The Role of the Prion Protein in Neurodegenerative Disorders

The cellular prion protein (PrPC) is a cell surface glycoprotein predominantly expressed in the central nervous system. A modification of the mainly α-helical PrPC into an isoform enriched in β-strands generates the prion, the infectious particle at the basis of fatal prion diseases. In spite of PrPC’s intimate involvement in prion propagation, its physiological function remains enigmatic. Past observations have supported the possibility that PrPC regulates Ca2+ homeostasis, a notion that has been recently reinforced by the demonstration that PrPC controls Ca2+ fluxes in domains close to the neuronal plasma membrane, and interacts physically with a ionotropic glutamate receptor, thus protecting from glutamate excitotoxicity. Recently, however, it has been proposed that PrPC serves as a high-affinity receptor for soluble amyloid-β (Aβ) oligomers implicated in Alzheimer’s disease (AD), and this interaction could thus be crucial for AD-related synaptic dysfunctions. In light of this background, using genetically-encoded Ca2+ probes targeting different cell domains of cerebellar granule neurons expressing, or not, PrPC, this work focused on whether PrPC regulates local Ca2+ fluxes arising from the activation of storeoperated Ca2+ entry (SOCE), and/or of glutamate receptors. We found that, with respect to PrPC-expressing neurons, the absence of PrPC caused alterations of several local Ca2+ fluxes, indicating that PrPC could act as a key component of the system(s) controlling neuronal Ca2+ homeostasis. As to the molecular mechanism enabling PrPC to exert such control, the results showed the implication of Fyn tyrosine kinase and of the Ca2+-induced-Ca2+-release from the ryanodine receptor. The study has also analyzed whether soluble Aβ oligomers could affect the PrPC-dependent regulation of Ca2+ homeostasis. Obtained results have shown that the acute treatment of neurons with Aβ oligomers abrogates the control of PrPC over Fyn and SOCE, and alters mitochondrial Ca2+ uptake after stimulation of ionotropic glutamate receptors. This data thus suggests a PrPC-dependent mechanism for Aβ-induced neuronal Ca2+ dyshomeostasis

The prion protein regulates glutamate-mediated Ca2+ entry and mitochondrial Ca2+ accumulation in neurons

The cellular prion protein (PrPC) whose conformational misfolding leads to the production of deadly prions, has a still-unclarified cellular function despite decades of intensive research. Following our recent finding that PrPC limits Ca2+ entry via store-operated Ca2+ channels in neurons, we investigated whether the protein could also control the activity of ionotropic glutamate receptors (iGluRs). To this end, we compared local Ca2+ movements in primary cerebellar granule neurons and cortical neurons transduced with genetically encoded Ca2+ probes and expressing, or not expressing, PrPC. Our investigation demonstrated that PrPC downregulates Ca2+ entry through each specific agonist-stimulated iGluR and after stimulation by glutamate. We found that, although PrP-knockout (KO) mitochondria were displaced from the plasma membrane, glutamate addition resulted in a higher mitochondrial Ca2+ uptake in PrP-KO neurons than in their PrPC-expressing counterpart. This was because the increased Ca2+ entry through iGluRs in PrP-KO neurons led to a parallel increase in Ca2+-induced Ca2+ release via ryanodine receptor channels. These data thus suggest that PrPC takes part in the cell apparatus controlling Ca2+ homeostasis, and that PrPC is involved in protecting neurons from toxic Ca2+ overloads

Sea guidelines: a comparative analysis: first outcomes

The European Directive 2001/42/EC (Directive) has introduced the Strategic Environmental Assessment (SEA), a procedure for assessing the effects of certain plans and programs on the environment. The Directive has been transposed in different ways and times within Europe: member states have frequently drawn up guidelines to facilitate SEA implementation, by adopting different approaches. So far a few studies have been performed to analyze SEA guidelines. In this paper we aim to analyze key elements of SEA guidelines released by seven European countries in order to evaluate the effectiveness of those documents and SEA implementation. We have found that no SEA guidelines satisfy all key elements we have identified. Based on the latter finding, this work is introductory to a further analysis which aims to characterize SEA guidelines and define a proposal of SEA guidelines for landscape planning in the Italian region of Sardinia.</br

Prevalence of cervical colonization by Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis and Mycoplasma genitalium in childbearing age women by a commercially available multiplex real-time PCR: An Italian observational multicentre study

Background: Mycoplasmas are frequently isolated from the genital tract. New molecular PCR-based methods for the detection of mycoplasmas can better define the real epidemiology of these microorganisms. The aim of this study was to evaluate the prevalence of mycoplasmas in a population of childbearing age women by means of PCR. Methods: This 21-month multicentre observational study was conducted at four Italian clinical microbiology laboratories. Women reporting symptoms of vaginitis/cervicitis, or with history of infertility, pregnancy, miscarriage or preterm birth were included. Detection of Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium was performed from cervical swabs by means of a commercially available multiplex real-time PCR. Results: a total of 1761 women fulfilled the inclusion criteria and were included in the study. The overall prevalence was: U. parvum 38.3%, U. urealyticum 9%, M. hominis 8.6% and M. genitalium 0.6%. The proportion of foreign patients positive for U. parvum was significantly higher compared to Italian patients (37% vs 30.1%, p = 0.007) and also for overall mycoplasma colonization (53.4% vs 45.8%, p = 0.011). The number of symptomatic patients positive for M. hominis was significantly higher than that of negative controls (2.9% vs 1%, p = 0.036). A significant positive trend in mycoplasma colonization was found in relation to the pregnancy week for U. urealyticum (p = 0.015), M. hominis (p = 0.044) and for overall mycoplasma colonization (p = 0.002). Conclusion: multiplex RT-PCR can be a valuable tool to evaluate the real epidemiology of cervical mycoplasma colonization. Keywords: Genital mycoplasmas, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum, Ureaplasma urealyticum, Real-time PC

A multicenter randomized phase 4 trial comparing sodium picosulphate plus magnesium citrate vs. polyethylene glycol plus ascorbic acid for bowel preparation before colonoscopy. The PRECOL trial

Background: Adequate bowel preparation before colonoscopy is crucial. Unfortunately, 25% of colonoscopies have inadequate bowel cleansing. From a patient perspective, bowel preparation is the main obstacle to colonoscopy. Several low-volume bowel preparations have been formulated to provide more tolerable purgative solutions without loss of efficacy. Objectives: Investigate efficacy, safety, and tolerability of Sodium Picosulphate plus Magnesium Citrate (SPMC) vs. Polyethylene Glycol plus Ascorbic Acid (PEG-ASC) solutions in patients undergoing diagnostic colonoscopy. Materials and methods: In this phase 4, randomized, multicenter, twoarm trial, adult outpatients received either SPMC or PEG-ASC for bowel preparation before colonoscopy. The primary aims were quality of bowel cleansing (primary endpoint scored according to Boston Bowel Preparation Scale) and patient acceptance (measured with six visual analogue scales). The study was open for treatment assignment and blinded for primary endpoint assessment. This was done independently with videotaped colonoscopies reviewed by two endoscopists unaware of study arms. A sample size of 525 patients was calculated to recognize a difference of 10% in the proportion of successes between the arms with a two-sided alpha error of 0.05 and 90% statistical power. Results: Overall 550 subjects (279 assigned to PEG-ASC and 271 assigned to SPMC) represented the analysis population. There was no statistically significant difference in success rate according to BBPS: 94.4% with PEG-ASC and 95.7% with SPMC (P = 0.49). Acceptance and willing to repeat colonoscopy were significantly better for SPMC with all the scales. Compliance was less than full in 6.6 and 9.9% of cases with PEG-ASC and SPMC, respectively (P = 0.17). Nausea and meteorism were significantly more bothersome with PEG-ASC than SPMC. There were no serious adverse events in either group. Conclusion: SPMC and PEG-ASC are not different in terms of efficacy, but SPMC is better tolerated than PEG-ASC. SPMC could be an alternative to lowvolume PEG based purgative solutions for bowel preparation

Demographic, tumor and clinical features of clinical trials versus clinical practice patients with HER2-positive early breast cancer: results of a prospective study

Several randomized clinical trials (RCTs) have demonstrated the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancer (BC). However, RCT patients may not invariably be representative of patients routinely seen in clinical practice (CP). To address this issue, we compared the clinical and tumor features of RCT and CP patients with HER2-positive BC

Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths.

Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.This work was supported in part by the Spanish Society of Cardiology [Grant 2016 to E.G-L.] and by the Instituto de Salud Carlos III (ISCIII) [grants RD012/0042/0066 and CB16/11/00432] and by the Spanish Ministry of Economy and Competitiveness [grant SAF2015-71863-REDT]. Grants are supported by the Plan Estatal de IþDþI 2013-2016–European Regional Development Fund (FEDER) “A way of making Europe”.S

Clinical characteristics of wild-type transthyretin cardiac amyloidosis – Disproving myths.

Aims: Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterised by concentric LV hypertrophy, preserved LVEF and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. Methods and Results: Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy 12mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.68 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 5214%, with 39 patients (37%) showing a LVEF<50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. Conclusion: The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.pre-print833 K

Incidence and burden of long COVID in Africa: a systematic review and meta-analysis

Long COVID, also known as "post-acute sequelae of COVID-19," affects at least 65 million individuals worldwide with a wide spectrum of symptoms that may last weeks, months, or permanently. Its epidemiology and burden in Africa are unclear. This meta-analysis examines long-term COVID-19 effects in the WHO African Region. A systematic search in several databases was carried out up to 12 February 2023 including observational studies from African countries reporting the cumulative incidence of long COVID signs and symptoms. Only studies conducted in African countries were included. Several sensitivity and meta-regression analyses were performed. Among 1547 papers initially screened, 25 were included, consisting of 29,213 participants. The incidence of any long COVID symptomatology was 48.6% (95% CI 37.4-59.8) as psychiatric conditions were the most frequent, particularly post-traumatic stress disorder reaching a cumulative incidence of 25% (95% CI 21.1-30.4). Higher age (p = 0.027) and hospitalization (p = 0.05) were associated with a higher frequency of long COVID. Long COVID poses a significant burden in Africa, particularly concerning psychiatric conditions. The study recommends identifying at-risk people and defining treatment strategies and recommendations for African long-COVID patients. High-quality studies addressing this condition in African setting are urgently needed