Short-term effects on emergency room access or hospital admissions for cardio-respiratory diseases: methodology and results after three years of functioning of a waste-to-energy incinerator in Turin (Italy).

This study is part of the health surveillance system set up with the construction of a waste-to-energy (WTE) plant in Turin (Italy). Circulatory and respiratory diseases in emergency room (ER) accesses and first hospital admissions were considered. Main concerns of population living in the area near WTE were to know whether single and repeated peaks in emissions would correspond to adverse health effects. We tackle this issue using spatio-temporal analyses, comparing an exposed group (EXP) living near the WTE with a reference group (NOEXP). Age-standardized rates of ER accesses between EXP and NOEXP were temporally compared, testing whether there have been significantly different changes over time. We also examined the relationship between emission peaks and ER accesses in the following days. Finally, with time-series analysis, we investigated variations in ER accesses and pollutants before and after WTE start-up. No significant relationship has been found for the outcome considered.

Cellular senescence in brain aging and neurodegeneration.

Cellular senescence is a state of terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory phenotype. In the brain, senescent cells naturally accumulate during aging and at sites of age-related pathologies. Here, we discuss the recent advances in understanding the accumulation of senescent cells in brain aging and disorders. Here we highlight the phenotypical heterogeneity of different senescent brain cell types, highlighting the potential importance of subtype-specific features for physiology and pathology. We provide a comprehensive overview of various senescent cell types in naturally occurring aging and the most common neurodegenerative disorders. Finally, we critically discuss the potential of adapting senotherapeutics to improve brain health and reduce pathological progression, addressing limitations and future directions for application and development.

Mesenchymal stem cell-derived HGF attenuates radiation-induced senescence in salivary glands via compensatory proliferation.

BACKGROUND & AIM: Irradiation of the salivary glands during head and neck cancer treatment induces cellular senescence in response to DNA damage and contributes to radiation-induced hyposalivation by affecting the salivary gland stem/progenitor cell (SGSC) niche. Cellular senescence, such as that induced by radiation, is a state of cell-cycle arrest, accompanied by an altered pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP) with potential detrimental effects on the surrounding microenvironment. We hypothesized that the pro-regenerative properties of mesenchymal stem cells (MSCs) may attenuate cellular senescence post-irradiation. Therefore, here we evaluated the effects of adipose-derived MSCs (ADSCs) on the radiation-induced response of salivary gland organoids (SGOs). METHODS: Proteomic analyses to identify soluble mediators released by ADSCs co-cultured with SGOS revealed secretion of hepatocyte growth factor (HGF) in ADSCs, suggesting a possible role in the stem cell crosstalk. Next, the effect of recombinant HGF in the culture media of ex vivo grown salivary gland cells was tested in 2D monolayers and 3D organoid models. RESULTS: Treatment with HGF robustly increased salivary gland cell proliferation. Importantly, HGF supplementation post-irradiation enhanced proliferation at lower doses of radiation (0, 3, 7 Gy), but not at higher doses (10, 14 Gy) where most cells stained positive for senescence-associated beta-galactosidase. Furthermore, HGF had no effect on the senescence-associated secretory phenotype (SASP) of irradiated SGOs, suggesting there may be compensatory proliferation by cell-division competent cells instead of a reversal of cellular senescence after irradiation. CONCLUSION: ADSCs may positively influence radiation recovery through HGF secretion and can promote the ex vivo expansion of salivary gland stem/progenitor cells to enhance the effects of co-transplanted SGSC.

Change in telomere length and cardiovascular risk factors in testicular cancer survivors.

BACKGROUND: Testicular cancer (TC) survivors cured with chemotherapy (CT) are prone to develop cardiovascular diseases, as part of an accelerated aging phenotype. A mechanism contributing to these events can be telomere shortening. PATIENTS AND METHODS: In a prospective cohort of patients with disseminated TC who received cisplatin-based CT, mean absolute leukocyte telomere length (TL) was measured before and 1 year after start of treatment. Cardiovascular risk factors, including development of the metabolic syndrome and hypogonadism, were assessed before and up to 5 years after CT. RESULTS: For the whole group (n = 55), TL did not change 1 year after CT (5.7 (2.2-13.4) vs. 5.8 kb (1.6-19.2), P = 0.335). At baseline, patients with a BMI >30 kg/m2 (n = 12) had shorter TL (4.9 (2.2-13.4) vs. 6.3 kb (3.1-12.9), P = 0.045), while no age-dependent differences were measured. Patients with TL shortening after 1 year (n = 7) showed a significant increase in diastolic blood pressure (P = 0.007) and triglycerides (P = 0.003), compared to those with unchanged TL. There was no association between telomere shortening after 1 year or short TL at baseline (n = 7+11) and development of metabolic syndrome (25% vs. 21%; P = 0.777), or hypogonadism (38% vs. 17%; P = 0.120) after 5 years. CONCLUSIONS: A small subset of TC patients treated with cisplatin-based CT showed telomere shortening 1 year after treatment. This shortening was associated to a rise in diastolic blood pressure and triglycerides, but not to newly developed metabolic syndrome and hypogonadism after 5 years.

Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease?

Exposure to environmental toxins is associated with a variety of age-related diseases including cancer and neurodegeneration. For example, in Parkinson's disease (PD), chronic environmental exposure to certain toxins has been linked to the age-related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti-cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence-associated secretory phenotype (SASP; that is the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age-related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. On the basis of recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder.

Circulating monocytes expressing senescence-associated features are enriched in COVID-19 patients with severe disease.

Accurate biomarkers for predicting COVID-19 severity have remained an unmet need due to an incomplete understanding of virus pathogenesis and heterogeneity among patients. Cellular senescence and its pro-inflammatory phenotype are suggested to be a consequence of SARS-CoV-2 infection and potentially drive infection-dependent pathological sequelae. Senescence-associated markers in infected individuals have been identified primarily in the lower respiratory tract, while little is known about their presence in more easily accessible bio-specimens. Here, we measured the abundance of senescence-associated signatures in whole blood, plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients and patients without an infection. Bulk transcriptomic and targeted proteomic assays revealed that the level of senescence-associated markers, including the senescence-associated secretory phenotype (SASP), is predictive of SARS-CoV-2 infection. Single-cell RNA-sequencing data demonstrated that a senescence signature is particularly enriched in monocytes of COVID-19 patients, partially correlating with disease severity. Our findings suggest that monocytes are prematurely induced to senescence by SARS-CoV-2 infection, might contribute to exacerbating a SASP-like inflammatory response and can serve as markers and predictors for COVID-19 and its sequelae.

Direct costs in diabetic and non diabetic people: the population-based Turin study, Italy.

BACKGROUND AND AIMS: We compared direct costs of diabetic and non diabetic people covered by the Italian National Health System, focusing on the influence of age, sex, type of diabetes and treatment. METHODS AND RESULTS: Diabetic people living in Turin were identified through the Regional Diabetes Registry and the files of hospital discharges and prescriptions. Data sources were linked to the administrative databases to assess health care services used by diabetic (n = 33,792) and non diabetic people(n = 863,123). Data were analyzed with the two-part model; the estimated direct costs per person/year were €3660.8 in diabetic people and €895.6 in non diabetic people, giving a cost ratio of 4.1. Diabetes accounted for 11.4% of total health care expenditure. The costs were attributed to hospitalizations (57.2%), drugs (25.6%), to outpatient care (11.9%), consumable goods (4.4%) and emergency care (0.9%). Estimated costs increased from € 2670.8 in diabetic people aged <45 years to € 3724.1 in those aged >74 years, the latter representing two third of the diabetic cohort; corresponding figures in non diabetic people were € 371.6 and € 2155.9. In all expenditure categories cost ratios of diabetic vs non diabetic people were higher in people aged <45 years, in type 1 diabetes and in insulin-treated type 2 diabetes. CONCLUSION: Direct costs are 4-fold higher in diabetic than in non diabetic people, mainly due to care of the elderly and inpatient care. In developed countries, demographic changes will have a profound impact on costs for diabetes in next years.

Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species.

We previously described a method for isolating murine hematopoietic stem cells capable of reconstituting lethally irradiated recipients, which depends solely on dual-wavelength flow cytometric analysis of murine bone marrow cells stained with the fluorescent DNA-binding dye Hoechst 33342. This method, which appears to rely on the differential ability of stem cells to efflux the Hoechst dye, defines an extremely small and homogeneous population of cells (termed SP cells). We show here that dual-wavelength analysis of Hoechst dye-stained human, rhesus and miniature swine bone marrow cells reveals a small, distinct population of cells that efflux the dye in a manner identical to murine SP cells. Like the murine SP cells, both human and rhesus SP cells are primarily CD34-negative and lineage marker-negative. In vitro culture studies demonstrated that rhesus SP cells are highly enriched for long-term culture-initiating cells (LTC-ICs), an indicator of primitive hematopoietic cells, and have the capacity for differentiation into T cells. Although rhesus SP cells do not initially possess any hematopoietic colony-forming capability, they acquire the ability to form colonies after long-term culture on bone marrow stroma, coincident with their conversion to a CD34-positive phenotype. These studies suggest the existence of a hitherto unrecognized population of hematopoietic stem cells that lack the CD34 surface marker classically associated with primitive hematopoietic cells.

[The use of municipality-level data on mortality in Italy: SENTIERI Project]. / L'utilizzo dei dati di mortalità a livello comunale in Italia: Progetto SENTIERI.

In Italy, complete municipality-level data on specific-cause mortality have been available at central level since 1980; Italy's National Institute of Statistics (Istat) collects data from all municipalities using two sources: i) the Office of Vital Statistics; and ii) the Civil Status Office. The Office of Vital Statistics records data on events such as births, deaths and migration for the population with official residence in the municipality, with the aim of describing the resident population's structure and composition. The Civil Status Office records data on the demographic dynamics (not only marital status but also causes of death); the data refer to the population living in the municipality, independently of official residence. Changes in the status of a municipality (e.g., the creation of a new municipality or the unification of diverse municipalities) are often not recorded simultaneously by these two offices, so that the data do not correspond.

To breathe or not to breathe: Understanding how oxygen sensing contributes to age-related phenotypes.

Aging is characterized by a progressive loss of tissue integrity and functionality due to disrupted homeostasis. Molecular oxygen is pivotal to maintain tissue functions, and aerobic species have evolved a sophisticated sensing system to ensure proper oxygen supply and demand. It is not surprising that aberrations in oxygen and oxygen-associated pathways subvert health and promote different aspects of aging. In this review, we discuss emerging findings on how oxygen-sensing mechanisms regulate different cellular and molecular processes during normal physiology, and how dysregulation of oxygen availability lead to disease and aging. We describe various clinical manifestations associated with deregulation of oxygen balance, and how oxygen-modulating therapies and natural oxygen oscillations influence longevity. We conclude by discussing how a better understanding of oxygen-related mechanisms that orchestrate aging processes may lead to the development of new therapeutic strategies to extend healthy aging.

Algorithmic assessment of cellular senescence in experimental and clinical specimens.

The development of genetic tools allowed for the validation of the pro-aging and pro-disease functions of senescent cells in vivo. These discoveries prompted the development of senotherapies-pharmaceutical interventions aimed at interfering with the detrimental effect of senescent cells-that are now entering the clinical stage. However, unequivocal identification and examination of cellular senescence remains highly difficult because of the lack of universal and specific markers. Here, to overcome the limitation of measuring individual markers, we describe a detailed two-phase algorithmic assessment to quantify various senescence-associated parameters in the same specimen. In the first phase, we combine the measurement of lysosomal and proliferative features with the expression of general senescence-associated genes to validate the presence of senescent cells. In the second phase we measure the levels of pro-inflammatory markers for specification of the type of senescence. The protocol can help graduate-level basic scientists to improve the characterization of senescence-associated phenotypes and the identification of specific senescent subtypes. Moreover, it can serve as an important tool for the clinical validation of the role of senescent cells and the effectiveness of anti-senescence therapies.

A Senescence-Centric View of Aging: Implications for Longevity and Disease.

Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of proinflammatory cytokines and molecules. From their initial discovery in the 1960s, senescent cells have been hypothesized as potential contributors to the age-associated loss of regenerative potential. Here, we discuss recent evidence that implicates cellular senescence as a central regulatory mechanism of the aging process. We provide a comprehensive overview of age-associated pathologies in which cellular senescence has been implicated. We describe mechanisms by which senescent cells drive aging and diseases, and we discuss updates on exploiting these mechanisms as therapeutic targets. Finally, we critically analyze the use of senotherapeutics and their translation to the clinic, highlighting limitations and suggesting ideas for future applications and developments.

Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection.

Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4(+) T cells, a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound and selective depletion of CD4+ T cells in the intestine within days of infection, before any such changes in peripheral lymphoid tissues. The loss of CD4+ T cells in the intestine occurred coincident with productive infection of large numbers of mononuclear cells at this site. The intestine appears to be a major target for SIV replication and the major site of CD4+ T cell loss in early SIV infection.

Critical view of the effect site modelling of propofol. / Visión crítica de la modelación del efecto de propofol.

Target controlled infusion (TCI) of Propofol has been the subject of discussion during its 20 years of use, including the validity of the models that represent the course of the effect, such as: Are the different EEG indexes representative of the effect? Is the reactivity of the EEG index used to build models comparable to each other? What is the real reacting time of each monitor? Is the ke0 influenced by the infusion speed? Is the ke0 or the time to peak effect affected by age? How valid are the current Emax models? Are the induction and wakening simple mirror phenomenon as they are represented in the E max models? This review discusses issues related to the complexity and difficulty in obtaining a representation of the effect, and the lack of agreed definitions to be able to construct representative models of the temporary installation of the effect of Propofol for its use in TCI.

An overview of the TROPICS NASA Earth Venture Mission.

The Time-Resolved Observations of Precipitation structure and storm Intensity with a Constellation of Smallsats (TROPICS) mission was selected by NASA as part of the Earth Venture-Instrument (EVI-3) program. The overarching goal for TROPICS is to provide nearly all-weather observations of 3D temperature and humidity, as well as cloud ice and precipitation horizontal structure, at high temporal resolution to conduct high-value science investigations of tropical cyclones. TROPICS will provide rapid-refresh microwave measurements (median refresh rate better than 60 min for the baseline mission) which can be used to observe the thermodynamics of the troposphere and precipitation structure for storm systems at the mesoscale and synoptic scale over the entire storm life cycle. TROPICS comprises six CubeSats in three low-Earth orbital planes. Each CubeSat will host a high-performance radiometer to provide temperature profiles using seven channels near the 118.75 GHz oxygen absorption line, water vapour profiles using three channels near the 183 GHz water vapour absorption line, imagery in a single channel near 90 GHz for precipitation measurements (when combined with higher-resolution water vapour channels), and a single channel near 205 GHz which is more sensitive to precipitation-sized ice particles. This observing system offers an unprecedented combination of horizontal and temporal resolution to measure environmental and inner-core conditions for tropical cyclones on a nearly global scale and is a major leap forward in the temporal resolution of several key parameters needed for assimilation into advanced data assimilation systems capable of utilizing rapid-update radiance or retrieval data. Launch readiness is currently projected for late 2019.

Long term effect of air pollution on incident hospital admissions: Results from the Italian Longitudinal Study within LIFE MED HISS project.

BACKGROUND: The LIFE MED HISS project aims at setting up a surveillance system on the long term effects of air pollution on health, using data from National Health Interview Surveys and other currently available sources of information in most European countries. Few studies assessed the long term effect of air pollution on hospital admissions in European cohorts. OBJECTIVE: The objective of this paper is to estimate the long term effect of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) on first-ever (incident) cause-specific hospitalizations in Italy. METHODS: We used data from the Italian Longitudinal Study (ILS), a cohort study based on the 1999-2000 National Health Interview Survey (NHIS), followed up for hospitalization (2001-2008) at individual level. The survey contains information on crucial potential confounders: occupational/educational/marital status, body mass index (BMI), smoking habit and physical activity. Annual mean exposure to PM2.5 and NO2 was assigned starting from simulated gridded data at spatial resolution of 4 × 4 km2 firstly integrated with data from monitoring stations and then up-scaled at municipality level. Statistical analyses were conducted using Cox proportional hazard models with robust variance estimator. RESULTS: For each cause of hospitalization we estimated the hazard ratios (HRs) adjusted for confounders with 95% Confidence Interval (CI) related to a 10 µg/m3 increase in pollutants. For PM2.5 and NO2, respectively, we found positive associations for circulatory system diseases [1.05(1.03-1.06); 1.05(1.03-1.07)], myocardial infarction [1.15(1.12-1.18); 1.15(1.12-1.18)], lung cancer [1.18(1.10-1.26); 1.20(1.12-1.28)], kidney cancer [1.24(1.11-1.29); 1.20(1.07-1.33)], all cancers (but lung) [1.06(1.04-1.08); 1.06(1.04-1.08)] and Low Respiratory Tract Infections (LRTI) [1.07 (1.04-1.11); 1.05 (1.02-1.08)]. DISCUSSION: Our results add new evidence on the effects of air pollution on first-ever (incident) hospitalizations, both in urban and rural areas. We demonstrated the feasibility of a low-cost monitoring system based on available data.

Identification of an immunoreceptor tyrosine-based activation motif of K1 transforming protein of Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is consistently identified in Kaposi's sarcoma and body cavity-based lymphoma. KSHV encodes a transforming protein called K1 which is structurally similar to lymphocyte receptors. We have found that a highly conserved region of the cytoplasmic domain of K1 resembles the sequence of immunoreceptor tyrosine-based activation motifs (ITAMs). To demonstrate the signal-transducing activity of K1, we constructed a chimeric protein in which the cytoplasmic tail of the human CD8alpha polypeptide was replaced with that of KSHV K1. Expression of the CD8-K1 chimera in B cells induced cellular tyrosine phosphorylation and intracellular calcium mobilization upon stimulation with an anti-CD8 antibody. Mutational analyses showed that the putative ITAM of K1 was required for its signal-transducing activity. Furthermore, tyrosine residues of the putative ITAM of K1 were phosphorylated upon stimulation, and this allowed subsequent binding of SH2-containing proteins. These results demonstrate that the KSHV transforming protein K1 contains a functional ITAM in its cytoplasmic domain and that it can transduce signals to induce cellular activation.

[Carpal tunnel syndrome (CTS) in the Piedmont Region: regional incidence and prevalence of CTS based on hospital records of patients who underwent surgery]. / La sindrome del tunnel carpale in Piemonte: un esempio regionale di stima di incidenza e prevalenza di casi trattati chirurgicamente.

BACKGROUND: Carpal tunnel syndrome (CTS) is the most frequent entrapment neuropathy of the upper extremities. Despite CTS being a priority for public health, only a few studies have investigated the prevalence and incidence in the general population. In Italy, administrative data are available only for CTS cases which were judged work-related by the Workers Compensation Board. These data indicate a steady increase in CTS over the last decade. Hospital admission archives (SDO) also contain information on CTS patients who underwent surgery. OBJECTIVES: To determine: 1) the incidence and prevalence of first CTS, based on hospital records of patients who underwent surgery in the Piedmont Region; 2) to describe the geographical and temporal variation. METHODS: Crude and standardized incidence rates of CTS were computed for the period 2002-2003; geographical variation was assessed using bayesan estimators to detect spatial clusters. Crude and standardized prevalence rates of first hospitalization were calculated for every two-year period between 1996 and 2003. RESULTS AND CONCLUSIONS: The crude incidence rate was 227.2 (C.I.95% 221.9-232.7) per 100,000 women and 54.4 (C.I. 95% 51.9-57.1) per 100,000 men. The prevalence of first hospitalization was very high and varied widely by geographic area. Two possible explanations for such wide variation between areas include differences in exposure to risk factors for CTS and in the diagnostic criteria used. The increasing prevalence over time was only partly explained by an increase in work-related cases. The development of standardized diagnostic criteria would improve understanding of the effect of workplace exposures on CTS. The number of new cases per year in Piedmont was estimated at 1,500, much higher than the compensation claims related to CTS. Health education campaigns addressed to general practitioners on compensation law could improve reporting to the workers' compensation board.

The impact of the summer 2003 heat waves on mortality in four Italian cities.

This study evaluates the impact of the 2003 heat wave on cause-specific mortality and the role of demographic characteristics and socioeconomic conditions that may have increased the risk of mortality in four Italian cities: Bologna, Milan, Rome and Turin. Daily mortality counts, for the resident population by age, sex and cause of death were considered. Daily excess mortality was calculated as the difference between the number of deaths observed and the smoothed average. The impact of heat on health is measured in terms of maximum apparent temperature. The greatest excess in mortality was observed in the north west of Italy (Turin, +23% and Milan, +23%). The old (75-84 years) and the very old (85+ years) were the age groups most affected, and when stratifying by sex, the increase in mortality seemed to be greater among females. The greatest excess in mortality was registered in those with low socioeconomic status in Rome (+17.8%) and in those with lower education levels in Turin (+43%). The analysis of cause-specific mortality not only confirms results from previous studies of an increase in heat-related mortality by respiratory and cardiovascular diseases, but also shows a significant excess in mortality for diseases of the central nervous system and for metabolic/endocrine disorders. Results from 2003 highlight the necessity of targeting future prevention programmes at the susceptible sub-groups identified. The introduction of warning systems alongside efficient preventive plans and the monitoring of mortality during heat waves may represent a valid tool for the reduction of heat-related deaths.

The impact of the summer 2003 heat waves on mortality in four Italian cities.

This study evaluates the impact of the 2003 heat wave on cause-specific mortality and the role of demographic characteristics and socioeconomic conditions that may have increased the risk of mortality in four Italian cities: Bologna, Milan, Rome and Turin. Daily mortality counts, for the resident population by age, sex and cause of death were considered. Daily excess mortality was calculated as the difference between the number of deaths observed and the smoothed average. The impact of heat on health is measured in terms of maximum apparent temperature. The greatest excess in mortality was observed in the north west of Italy (Turin, +23% and Milan, +23%). The old (75-84 years) and the very old (85+ years) were the age groups most affected, and when stratifying by sex, the increase in mortality seemed to be greater among females. The greatest excess in mortality was registered in those with low socioeconomic status in Rome (+17.8%) and in those with lower education levels in Turin (+43%). The analysis of cause-specific mortality not only confirms results from previous studies of an increase in heat-related mortality by respiratory and cardiovascular diseases, but also shows a significant excess in mortality for diseases of the central nervous system and for metabolic/endocrine disorders. Results from 2003 highlight the necessity of targeting future prevention programmes at the susceptible sub-groups identified. The introduction of warning systems alongside efficient preventive plans and the monitoring of mortality during heat waves may represent a valid tool for the reduction of heat-related deaths.