RESUMEN
AA-amyloidosis is frequent in shelter cats, and chronic kidney disease is the foremost cause of death. The aims were to describe kidney laboratory and microscopic findings in shelter cats with AA-amyloidosis. Cats were included if kidney specimens were collected post-mortem and laboratory data were available within 6 months before death. Renal lesions were evaluated with optical and electron microscopy. Mass spectrometry was used to characterize amyloid. Nine domestic short-hair cats were included; 4 females and 5 males with a median age of 8 years (range = 2-13). All cats had blood analyses and urinalyses available. Serum creatinine concentrations were increased in 6 cats and symmetric dimethylarginine was increased in all of the cats. All of the cats had proteinuria. Eight of 9 cats had amyloid in the medulla, and 9 had amyloid in the cortex (glomeruli). All cats had amyloid in the interstitium. Six cats had concurrent interstitial nephritis and 1 had membranoproliferative glomerulonephritis. All cats had extrarenal amyloid deposits. Amyloid was AA in each case. In conclusion, renal deposition of amyloid occurs in both cortex and medulla in shelter cats and is associated with azotemia and proteinuria. Renal involvement of systemic AA-amyloidosis should be considered in shelter cats with chronic kidney disease. The cat represents a natural model of renal AA-amyloidosis.
RESUMEN
Several risk factors for Coronavirus-2019 (COVID-19) disease have been highlighted in clinical evidence. Among the various risk factors are advanced age, metabolic illness such as diabetes, heart disease, and diseases of the respiratory system. Cystic Fibrosis (CF) is a rare disease with autosomal recessive transmission, characterised by a lack of synthesis of the CFTR channel protein, and multi-organ clinical symptoms mainly affecting the respiratory tract with recurrent pulmonary exacerbations. In view of the pathophysiological mechanisms, CF disease should be in theory considered a risk factor for SARS-CoV2 or severe COVID-19. However, recent clinical evidence seems to point in the opposite direction, suggesting that CF could be a protective factor against severe COVID-19. Possibly, the lack of presence or function of the CFTR channel protein could be linked to the expression of the membrane glycoprotein ACE-2, a key enzyme for the endocellular penetration of SARS-CoV-2 and related to the pathophysiology of COVID-19 disease. Furthermore, CFTR channel modulating agents could indirectly influence the expression of ACE-2, playing an important role in restoring the proper functioning of mucociliary clearance and the pulmonary microbiome in the host response to SARS-CoV-2 infection. In this review, the authors attempt to shed light on these important associations of issues that are not yet fully elucidated.
Asunto(s)
COVID-19 , Fibrosis Quística , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , ARN Viral , SARS-CoV-2RESUMEN
Chimeric Antigen Receptor (CAR)-modified T lymphocytes represent one of the most innovative and promising approaches to treating hematologic malignancies. CAR-T cell therapy is currently being used for the treatment of relapsed/refractory (r/r) B-cell malignancies including Acute Lymphoblastic Leukemia, Large B-Cell Lymphoma, Follicular Lymphoma, Multiple Myeloma and Mantle Cell Lymphoma. Despite the unprecedented clinical success, one of the major issues of the approved CAR-T cell therapy - tisagenlecleucel, axicabtagene, lisocabtagene, idecabtagene, ciltacabtagene and brexucabtagene - is the uncertainty about its persistence which in turn could lead to weak or no response to therapy with malignancy recurrence. Here we show that the prognosis of patients who do not respond to CAR-T cell therapy is still an unmet medical need. We performed a systematic review and meta-analysis collecting individual data on Duration of Response from at least 12-month follow-up studies. We found that the pooled prevalence of relapse within the first 12 months after CAR-T infusion was 61% (95% CI, 43%-78%); moreover, one year after the infusion, the analysis highlighted a pooled prevalence of relapse of 24% (95% CI, 11%-42%). Our results suggest that identifying potential predictive biomarkers of response to CAR-T therapy, especially for patients affected by the advanced stage of blood malignancies, could lead to stratification of the eligible population to that therapy, recognizing which patients will benefit and which will not, helping regulators to make decision in that way.
Asunto(s)
Neoplasias Hematológicas , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Adulto , Linfocitos T , Neoplasias Hematológicas/terapia , Enfermedad Crónica , Recurrencia , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Cardiorenal syndrome encompasses a spectrum of disorders involving heart and kidney dysfunction, and sharing common risk factors, such as hypertension and diabetes. Clinical studies have shown that patients with and without diabetes may benefit from using sodium-glucose cotransporter 2 inhibitors to reduce the risk of heart failure and ameliorate renal endpoints. Because the underlying mechanisms remain elusive, we investigated the effects of dapagliflozin on the progression of renal damage, using a model of non-diabetic cardiorenal disease. Dahl salt-sensitive rats were fed a high-salt diet for five weeks and then randomized to dapagliflozin or vehicle for the following six weeks. After treatment with dapagliflozin, renal function resulted ameliorated as shown by decrease of albuminuria and urine albumin-to-creatinine ratio. Functional benefit was accompanied by a decreased accumulation of extracellular matrix and a reduced number of sclerotic glomeruli. Dapagliflozin significantly reduced expression of inflammatory and endothelial activation markers such as NF-κB and e-selectin. Upregulation of pro-oxidant-releasing NADPH oxidases 2 and 4 as well as downregulation of antioxidant enzymes were also counteracted by drug treatment. Our findings also evidenced the modulation of both classic and non-classic renin-angiotensin-aldosterone system (RAAS), and effects of dapagliflozin on gene expression of ion channels/transporters involved in renal homeostasis. Thus, in a non-diabetic model of cardiorenal syndrome, dapagliflozin provides renal protection by modulating inflammatory response, endothelial activation, fibrosis, oxidative stress, local RAAS and ion channels.
Asunto(s)
Síndrome Cardiorrenal , Diabetes Mellitus , Animales , Ratas , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Síndrome Cardiorrenal/tratamiento farmacológico , Síndrome Cardiorrenal/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Riñón/metabolismo , Ratas Endogámicas DahlRESUMEN
PURPOSE: Individuals with Common Mental Disorders (CMDs) may have a higher cancer mortality. The purpose of this study was to examine cancer-related mortality among patients with CMDs and verify which cancer types are predominantly involved. METHODS: We used the Regional Mental Health Registry of the Emilia-Romagna region, in Northern Italy to identify patients aged ≥ 18 years who received an ICD 9-CM diagnosis of CMDs (i.e., depressive and neurotic disorders) over a 10 year period (2008-2017). Information on cause of death was retrieved from the Regional Cause of Death Registry. Comparisons were made with data from the regional population without CMDs. RESULTS: Among 101,487 patients suffering from CMDs (55.7% depression; 44.3% neurotic disorders), 3,087 (37.8%) died from neoplasms. The total standardized mortality ratio (SMR) was 1.82 (95% CI 1.78-1.86) while the SMR for all neoplasms was 2.08 (95% CI 2.01-2.16). Individuals of both genders, with both depressive and neurotic disorders had a higher risk of death from almost all cancers compared with the regional population. CONCLUSION: Patients with CMDs have considerably higher cancer mortality risk than the general population. Higher mortality was observed for a broad range of cancers associated with different aetiologies. It is imperative to promote cancer awareness, prevention and treatment for people with CMDs.
Asunto(s)
Trastornos Mentales , Neoplasias , Humanos , Masculino , Femenino , Estudios Retrospectivos , Trastornos Mentales/psicología , Trastornos Neuróticos , Salud MentalRESUMEN
After the outbreak of the pandemic due to COVID-19 infection, several vaccines were developed on short timelines to counteract the public health crisis. To allow the administration of mRNA vaccines through a faster-paced approval process, the Emergency Use Authorization (EUA) was applied. The Ba.5 (omicron) variant of SARS-CoV-2 is the predominant one at this moment. Its highly mutable single-stranded RNA genome, along with its high transmissivity, generated concern about the effectiveness of vaccination. The interaction between the vaccine and the host cell is finely regulated by miRNA machinery, a complex network that oversees a wide range of biological processes. The dysregulation of miRNA machinery has been associated with the development of clinical complications during COVID-19 infection and, moreover, to several human pathologies, among which is cancer disease. Now that in some areas, four doses of mRNA vaccine have been administered, it is natural to wonder about its effectiveness and long-term safety.
Asunto(s)
COVID-19 , MicroARNs , Humanos , MicroARNs/genética , ARN Mensajero/genética , COVID-19/prevención & control , SARS-CoV-2 , Vacunación , TecnologíaRESUMEN
Background and Objectives: To assess the potential prognostic role of the systemic immune-inflammation index (SII) in predicting oncological outcomes in a cohort of patients treated with radical cystectomy (RC). Materials and Methods: From 2016 to 2022, a retrospective monocentric study enrolled 193 patients who were divided into two groups based on their SII levels using the optimal cutoff determined by the Youden index. The SII was obtained from a preoperative blood test approximately one month before RC. Univariable and multivariable logistic regression analyses were conducted to investigate the capacity of SII to predict lymph node invasion (N), advanced pT stage (pT3/pT4), and locally advanced condition at the time of RC. Multivariable Cox regression models adjusted for preoperative and postoperative features were used to analyze the prognostic effect of SII on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: The optimal cutoff value of the SII was 640.27. An elevated SII was seen in 113 (58.5%) patients. Using the multivariable preoperative logistic regression models, an elevated SII was correlated with nodal invasion (N; p = 0.03), advanced pT stage (p = 0.04), and locally advanced disease (p = 0.005), with enhancement of AUCs for predicting locally advanced disease (p = 0.04). In multivariable Cox regression models that considered preoperative clinicopathologic factors, an elevated SII was linked to poorer RFS (p = 0.005) and OS (p = 0.01). Moreover, on multivariable Cox regression postoperative models, a high SII was linked to RFS (p = 0.004) and to OS (p = 0.01). Conclusions: In this monocentric retrospective study, higher preoperative SII values predicted worse oncological outcomes in patients with bladder cancer (BCa) who underwent RC.
Asunto(s)
Cistectomía , Neoplasias de la Vejiga Urinaria , Humanos , Estudios Retrospectivos , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/cirugía , Pronóstico , Biomarcadores , InflamaciónRESUMEN
The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin-Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1-7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Animales , Enfermedad Crónica , Insuficiencia Cardíaca/metabolismo , Hormonas/metabolismo , HumanosRESUMEN
SMC5/6 function in genome integrity remains elusive. Here, we show that SMC5 dysfunction in avian DT40 B cells causes mitotic delay and hypersensitivity toward DNA intra- and inter-strand crosslinkers (ICLs), with smc5 mutants being epistatic to FANCC and FANCM mutations affecting the Fanconi anemia (FA) pathway. Mutations in the checkpoint clamp loader RAD17 and the DNA helicase DDX11, acting in an FA-like pathway, do not aggravate the damage sensitivity caused by SMC5 dysfunction in DT40 cells. SMC5/6 knockdown in HeLa cells causes MMC sensitivity, increases nuclear bridges, micronuclei, and mitotic catastrophes in a manner similar and non-additive to FANCD2 knockdown. In both DT40 and HeLa systems, SMC5/6 deficiency does not affect FANCD2 ubiquitylation and, unlike FANCD2 depletion, RAD51 focus formation. SMC5/6 components further physically interact with FANCD2-I in human cells. Altogether, our data suggest that SMC5/6 functions jointly with the FA pathway to support genome integrity and DNA repair and may be implicated in FA or FA-related human disorders.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Anemia de Fanconi , ARN Helicasas DEAD-box , Daño del ADN/genética , ADN Helicasas/genética , Reparación del ADN/genética , Anemia de Fanconi/genética , Inestabilidad Genómica , Células HeLa , HumanosRESUMEN
Pterygium is a progressive disease of the human eye arising from sub-conjunctival tissue and extending onto the cornea. Due to its invasive growth, pterygium can reach the pupil compromising visual function. Currently available medical treatments have limited success in suppressing efficiently the disease. Previous studies have demonstrated that curcumin, polyphenol isolated from the rhizome of Curcuma longa, induces apoptosis of human pterygium fibroblasts in a dose- and time-dependent manner showing promising activity in the treatment of this ophthalmic disease. However, this molecule is not very soluble in water in either neutral or acidic pH and is only slightly more soluble in alkaline conditions, while its dissolving in organic solvents drastically reduces its potential use for biomedical applications. A nanoformulation of curcumin stabilized silver nanoparticles (Cur-AgNPs) seems an effective strategy to increase the bioavailability of curcumin without inducing toxic effects. In fact, silver nitrates have been used safely for the treatment of many ophthalmic conditions and diseases for a long time and the concentration of AgNPs in this formulation is quite low. The synthesis of this new compound was achieved through a modified Bettini's method adapted to improve the quality of the product intended for human use. Indeed, the pH of the reaction was changed to 9, the temperature of the reaction was increased from 90 °C to 100 °C and after the synthesis the Cur-AgNPs were dispersed in Borax buffer using a dialysis step to improve the biocompatibility of the formulation. This new compound will be able to deliver both components (curcumin and silver) at the same time to the affected tissue, representing an alternative and a more sophisticated strategy for the treatment of human pterygium. Further in vitro and in vivo assays will be required to validate this formulation.
Asunto(s)
Curcumina , Queratinocitos/metabolismo , Nanopartículas del Metal , Pterigion , Plata , Curcumina/química , Curcumina/farmacología , Humanos , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Pterigion/tratamiento farmacológico , Pterigion/metabolismo , Plata/química , Plata/farmacologíaRESUMEN
Poor prognosis in heart failure and the lack of real breakthrough strategies validate targeting myocardial remodelling and the intracellular signalling involved in this process. So far, there are no effective strategies to counteract hypertrophy, an independent predictor of heart failure progression and death. Glucocorticoid-induced leucine zipper (GILZ) is involved in inflammatory signalling, but its role in cardiac biology is unknown. Using GILZ-knockout (KO) mice and an experimental model of hypertrophy and diastolic dysfunction, we addressed the role of GILZ in adverse myocardial remodelling. Infusion of angiotensin II (Ang II) resulted in myocardial dysfunction, inflammation, apoptosis, fibrosis, capillary rarefaction and hypertrophy. Interestingly, GILZ-KO showed more evident diastolic dysfunction and aggravated hypertrophic response compared with WT after Ang II administration. Both cardiomyocyte and left ventricular hypertrophy were more pronounced in GILZ-KO mice. On the other hand, Ang II-induced inflammatory and fibrotic phenomena, cell death and reduction in microvascular density, remained invariant between the WT and KO groups. The analysis of regulators of hypertrophic response, GATA4 and FoxP3, demonstrated an up-regulation in WT mice infused with Ang II; conversely, such an increase did not occur in GILZ-KO hearts. These data on myocardial response to Ang II in mice lacking GILZ indicate that this protein is a new element that can be mechanistically involved in cardiovascular pathology.
Asunto(s)
Diástole , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Factores de Transcripción/deficiencia , Angiotensina II , Animales , Presión Sanguínea , Capilares/patología , Muerte Celular , Matriz Extracelular/metabolismo , Fibrosis , Hipertrofia , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Inflamación/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Severe Acute Respiratory Syndrome due to Coronavirus-19 (SARS-CoV-2) is caused by combined alveolar-capillary lung damage, with bilateral pneumonia and thrombosis, which often causes respiratory failure. Proper COVID-19 management requires high skills in airway control and the need to perform aerosol-generating procedures such as bronchoscopy, which can increase the possibility of virus spreading among healthcare professionals. In an epidemiologically delicate moment, the multidisciplinary decision on "WHEN, HOW and WHY" to perform bronchoscopies minimizing the risk of COVID-19 transmission, represented a great challenge for all specialists engaged in bronchoscopic procedures. In this work authors want to share all technical aspects of 87 videobronchoscopies performed in confirmed or suspected COVID-19 patients, from 3rd to 6th January 2020, describing the reason, the organizational and operational model and patients characteristics. Was also evaluated the impact of high-risk procedures such as bronchoscopy on the personnel involved. The disclosure of all technical details, represents, in the opinion of the authors, an important contribution, capable of providing support to all physicians engaged in bronchoscopy procedures in confirmed or suspected COVID-19 patients.
Asunto(s)
Manejo de la Vía Aérea , Broncoscopía , COVID-19/prevención & control , Control de Infecciones/organización & administración , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Broncoscopios , COVID-19/diagnóstico , COVID-19/transmisión , Humanos , Selección de Paciente , Equipo de Protección PersonalRESUMEN
Atrial fibrillation (AF) is a significant cause of morbidity and mortality as well as a public health burden considering the high costs of AF-related hospitalizations. Pre-clinical and clinical evidence showed a potential role of the renin angiotensin system (RAS) in the etiopathogenesis of AF. Among RAS mediators, angiotensin II (AII) and angiotensin 1-7 (A1-7) have been mostly investigated in AF. Specifically, the stimulation of the pathway mediated by AII or the inhibition of the pathway mediated by A1-7 may participate in inducing and sustaining AF. In this review, we summarize the evidence showing that both RAS pathways may balance the onset of AF through different biological mechanisms involving inflammation, epicardial adipose tissue (EAT) accumulation, and electrical cardiac remodeling. EAT is a predictor for AF as it may induce its onset through direct (infiltration of epicardial adipocytes into the underlying atrial myocardium) and indirect (release of inflammatory adipokines, the stimulation of oxidative stress, macrophage phenotype switching, and AF triggers) mechanisms. Classic RAS blockers such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may prevent AF by affecting the accumulation of the EAT, representing a useful therapeutic strategy for preventing AF especially in patients with heart failure and known left ventricular dysfunction. Further studies are necessary to prove this benefit in patients with other cardiovascular diseases. Finally, the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.
Asunto(s)
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Fibrilación Atrial/metabolismo , Remodelación Atrial , Fragmentos de Péptidos/metabolismo , Fibrilación Atrial/fisiopatología , HumanosRESUMEN
There was a mistake in Prof. Giuseppe Massimo Claudio Rosano's affiliation.
RESUMEN
The results of trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors raised the possibility that this class of drugs provides cardiovascular benefits independently from their anti-diabetic effects, although the mechanisms are unknown. Therefore, we tested the effects of SGLT2 inhibitor dapagliflozin on the progression of experimental heart disease in a non-diabetic model of heart failure with preserved ejection fraction. Dahl salt-sensitive rats were fed a high-salt diet to induce hypertension and diastolic dysfunction and were then treated with dapagliflozin for six weeks. Dapagliflozin ameliorated diastolic function as documented by echo-Doppler and heart catheterization, while blood pressure remained markedly elevated. Chronic in vivo treatment with dapagliflozin reduced diastolic Ca2+ and Na+ overload and increased Ca2+ transient amplitude in ventricular cardiomyocytes, although no direct action of dapagliflozin on isolated cardiomyocytes was observed. Dapagliflozin reversed endothelial activation and endothelial nitric oxide synthase deficit, with reduced cardiac inflammation and consequent attenuation of pro-fibrotic signaling. The potential involvement of coronary endothelium was supported by the endothelial upregulation of Na+/H+ exchanger 1in vivo and direct effects on dapagliflozin on the activity of this exchanger in endothelial cells in vitro. In conclusions, several mechanisms may cumulatively play a significant role in the dapagliflozin-associated cardioprotection. Dapagliflozin ameliorates diastolic function and exerts a positive effect on the myocardium, possibly targeting coronary endothelium. The lower degree of endothelial dysfunction, inflammation and fibrosis translate into improved myocardial performance.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Vasos Coronarios/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Glucósidos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Animales , Señalización del Calcio , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Diástole , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas Endogámicas Dahl , Sodio/metabolismo , Transportador 1 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Pathological gambling has been reported as a direct complication of Parkinson's disease and its pharmacological treatment based on dopamine agonists. Moreover, further medications (not dopamine agonists) were associated to the occurrence of gambling disorder. We aim to analyze the spontaneous reports of gambling disorder on the whole Italian territory with a focus on Campania Region (Southern Italy) from January 1st 2002 to July 31st 2018. We analyzed gambling disorder's reports across the 2002-2018 period in the Italian spontaneous reporting database (Rete Nazionale di Farmacovigilanza-RNF), with a focus on Campania region. 94 suspected cases of gambling disorder associated to apomorphine, aripiprazole, cabergoline, levodopa, levodopa and derivatives in association with entacapone/benserazide and carbidopa, pergolide, pramipexole, ropinirole, and rotigotine were reported into the RNF. Of these cases, two related to pramipexole and one to aripiprazole were sent to Campania Pharmacovigilance Regional Centre. Although it is widely recognized that dopamine agonists may induce behavioral disorders, Parkinson's disease is itself associated to pathological gambling, compulsive shopping and eating. Since our results could not clarify the correlation between Parkinson's disease, its pharmacological treatment and pathological gambling, in order to better define this correlation there is a need to conduct further ad hoc observational studies.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Juego de Azar/etiología , Agonistas de Dopamina/efectos adversos , Juego de Azar/psicología , Humanos , Italia , Levodopa/efectos adversos , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Pramipexol/efectos adversosRESUMEN
The increasing number of bridges approaching their design life has prompted researchers and operators to develop innovative structural health monitoring (SHM) techniques. An acoustic emissions (AE) method is a passive SHM approach based on the detection of elastic waves in structural components generated by damages, such as the initiation and propagation of cracks in concrete and the failure of steel wires. In this paper, we discuss the effectiveness of AE techniques by analyzing records acquired during a load test on a full-size prestressed concrete bridge span. The bridge is a 1968 structure currently decommissioned but perfectly representative, by type, age, and deterioration state of similar bridges in operation on the Italian highway network. It underwent a sequence of loading and unloading cycles with a progressively increasing load up to failure. We analyzed the AE signals recorded during the load test and examined how far their features (number of hits, amplitude, signal strength, and peak frequency) allow us to detect, quantify, and classify damages. We conclude that AE can be successfully used in permanent monitoring to provide information on the cracking state and the maximum load withstood. They can also be used as a non-destructive technique to recognize whether a structural member is cracked. Finally, we noticed that AE allow classifying different types of damage, although further experiments are needed to establish and validate a robust classification procedure.
RESUMEN
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Células Musculares/citología , Infarto del Miocardio/tratamiento farmacológico , Miocardio/citología , Células Madre/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ratones , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Infarto del Miocardio/etiología , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Fosforilación/efectos de los fármacos , Pravastatina/administración & dosificación , Pravastatina/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/farmacología , Simvastatina/administración & dosificación , Simvastatina/farmacología , Células Madre/citología , Células Madre/metabolismoRESUMEN
BACKGROUND: Chronic kidney disease (CKD) has typically a non-immune mediated origin in cats and immune-complex glomerulonephritis (ICGN) is scarcely described. Aims of this study were to characterize ICGN by light and electron microscopy and identify associations with clinico-pathological findings. In addition, comparisons between cats with ICGN and non immune-complex glomerulonephritis (non-ICGN) were performed. Renal samples examined between 2010 and 2019 were considered if both light and electron microscopy were performed. Signalment, feline immunodeficiency virus (FIV) and leukemia virus (FeLV) status, serum creatinine concentration, urine protein-to-creatinine (UPC) ratio, systolic blood pressure (SBP) and International Renal Interest Society (IRIS) stage were retrieved and used for comparisons. RESULTS: Sixty-eight client-owned cats were included. Thirty-seven cats (54.4%) had ICGN and 31 (45.6%) non-ICGN. Eighteen (48.6%) with ICGN had membranous glomerulonephropathy (MGN), 14 (37.8%) membranoproliferative glomerulonephritis (MPGN), and 5 (13.5%) mesangioproliferative glomerulonephritis (MeGN). Clinico-pathological data were not associated with any type of ICGN. Among cats with non-ICGN, 11 (35.5%) had end-stage CKD, 9 (29%) focal segmental glomerulosclerosis, 6 (19.4%) global and multifocal mesangiosclerosis, 2 (6.5%) glomerular atrophy, 2 (6.5%) renal dysplasia and 1 (3.1%) amyloidosis. Eight (25.8%) cats with non-ICGN had chronic interstitial nephritis (CIN) grade 1, 13 (41.9%) grade 2 and 10 (32.3%) grade 3; creatinine and UPC ratio increased with CIN grades (p = 0.001, p < 0.001). Cats with ICGN were more frequently FIV or FeLV-infected (OR:11.4; 95%CI:1.4-94.4; p = 0.024), had higher UPC ratio (OR:6.8; 95%CI:2.5-18.2; p < 0.001) and were younger (OR:0.9; 95%CI:0.7-1.0; p = 0.042) than cats with non-ICGN. CONCLUSIONS: MGN and MPGN were the most common morphological diagnoses of ICGN in cats. Unfortunately, none of the investigated findings differentiated ICGN morphological diagnoses. Serum creatinine concentration and UPC ratio were directly associated with grades of CIN (p = 0.001 and p < 0.001, respectively), confirming previous literature. More ICGN than non-ICGN was observed in cats with retroviral infections, younger cats and higher UPC ratio.
Asunto(s)
Enfermedades de los Gatos/patología , Glomerulonefritis/veterinaria , Enfermedades del Complejo Inmune/veterinaria , Animales , Gatos , Femenino , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Enfermedades del Complejo Inmune/patología , Riñón/patología , Masculino , Estudios RetrospectivosRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Medication errors, such as unnecessary treatment discontinuation during treatment with direct-acting antivirals (DAAs), can lead to imbalances in the benefit-to-risk ratio. This risk is especially high when the medication error leads to adverse drug reactions (ADRs). However, to date, evidence on the frequency of this phenomenon is scarce. This study aims to provide better insight into ADRs possibly due to medication errors leading to DAA discontinuation and their preventability. METHODS: The Italian Pharmacovigilance Network database was used to extract individual case safety reports (ICSRs) generated from July 2012 to March 2017 via the Campania Region (Italy) spontaneous reporting system. ICSRs that included ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, dasabuvir, daclatasvir, sofosbuvir, simeprevir or elbasvir/grazoprevir as suspected drugs were included in this study. A preventability assessment was then performed utilizing the "P-Method," an algorithm that evaluates known risk factors due to medication errors that can be detected in ICSRs. RESULTS AND DISCUSSION: Of the 355 cases included in this study, 6 (1.69%) were classified as preventable and 52 (14.6%) were classified as potentially preventable. The most frequently identified critical criteria (risk factor) for preventable or potentially preventable cases were drug-drug interactions and incorrect drug dosing as part of the antiviral treatment scheme. In total, 89 of the 355 cases (25.1%) discontinued use of the DAAs due to ADRs, of which 20 of the 89 cases (22.5%) were due to an unimportant medical event as classified by the European Medicine Agency important medical event list. WHAT IS NEW AND CONCLUSION: This study found a proportion of preventable/potentially preventable ADRs involving DAA, which could be improved in the Campania Region (Italy). Additionally, the study identified a high proportion of seemingly unnecessary DAA discontinuations among patients who experienced ADRs.