Disentangling brain PrP^(C)proteoforms and their roles in physiology and disease

The cellular prion protein(PrPC),a cell surface glycoprotein of 209 amino acids,has been considerably studied over the decades mainly due to its critical involvement in transmissible spongiform encephalopathies,or prion diseases.Indeed,it is the misfolding and aggregation of PrPC into pathological assemblies-named PrPSc-that constitute prions,the agents causing these unusual neurodegenerative diseases affecting humans and animals(Prusiner,1982).Furthermore,increasing evidence support its relevance also in other neurodegenerative diseases(NDDs),such as Alzheimer’s and Parkinson’s diseases(Corbett et al.,2020).

Calcium-sensitive protein MLC1 as a possible modulator of the astrocyte functional state

Astrocytes,the main population of glial cells in the central nervous system(CNS),exert essential tasks for the control of brain tissue homeostasis,supporting neuron and other glial cell activity from the developmental stage to adult life.To maintain the optimal functionality of the brain,astroglial cells are particularly committed to reacting to every change in tissue homeostatic conditions,from mild modifications of the physiological environment,a process called astrocyte activation,to the more severe alterations occurring in pathological situations causing astrocyte reactivity or reactive astrogliosis(Escartin et al.,2021).During these reactive states,astrocytes mount an active,progressive response encompassing morphological,molecular,and interactional remodeling,leading to the acquisition of new functions and the loss of others,whose intensity,duration,and reversibility are dependent on the nature of the stimulus and regulated in a context-specific manner.

Osteoporosis in celiac disease and in endocrine and reproductive disorders

As the increase in lifespan brings to light diseases that were previously not clinically detectable,osteoporosis has become an issue of worldwide significance. The disease is marked by a loss of bone mass; the bones become less dense,fragile and more prone to fracturing. Because it is regulated by endocrine and environmental factors,osteoporosis presents a multifactorial etiopathogenesis,with the genetic component accounting for 70% of an individual variation in bone mass density (BMD),the principal determinant,with age,of fracture risk. Pathological conditions such as celiac disease (CD) exacerbate the process of bone loss,so that the occurrence of osteoporosis in celiac subjects is of particular note: indeed,the screening of osteoporosis patients for this disease is advisable,since it may be the only sign of undiagnosed CD. An increase in interleukin IL-1β,of the IL-1 system,in the relatives of celiac patients confirms the genetic predisposition to osteoporosis and its presence is evidence of an association between the two conditions. The direct effect on the bones of CD is secondary to poor absorption of calcium and vitamin D. In women osteoporosis is indirectly associated with early menopause and amenorrhea,and it may follow prolonged breast-feeding and frequent pregnancies,while in men it is associated with hypogonadism and GH deficit. These endocrine and non-endocrine factors exert their effects on bones by modulating the RANK/RANK-L/OPG system. An appropriate lifestyle from adolescence onwards,together with early diagnosis of and treatment for CD and primary and secondary endocrine pathologies are important for the prevention of damage to the bones.

Impact of comorbidities on the severity of chronic hepatitis B at presentation

AIM:To evaluate the clinical relevance of each cofactor on clinical presentation of chronic hepatitis B.METHODS:Out of 1366 hepatitis B surface antigen(HBsAg) positive subjects consecutively observed in 79 Italian hospitals,53(4.3%) showed as the only cofactor hepatitis D virus(HDV) infection [hepatitis B virus(HBV)/HDV group],130(9.5%) hepatitis C virus(HCV)(group HBV/HCV),6(0.4%) human immunodeficiencyvirus(HIV)(group HBV/HIV),138(10.2%) alcohol abuse(group HBV/alcohol);109(8.0%) subjects had at least two cofactors and 924 were in the cofactor-free(CF) group.RESULTS:Compared with patients in group CF those in group HBV/alcohol were older and more frequently had cirrhosis(P < 0.001),those in group HBV/HDV were younger(P < 0.001),more frequently resided in the south of the country and had cirrhosis(P <0.001),those in group HBV/HCV were older(P < 0.001) and more frequently had cirrhosis(P < 0.001).These cofactors were all independent predictors of liver cirrhosis in HBsAg positive patients.Multivariate analysis showed that an older age [odds ratio(OR) 1.06,95% CI:1.05-1.08],alcohol abuse with more than 8 drinks daily(OR 2.89,95% CI:1.81-4.62) and anti-HDV positivity(OR 3.48,95% CI:2.16-5.58) are all independently associated with liver cirrhosis.This association was found also for anti-HCV positivity in univariate analysis,but it was no longer associated(OR 1.23,95% CI:0.84-1.80) at multivariate analysis.CONCLUSION:Older age,HDV infection and alcohol abuse are the major determinants of severe liver disease in chronic HBV infection,while HCV replication plays a lesser role in the severity of hepatic damage.

Acute alcoholic hepatitis, end stage alcoholic liver disease and liver transplantation: An Italian position statement

Alcoholic liver disease encompasses a broad spectrum of diseases ranging from steatosis steatohepatitis, fibrosis, and cirrhosis to hepatocellular carcinoma. Forty-four per cent of all deaths from cirrhosis are attributed to alcohol. Alcoholic liver disease is the second most common diagnosis among patients undergoing liver transplantation (LT). The vast majority of transplant programmes (85%) require 6 mo of abstinence prior to transplantation; commonly referred to as the &#x0201c;6-mo rule&#x0201d;. Both in the case of progressive end-stage liver disease (ESLD) and in the case of severe acute alcoholic hepatitis (AAH), not responding to medical therapy, there is a lack of evidence to support a 6-mo sobriety period. It is necessary to identify other risk factors that could be associated with the resumption of alcohol drinking. The &#x0201c;Group of Italian Regions&#x0201d; suggests that: in a case of ESLD with model for end-stage liver disease &#x0003c; 19 a 6-mo abstinence period is required; in a case of ESLD, a 3-mo sober period before LT may be more ideal than a 6-mo period, in selected patients; and in a case of severe AAH, not responding to medical therapies (up to 70% of patients die within 6 mo), LT is mandatory, even without achieving abstinence. The multidisciplinary transplant team must include an addiction specialist/hepato-alcohologist. Patients have to participate in self-help groups.

Cultural Isolation and Characteristics of the Blood Microbiome of Healthy Individuals

Background: On the analogy of the non-pathogenic microbiota found in oral cavity, skin and gastrointestinal tract, existence of blood microbiota was confirmed by DNA sequencing, but never deeply characterized. Hypothesis for the existence of dormant blood microbiota in healthy humans have been arisen and single species have been isolated. The aim of our study was to resuscitate and investigate the biodiversity of bacterial and fungal dormant blood microbiota in healthy individuals by blood culturing and NGS DNA sequencing. Results: Twenty eight blood samples of healthy individuals, seven for each blood type, were studied. Several culture media were tested. Blood microbiota resuscitation was performed in BHI broth supplemented with vitamin K 1 mg/ml, 2% sucrose, 0.25% sodium citrate and 0.2% yeastolate at 43?C for 72 h. All tested blood samples were culture positive, as confirmed by Gram staining and TEM. TEM images demonstrated well defined cell structures. Analysis for bacterial and eukaryotic species was performed by 16S rRNA and ITS2 targeted sequencing. The obtained sequences were clustered (≥97% identity) in Operational Taxonomic Units (OTUs). Among cultured and uncultured samples we identified OTUs similarity with 47 bacterial orders belonging to 15 phyla and 39 fungi orders blonging to 2 phyla. For the first time we demonstrated isolation and sequencing identification of fungal blood microbiota in healthy individuals. Blood-group differences were identified among the bacterial microbiome compositions. Conclusion: The dormant blood microbiome is innate of the healthy individuals. Interventional strategies to bind the host blood microbiome with the states of health and disease remain an unmet research goal.

Effects of Exposure to Extremely Low Frequency Electro-magnetic Fields on Circadian Rhythms and Distribution of Some Leukocyte Differentiation Antigens in Dairy Cows

Objective To investigate the effects of extremely low frequency magnetic and electric fields （ELFEMFs） emitted from 380 kV transmission lines on some leukocyte differentiation antigens in dairy cows. Methods The study was carded out in 5 cows exposed to 1.98-3.28 μT of ELFEMFs and in 5 control cows exposed to 0.2-0.7 μT of ELFEMFs. Following haematological and immunologic parameters were measured in both groups： WBC, CD45R, CD6, CD4, CD8, CD21, and CD11B leukocyte antigen expression. Results Some of the haematological and immunologic parameters under investigation were similar in both groups. However, CD8 （T lymphocyte surface antigen） was higher in the exposed group （1.35 ±0.120 vs 0.50 ±0.14×10^3/mL）. Furthermore, the CD4/CD8 ratio （0.84 ±0.05 and 2.19±0.16 for exposed and not exposed cows respectively） and circadian rhythm were different between the two groups. Conclusion Exposure to ELFEMFs is responsible of the abnormal temporal variations and distribution of some haematological and immunological parameters in dairy cows.

Risk factors of extraneural spreading in astrocytomas and oligodendrogliomas in donors with gliomas: A systematic review

BACKGROUND Patients with a history of primary brain tumors can be eligible for organ donation under extended criteria.The risk assessment of tumor transmission via organ transplant in primary brain tumors is primarily based on the assessment of tumor histotype and grade.Previous surgeries,chemo-/radiotherapy,and ventriculoperitoneal shunt placement can lead to a disruption of the blood-brain barrier,concurring to an increase in the transmission risk.AIM To investigate the role of tumor transmission risk factors in donors with oligodendrogliomas and astrocytomas.METHODS We searched PubMed and EMBASE databases for studies reporting extraneural spreading of oligoden-drogliomas and astrocytomas and extracted clinical-pathological data on the primary tumor histotype and grade,the elapsed time from the diagnosis to the onset of metastases,sites and number of metastases,prior surgeries,prior radiotherapy and/or chemotherapy,ventriculoatrial or ventriculo-peritoneal shunt placement,and the presence of isocitrate dehydrogenase 1/2 mutation and 1p/19q codeletion.Statistical analysis was performed using R software.Statistical correlation between chemotherapy or radiotherapy and the presence of multiple extra-central nervous system metastases was analyzed usingχ2 and Fischer exact test.The Kaplan-Meier method was used to evaluate the presence of a correlation between the metastasis-free time and:(1)Localization of metastases;(2)The occurrence of intracranial recurrences;and(3)The occurrence of multiple metastases.RESULTS Data on a total of 157 patients were retrieved.The time from the initial diagnosis to metastatic spread ranged from 0 to 325 mo in patients with oligodendrogliomas and 0 to 267 mo in those with astrocytomas.Respectively,19%and 39%of patients with oligodendroglioma and astrocytoma did not receive any adjuvant therapy.The most frequent metastatic sites were bone,bone marrow,and lymph nodes.The lungs and the liver were the most commonly involved visceral sites.There was no significant correlation between the occurrence of multiple metastases and the administration of adjuvant chemo-/radiotherapy.Patients who developed intracranial recurrences/metastases had a significantly longer extraneural metastasis-free time compared to those who developed extraneural metastases in the absence of any intra-central nervous system spread.CONCLUSION A long follow-up time does not exclude the presence of extraneural metastases.Therefore,targeted imaging of bones and cervical lymph nodes may improve safety in the management of these donors.

Blood exosomes as a tool for monitoring treatment efficacy and progression of neurodegenerative diseases

Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis,and prion disease are representative neurodegenerative diseases that share common sub-cellular features,the most obvious of which is a strong association with the accumulation of misfolded,aggregated,and insoluble forms of proteins in the brain,as evidenced in post-mortem brain tissues of patients.Diagnosis of neurodegenerative diseases is often

Procalcitonin and mid-regional pro-adrenomedullin as promising markers for sepsis diagnosis and prognosis

To the Editor,We read with great interest the recent review by Limongi et al.on sepsis biomarkers[1].Recently,the combined use of two biomarkers,procalcitonin(PCT)and mid-regional proadrenomedullin(MR-pro ADM)has been reported in sepsis diagnosis and prognosis.PCT is a polypeptide produced as a precursor of calcitonin by thyroid C cells normally

Sensor with Intact or Modified Yeast Cells as Rapid Device for Toxicological Test of Chemicals

Aerobic catabolism of S. cerevisiae (cell respiration) is a rapid, cost-effective, and reproducible toxicological endpoint of the whole cells biosensor. To increase the signal intensity, a protocol for the immobilization and modification of the yeast cells is described. In particular, the enzymatic treatment of the immobilized yeast cells allows removing the cell wall and obtaining structurally modified cells namely spheroplasts. Both immobilization and exposure of sensitive cells like spheroplasts confirmed to improve the method’s sensitivity vs. the chemicals. The present paper reports the test of different chemicals (including Mercury and wood preservative like Tanalith) present in consumer products, performed both by sensor with intact and modified whole cells.

Therapeutic implications of colon cancer stem cells

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.

Molecular epidemiology and phylogeny of Nipah virus infection:A mini review

Nipah virus(Ni V) is a member of the genus Henipavirus of the family Paramyxoviridae,characterized by high pathogenicity and endemic in South Asia.It is classified as a Biosafety Level-4(BSL-4) agent.The case-fatality varies from 40%-70% depending on the severity of the disease and on the availability of adequate healthcare facilities.At present no antiviral drugs are available for Ni V disease and the treatment is just supportive.Phylogenetic and evolutionary analyses can be used to help in understanding the epidemiology and the temporal origin of this virus.This review provides an overview of evolutionary studies performed on Nipah viruses circulating in different countries.Thirty phylogenetic studies have been published from 2000 to 2015 years,searching on pub-med using the key words ‘Nipah virus AND phylogeny' and twenty-eight molecular epidemiological studies from 2006 to 2015 have been performed,typing the key words ‘Nipah virus AND molecular epidemiology'.Overall data from the published study demonstrated as phylogenetic and evolutionary analysis represent promising tools to evidence NiV epidemics,to study their origin and evolution and finally to act with effective preventive measure.

Relationship between gastrointestinal and extra-gastrointestinal symptoms and delayed gastric emptying in functional dyspeptic patients

AIM: Delayed gastric emptying and an enlarged fasting gastric antrum are common findings in functional dyspepsia but their relationship with gastrointestinal (GI), and the frequently associated extra-GI symptoms remains unclear.This study evaluated the relationship between GI and extra-GI symptoms, fasting antral volume and delayed gastric emptying in functional dyspepsia.METHODS: In 108 functional dyspeptic patients antral volume and gastric emptying were assessed with ultrasonography (US). Symptoms were assessed with standardized questionnaire. The association of symptoms and fasting antral volume with delayed gastric emptying was estimated with logistic regression analysis.RESULTS: Delayed gastric emptying was detected in 39.8% of the patients. Postprandial drowsiness (AOR 11.25; 95%CI 2.75-45.93), nausea (AOR 3.51; 95%CI 1.19-10.32), fasting antral volume (AOR 1.93; 95%CI 1.22-3.05), were significantly associated with delayed gastric emptying. Symptoms, mainly the extra-GI ones as postprandial drowsiness and nausea, combined with fasting antral volume predicted the modality of gastric emptying with a sensitivity and specificity of 78%.CONCLUSION: In functional dyspeptic patients, (1) an analysis of fasting antral volume and of symptoms can offer valuable indication on the modality of gastric emptying,and (2) it seems appropriate to inquire on postprandial drowsiness that showed the best correlation with delayed gastric emptying.

The phylogenetic and evolutionary history of Kokobera virus

Objective: To estimate the genetic diversity of Kokobera virus, the date of origin and the spread among different viruses in the endemic regions of Australia. Methods: Two datasets were built. The first consisting of 29 sequences of the NS5/3' UTR region of Kokobera group downloaded from Gen Bank, the second including only 24 sequences of Kokobera viruses, focus is on this group. Results: Bayesian time analysis revealed two different entries in Australia of Kokobera virus in the 50 s years with the dated ancestor in 1861 year. Clade A and B showed a clear separation of the Kokobera sequences according to the geographic region. Conclusions: Data from the study showed as Kokobera virus, despite of its ancient origin and its circulation before the European colonization, remained limited to the Australian Country and nowadays limited mostly to the regions were Australian marsupials are mostly found.

Long term immunological perturbations post DAA therapy in chronic HCV/HIV co-infected patients

Direct-acting antiviral(DAA)therapies are efficacious for the achievement of sustained virologic response(SVR)in almost all treated hepatitis C virus(HCV)-infected patients.However,the impacts of HCV eradication on immune function and chronic immune activation in the long-term remain controversial and limited,especially in patients co-infected with human immunodeficiency virus(HIV).Indeed,although restoration of many immune responses clearly can be observed,several features of immune perturbations persist over time after HCV clearance.Understanding the degree and reasons of the partial recovery of the immune system in chronic HCV/HIV coinfection after HCV elimination is pivotal to avoid disease progression and possible long-term clinical outcomes in cured patients,as well as contributing to the development of immunotherapy drug design.

Local Role of Food Producers' Communities for a Global One-Health Framework: The Experience of Translational Research in an Italian Dairy Chain

Community is the foundation of public health: the present paper reports the approach and strategy for intervention on the dairy production community developed by the Italian project ALERT (www.alert2015.it), which implements the transfer of technical innovation and technological know-how from public research. Starting from the local role of primary producers, North-South and South-South networking (www.noodlesonlus.org) is needed to share solutions for transnational problems like climatic change, contaminated agro-farming sites and food waste and losses in the era of food crisis. Based on risk analysis, science-society dialogue and global health, the main drivers of this experience of translational research are One Health, i.e. the web of inter-relationships among environment, farm animals and human health, and sustainable food safety (prevention actions on diet of young women, today, to protect next generation’s health) to increase population life expectancy in good health.

Sex effect on presenilins expression in post-natal rat brain

Presenilin 1 and presenilin 2 are widely expressed during brain development. Several mutations in these proteins have been associated with autosomal-dominant inherited forms of Alzheimer disease. Their expression is regulated by various cellular and extracellular factors, which change with age and sex. Both age and sex are key risk factors for Alzheimer’s disease, but the issue of whether the expression of presenilins is influenced by the sex during early postnatal development of the brain has been poorly investigated so far. In this study, we report that transcript levels of presenilins, and the subset of neurons expressing these proteins in various brain areas of the developing post-natal brain are different in male and female rats, suggesting that their function(s) may contribute to sexual dimorphism in the brain, both at morphological and functional levels.

Reproducing Cochlear Signals by a Minimal Electroacoustic Model

Transient-Evoked Otoacoustic Emissions (TEOAEs) were studied, with particular reference to their subject-dependent features. To this end, an electric model of the ear was implemented and validated. Simulated and natural TEOAEs were analyzed through a nonlinear analysis technique. The simulated signals were able to reproduce the dynamical features of the experimentally observed TEOAEs and, most importantly, the natural variability among individuals. The unexpected inverse relation between model complexity and adherence to the natural signals is commented.

注射吸毒者中暴发高病死率的HAV感染

Background/Aims: In 2002, the first reported outbreak of hepatitis A virus (HAV) infection involving mostly intravenous drug users (IDU) occurred in Italy. We attempted a thorough evaluation of the outbreak, including epidemiological, clinical and virological analyses. Methods: We conducted an epidemiological investigation, including a case-control study, to identify the source and themodes of HAV transmission. Hepatitis B and C (HCV) viruses and human immunodeficiency vir us (HIV) coinfections were clinically analysed. Sequence analysis of the VP1/2A junction of the HAV isolates was also performed. Results: Of the 47 symptomatic cases, 35 were IDUs. The only associated risk factor was contact (not related to injecting practices) with a jaundiced person (odds ratio: 5.8; 95%confidence i nterval: 1.3-29.9). Of the cases, 58%were anti-HCV positive and 4.7%anti-HI V positive. Three individuals died of acute liver failure: 2 were HCV-coinfecte d alcohol abusers, with underlying liver cirrhosis; 1 was HCV/HIV-coinfected. H AV-RNA was found in 15 of the 24 tested patients: genotype IB (8 cases) and III A (7 cases) were detected. Conclusions: HAV was probably transmitted through the fecal-oral route, although parenteral transmission cannot be excluded. The hig h fatality ratewas probably due to severe underlying liver damage. The occurrenc e of this outbreak highlights the need for routine HAV vaccination for IDUs.