The NuRD Complex in Neurodevelopment and Disease: A Case of Sliding Doors

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to “open” the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum. Importantly, components of the NuRD complex have been found to carry mutations that profoundly affect neurological and cognitive development in humans. Here, we discuss recent literature concerning the molecular structure of NuRD complexes and how the subunit composition and numerous permutations greatly determine their functions in the nervous system. We will also discuss the role of the CHD family members in an array of neurodevelopmental disorders. Special emphasis will be given to the mechanisms that regulate the NuRD complex composition and assembly in the cortex and how subtle mutations may result in profound defects of brain development and the adult nervous system

Therapeutic advances in ADPKD: the future awaits

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies, representing the fourth cause of end stage renal disease (ESRD), with an estimated prevalence between 1:1000 and 1:2500. It is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy. The advances in the knowledge of multiple molecular pathways involved in the pathophysiology of ADPKD led to the development of several treatments which are currently under investigation. Recently, the widespread approval of tolvaptan and, in Italy, of long-acting release octreotide (octreotide-LAR), represents but the beginning of the new therapeutic management of ADPKD patients. Encouraging results are expected from ongoing randomized controlled trials (RCTs), which are investigating not only drugs acting on the calcium/cyclic adenosin monoposphate (cAMP) pathway, the most studied target so far, but also molecules targeting specific pathophysiological pathways (e.g. epidermal growth factor (EGF) receptor, AMP-activated protein kinase (AMPK) and KEAP1-Nrf2) and sphingolipids. Moreover, studies on animal models and cultured cells have also provided further promising therapeutic strategies based on the role of intracellular calcium, cell cycle regulation, MAPK pathway, epigenetic DNA, interstitial inflammation, and cell therapy. Thus, in a near future, tailored therapy could be the key to changing the natural history of ADPKD thanks to the vigorous efforts that are being made to implement clinical and preclinical studies in this field. Our review aimed to summarize the spectrum of drugs that are available in the clinical practice and the most promising molecules undergoing clinical, animal, and cultured cell studies. Graphical abstract: [Figure not available: see fulltext.

Is quarantine for covid-19 pandemic associated with psychological burden in primary ciliary dyskinesia?

Background: Information on psychological impact of COVID-19 quarantine in primary ciliary dyskinesia (PCD), a chronic disorder with recurrent pulmonary exacerbations, is lacking. Psychological well-being was prospectively assessed during COVID-19 lockdown in Italy in a PCD population. Methods: we recruited 27 PCD patients and 27 healthy controls. To assess psychological well-being, psychological general well-being index and parenting stress index-short questionnaires were administered to participants ≥15 years-old and to mothers of participants <15 years-old, respectively. The PCD exacerbations since outbreak onset and frequency of quarantine weekly chest physiotherapy were compared to the same period of 2019. Outcomes: 70% of PCD mothers and 90% of PCD patients did not show parental stress levels or distress levels, respectively, and these groups showed no significant difference in stress compared to controls. The PCD pulmonary exacerbations occurred less frequently and weekly chest physiotherapy sessions significantly increased compared to the same period during 2019 (p < 0.05). Interpretation: During COVID-19 quarantine, a PCD population showed psychological well-being. Low exacerbation rate, explained by lower infectious exposure or improved compliance to chest physiotherapy, likely contributed to psychological well-being. Evaluating psychological burden and parental stress is a valuable tool for measuring the emotional impact of PCD and improving PCD medical care

Stepwise shortening of agalsidase beta infusion duration in Fabry disease: Clinical experience with infusion rate escalation protocol

Background: Although enzyme replacement therapy with agalsidase beta resulted in a variety of clinical benefits, life-long biweekly intravenous infusion may impact on patients’ quality of life. Moreover, regular infusions are time-consuming: although a stepwise shortening of infusion duration is allowed up to a minimum of 1.5 hr, in most centers it remains ≥3 hr, and no data exists about the safety and tolerability of agalsidase beta administration at maximum tolerated infusion rate. Methods: In this study, we reported our experience with a stepwise infusion rate escalation protocol developed in our center in a cohort of 53 Fabry patients (both already receiving and treatment-naΪve), and explored factors predictive for the infusion rate increase tolerability. Results: Fifty-two patients (98%) reduced infusion duration ≤3 hr; of these, 38 (72%) even reached a duration ≤2 hr. We found a significant difference between the mean duration reached by already treated and naΪve patients (p <.01). More severely affected patients (male patients and those with lower enzyme activity) received longer infusions for higher risk of infusion-associated reactions (IARs). A significant correlation between anti-agalsidase antibodies and IARs was found. Conclusion: Our infusion rate escalation protocol is safe and could improve patient compliance, satisfaction and quality of life

Artificial dermal substitutes for tissue regeneration: comparison of the clinical outcomes and histological findings of two templates

Objective: Artificial dermal substitutes (DSs) are fundamental in physiological wound healing to ensure consistent and enduring wound closure and provide a suitable scaffold to repair tissue. We compared the clinical and histological features of two DSs, Pelnac and Integra, in the treatment of traumatic and iatrogenic skin defects. Methods: This prospective observational study involved 71 randomly selected patients from our hospital. Wound healing was analyzed using the Wound Surface Area Assessment, the Vancouver Scar Scale, and a visual analog scale. Histological and immunohistochemical evaluations were also performed. Results: At 2 weeks, greater regeneration with respect to proliferation of the epidermis and renewal of the dermis was observed with Pelnac than with Integra. At 4 weeks, the dermis had regenerated with both DSs. Both templates induced renewed collagen and revascularization. Differences in the Vancouver Scar Scale score were statistically significant at 4 weeks and 1 year. Pelnac produced a significant increase in contraction at 2 weeks with increasing effectiveness at 4 weeks. Integra produced a higher percentage reduction in the wound surface area and a shorter healing time than Pelnac for wounds >1.5 cm deep. Conclusion: Our observational data indicate that both DSs are effective and applicable in different clinical contexts

Non-familial paid caregivers as potential flu carriers and cause of spread: the primary prevention of flu measured through their adhesion to flu vaccination campaigns&#8212;A Florentine experience

Introduction: Influenza vaccination is recommended for caregivers of elderly people. In a study aimed at assessing the level of health literacy (HL) in a sample non-familial caregivers in the Florence Health District (Tuscany), data were collected regarding access and adherence to the flu vaccination campaigns. Methods: The sample consists of 47 non-familial paid caregivers. We collected information regarding socio-demographic characteristics, services provided and daily work time, whether or not influenza vaccination was administered for the 2016/2017 season and in the previous three years. The level of HL was assessed through the Newest Vital Sign. Results: 63.8% of non-familial caregivers have not joined the flu campaigns over the last four years, 14.9% have been vaccinated only sometimes (in some epidemic seasons), and 21.3% have received a flu shot in all the seasons investigated. Most of the non-familial caregivers who do not get vaccinated (27.7%) do not perceive that they are in direct contact with a person at-risk; those who get the vaccine regularly (12.8%) reported they want to protect the assisted person as motivation for vaccine uptake. Vaccination was not associated with HL. Conclusion: Adhesion to anti-flu vaccination campaigns for these homecare workers has been resulted rather poor. Coverage does not seem to be related with HL level. It seems appropriate to promote extensively flu vaccination among family carers by actively offering the vaccination in appropriate forms, places and times, to avoid serious consequences on elderly people with higher risk of comorbidity and frailty

Dark Matter Search in the Edelweiss Experiment

Preliminary results obtained with 320g bolometers with simultaneous ionization and heat measurements are described. After a few weeks of data taking, data accumulated with one of these detectors are beginning to exclude the upper part of the DAMA region. Prospects for the present run and the second stage of the experiment, EDELWEISS-II, using an innovative reversed cryostat allowing data taking with 100 detectors, are briefly described.Comment: IDM 2000, 3rd International Workshop on the Identification of Dark Matter, York (GB), 18-22/09/2000, v2.0 minor modification

Thermography as a method to detect dental anxiety in oral surgery

(1) Background: the aim of this study was to evaluate if dental anxiety can be measured objectively using thermal infrared imaging. (2) Methods: Patients referred to the Department of Oral Surgery of the University of Naples Federico II and requiring dental extractions were consecutively enrolled in the study. Face thermal distribution images of the patients were acquired before and during their first clinical examination using infrared thermal cameras. The data were analyzed in relation to five regions of interest (ROI) of the patient’s face (nose, ear, forehead, zygoma, chin). The differences in the temperatures assessed between the two measurements for each ROI were evaluated by using paired T‐test. The Pearson correlation and linear regression were performed to evaluate the association between differences in temperatures and Modified Dental Anxiety Scale (MDAS) questionnaire score, age, and gender; (3) results: sixty participants were enrolled in the study (28 males and 32 females; mean age 57.4 year‐old; age range 18–80 year‐old). Only for nose and ear zone there was a statistically significant difference between measurements at baseline and visit. Correlation between the thermal imaging measurements and the scores of the MDAS questionnaire was found for nose and ear, but not for all of the other regions. (4) Conclusions: the study demonstrated a potential use of thermal infrared imaging to measure dental anxiety