Contribution of polymorphic variation of inositol hexakisphosphate kinase 3 (IP6K3) gene promoter to the susceptibility to late onset Alzheimer's disease

Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the IP6K3 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNPs in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to upregulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis

IP6K3 and IPMK variations in LOAD and longevity: evidence for a multifaceted signaling network at the crossroad between neurodegeneration and survival

Several studies reported that genetic variants predisposing to neurodegeneration were at higher frequencies in centenarians than in younger controls, suggesting they might favor also longevity. IP6K3 and IPMK regulate many crucial biological functions by mediating synthesis of inositol poly- and pyrophosphates and by acting non-enzymatically via protein–protein interactions. Our previous studies suggested they affect Late Onset Alzheimer Disease (LOAD) and longevity, respectively. Here, in the same sample groups, we investigated whether variants of IP6K3 also affect longevity, and variants of IPMK also influence LOAD susceptibility. We found that: i) a SNP of IP6K3 previously associated with increased risk of LOAD increased the chance to become long-lived, ii) SNPs of IPMK, previously associated with decreased longevity, were protective factors for LOAD, as previously observed for UCP4. SNP-SNP interaction analysis, including our previous data, highlighted phenotype-specific interactions between sets of alleles. Moreover, linkage disequilibrium and eQTL data associated to analyzed variants suggested mitochondria as crossroad of interconnected pathways crucial for susceptibility to neurodegeneration and/or longevity. Overall, data support the view that in these traits interactions may be more important than single polymorphisms. This phenomenon may contribute to the non-additive heritability of neurodegeneration and longevity and be part of the missing heritability of these traits

Predictor Analysis in Radiofrequency Ablation of Benign Thyroid Nodules: A Single Center Experience

PURPOSE: To confirm the efficacy of ultrasound (US) guided radiofrequency ablation (RFA) in the treatment of benign thyroid nodules, we evaluated as primary outcome the technical efficacy and clinical success in a single center dataset. The secondary outcome was to find a correlation between nodules’ pre-treatment features and volume reduction rate (VRR) ≥75% at 12 months after RFA and during follow-up period. METHODS: This retrospective study included 119 consecutive patients (99 females, 20 males, 51.5 ± 14.4 years) with benign thyroid nodules treated in our hospital between October 2014 and December 2018 with a mean follow-up of 26.8 months (range 3–48). Clinical and US features before and after RFA were evaluated by a US examination at 1, 3, 6, 12 months and annually thereafter up to 48 months. RESULTS: The median pre-treatment volume was 22.4 ml; after RFA we observed a statistically significant volume reduction from the first month (11.7 ml) to the last follow-up (p 22.4 ml (HR 0.54, p 0.036) were found to be independent positive and negative predictors of VRR ≥75% respectively. One-month post RFA VRR ≥50% represented the best positive predictor of technical success. CONCLUSIONS: This study confirmed the efficacy of RFA in the treatment of benign thyroid nodules. In particular we show that by selecting macrocystic nodules smaller than 22.4 ml better long-term response can be achieved, which is predicted by an early shrinkage of the nodule

Clinical characteristics of patients with endometrial cancer and adenomyosis

open11noA better endometrial cancer (EC) prognosis in patients with coexistent adenomyosis has been reported. Unfortunately, it is still unclear if this better prognosis is related to a more favorable clinical profile of adenomyosis patients. We aimed to evaluate differences in the clinical profiles of EC patients with and without adenomyosis. A systematic review and meta-analysis was performed by searching seven electronics databases for all studies that allowed extraction of data about clinical characteristics in EC patients with and without adenomyosis. Clinical characteristics assessed were: age, Body Mass Index (BMI), premenopausal status, and nulliparity. Mean difference in mean ± standard deviation (SD) or odds ratio (OR) for clinical characteristics between EC patients with and without adenomyosis were calculated for each included study and as a pooled estimate, and graphically reported on forest plots with a 95% confidence interval (CI). The Z test was used for assessing the overall effect by considering a p value < 0.05 as significant. Overall, eight studies with 5681 patients were included in the qualitative analysis, and seven studies with 4366 patients in the quantitative analysis. Pooled mean difference in mean ± SD between EC women with and without adenomyosis was −1.19 (95% CI: −3.18 to 0.80; p = 0.24) for age, and 0.23 (95% CI: −0.62 to 1.07; p = 0.60) for BMI. When compared to EC women without adenomyosis, EC women with adenomyosis showed a pooled OR of 1.53 (95% CI: 0.92 to 2.54; p = 0.10) for premenopausal status, and of 0.60 (95% CI: 0.41 to 0.87; p = 0.007) for nulliparity. In conclusion, there are not significant differences in clinical characteristics between EC patients with and without adenomyosis, with the exception for nulliparity. Clinical features seem to not underlie the better EC prognosis of patients with adenomyosis compared to patients without adenomyosis.openCasadio P.; Raffone A.; Maletta M.; Travaglino A.; Raimondo D.; Raimondo I.; Santoro A.; Paradisi R.; Zannoni G.F.; Mollo A.; Seracchioli R.Casadio P.; Raffone A.; Maletta M.; Travaglino A.; Raimondo D.; Raimondo I.; Santoro A.; Paradisi R.; Zannoni G.F.; Mollo A.; Seracchioli R

Reentrant Spin-Peierls Transition in Mg-Doped CuGeO_3

We report a synchrotron x-ray scattering study of the diluted spin-Peierls (SP) material Cu_{1-x}Mg_xGeO_3. In a recent paper we have shown that the SP dimerization attains long-range order only for x < x_c = 0.022(0.001). Here we report that the SP transition is reentrant in the vicinity of the critical concentration x_c. This is manifested by broadening of the SP dimerization superlattice peaks below the reentrance temperature, T_r, which may mean either the complete loss of the long-range SP order or the development of a short-range ordered component within the long-range ordered SP state. Marked hysteresis and very large relaxation times are found in the samples with Mg concentrations in the vicinity of x_c. The reentrant transition is likely related to the competing Neel transition which occurs at a temperature similar to T_r. We argue that impurity-induced competing interchain interactions play an essential role in these phenomena.Comment: 5 pages, 4 embedded eps figure

A Genome-Wide Screening and SNPs-to-Genes Approach to Identify Novel Genetic Risk Factors Associated with Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer’s disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel SNPs-to-genes approach and functional annotation analysis. We identified two novel potential loci for FTD. Suggestive SNPs reached p-values ~10-7 and OR > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation, and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-GWAS. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis

3D Patient-Specific Virtual Models for Presurgical Planning in Patients with Recto-Sigmoid Endometriosis Nodules: A Pilot Study

Background and Objective: In recent years, 3D printing has been used to support surgical planning or to guide intraoperative procedures in various surgical specialties. An improvement in surgical planning for recto-sigmoid endometriosis (RSE) excision might reduce the high complication rate related to this challenging surgery. The aim of this study was to build novel presurgical 3D models of RSE nodules from magnetic resonance imaging (MRI) and compare them with intraoperative findings. Materials and Methods: A single-center, observational, prospective, cohort, pilot study was performed by enrolling consecutive symptomatic women scheduled for minimally invasive surgery for RSE between November 2019 and June 2020 at our institution. Preoperative MRI were used for building 3D models of RSE nodules and surrounding pelvic organs. 3D models were examined during multi-disciplinary preoperative planning, focusing especially on three domains: degree of bowel stenosis, nodule's circumferential extension, and bowel angulation induced by the RSE nodule. After surgery, the surgeon was asked to subjectively evaluate the correlation of the 3D model with the intra-operative findings and to express his evaluation as "no correlation", "low correlation", or "high correlation" referring to the three described domains. Results: seven women were enrolled and 3D anatomical virtual models of RSE nodules and surrounding pelvic organs were generated. In all cases, surgeons reported a subjective "high correlation" with the surgical findings. Conclusion: Presurgical 3D models could be a feasible and useful tool to support surgical planning in women with recto-sigmoidal endometriotic involvement, appearing closely related to intraoperative findings

Detection and Classification of Hysteroscopic Images Using Deep Learning

Background: Although hysteroscopy with endometrial biopsy is the gold standard in the diagnosis of endometrial pathology, the gynecologist experience is crucial for a correct diagnosis. Deep learning (DL), as an artificial intelligence method, might help to overcome this limitation. Unfortunately, only preliminary findings are available, with the absence of studies evaluating the performance of DL models in identifying intrauterine lesions and the possible aid related to the inclusion of clinical factors in the model. Aim: To develop a DL model as an automated tool for detecting and classifying endometrial pathologies from hysteroscopic images. Methods: A monocentric observational retrospective cohort study was performed by reviewing clinical records, electronic databases, and stored videos of hysteroscopies from consecutive patients with pathologically confirmed intrauterine lesions at our Center from January 2021 to May 2021. Retrieved hysteroscopic images were used to build a DL model for the classification and identification of intracavitary uterine lesions with or without the aid of clinical factors. Study outcomes were DL model diagnostic metrics in the classification and identification of intracavitary uterine lesions with and without the aid of clinical factors. Results: We reviewed 1500 images from 266 patients: 186 patients had benign focal lesions, 25 benign diffuse lesions, and 55 preneoplastic/neoplastic lesions. For both the classification and identification tasks, the best performance was achieved with the aid of clinical factors, with an overall precision of 80.11%, recall of 80.11%, specificity of 90.06%, F1 score of 80.11%, and accuracy of 86.74 for the classification task, and overall detection of 85.82%, precision of 93.12%, recall of 91.63%, and an F1 score of 92.37% for the identification task. Conclusion: Our DL model achieved a low diagnostic performance in the detection and classification of intracavitary uterine lesions from hysteroscopic images. Although the best diagnostic performance was obtained with the aid of clinical data, such an improvement was slight

Mirror system of the RICH detector of the NA62 experiment

A large RICH detector is used in NA62 to suppress the muon contamination in the charged pion selection by a factor 100 in the momentum range between 15 and 35 GeV/c. The detector consists of a 17 m long tank (vessel), filled with neon gas at atmospheric pressure. Cherenkov light is reflected by a mosaic of 20 spherical mirrors with 17 m focal length, placed at the downstream end, and collected by 1952 photomultipliers (PMTs) placed at the upstream end. In this paper the characterization of the mirrors before installation and the mirror support system are described. The mirror installation procedure and the laser alignment are also illustrated

Spin-Glass State in CuGa2O4\rm CuGa_2O_4

Magnetic susceptibility, magnetization, specific heat and positive muon spin relaxation (\musr) measurements have been used to characterize the magnetic ground-state of the spinel compound $\rm CuGa_2O_4$. We observe a spin-glass transition of the S=1/2 $\rm Cu^{2+}$ spins below $\rm T_f=2.5K$ characterized by a cusp in the susceptibility curve which suppressed when a magnetic field is applied. We show that the magnetization of $\rm CuGa_2O_4$ depends on the magnetic histo Well below $\rm T_f$, the muon signal resembles the dynamical Kubo-Toyabe expression reflecting that the spin freezing process in $\rm CuGa_2O_4$ results Gaussian distribution of the magnetic moments. By means of Monte-Carlo simulati we obtain the relevant exchange integrals between the $\rm Cu^{2+}$ spins in this compound.Comment: 6 pages, 16 figure