: 15 analoghi della somatostatina di I (SSA), 4 analogo di II generazione/Pasireotide (PAS), 10 Pegvisomant (PEG), 12 operati con successo. I pazienti sono stati sottoposti a: OGTT (75 gr di glucosio), CGM (72 ore), polisonnografia (PSG), monitoraggio pressorio delle 24 h, ecocardiografia con doppler e colordoppler. RISULTATI 14/41 diagnosi di IFG (8 SSA, 2 PEG, 4 senza terapia); 9/41 diagnosi di IGT (4 SSA, 3 PAS, 2 senza terapia); 4/41 diagnosi di diabete mellito (3 SSA, 1 PEG). • La glicemia media dell’OGTT significativamente più alta rispetto alla glicemia media CGM in toto (p꞊0.0001) e nei sottogruppi di terapia (SSA vs PEG) (p꞊0.0019); • glicemia media OGTT significativamente più alta nel gruppo di pazienti SSA, sia rispetto ai pazienti Peg (p=0,047) sia rispetto alla sola chirurgia (p=0,037); • correlazione diretta picco CGM (p꞊0.0021); • correlazione diretta tra media OGTT e AUC CGM per iperglicemia (p꞊0.0016); • correlazione diretta tra AUC CGM per iperglicemia (p꞊0.05). Non sono emerse differenze statisticamente significative tra presenza, severità di OSAS, tipo di terapia, profilo glico-metabolico DISCUSSIONE I pazienti trattati con SSA presentano un’alterata risposta in termini di secrezione insulinica ad un input particolarmente consistente, quale il carico orale di glucosio. L’analogo della somatostatina infatti, ha un duplice effetto sul metabolismo glicidico: da un lato riducendo i valori del GH riduce l’insulino resistenza e la produzione di glucosio, dall’altro esercita un’azione inibitoria sia verso la secrezione di insulina che di glucagone, compromettendo il controllo glicemico. I dati ottenuti dal nostro studio ci lascerebbero quindi ipotizzare che i valori glicemici a digiuno si mantengano stabili per il miglioramento della sensibilità insulinica, che ne va a controbilanciare la ridotta secrezione. Abbiamo escluso la presenza di ipoglicemie a digiuno, ipotizzata nei pazienti trattati con SSA per un eventuale deficit di controregolazione. Una problematica aperta è quella relativa ai pazienti critici, resistenti a terapia con analoghi classici e pegvisomant. Questi, pur traendo beneficio in termini di controllo biochimico di malattia acromegalica dall’utilizzo di pasireotide, presentano un deterioramento del quadro glicometabolico. L’utilizzo del CGMS potrebbe rappresentare un valido ausilio nella scelta terapeutica dell’aspetto glicometabolico e del suo monitoraggio

Wearable full-body motion tracking of activities of daily living predicts disease trajectory in Duchenne muscular dystrophy

Artificial intelligence has the potential to revolutionize healthcare, yet clinical trials in neurological diseases continue to rely on subjective, semiquantitative and motivation-dependent endpoints for drug development. To overcome this limitation, we collected a digital readout of whole-body movement behavior of patients with Duchenne muscular dystrophy (DMD) (n = 21) and age-matched controls (n = 17). Movement behavior was assessed while the participant engaged in everyday activities using a 17-sensor bodysuit during three clinical visits over the course of 12 months. We first defined new movement behavioral fingerprints capable of distinguishing DMD from controls. Then, we used machine learning algorithms that combined the behavioral fingerprints to make cross-sectional and longitudinal disease course predictions, which outperformed predictions derived from currently used clinical assessments. Finally, using Bayesian optimization, we constructed a behavioral biomarker, termed the KineDMD ethomic biomarker, which is derived from daily-life behavioral data and whose value progresses with age in an S-shaped sigmoid curve form. The biomarker developed in this study, derived from digital readouts of daily-life movement behavior, can predict disease progression in patients with muscular dystrophy and can potentially track the response to therapy

The prevalence of secondary neoplasms in acromegalic patients:possible preventive and/or protective role of metformin

Background Acromegaly is a rare disease due to chronic growth hormone (GH) excess and the consequent increase in insulin-like growth factor-1 (IGF-1) levels. Both GH and IGF-1 play a role in intermediate metabolism affecting glucose homeostasis. The association between hyperinsulinemia/impaired glucose tolerance and an increased risk of cancer has been clarified. Insulin has a mitogenic effect through its interaction with the IGF-1 receptor (IGF-1R) that also binds IGF-1. On the other hand, metformin, an anti-hyperglycemic drug that decreases serum levels of insulin and IGF-1, could have a protective role in the treatment of endocrine tumors. Methods A retrospective, observational, multicenter study in 197 acromegalic patients, receiving/not receiving metformin, was performed to assess whether the prevalence of neoplasms might be correlated with insulin resistance and could eventually be modified by metformin treatment. Results In general, the occurrence of secondary neoplasia among our patients was significantly (pV = 0.035) associated with a positive family history of malignancy and with disease duration; a trend towards significance was observed in patients aged > 50 years. Acromegalic subjects who had undergone surgery showed a lower probability of developing a malignant tumor, whereas a higher prevalence of malignancies was observed in obese patients. No significant statistical difference was found when comparing metformin-treated or -untreated subjects for the presence of a second tumor. More interestingly, a trend towards statistical significance (pV = 0.065) was demonstrated in the metformin-treated group for the onset of a benign neoplasm. Conclusion Metformin could act directly on tumor cell metabolism and may have an adjuvant role in benign lesion progression

From traumatic childhood to cocaine abuse: the critical function of the immune system

Background: Experiencing traumatic childhood is a risk factor for developing substance use disorder (SUD), but the mechanisms that underlie this relationship have not been determined. Adverse childhood experiences affect the immune system and the immune system mediates the effects of psychostimulants. However, whether this system is involved in the etiology of SUD in individuals who have experience early life stress is unknown. Methods:In this study, we performed a series of ex vivo and in vivo experiments in mice and humans to define the function of the immune system in the early-life stress-induced susceptibility to the neurobehavioral effects of cocaine. Results: We provide evidence that exposure to social-stress (S-S) at an early age permanently sensitizes the peripheral (splenocytes) and brain (microglia) immune responses to cocaine in mice. In the brain, microglial activation in the ventral tegmental area (VTA) of S-S mice was associated with functional alterations in dopaminergic neurotransmission, as measured by whole-cell voltage clamp recordings in dopamine (DA) neurons. Notably, preventing immune activation during the S-S exposure reverted the effects of DA in the VTA and the cocaine-induced behavioral phenotype to control levels. In humans, cocaine modulated Toll-like receptor 4-mediated innate immunity, an effect that was enhanced in cocaine addicts who had experienced a difficult childhood. Conclusions Collectively, our findings demonstrate that sensitization to cocaine in early-life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans

N-Glycans mutations rule oligomeric assembly and functional expression of P2X3 receptor for extracellular ATP

N-Glycosylation affects the function of ion channels at the level of multisubunit assembly, protein trafficking, ligand binding and channel opening. Like the majority of membrane proteins, ionotropic P2X receptors for extracellular ATP are glycosylated in their extracellular moiety. Here, we used site-directed mutagenesis to the four predicted N-glycosylation sites of P2X3 receptor (Asn139, Asn170, Asn194 and Asn290) and performed comparative analysis of the role of N-glycans on protein stability, plasma membrane delivery, trimer formation and inward currents. We have found that in transiently transfected HEK293 cells, Asn170 is apparently the most important site for receptor stability, since its mutation causes a primary loss in protein content and indirect failure in membrane expression, oligomeric association and inward current responses. Even stronger effects are obtained when mutating Thr172 in the same glycosylation consensus. Asn194 and Asn290 are the most dispensable, since even their simultaneous mutation does not affect any tested receptor feature. All double mutants containing Asn170 mutation or the Asn139/Asn290 double mutant are instead almost unable to assemble into a functional trimeric structure. The main emerging finding is that the inability to assemble into trimers might account for the impaired function in P2X3 mutants where residue Asn170 is replaced. These results improve our knowledge about the role of N-glycosylation in proper folding and oligomeric association of P2X3 recepto

Convex domains of Finsler and Riemannian manifolds

A detailed study of the notions of convexity for a hypersurface in a Finsler manifold is carried out. In particular, the infinitesimal and local notions of convexity are shown to be equivalent. Our approach differs from Bishop's one in his classical result (Bishop, Indiana Univ Math J 24:169-172, 1974) for the Riemannian case. Ours not only can be extended to the Finsler setting but it also reduces the typical requirements of differentiability for the metric and it yields consequences on the multiplicity of connecting geodesics in the convex domain defined by the hypersurface.Comment: 22 pages, AMSLaTex. Typos corrected, references update

Partial response to first generation SSA guides the choice and predict the outcome of second line therapy in acromegaly

Treatment of acromegaly resistant to first generation somatostatin analogues (first gen-SSA) is often difficult. We aimed to investigate the role of partial response and resistance to first gen-SSA in the choice of second line treatments and their outcomes

Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53

The aim of this international collaborative effort was to report 36-month longitudinal changes using the 6MWT in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53