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Michelantonio De Fano, Alberto Falorni, Massimo Malara, Francesca Porcellati, Carmine Giuseppe Fanelli Department of Medicine and Surgery, Endocrine and Metabolic Sciences Section, University of Perugia, Perugia, ItalyCorrespondence: Michelantonio De Fano; Carmine Giuseppe Fanelli, Email michelantonio.defano@gmail.com; carmine.fanelli@unipg.itAbstract: Patients suffering from acromegaly and Cushing’s Disease (CD) face the risk of several clinical complications. The onset of diabetes mellitus (DM) is among the most important: exposure to elevated growth hormone or cortisol levels is associated with insulin resistance (IR). DM contributes to increasing cardiovascular risk for these subjects, which is higher compared to healthy individuals. Hyperglycemia may also be caused by pasireotide, a second-generation somatostatin receptor ligand (SRLs), currently used for the treatment of these diseases. Accordingly, with 2014 medical expert recommendations, the management of hyperglycemia in patients with CD and treated with pasireotide is based on lifestyle changes, metformin, DPP-4 inhibitors (DPP-4i) and, subsequently, GLP-1 Receptor Agonists (GLP-1 RAs). There is no position for SGLT2-inhibitors (SGLT2-i). However, a very recent experts’ consensus regarding the management of pasireotide-induced hyperglycemia in patients with acromegaly suggests the use of GLP-1 RAs as first line treatment (in suitable patients) and the use of SGLT2-i as second line treatment in patients with high cardiovascular risk or renal disease. As a matter of fact, beyond the hypoglycemic effect of GLP1-RAs and SGLT2-i, there is increasing evidence regarding their role in the reduction of cardiovascular risk, commonly very high in acromegaly and CD and often tough to improve despite biochemical remission. So, an increasing use of GLP1-RAs and SGLT2-i to control hyperglycemia is desirable in these diseases. Obviously, all of that must be done with due attention in order to minimize the occurrence of adverse events. For this reason, large studies are needed to analyze the presence of potential limitations.Keywords: acromegaly, Cushing’s disease, pasireotide, hyperglycemia, diabetes mellitus, cardiovascular risk

Abstract The expansion of urbanization in natural environments increases interactions between wildlife, domestic animals, and humans. In Italy, the red fox (Vulpes vulpes) is one of the most common wild carnivores. This species can serve as a reservoir and sentinel host for several infectious diseases. We aimed to improve knowledge about the exposure of red foxes to selected zoonotic (Anaplasma spp, Ehrlichia spp., Borrelia spp., and hepatitis E virus) and carnivore-specific pathogens (canine parvovirus, canine distemper virus, pseudorabies virus, and Dirofilaria spp.) through a retrospective survey performed in the Tuscany region during the spring season of 2013. Using specific ELISAs and serum samples (n = 38) collected during a culling campaign, a prevalence of 2.6% for canine distemper virus, 18.4% for canine parvovirus, 5.2% for Anaplasma spp., 2.6% for Ehrlichia spp., 7.9% for Dirofilaria spp., 21.05% for hepatitis E virus, and 10.5% for pseudorabies virus was observed. Conversely, antibodies against Borrelia spp. were not identified in any of the animals. Our results revealed no significant sex-related differences in seroprevalence and confirmed hepatitis E virus as the most common pathogen in the analyzed samples. All of the animals that tested positive for tick-borne zoonotic agents presented ticks at the time of sampling. Our study confirms the exposure of red foxes in the Tuscany region to viral and bacterial infections raising medical and veterinary concern and indicating the need for large-scale surveillance to fully assess the epidemiological significance of these findings.

Landslides and slope failures represent critical hazards for both the safety of local communities and the potential damage to economically relevant infrastructure such as roads, hydroelectric plants, pipelines, etc. Numerous surveillance methods, including ground-based radar, InSAR, Lidar, seismometers, and more recently computer vision, are available to monitor landslides and slope instability. However, the high cost, complexity, and intrinsic technical limitations of these methods frequently require the design of alternative and complementary techniques. Here, we provide an improved methodology for the application of image-based computer vision in landslide and rockfall monitoring. The newly developed open access Python-based software, Akh-Defo, uses optical flow velocity, image differencing and similarity index map techniques to calculate land deformation including landslides and rockfall. Akh-Defo is applied to two different datasets, notably ground- and satellite-based optical imagery for the Plinth Peak slope in British Columbia, Canada, and satellite optical imagery for the Mud Creek landslide in California, USA. Ground-based optical images were processed to evaluate the capability of Akh-Defo to identify rockfalls and measure land displacement in steep-slope terrains to complement LOS limitations of radar satellite images. Similarly, satellite optical images were processed to evaluate the capability of Akh-Defo to identify ground displacement in active landslide regions a few weeks to months prior to initiation of landslides. The Akh-Defo results were validated from two independent datasets including radar-imagery, processed using state of the art SqueeSAR algorithm for the Plinth Peak case study and very high-resolution temporal Lidar and photogrammetry digital surface elevation datasets for the Mud Creek case study. Our study shows that the Akh-Defo software complements InSAR by mitigating LOS limitations via processing ground-based optical imagery. Additionally, if applied to satellite optical imagery, it can be used as a first stage preliminary warning system (particularly when run on the cloud allowing near real-time processing) prior to processing more expensive but more accurate InSAR products such as SqueeSAR.

Autoimmune Addison’s disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator (AIRE).

Daniele Cappellani,1 Enrico Macchia,1 Alberto Falorni,2 Piero Marchetti3 1Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy; 2Department of Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Perugia, Italy; 3Department of Clinical and Experimental Medicine, Division of Metabolism and Cell Transplantation, University of Pisa, Pisa, ItalyCorrespondence: Daniele CappellaniDepartment of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Ospedale Cisanello, via Paradisa 2, Pisa 56124, ItalyTel +39 50 995001Fax +39 50 578772Email d.cappellani@hotmail.itAbstract: Insulin autoimmune syndrome (IAS), also named Hirata’s disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin autoantibodies (IAA). IAS is a form of immune-mediated hypoglycemia, which develops when a triggering factor (ie, a medication or a viral infection) acts on an underlying predisposing genetic background. IAS pathogenesis involves the formation of insulin-IAA complexes that induce glycemic alterations with a double-phase mechanism: IAA prevent insulin to bind its receptor in the postprandial phase, possibly resulting in mild hyperglycemia; thereafter, insulin is released from the complexes irrespective of blood glucose concentrations, thus inducing hypoglycemia. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. The gold standard for the definitive diagnosis is the finding of IAA in a blood sample. Because IAS is frequently a self-remitting disease, its management mostly consists of supportive measures, such as dietary modifications, aimed at preventing the development of hypoglycemia. Pharmacological therapies may occasionally be necessary for patients presenting with severe manifestations of IAS. Available therapies may include drugs that reduce pancreatic insulin secretion (somatostatin analogues and diazoxide, for instance) and immunosuppressive agents (glucocorticoids, azathioprine and rituximab). The purpose of this review is to provide a comprehensive analysis of the disease, by describing the burden of knowledge that has been obtained in the 50 years following its first description, took in 1970, and by highlighting the points that are still unclear in its pathogenesis and management.Keywords: insulin autoimmune syndrome, IAS, Hirata, hypoglycemia, autoimmunity

Microelectromechanical systems (MEMS) are nowadays widespread in the sensor market, with several different applications. New production techniques and ever smaller device geometries require a continuous investigation of potential failure mechanisms in such devices. This work presents an experimental on-chip setup to assess the geometry- and material-dependent strength of stoppers adopted to limit the deformation of movable parts, using an electrostatically actuated device. A series of comb-finger and parallel plate capacitors are used to provide a rather large stroke to a shuttle, connected to the anchors through flexible springs. Upon application of a varying voltage, failure of stoppers of variable size is observed and confirmed by post-mortem ΔC–V curves. The results of the experimental campaign are collected to infer the stochastic property of the strength of polycrystalline, columnar silicon films.

Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS.

The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene, located in the chromosomal region 21q22.3. The related protein, AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin and anchorage to multimolecular complexes involved in the initiation and post-initiation events of tissue-specific antigen-encoding gene transcription. Once synthesized, the self-antigens are presented to, and cause deletion of, the self-reactive thymocyte clones. The clinical diagnosis of APS1 is based on the classic triad idiopathic hypoparathyroidism (HPT)—chronic mucocutaneous candidiasis—autoimmune Addison's disease (AAD), though new criteria based on early non-endocrine manifestations have been proposed. HPT is in most cases the first endocrine component of the syndrome; however, APS1-associated AAD has received the most accurate biochemical, clinical, and immunological characterization. Here is a comprehensive review of the studies on APS1-associated AAD from initial case reports to the most recent scientific findings.

Vitamin D inadequacy is pervasive in the oldest-old. Many vitamin D metabolites are available for supplementation, their effects on the recovery of adequate serum levels remain unknown. We investigate the effects of supplementation with cholecalciferol (D3) and calcifediol (25D3) on serum levels of 25(OH)D, 1-25(OH)D, bone and inflammatory markers, ultimately identifying clinical predictors of successful treatment. Sixty-seven oldest-old individuals were randomized to weekly administration of 150 mcg of 25D3 or D3, from hospital admission to 7 months after discharge. Supplementation of 25D3 and D3 were associated with increasing serum levels of 25(OH)D (p < 0.001) and 1-25(OH)D (p = 0.01). Participants on 25D3 experienced a steeper rise than those on D3 (group*time interaction p = 0.01), after adjustment for intact parathyroid hormone (iPTH) levels the differences disappeared (intervention*iPTH interaction p = 0.04). Vitamin D supplementation was associated with a decreasing trend of iPTH and C-reactive protein (CRP) (p < 0.001). Polypharmacy and low handgrip strength were predictors of failure of intervention, independent of vitamin D metabolites. In conclusion, D3 and 25D3 supplementation significantly increase vitamin D serum levels in the oldest-old individuals, with a tendency of 25D3 to show a faster recovery of acceptable iPTH levels than D3. Polypharmacy and low muscle strength weaken the recovery of adequate vitamin D serum levels.

Type-1 diabetes (T1D) is a metabolic disease involving the autoimmune destruction of insulin-producing pancreatic beta cells. It is often diagnosed by the detection of autoantibodies, typically those recognizing insulin itself or the 65-kDa isoform of glutamic acid decarboxylase (GAD65). Oral insulin can be used to induce systemic immunological tolerance and thus prevent or delay the onset of T1D, suggesting that combination treatments with other autoantigens such as GAD65 could be even more successful. GAD65 has induced oral tolerance and prevented T1D in preclinical studies but it is difficult to produce in sufficient quantities for clinical testing. Here we combined edible plant systems, namely spinach (Spinacia oleracea cv Industra) and red beet (Beta vulgaris cv Moulin Rouge), with the magnICON® expression system to develop a safe, cost-effective and environmentally sustainable platform for the large-scale production of GAD65. The superior red beet platform was extensively characterized in terms of recombinant protein yields and bioequivalence to wild-type plants, and the product was tested for its ability to resist simulated gastric digestion. Our results indicate that red beet plants are suitable for the production of a candidate oral vaccine based on GAD65 for the future preclinical and clinical testing of T1D immunotherapy approaches.

To design holographic and impulse ground penetrating radar (GPR) sensors suitable for humanitarian de-mining in the Donbass (Ukraine) conflict zone, we measured critical electromagnetic parameters of typical local soils using simple methods that could be adapted to any geologic setting. Measurements were recorded along six profiles, each crossing at least two mapped soil types. The parameters selected to evaluate GPR and metal detector sensor performance were magnetic permeability, electrical conductivity, and dielectric permittivity. Magnetic permeability measurements indicated that local soils would be conducive to metal detector performance. Electrical conductivity measurements indicated that local soils would be medium to high loss materials for GPR. Calculation of the expected attenuation as a function of signal frequency suggested that 1 GHz may have optimized the trade-off between resolution and penetration and matched the impulse GPR system power budget. Dielectric permittivity was measured using both time domain reflectometry and impulse GPR. For the latter, a calibration procedure based on an in-situ measurement of reflection coefficient was proposed and the data were analyzed to show that soil conditions were suitable for the reliable use of impulse GPR. A distinct difference between the results of these two suggested a dry (low dielectric) soil surface, grading downward into more moist (higher dielectric) soils. This gradation may provide a matching layer to reduce ground surface reflections that often obscure shallow subsurface targets. In addition, the relatively high dielectric deeper (10 cm–20 cm) subsurface soils should provide a strong contrast with plastic-cased mines.

PREVIEW is an European Commission FP6 Integrated Project with the aim of developing, at an European level, innovative geo-information services for atmospheric, geophysical and man-made risks. Within this framework, the Landslides Platform Service 2 (forecasting of shallow rapid slope movements) has developed an integrated procedure for the forecasting and warning of distributed shallow landsliding to be used for civil protection purposes. The Service consists of an automated end-to-end forecasting chain which uses data from a probabilistic downscaled short-term rainfall forecast, soil saturation estimates and meteorological radar outputs. The above data are entered into a hydro-geological model that makes use of an infinite slope approach to calculate the distributed Factor of Safety over the entire basin. All outputs, and much of the input data, are shown on a WebGIS system so that end-users can interactively access and download data. A distinctive feature of the service is the use of an innovative soil depth model for predicting the distributed thickness of the regolith cover within the basin, which is one of the most important parameters controlling shallow landslide triggering. The service was developed in a pilot test site in NE Italy, the Armea basin. Validation makes use of two rainfall events: one that occurred in 2000 and a smaller, more recent event (2006) that caused fewer landslides. Rainfall data have been used to compute a distributed factor-of-safety map that has been overlaid onto the landslide inventory. Instead of a traditional validation approach based on the number count of correctly identified landslides, we carried out an alternative procedure based on the landslides area that gave outcomes which, for this preliminary stage of the research, can be considered promising.

BackgroundThe aim of this study was to investigate sex differences and associations of high molecular weight (HMW) adiponectin, leptin and proinflammatory adipokines, individually or in combinations, with adiposity and insulin resistance (IR) measures in prepubertal childhood.MethodologyWe studied 305 prepubertal children (boys/girls: 144/161; Tanner stage 1; age: 5-13 yr), included in a cohort of 44,231 adolescents who participated in an extensive Italian school-based survey. According to Cole's criteria, 105 individuals were lean (L; boys/girls: 59/46), 60 overweight (OW; boys/girls: 32/28) and 140 obese (OB; boys/girls: 70/70). Measurements comprised total and HMW adiponectin, leptin, as well as a panel of proinflammatory adipokines/chemokines associated with diabetes risk.Principal findingsLeptin-, and the leptin-to-HMW adiponectin ratio (L/HMW)-, increased progressively (pConclusionsIn prepubertal children, leptin emerges as a sex-independent discrimination marker of adiposity degree and as a useful, sex-associated predictor of the systemic insulin resistance.

In this work, the mechanical design and the experimental validation of a micro-electromechanical frequency-modulated (FM) pitch gyroscope are presented. The proposed device is fabricated through the ThELMA © surface micromachining process of STMicroelectronics and it represents, to the authors’ knowledge, the first small-footprint (690 µm × 946 µm) prototype of FM gyroscope able to measure an in-plane angular rate. The measured scale factor, defined as the mean angular gain, equals 0.973 Hz/Hz, in close agreement with theoretical predictions. It depends only on the mass distribution in the mechanical structure and is, consequently, not influenced by environmental fluctuations.

In this paper a Cross Axis evaluation methodology is presented. The Cross Axis Sensitivity value depends on backend testing position tolerances as well as technological features and design properties of the MEMS gyroscope. A numerical model was developed to take into account the sources of cross axis related to the last two contributions, not considering backend tolerances. Given a specific structure for the AM gyroscope, the asymmetries in the MEMS structure are acknowledged as the main sources for the cross axis. The results of the harmonic FEM simulations were finally compared with real testing data, thus proving the validity of the developed FEM model.

BackgroundGene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.AimTo investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.MethodsA sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.ResultsWe report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively.ConclusionsVariants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.