Bone metabolism in patients with type 1 neurofibromatosis: key role of sun exposure and physical activity

Bone metabolism has been rarely investigated in children affected by Neurofibromatosis type 1 (NF1). Aim of the present study was to assess bone mineral metabolism in children and adults NF1 patients, to determine the relevant factors potentially involved in the development of reduced bone mineral density (BMD), and provide possible therapeutic intervention in NF1 patients. 114 NF1 patients and sex and age matched controls were enrolled into the study. Clinical and biochemical factors reflecting bone metabolism were evaluated. Factors potentially affecting BMD were also investigated including: physical activity, sun exposure, vitamin D intake. Whenever the presence of vitamin D deficiency was recorded, cholecalciferol supplementation was started and z-score data obtained at Dual-Energy X-ray Absorptiometry (DXA) during supplementation were compared with previous ones. NF1 patients showed lower Z-scores at Dual-Energy X-ray Absorptiometry DXA than controls. Physical activity was significantly reduced in NF1 patients than in controls. Sun exposure was significantly lower in NF1 compared to control subjects. At linear regression analysis vitamin D was the most predictive factor of reduced z-score at DXA (p = 0.0001). Cholecalciferol supplementation significantly increased BMD z-score (p < 0.001). We speculated that a combination of different factors, including reduced sun exposure, possibly associated with reduced serum vitamin D levels, and poor physical activity, concur to the impaired bone status in NF1 patients. We also demonstrated that treatment with vitamin D can be effective in improving z-score value in NF1 patients, including children. In conclusion, the findings of the current study are expected to have important implications for the follow-up and prevention of osteopenia/osteoporosis in this common genetic disease

Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability

The SGLT2-inhibitor dapagliflozin improves neutropenia and neutrophil dysfunction in a mouse model of the inherited metabolic disorder GSDIb

Glycogen Storage Disease type 1b (GSDIb) is a genetic disorder with long term severe complications. Accumulation of the glucose analog 1,5-anhydroglucitol-6-phosphate (1,5AG6P) in neutrophils inhibits the phosphorylation of glucose in these cells, causing neutropenia and neutrophil dysfunctions. This condition leads to serious infections and inflammatory bowel disease (IBD) in GSDIb patients. We show here that dapagliflozin, an inhibitor of the renal sodium-glucose co-transporter-2 (SGLT2), improves neutrophil function in an inducible mouse model of GSDIb by reducing 1,5AG6P accumulation in myeloid cells

Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings

Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss-of-function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain-of-function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1

Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings

Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss-of-function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain-of-function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1

The Urban-Rural Continuum. The Bioclimatic Approach to Design, Between Past and Future

L’ambiente costruito rurale, insieme multiscalare di trasformazioni praticate dall’uomo per accogliere le attività collegate all’agricoltura, suggerisce varie riflessioni sull’approccio bioclimatico nel progetto di architettura. Il contributo mette subito in evidenza il tema del continuum urbano-rurale (luogo intermedio e contraddittorio che condensa le trasformazioni che stanno avvenendo nella contemporaneità, offrendo un banco di prova necessario per tutti i campi del sapere e per tutte le discipline tecnologiche) per evidenziare che la contrapposizione tra urbano e rurale non solo è superata nei fatti, ma anche è teoricamente inadeguata a identificare l’ambiente costruito rurale, nonostante sia stata utilizzata sin da antico, sui livelli sia analitico che progettuale. Il superamento di tale contrapposizione viene confermato dal legame tra attività agricole e costruttive, di cui viene proposta una lettura in chiave tecnologica, con riferimento alle sfere del prodotto e del processo, dopo averne ricordato le origini culturali remote e profondamente radicate. Il possibile duplice e contraddittorio carattere dell’ambiente costruito rurale, vernacolare o colto, viene illustrato con riferimento alla specificità degli aspetti bioclimatici riconosciuti negli edifici tradizionali (sostenibilità ante litteram), evidenziando come nel XX secolo si sia cancellato il legame con il fattore sito e con la tradizionale cultura costruttiva, creando le premesse per una ingente e diffusa emergenza qualitativa anche per le costruzioni che ospitano attività produttive primarie. Accennando all’interrogativo se oggi abbia senso una precisa tipologia di edificio produttivo rurale e evidenziando l’importanza delle interrelazioni con gli aspetti socioeconomici del settore produttivo dell’agricoltura, il contributo sottolinea che il costruito rurale nel suo insieme contribuisce all’identità ibrida del paesaggio contemporaneo e conclude dimostrando che proprio l’approccio bioclimatico possa svolgere un ruolo di collante, sia teoretico che operativo, perché contribuisce a creare una comune metodologia, adeguata ad affrontare le sfide contemporanee. superando una certa tendenza alla improvvisazione e eccessivi specialismi e facendo leva su opportune azioni di formazione e divulgazione.The rural built environment, as a multiscale whole of human transformations aimed at accommodating agriculture-related activities, prompts various reflections on the bioclimatic approach in architectural design. This contribution, firstly, highlights the theme of the urban-rural continuum (an intermediate and contradictory place, which epitomizes on-going contemporary transformations) in order to demonstrate that the contrast between urban and rural – although it has been used, since ancient times, on both analytical and design level – has not only been superseded, but is also, theoretically, inadequate for identifying the rural built environment. The link between agricultural and construction activities confirms the overcoming of this contrast; a reading in technological terms is proposed, with reference to the spheres of the product and the process, whilst recollecting its remote and deeply rooted cultural origins. The possible dual and contradictory character (vernacular or scholarly) of the rural built environment is illustrated with reference to the specificity of the bioclimatic aspects recognized in traditional buildings (“ante litteram sustainability”), highlighting how the relationship with the site-factor (microclimatic characteristics and local construction culture) was annulled in the 20th century, also creating the basis for a widespread emergency for the quality of the buildings employed in agricultural activities. Touching upon the question of whether the rural building can be a typology distinct from other production buildings, this paper highlights the importance of the relationships with the socio-economic aspects of the agricultural sector, underlining the fact that the main identity for rural buildings in every age, in addition to the role that they play in the landscape, should be a stronger bond with the environmental elements, showing the centrality of the bioclimatic approach in updating the primordial interactions between agriculture and construction. Furthermore, the distinction between vernacular or scholarly character of the rural buildings prompted a reflection on the contemporary epistemological bases of the bioclimatic approach to general architectural design, which risks being ineffective whether it remains on an empirical level or if it is confined to a hyper-specialized niche. Finally, the bioclimatic approach is indicated as a common analytical and design methodological basis, useful for addressing the contradictory nature of the urban-rural continuum, in the framework of contemporary challenges