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OBJECTIVES: The aim of the study was to assess long-term health-related quality of life (HRQoL) in children and adolescents with coeliac disease (CD), and their parents. METHODS: We re-evaluated prospectively the HRQoL and clinical characteristics of 80 families, assessed 5 years earlier, using a disease-specific questionnaire, the CD Dutch Questionnaire (CDDUX), and a generic questionnaire, the Paediatric Quality of Life Inventory (PedsQL). RESULTS: After a 10-year follow-up, there was no significant change in the total CDDUX and PedsQL scores in children and their parents when compared to the evaluation conducted 5 years earlier. The total CDDUX score reflected a neutral QoL, while for the generic PedsQL was good-very good. The only significant decrease after 5 years was the PedsQL subdomain Emotional functioning. Patients who admitted voluntarily eating gluten reported lower score in CDDUX Diet. Lower scores in subdomain "Physical functioning" (PedsQL) were reported in patients with positivity of TTG or associated diseases. CONCLUSIONS: The CDDUX score indicated a consistently stable and neutral QoL perception among coeliac patients and caregivers, even after 10-year postdiagnosis, suggesting minimal fluctuations in the impact of CD on disease-specific health domains over time. Furthermore, the consistently good PedsQL score could be a reflection of the resilience of coeliac families in coping with this chronic condition. Gluten-free diet compliance was confirmed to be determinant of HRQoL in the long term. The study confirms the importance of extending surveillance on these patients, possibly using different questionnaires, to assess QoL from different perspectives.
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Enfermedad Celíaca , Calidad de Vida , Niño , Adolescente , Humanos , Calidad de Vida/psicología , Estudios de Seguimiento , Enfermedad Celíaca/psicología , Padres/psicología , Encuestas y CuestionariosRESUMEN
Cigarette smoking is a primary contributor to mortality risks and is associated with various diseases. Among these, COPD represents a significant contributor to global mortality and disability. The objective of this study is to investigate the effect of smoking on a selected battery of variables, with an emphasis on DNA damage. A total of 87 elderly patients diagnosed with COPD, divided into three groups based on their smoking history (current, former, never-smokers), were evaluated using a cross-sectional approach. Clinical features including mortality and inflammatory/oxidative parameters (Lymphocytes/Monocytes, Neutrophils/Lymphocytes, Platelets/Lymphocytes ratio), SII, MDA, 8-Oxo-dG, and IL6 (ELISA assay), as well as DNA damage (comet assay), were investigated. Virus infection, i.e., influenza A virus subtype H1N1, JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), and Torquetenovirus (TTV), was also tested. Current smokers exhibit higher levels of comorbidity (CIRS; p < 0.001), Platelets/Lymphocytes ratio (p < 0.001), systemic immune inflammation (p < 0.05), and DNA damage (p < 0.001). Former smokers also showed higher values for parameters associated with oxidative damage and showed a much lower probability of surviving over 5 years compared to never- and current smokers (p < 0.0017). This study showed a clear interaction between events which are relevant to the oxidative pathway and cigarette smoking. A category of particular interest is represented by former smokers, especially for lower survival, possibly due to the presence of more health problems. Our findings raise also the attention to other parameters which are significantly affected by smoking and are useful to monitor COPD patients starting a program of pulmonary rehabilitation (DNA damage, inflammation parameters, and selected viral infections).
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Fumar Cigarrillos , Daño del ADN , Estrés Oxidativo , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Masculino , Femenino , Anciano , Fumar Cigarrillos/efectos adversos , Estudios Transversales , Persona de Mediana Edad , Biomarcadores , InflamaciónRESUMEN
INTRODUCTION: Immunosenescence and inflammaging have been implicated in the pathophysiology of frailty. Torquetenovirus (TTV), a single-stranded DNA anellovirus, the major component of the human blood virome, shows an increased replication rate with advancing age. An elevated TTV viremia has been associated with an impaired immune function and an increased risk of mortality in the older population. The objective of this study was to analyze the relation between TTV viremia, physical frailty, and cognitive impairment. METHODS: TTV viremia was measured in 1,131 nonfrail, 45 physically frail, and 113 cognitively impaired older adults recruited in the MARK-AGE study (overall mean age 64.7 ± 5.9 years), and then the results were checked in two other independent cohorts from Spain and Portugal, including 126 frail, 252 prefrail, and 141 nonfrail individuals (overall mean age: 77.5 ± 8.3 years). RESULTS: TTV viremia ≥4log was associated with physical frailty (OR: 4.69; 95% CI: 2.06-10.67, p < 0.0001) and cognitive impairment (OR: 3.49, 95% CI: 2.14-5.69, p < 0.0001) in the MARK-AGE population. The association between TTV DNA load and frailty status was confirmed in the Spanish cohort, while a slight association with cognitive impairment was observed (OR: 1.33; 95% CI: 1.000-1.773), only in the unadjusted model. No association between TTV load and frailty or cognitive impairment was found in the Portuguese sample, although a negative association between TTV viremia and MMSE score was observed in Spanish and Portuguese females. CONCLUSIONS: These findings demonstrate an association between TTV viremia and physical frailty, while the association with cognitive impairment was observed only in the younger population from the MARK-AGE study. Further research is necessary to clarify TTV's clinical relevance in the onset and progression of frailty and cognitive decline in older individuals.
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Disfunción Cognitiva , Fragilidad , Torque teno virus , Femenino , Anciano , Humanos , Anciano de 80 o más Años , Fragilidad/epidemiología , Torque teno virus/fisiología , Viremia/complicaciones , Anciano Frágil/psicología , Evaluación Geriátrica , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/epidemiologíaRESUMEN
Nicotine, the primary psychoactive agent in tobacco leaves, has led to the widespread use of tobacco, with over one billion smokers globally. This article provides a historical overview of tobacco and discusses tobacco dependence, as well as the biological effects induced by nicotine on mammalian cells. Nicotine induces various biological effects, such as neoangiogenesis, cell division, and proliferation, and it affects neural and non-neural cells through specific pathways downstream of nicotinic receptors (nAChRs). Specific effects mediated by α7 nAChRs are highlighted. Nicotine is highly addictive and hazardous. Public health initiatives should prioritize combating smoking and its associated risks. Understanding nicotine's complex biological effects is essential for comprehensive research and informed health policies. While potential links between nicotine and COVID-19 severity warrant further investigation, smoking remains a significant cause of morbidity and mortality globally. Effective public health strategies are vital to promote healthier lifestyles.
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Receptores Nicotínicos , Tabaquismo , Animales , Humanos , Nicotina/efectos adversos , Receptores Nicotínicos/metabolismo , Fumar , Mamíferos/metabolismoRESUMEN
BACKGROUND: To verify the long-term (24-week) efficacy, safety, and tolerability of fremanezumab in real-life patients with high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM: ≥ 15 days/month), and multiple preventive treatment failures. METHODS: This is a prospective, cohort, real-life study at 28 headache centers on consecutive patients affected by HFEM or CM with multiple preventive treatment failures who were prescribed subcutaneous fremanezumab (225 mg monthly/675 mg quarterly) for ≥ 24 weeks. Primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM at weeks 21-24 compared to baseline. Secondary endpoints encompassed changes in monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS, HIT-6 and MIDAS scores at the same time interval. Changes in MMDs/MHDs, monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS and HIT-6 scores at week 4 were also monitored. RESULTS: Four hundred ten patients who had received ≥ 1 dose of fremanezumab were considered for safety analysis while 148 patients treated for ≥ 24 weeks were included in the efficacy analysis. At weeks 21-24, fremanezumab significantly (p < 0.001) reduced MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM compared to baseline. The proportions of ≥ 50%, ≥ 75% and 100% responders at weeks 21-24were 75.0%, 30.8%, 9.6% (HFEM), and 72.9, 44.8 and 1% (CM). A significant (p < 0.001) decrease in MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM was already present at week 4. The proportions of ≥ 50%, ≥ 75%, and 100% responders at week 4 were 67.6%, 32.4%, 11.8% (HFEM) and 67.3%, 40%, 1.8% (CM). CM remitted to episodic migraine and medication overuse to no-medication overuse in 83.3 and 75% of patients at week 24, and in 80 and 72.4% at week 4. Adverse events were rare (2.4%), mild and transient. No patient discontinued treatment for any reason. CONCLUSIONS: Fremanezumab is characterized by an early and sustained efficacy in HFEM and CM patients with multiple preventive treatment failures in real-life, revealing an optimal safety and tolerability profile.
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Trastornos Migrañosos , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Método Doble Ciego , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Cefalea , Insuficiencia del TratamientoRESUMEN
Italian Migraine Registry (I-GRAINE) is a multicenter (n = 38), prospective, observational, non-interventional study aimed at providing big data on migraine to ensure proper clinical disease management, according to scientific, and sustainability criteria. We enrolled consecutive patients affected by episodic or chronic migraine according to the systematic random method. Information on sociodemographic characteristics, lifestyle, migraine features, patient's journey, and healthcare resource use were gathered using face-to-face interviews.On the date of 31 December 2021, we enrolled 231 patients at 12 headache centers. Most of them were women (84.4%), with high migraine frequency (9.6 ± 6.9 days/month) and severe disability (MIDAS score: 43.0 ± 40.8; HIT-6 score: 60.4 ± 10.6). Only a minority of patients (38.1%) had previously visited a headache center.A clear-cut difference emerged in the proportion of responders to nonspecific acute treatments (43.5-66.7%) compared to triptans (76.3%) and in responders to unspecific prophylaxis (5.4-35%) compared to anti-CGRP monoclonal antibodies (69.2-78.6%). Most patients underwent ≥ 1 specialist visit (66.9%) or diagnostic investigation (77.4%) over the last 3 years-mostly subsidized by our national health system-inappropriate in 64.9% and 25% of the cases, respectively.The I-GRAINE registry is expected to provide a large and exponentially increasing collection of clinical, biological, and epidemiologic information and will contribute to moving migraine out of the shadow cone of marginalization, which has been often relegated up to now.
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Trastornos Migrañosos , Femenino , Cefalea , Humanos , Masculino , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/epidemiología , Estudios Prospectivos , Sistema de Registros , Triptaminas/uso terapéuticoRESUMEN
The aims of our study are to: (i) investigate the ability of nicotine to modulate the expression level of inflammatory cytokines in A549 cells infected with SARS-CoV-2; (ii) elucidate the ultrastructural features caused by the combination nicotine+SARS-CoV-2; and (iii) demonstrate the mechanism of action. In this study, A549 cells pretreated with nicotine were either exposed to LPS or poly(I:C), or infected with SARS-CoV-2. Treated and untreated cells were analyzed for cytokine production, cytotoxicity, and ultrastructural modifications. Vero E6 cells were used as a positive reference. Cells pretreated with nicotine showed a decrease of IL6 and TNFα in A549 cells induced by LPS or poly(I:C). In contrast, cells exposed to SARS-CoV-2 showed a high increase of IL6, IL8, IL10 and TNFα, high cytopathic effects that were dose- and time-dependent, and profound ultrastructural modifications. These modifications were characterized by membrane ruptures and fragmentation, the swelling of cytosol and mitochondria, the release of cytoplasmic content in extracellular spaces (including osmiophilic granules), the fragmentation of endoplasmic reticulum, and chromatin disorganization. Nicotine increased SARS-CoV-2 cytopathic effects, elevating the levels of inflammatory cytokines, and inducing severe cellular damage, with features resembling pyroptosis and necroptosis. The protective role of nicotine in COVID-19 is definitively ruled out.
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Nicotina , SARS-CoV-2 , Células A549 , COVID-19 , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Humanos , Interleucina-6 , Lipopolisacáridos , Nicotina/efectos adversos , Nicotina/farmacología , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. METHODS: This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals. RESULTS: Sixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85-0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason. CONCLUSIONS: Fremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.
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Trastornos Migrañosos , Anticuerpos Monoclonales , Estudios de Cohortes , Método Doble Ciego , Cefalea/prevención & control , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM). METHODS: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. RESULTS: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57-11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05-2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15-3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04-2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07-0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42-8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14-2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22-3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. CONCLUSIONS: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.
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Hiperalgesia , Trastornos Migrañosos , Adulto , Humanos , Estudios Prospectivos , Hiperalgesia/tratamiento farmacológico , Método Doble Ciego , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/diagnóstico , Anticuerpos Monoclonales/uso terapéutico , Cefalea/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: To develop a dedicated Italian chronic migraine (CM) database (IRON project) to overcome disease misconceptions, improve clinical administration, reduce patients' burden, and rationalize economic resource allotment. BACKGROUND: Proper CM management requires a comprehensive appraisal of its full clinical, social, and economic complexity. METHODS: In this cross-sectional study, CM patients were screened in 24 certified headache centers with face-to-face interviews. Information on sociodemographic factors, medical history, characteristics of CM, and of prior episodic migraine (EM), and healthcare resource use was gathered using a semistructured web-based questionnaire. RESULTS: A total of 866 CM patients were enrolled. CM started ~20 years after EM onset (age at EM onset 17.4 ± 9.1 vs. age at CM onset 35.3 ± 12.5 [mean ± SD]). CM prophylaxis, used by 430/866 (49.6%) of the patients, was often ineffective, not tolerated, and prematurely discontinued. Medications and diagnostic workup, frequently inappropriate, were mostly subsidized by the Italian national health service. CM patients with ≥25 headache days/month revealed substantial clinical differences and heavier disability and economic burden compared with those with <25 headache days/month. CONCLUSIONS: CM is a heterogeneous headache disorder deserving more in-depth clinical characterization, sharper diagnostic criteria, and tailored treatments. CM registries are expected to improve clinical management, resulting in increased disease awareness, better healthcare resource allocation, and reduced economic burden.
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Progresión de la Enfermedad , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/terapia , Aceptación de la Atención de Salud/estadística & datos numéricos , Adulto , Estudios Transversales , Bases de Datos Factuales , Femenino , Humanos , Italia , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Trastornos Migrañosos/patología , Clínicas de Dolor , Factores Socioeconómicos , Medicina Estatal , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To evaluate the psychological state of healthcare workers (HCWs) in the field of rehabilitation during the COVID-19 pandemic. METHODS: Cross-sectional observational study. Sample of 334 HCWs including: nurses, medical doctors, therapists, scientists, and clerical workers working at the IRCCS San Raffaele Roma rehabilitation hospital during the second wave of the COVID-19 pandemic. Anonymous web-based questionnaire included 14-item Resilience Scale, Brief-COPE, Hospital Anxiety Depression Scale, Fear of COVID-19 Scale. Occupational and sociodemographic characteristics. RESULTS: High levels of resilience, low levels of anxiety, depression, and fear were observed in the study population; the most frequently used coping strategies in the Brief-COPE were acceptance, planning, and active coping. Specifically, 87% of the participants reported a moderate to high level of resilience, with the highest level observed in nurses while physicians show the lowest level. HCWs showed symptoms of anxiety (29%), depressive symptoms (10%), and fear caused by the COVID-19 pandemic (44%). Statistically significant differences were observed between different occupations for fear (p <0.05) and resilience (p <0.01). Levels of anxiety and fear appeared to be higher in female and younger workers. The latter group - who also reported higher levels of depression - showed lower levels of resilience. CONCLUSIONS: In our study hospital and non-hospital workers show different emotional, cognitive, and behavioural resources when facing stressful situations, like in the case of the SARS-CoV-2 pandemics. Our results support the role of resilience and the proper use of problem-focused and emotion-focused coping strategies as protective factors from psychological distress.
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COVID-19 , Pandemias , Adaptación Psicológica , Ansiedad/epidemiología , Estudios Transversales , Depresión/epidemiología , Femenino , Personal de Salud , Humanos , SARS-CoV-2RESUMEN
Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this system, and especially of the SLC6A4 gene, may be associated with psychiatric disorders. In this study we aimed to evaluate the pleiotropic nature of SLC6A4 alterations and their association with the overall risk of brain diseases rather than disorder-specific. SLC6A4 variants, namely 5HTTLPR, STin2, rs2066713, rs25531, rs4251417, rs6354 and rs7224199 were investigated in 4 independent cohorts of subjects with specific psychiatric disorders, including Alcohol dependence disorder (ALC), Alzheimer disease (ALZ), Schizophrenia (SCZ) and Bipolar disorder (BPD). Other variables (biochemical parameters and Psychiatric scales scores) were also tested for association. SLC6A4 polymorphisms are not associated with the risk of developing major psychiatric disorders (SCZ and BPD); however some signals were detected in ALC (HTTLPR pd = 9.25 × 10-03, pr = 7.24 × 10-03; rs2066713 pd = 6.35 × 10-08; rs25531 pd = 2.95 × 10-02; rs4251417 pd = 2.46 × 10-03), and ALZ (rs6354 pr = 1.22 × 10-02; rs7224199 pd = 1.00 × 10-08, pr = 2.65 × 10-02) cohorts. Some associations were also observed on exploratory analyses. Our findings did not reveal any major influence on SCZ and BPD development; On the other hand, some alteration of the SLC6A4 sequence were associated with an increased risk of ALC and ALZ disorders, suggesting common pathways. The results of this study should be carefully interpreted since it suffers of some inherent limitations (e.g. cohort size, slight ethnic heterogeneity). Further analyses may provide better detail on the molecular processes behind SLC6A4 alterations.
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Alcoholismo/genética , Enfermedad de Alzheimer/genética , Trastornos Mentales/genética , Polimorfismo Genético , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alcoholismo/complicaciones , Alcoholismo/epidemiología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Comorbilidad , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Grecia/epidemiología , Humanos , Italia/epidemiología , Desequilibrio de Ligamiento , Trastornos Mentales/epidemiología , Persona de Mediana Edad , Adulto JovenRESUMEN
The following authors have double affiliations: Stefania Boccia, Marco Di Nicola and they should read.
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(1) Background: Nicotine is implicated in the SARS-COV-2 infection through activation of the α7-nAChR and over-expression of ACE2. Our objective was to clarify the role of nicotine in SARS-CoV-2 infection exploring its molecular and cellular activity. (2) Methods: HBEpC or si-mRNA-α7-HBEpC were treated for 1 h, 48 h or continuously with 10-7 M nicotine, a concentration mimicking human exposure to a cigarette. Cell viability and proliferation were evaluated by trypan blue dye exclusion and cell counting, migration by cell migration assay, senescence by SA-ß-Gal activity, and anchorage-independent growth by cloning in soft agar. Expression of Ki67, p53/phospho-p53, VEGF, EGFR/pEGFR, phospho-p38, intracellular Ca2+, ATP and EMT were evaluated by ELISA and/or Western blotting. (3) Results: nicotine induced through α7-nAChR (i) increase in cell viability, (ii) cell proliferation, (iii) Ki67 over-expression, (iv) phospho-p38 up-regulation, (v) EGFR/pEGFR over-expression, (vi) increase in basal Ca2+ concentration, (vii) reduction of ATP production, (viii) decreased level of p53/phospho-p53, (ix) delayed senescence, (x) VEGF increase, (xi) EMT and consequent (xii) enhanced migration, and (xiii) ability to grow independently of the substrate. (4) Conclusions: Based on our results and on evidence showing that nicotine potentiates viral infection, it is likely that nicotine is involved in SARS-CoV-2 infection and severity.
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COVID-19/patología , Células Epiteliales/efectos de los fármacos , Nicotina/efectos adversos , Sistema Respiratorio/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/virología , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/virología , Humanos , Receptores Nicotínicos/metabolismo , Sistema Respiratorio/virología , SARS-CoV-2/patogenicidad , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Fumar/efectos adversos , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
AIMS: While several generic preparations of levodopa/carbidopa and levodopa/benserazide (LBD) are currently available, pharmacokinetic (PK) equivalence and therapeutic equivalence studies with levodopa generics are not available in Italy. Lack of data on generic formulations is a critical factor for their limited use in this country and often lead patients to refuse the generic version of the branded drug. METHODS: An experimental, 2-centre, randomized, double-blind, 2-sequence, noninferiority cross-over study was designed to evaluate both the PK equivalence and clinical equivalence of multiple doses of the generic preparation of LDB, Teva Italia, compared to the originator (Madopar). Forty-three out-patients with a diagnosis of idiopathic Parkinson's disease on LDB, were recruited and randomly assigned to 1 of 2 study sequences: generic-originator or originator-generic. Clinical evaluations were performed at the end of each study period. A PK study with an LDB fixed dose (100 + 25 mg) was performed in a subpopulation of 14 subjects. RESULTS: Clinical data showed a reduction of 0.49 and 1.54 in the mean UPDRS III scores for the LDB and the originator, respectively. The 95% CIs [-2.21: 0.11] of the mean difference original vs LDB are smaller than the clinically significant difference of 3 UPDRS III points, supporting the conclusion that the treatment with LDB is not inferior to the originator. No statistically significant differences were found with respect to area under the curve to last dose, half-life, maximum concentration, time to maximum concentration and last observed concentration. CONCLUSION: These findings prove the therapeutic clinical equivalence as well the PK equivalence of the generic LDB and the originator (Madopar).
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Benserazida/farmacocinética , Dopaminérgicos/farmacocinética , Medicamentos Genéricos/farmacocinética , Levodopa/farmacocinética , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Benserazida/administración & dosificación , Benserazida/efectos adversos , Estudios Cruzados , Dopaminérgicos/administración & dosificación , Dopaminérgicos/efectos adversos , Método Doble Ciego , Combinación de Medicamentos , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Humanos , Levodopa/administración & dosificación , Levodopa/efectos adversos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and manageable lung disease characterized by large heterogeneity in disease presentation and grades impairment. Inhaled corticosteroids (ICS) are commonly used to manage COPD/COPD-exacerbation. The patient's response is characterized by interindividual variability without disease progression/survival modification. Objectives: We hypothesize that a therapeutic intervention may be more effective if single nucleotide polymorphisms (SNPs) are investigated. Methods: In 71 COPD patients under pulmonary rehabilitation, a small number of powerful SNPs, selected according to current literature, were analyzed; namely the glucocorticoid receptor gene NR3C1 (rs6190/rs6189/rs41423247), the glucocorticoid-induced transcript 1 gene (GLCCI1 rs37972), and the related co-chaperone FKBP5 gene (rs4713916). MDR1 rs2032582 was also evaluated. Lung function outcomes were assessed. Results: A significant association with functional outcomes, namely FEV1 (forced expiration volume/one second) and 6MWD (six-minutes walking distance), was found for rs4713916 and weakly for rs37972. The genotype rs4713916(GA) and, in a lesser extent, the genotype rs37972(TT), were more favorable than the wild-type. Conclusions: Our study supports a possible picture of pharmacogenomic control for COPD intervention. rs4713916 and, possibly, rs37972 may be useful predictors of clinical outcome. These results may help to tailor an optimal dose for individual COPD patients based on their genetic makeup.
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Corticoesteroides/uso terapéutico , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/genética , Proteínas de Unión a Tacrolimus/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Administración por Inhalación , Corticoesteroides/administración & dosificación , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Glucocorticoides/genética , Resultado del TratamientoRESUMEN
Sarcopenia and frailty are associated with several important health-related adverse events, including disability, loss of independence, institutionalization and mortality. Sarcopenia can be considered a biological substrate of frailty, and the prevalence of both these conditions progressively increases with age. Telomeres are nucleoprotein structures located at the end of linear chromosomes and implicated in cellular ageing, shorten with age, and are associated with various age-related diseases. In addition, telomere length (TL) is widely considered a molecular/cellular hallmark of the ageing process. This narrative review summarizes the knowledge about telomeres and analyzes for the first time a possible association of TL with sarcopenia and frailty. The overview provided by the present review suggests that leukocyte TL as single measurement, calculated by quantitative real-time polymerase chain reaction (qRT-PCR), cannot be considered a meaningful biological marker for complex, multidimensional age-related conditions, such as sarcopenia and frailty. Panels of biomarkers, including TL, may provide more accurate assessment and prediction of outcomes in these geriatric syndromes in elderly people.
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Envejecimiento/fisiología , Fragilidad/genética , Sarcopenia/genética , Acortamiento del Telómero , Humanos , Homeostasis del TelómeroRESUMEN
BACKGROUND: Chronic rhinitis, pharyngitis and sinusitis are common health problems with a significant impact on public health, and are suspected to be influenced by ageing factors. Nasal inhalation with thermal water may be used to reduce symptoms, inflammation and drug intake. A pre-post clinical study was conducted in 183 consecutive adult and elderly patients with chronic rhinitis, pharyngitis or sinusitis, to evaluate whether thermal water nasal inhalations could improve their symptoms, clinical signs and rhinomanometry measurements, and influence inflammatory biomarkers levels in nasal epithelial cells. RESULTS: Participants profile revealed that they were aged on average (mean age and SD 60.6 ± 15.2 years, median 65, range 20-86, 86 aged ≤ 65 years (47%), 96 aged > 65 years (53%)) and extremely concerned about wellbeing. Older age was associated with better compliance to inhalation treatment. Total symptom and clinical evaluation scores were significantly ameliorated after treatment (p < 0.001), with no substantial difference according to age, while rhinomanometry results were inconsistent. Persistence of symptom improvement was confirmed at phone follow up 1 year later (n = 74). The training set of 48 inflammatory genes (40 patients) revealed a strong increase of CXCR4 gene expression after nasal inhalations, confirmed both in the validation set (143 patients; 1.2 ± 0.68 vs 3.3 ± 1.2; p < 0.0001) and by evaluation of CXCR4 protein expression (40 patients; 1.0 ± 0.39 vs 2.6 ± 0.66; p < 0.0001). CXCR4 expression was consistently changed in patients with rhinitis, pharyngitis or sinusitis. The increase was smaller in current smokers compared to non-smokers. Results were substantially unchanged when comparing aged subjects (≥ 65 years) or the eldest quartile (≥ 71 years) to the others. Other genes showed weaker variations (e.g. FLT1 was reduced only in patients with sinusitis). CONCLUSIONS: These results confirm the clinical impact of thermal water nasal inhalations on upper respiratory diseases both in adults and elders, and emphasize the role of genes activating tissue repair and inflammatory pathways. Future studies should evaluate CXCR4 as possible therapeutic target or response predictor in patients with chronic rhinitis, pharyngitis or sinusitis. TRIAL REGISTRATION: Communication to Italian Ministry of Health - ICPOM 000461. Registered 10/11/2014.
RESUMEN
BACKGROUND: Numerous health benefits have been attributed to the Ginkgo biloba leaf extract (GBLE), one of the most extensively used phytopharmaceutical drugs worldwide. Recently, concerns of the safety of the extract have been raised after a report from US National Toxicology Program (NTP) claimed high doses of GBLE increased liver and thyroid cancer incidence in mice and rats. A safety study has been designed to assess, in a population of elderly residents in nursing homes, clinical and genomic risks associated to GBLE treatment. METHODS: GiBiEx is a multicentre randomized clinical trial, placebo controlled, double blinded, which compared subjects randomized to twice-daily doses of either 120-mg of IDN 5933 (also known as Ginkgoselect®Plus) or to placebo for a 6-months period. IDN 5933 is extracted from dried leaves and contains 24.3% flavone glycosides and 6.1% of terpene lactones (2.9% bilobalide, 1.38% ginkgolide A, 0.66% ginkgolide B, 1.12% ginkgolide C) as determined by HPLC. The study was completed by 47 subjects, 20 in the placebo group and 27 in the treatment group. Clinical (adverse clinical effect and liver injury) and genomic (micronucleus frequency, comet assay, c-myc, p53, and ctnnb1 expression profile in lymphocytes) endpoints were assessed at the start and at the end of the study. RESULTS: No adverse clinical effects or increase of liver injury markers were reported in the treatment group. The frequency of micronuclei [Mean Ratio (MR) = 1.01, 95% Confidence Intervals (95% CI) 0.86-1.18), and DNA breaks (comet assay) (MR = 0.91; 95% CI 0.58-1.43), did not differ in the two study groups. No significant difference was found in the expression profile of the three genes investigated. CONCLUSIONS: None of the markers investigated revealed a higher risk in the treatment group, supporting the safety of IDN 5933 at doses prescribed and for duration of six months. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03004508 , December 20, 2016. Trial retrospectively registered.
Asunto(s)
Daño del ADN/efectos de los fármacos , Ginkgo biloba/química , Extractos Vegetales , Hojas de la Planta/química , Anciano , Anciano de 80 o más Años , Femenino , Genoma/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Pruebas de Función Hepática , Masculino , Pruebas de Micronúcleos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/efectos adversos , Extractos Vegetales/farmacologíaRESUMEN
The buccal micronucleus cytome (BMNcyt) assay in uncultured exfoliated epithelial cells from oral mucosa is widely applied in biomonitoring human exposures to genotoxic agents and is also proposed as a suitable test for prescreening and follow-up of precancerous oral lesions. The main limitation of the assay is the large variability observed in the baseline values of micronuclei (MNi) and other nuclear anomalies mainly related to different scoring criteria. The aim of this international collaborative study, involving laboratories with different level of experience, was to evaluate the inter- and intra-laboratory variations in the BMNcyt parameters, using recently implemented guidelines, in scoring cells from the same pooled samples obtained from healthy subjects (control group) and from cancer patients undergoing radiotherapy (treated group). The results indicate that all laboratories correctly discriminated samples from the two groups by a significant increase of micronucleus (MN) and nuclear bud (NBUD) frequencies and differentiated binucleated (BN) cells, associated with the exposure to ionizing radiation. The experience of the laboratories was shown to play an important role in the identification of the different cell types and nuclear anomalies. MN frequency in differentiated mononucleated (MONO) and BN cells showed the greatest consistency among the laboratories and low variability was also detected in the frequencies of MONO and BN cells. A larger variability was observed in classifying the different cell types, indicating the subjectivity in the interpretation of some of the scoring criteria while reproducibility of the results between scoring sessions was very good. An inter-laboratory calibration exercise is strongly recommended before starting studies with BMNcyt assay involving multiple research centers.