Co-occurrence of Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type 1B: coincidence or common molecular mechanism?

Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith–Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed Multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the KCNQ1OT1:TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient. However, we cannot exclude that the rare combination of the epigenetic defect on chromosome 11 and the UPD on chromosome 20 may originate from a common so far undetermined predisposing molecular lesion. A better comprehension of the molecular mechanisms underlying the co-occurrence of two imprinting disorders will improve genetic counselling and estimate of familial recurrence risk of these rare cases. Furthermore, our study also supports the importance of multilocus molecular testing for revealing MLID as well as complex cases of imprinting disorders

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Clinical benefits and acceptability of two commercial arm exoskeletons for patients with muscular dystrophy

Restore a lost function is a special experience for people affected by neuromuscular evolutive diseases as muscular dystrophy. Upper limb stiffness and activity limitations have a crucial role in reducing patients’ autonomy and worsening quality of life. Even if the commercial products might assure a benefit to some users and meet most of their requirements, so far a validation of the use of such devices by people with neuromuscular diseases is missing. We aim at field-testing the improvement in arm functions provided by the use of two commercial devices (Jaeco Wrex and Armon Ayura) and assessing their impact on users’ quality of life and independence. This step is essential to assure a widespread access to these devices for most of the potential users, possibly presenting direction and guidance to health providers. The results acquired from the first three subjects, with a different disease progression, showed that the functional improvements gained with the use of these exoskeletons are limited and largely depends on the user’s impairment. Results showed that if the patient is severely impaired, the exoskeletons are not sufficient to gain functional movements. In contrast, if the patient is moderately impaired, both devices help the subject, even if some limitations of the movements occur. Finally, if the subject is slightly impaired, both devices decrease the performance. However, all the patients have appreciated the good usability of both devices

Pathogenesis of nephrolithiasis: recent insight from cell biology and renal pathology

Randall’s plaques are very common in idiopathic calcium-oxalate nephrolithiasis. These papillary plaques have an apatite mineral structure. While these calcium deposits are generally assumed to be secondary to a purely physico-chemical phenomenon, we advance the hypothesis that they form due to a truly ectopic biomineralization in the renal tissue, and that Henle’s loop epithelial cells, or pericyte-like interstitial cells, or papillary stem cells differentiating along a bone lineage might be involved

WMR Peptide as Antifungal and Antibiofilm against Albicans and Non-Albicans Candida Species: Shreds of Evidence on the Mechanism of Action

Candida species are the most common fungal pathogens infecting humans and can cause severe illnesses in immunocompromised individuals. The increased resistance of Candida to traditional antifungal drugs represents a great challenge in clinical settings. Therefore, novel approaches to overcome antifungal resistance are desired. Here, we investigated the use of an antimicrobial peptide WMR against Candida albicans and non-albicans Candida species in vitro and in vivo. Results showed a WMR antifungal activity on all Candida planktonic cells at concentrations between 25 μM to >50 μM and exhibited activity at sub-MIC concentrations to inhibit biofilm formation and eradicate mature biofilm. Furthermore, in vitro antifungal effects of WMR were confirmed in vivo as demonstrated by a prolonged survival rate of larvae infected by Candida species when the peptide was administered before or after infection. Additional experiments to unravel the antifungal mechanism were performed on C. albicans and C. parapsilosis. The time-killing curves showed their antifungal activity, which was further confirmed by the induced intracellular and mitochondrial reactive oxygen species accumulation; WMR significantly suppressed drug efflux, down-regulating the drug transporter encoding genes CDR1. Moreover, the ability of WMR to penetrate within the cells was demonstrated by confocal laser scanning microscopy. These findings provide novel insights for the antifungal mechanism of WMR against Candida albicans and non-albicans, providing fascinating scenarios for the identification of new potential antifungal targets

Co-Occurrence of Beckwith–Wiedemann Syndrome and Early-Onset Colorectal Cancer

CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (KCNQ1OT1:TSS-DMR that leads to bi-allelic expression of the lncRNA KCNQ1OT1 and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the KCNQ1OT1:TSS-DMR, initiate the tumorigenesis process. Further somatic genetic and epigenetic changes enhancing the activation of the WNT/beta-catenin pathway likely contributed to increase the growth advantage of cancer cells. Although this study does not provide any conclusive cause–effect relationship between BWSp and CRC, it is tempting to speculate that the imprinting defect of BWSp might accelerate tumorigenesis in adult cancer in the presence of predisposing genetic variants

Manipulation of Transition Metal Migration via Cr-Doping for Better-Performance Li-Rich, Co-Free Cathodes

The irreversible migration of transition metals is a primary issue, resulting in detrimental structural changes and poor battery performance in Li-rich layered oxide (LLO) cathodes. Herein, we propose that manipulating the migration of transition metals between octahedral and tetrahedral sites effectively inhibits undesirable phase transitions by stabilizing the delithiated structure of LLOs at high potential. This is demonstrated by introducing Cr into the Co-free LLO, Li1.2Ni0.2Mn0.6O2. A new spinel-like phase, accompanied by significant lattice variation, was observed in the heavily cycled Co-free LLO at high potential by using operando synchrotron characterizations. Benefiting from a well-maintained solid-solution reaction after long-term cycling, Cr-doped Li1.2Ni0.2Mn0.6O2 delivers up to 99% of its initial discharge capacity after 200 cycles at 1C (∼200 mAh g-1), far surpassing the pristine material (∼74%). The work provides valuable insights into the structural degradation mechanisms of LLOs and underscores the importance of stabilizing the delithiated structure at high potential

An assistive upper-limb exoskeleton controlled by multi-modal interfaces for severely impaired patients: development and experimental assessment.

Active exoskeletons can help adults with muscular dystrophy regain independence and self-esteem, which have been limited due to their severe and progressive muscular weakness. A four degrees-of-freedom fully actuated upper limb exoskeleton, equipped with a spring-based anti-gravity system, has been designed, prototyped, and tested on end-users. While wearing the exoskeleton, the user directly controls the system by actively driving the end-effector position (i.e., the hand) using a joystick or vocal control. The exoskeleton’s kinematic model has been determined so that, given a desired user’s position in the task-space, a differential inverse kinematics algorithm computes the desired joint-space motion trajectories. The dynamic model was investigated in the vertical plane, demonstrating that gravity torques were considerably higher than velocity-induced and inertia torques, which have been therefore neglected. A pilot study on 14 Muscular Dystrophy patients was conducted. Outcome measures included: (i) externally-assessed functional benefit evaluated through the Performance of Upper Limbs module, (ii) self-perceived functional benefit assessed through the ABILHAND questionnaire, and (iii) usability of the system assessed through the System Usability Scale. All participants strongly increased their range of motion, and they were able to perform activities that were not possible without the exoskeleton, such as feeding. The externally-assessed and self-perceived functional improvements were statistically improved when wearing the exoskeleton (PUL p-value, ABILHAND p-value). System usability was evaluated to be excellent. Patients’ feedbacks were encouraging and outlined future development steps