A descriptive analysis of COVID-19 associated mortality in Parma Province: concordance between official national mortality register provided by ISTAT (National Institute of Statistics) and local ADS (Automated Data System) real-time surveillance flow.

BACKGROUND AND AIM: The Public Health Department of the Parma Local Health Authority (AUSL) has implemented a computerized system called ADS (Automated Data System) to collect data on COVID-19 cases and related deaths, as required by the Emilia-Romagna Region and the Italian Ministry of Health, to improve the daily flow of real-time information. However, official mortality data for all causes was collected even from the National Institute of Statistics (ISTAT) through death forms that were completed by certifying doctors in each municipality. This analysis aims to verify the agreement between the data collected by ISTAT and the data collected by ADS. METHODS: The study period went from January 1st to December 31st, 2021. The population under observation consisted of residents in the province of Parma who died due to COVID-19, as identified through the ISTAT and/or ADS data flow. RESULTS: In 2021, a total of 448 deaths due to COVID-19 were reported in the Parma Province, with a median age of 83 years. The ADS system identified 408 of these deaths, whereas ISTAT certified only 347. Three hundred and seven deaths were identified by both flows. CONCLUSIONS: The survey suggests that the ADS surveillance system may have overestimated the COVID-19 mortality data compared to the ISTAT flow. The ADS has been valuable in the immediate response to emergencies, providing a more sensitive system that prioritizes the precautionary principle and enables decisions aimed at minimizing risks for vulnerable populations. However, it is not recommended for routine surveillance, as it is less reliable compared to the ISTAT flow.

Clinical approach to prostatic diseases in the dog.

In small animal practice, prostatic diseases are increasingly encountered. All dogs may experience prostatic disease, but particular care should be addressed to breeding dogs, in which prostatic affection may lead to decrease in semen quality and fertility. The most common prostatic disease is the benign prostatic hyperplasia (BPH) followed by prostatitis, prostatic neoplasia and prostate squamous metaplasia. These diseases do not have pathognomonic symptoms, therefore, making a correct diagnosis may not be easy. An accurate clinical examination and a correct diagnostic protocol are essential in order to begin the most appropriate treatment, and also to do a good prophylaxis where it is possible. BPH therapy is usually recommended when mild-severe signs are present or if symptoms disturb the patient. New therapeutic approaches, both medical and surgical, allow to maintain fertility in most animals with prostatic disorders. Prostate cancer is relatively infrequent. Elective therapy is the surgical one, but it is considered palliative and can result in important post-operative complications. The aim of this paper is to lay down the most appropriate diagnostic process describing the aetiologies of prostatic disease, their symptoms, the right investigative tools and therapy.

Characterization of human gene locus CYYR1: a complex multi-transcript system.

Cysteine/tyrosine-rich 1 (CYYR1) is a gene we previously identified on human chromosome 21 starting from an in-depth bioinformatics analysis of chromosome 21 segment 40/105 (21q21.3), where no coding region had previously been predicted. CYYR1 was initially characterized as a four-exon gene, whose brain-derived cDNA sequencing predicts a 154-amino acid product. In this study we provide, with in silico and in vitro analyses, the first detailed description of the human CYYR1 locus. The analysis of this locus revealed that it is composed of a multi-transcript system, which includes at least seven CYYR1 alternative spliced isoforms and a new CYYR1 antisense gene (named CYYR1-AS1). In particular, we cloned, for the first time, the following isoforms: CYYR1-1,2,3,4b and CYYR1-1,2,3b, which present a different 3' transcribed region, with a consequent different carboxy-terminus of the predicted proteins; CYYR1-1,2,4 lacks exon 3; CYYR1-1,2,2bis,3,4 presents an additional exon between exon 2 and exon 3; CYYR1-1b,2,3,4 presents a different 5' untranslated region when compared to CYYR1. The complexity of the locus is enriched by the presence of an antisense transcript. We have cloned a long transcript overlapping with CYYR1 as an antisense RNA, probably a non-coding RNA. Expression analysis performed in different normal tissues, tumour cell lines as well as in trisomy 21 and euploid fibroblasts has confirmed a quantitative and qualitative variability in the expression pattern of the multi-transcript locus, suggesting a possible role in complex diseases that should be further investigated.

Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours.

Birt-Hogg-Dubè (BHD) is an autosomal dominant syndrome characterised by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cancer. The association of benign cutaneous lesions and increased cancer risk is also a feature of Cowden Syndrome (CS), an autosomal dominant disease caused by PTEN mutations. BHD and CS patients may develop oncocytomas, rare neoplasias that are phenotypically characterised by a prominent mitochondrial hyperplasia. We here describe the genetic analysis of a parotid and a thyroid oncocytoma, developed by a BHD and a CS patient, respectively. The BHD lesion was shown to maintain the wild-type allele of FLCN, while losing one PTEN allele. On the other hand, a double heterozygosity for the same two genes was found to be the only detectable tumorigenic hit in the CS oncocytoma. Both conditions occurred in a context of high chromosomal stability, as highlighted by comparative genomic hybridisation analysis. We conclude that, similarly to PTEN, FLCN may not always follow the classical Two Hits model of tumorigenesis and may hence belong to a class of non-canonical tumour suppressor genes. We hence introduce a role of PTEN/FLCN double heterozygosity in syndromic oncocytic tumorigenesis, suggesting this to be an alternative determinant to pathogenic mitochondrial DNA mutations, which are instead the genetic hallmark of sporadic oncocytic tumours.

The RET51/FKBP52 complex and its involvement in Parkinson disease.

The tyrosine kinase receptor RET51 is expressed in distinct families of neurons where it promotes different functions. FKBP52 is an immunophilin with neuroprotective effects on different kinds of neurons. In this paper, we demonstrate that RET51 activation by both glial cell line-derived neurotrophic factor (GDNF) and NGF triggers the formation of RET51/FKBP52 complex. The substitution of the tyrosine 905 of RET51, a key residue phosphorylated by both GDNF and NGF, disrupts the RET51/FKBP52 complex. NGF and GDNF have a functional role in dopaminergic (DA) neurons where RET51 and FKBP52 are expressed with a yet undefined function. To clarify if RET51/FKBP52 complex should exert its function in DA neurons, we used an indirect approach by screening the genes encoding for RET51 and FKBP52 in a group of 30 Parkinson's disease patients. The degeneration of DA neurons is the main feature of PD, which is associated to a complex multifactorial aetiology combining environmental, age-related and genetic factors. We found a compound heterozygous carrying two mutations in RET and FKBP52 that are sufficient to disrupt the RET51/FKBP52 complex, indicating its potential role in PD.

Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels.

We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an approximately 50% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca2+ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases.

An inherited mitochondrial DNA disruptive mutation shifts to homoplasmy in oncocytic tumor cells.

A disruptive frameshift mtDNA mutation affecting the ND5 subunit of complex I is present in homoplasmy in a nasopharyngeal oncocytic tumor and inherited as a heteroplasmic germline mutation recurring in two of the patient's siblings. Homoplasmic ND5 mutation in the tumor correlates with lack of the ND6 subunit, suggesting complex I disassembly. A few oncocytic areas, expressing ND6 and heteroplasmic for the ND5 mutation, harbor a de novo homoplasmic ND1 mutation. Since shift to homoplasmy of ND1 and ND5 mutations occurs exclusively in tumor cells, we conclude that complex I mutations may have a selective advantage and accompany oncocytic transformation.