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1.
Eur Rev Med Pharmacol Sci ; 25(18): 5876-5884, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34604981

RESUMO

The risk stratification of young adults between subjects who will develop a mild form COVID-19 and subjects who will undergo a severe disease remains inaccurate. In this review, we propose that the Barker hypothesis might explain the increased susceptibility to severe forms of COVID-19 in subjects who underwent intrauterine growth restriction (IUGR). In this paper evidence indicating an association between a low birth weight and an adult phenotype which might favor a severe outcome of SARS-CoV-2 infection are presented: lower lung functional capacity; increased respiratory morbidity; changes in fibrinogen and Factor VII serum levels and dysregulation of the hemostasis and thrombosis system; acquisition of a pro-thrombotic phenotype; low nephron number, with decreased ability to sustain renal function and increased renal morbidity; heart remodeling, with a less efficient cardiac function; endothelial dysfunction, a risk factor for the insurgence of the multiple organ failure; remodeling of arteries, with changes in the elastic properties of the arterial wall, predisposing to the insurgence and progression of atherosclerosis; dysfunction of the innate immune system, a risk factor for immune diseases in adulthood. These data suggest that young and adult subjects born too small (IUGR) or too early (pre-terms) might represent a subgroup of "at risk subjects", more susceptible toward severe forms of COVID-19. Given that LBW may be considered a surrogate of IUGR, this phenotypic marker should be included among the indispensable clinical data collected in every patient presenting with SARS-COV-2 infection, irrespectively of his/her age.

2.
Eur Rev Med Pharmacol Sci ; 25(17): 5518-5524, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34533802

RESUMO

OBJECTIVE: In liver cirrhosis, a complex coagulopathy does exist. The aim was to investigate whether a possible chronic consumption coagulopathy is the underlying phenomenon of the disease. PATIENTS AND METHODS: We measured endogenous thrombin generation with and without thrombomodulin (ETP ratio) along with D-Dimer in a group of consecutive 282 cirrhotic patients. Fibrinogen, Platelet count and the Hemorrhagic score were previously computed in the same patients. The ETP ratio represents the resistance to the anticoagulant activity of TM and should be considered as an index of a procoagulant imbalance. RESULTS: ETP ratio and D-Dimer showed higher values in the cirrhotic patients when compared to controls thus showing a hypercoagulable state. When the patients were divided based on the Hemorrhagic score >7, we found that Fibrinogen, ETP ratio, D-Dimer and the platelet count were significantly different between the two groups. Again, when we considered ETP ratio >0.88, the median value of the cirrhotic patients, all parameters, were statistically different between the two groups. D-Dimer were higher while fibrinogen and platelet count were statistically lower in cirrhotic patients with higher ETP ratio values. Even when the same patients were divided based on their platelet count ( 100 x 109/L) the results showed a similar behavior. ROC curves showed significant AUCs when the hemorrhagic score was challenged against Fibrinogen, D-Dimer, Platelet count and ETP ratio. CONCLUSIONS: In liver cirrhosis hypercoagulable state is associated with an increase in D-Dimer levels along with a decrease in fibrinogen and platelet count thus indicating a low-grade intravascular coagulation which predicts a high hemorrhagic risk.

3.
Eur Rev Med Pharmacol Sci ; 25(15): 5063-5069, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34355379

RESUMO

OBJECTIVE: Vaccine-induced immune thrombocytopenia (VITT) is a new syndrome occurring primarily in healthy young adults, with a female predominance, after receiving the first dose of ChAdOx1 nCoV-19 vaccine. We describe VITT syndrome characterized by severe thrombosis and thrombocytopenia found in our patient, with fatal outcome. CASE REPORT: A 58-year-old man, after 13 days from the first administration of ChAdOx1 nCoV-19 vaccine (AstraZeneca), presented with abdominal pain, diarrhea and vomitus. Laboratory tests revealed a severe thrombocytopenia, low fibrinogen serum levels and marked increase of D-dimer serum levels. The patient quickly developed a multiple organ failure, till death, three days after the hospital admission. RESULTS: At histology, in the lungs, interalveolar septa appeared thickened with microthrombi in the capillaries and veins. Interalveolar septa appeared thickened and showed vascular proliferation. Thrombi were detected in the capillaries of glomerular tufts. In the hearth, thrombi were observed in veins and capillaries. In the liver, voluminous fibrin thrombi were diffusely observed in the branches of the portal vein. Microthrombi were also found in the vasa vasorum of the wall of abdominal aorta. In the brain, microthrombi were observed in the capillaries of the choroid plexuses. Diffuse hemorrhagic necrosis was observed in the intestinal wall with marked congestion of the venous vessels. CONCLUSIONS: In our patient, the majority of data necessary for a VITT final diagnosis were present: thrombocytopenia and thrombosis in pulmonary, portal, hepatic, renal and mesenteric veins, associated with a marked increase of D-dimer serum levels. The finding of cerebral thrombosis in choroid plexuses, is a new finding in VITT. These features are suggestive for a very aggressive form of VITT.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Púrpura Trombocitopênica Idiopática/etiologia , Trombose/etiologia , Aorta/patologia , COVID-19/sangue , Vacinas contra COVID-19/administração & dosagem , Plexo Corióideo/patologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Íleo/patologia , Rim/patologia , Fígado/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Púrpura Trombocitopênica Idiopática/sangue , Trombose/sangue
4.
Eur Rev Med Pharmacol Sci ; 25(13): 4639-4643, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34286505

RESUMO

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is characterized by quantitative and qualitative changes in surfactant composition, leading to surfactant dysregulation with alveolar collapse and acute respiratory hypoxic failure. Recently, surfactant has been hypothesized to play a relevant role in COVID-19, representing a strong defender against SARS-CoV-2 infection. The aim of our work was the study of immunohistochemical surfactant expression in the lungs of patients died following SARS-CoV-2 ARDS, in order to shed light on a possible therapeutic surfactant administration. PATIENTS AND METHODS: We investigated four patients who died due to ARDS following SARS-COV-2 infection and four patients submitted to lung biopsy, in the absence of SARS-CoV-2 infection. In all 8 cases, lung specimens were immunostained with anti-surfactant protein A (SP-A) and B (SP-B). RESULTS: In control subjects, reactivity for SP-B was restricted to type II alveolar cells. Immunostaining for SP-A was observed on the surface of alveolar spaces. In the COVID-19 positive lungs, immunoreactivity for SP-B was similar to that observed in control lungs; SP-A was strongly expressed along the alveolar wall. Moreover, dense aggregates of SP-A positive material were observed in the alveolar spaces. CONCLUSIONS: Our immunohistochemical data show the dysregulation of surfactant production in COVID-19 patients, particularly regarding SP-A expression. The increased presence of SP-A in condensed masses inside alveolar spaces could invalidate the therapeutic efficacy of the treatment with exogenous surfactant.


Assuntos
COVID-19/metabolismo , Imuno-Histoquímica , Precursores de Proteínas/análise , Proteína A Associada a Surfactante Pulmonar/análise , Proteínas Associadas a Surfactantes Pulmonares/análise , COVID-19/diagnóstico por imagem , Humanos , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Alvéolos Pulmonares/diagnóstico por imagem , Alvéolos Pulmonares/metabolismo , Proteína A Associada a Surfactante Pulmonar/genética , Proteína A Associada a Surfactante Pulmonar/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/genética , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo
5.
Eur Rev Med Pharmacol Sci ; 25(12): 4336-4344, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34227068

RESUMO

OBJECTIVE: Wilson's Disease (WD) is an autosomal recessive copper overload. Several mutations of the copper pump named ATP7B have been involved. WD is difficult to diagnose mainly because of its heterogeneity of presentation. The histologic spectrum is wide and not specific, ranging from very mild changes to severe disease. The histological picture of WD may overlap different conditions, including ALD, NAFLD, viral hepatitis or autoimmune liver disease. PATIENTS AND METHODS: We describe our experience on WD based on a single-center series of liver biopsies. One-hundred twenty-seven liver samples from 43 Sardinian WD patients were reviewed. The most reported pattern was steatohepatitis, accounting 82/127 biopsies (64.6%), followed by hepatitis in 25 biopsies (19.7%), and steatosis in 20 biopsies (15.7%). RESULTS: As for the elementary lesions, inflammation, steatosis, glycogenated nuclei and ballooning were the most frequent, being found in 107, 102, 90 and 86 biopsies out of the 127. Notably, all these lesions showed a predominant periportal location. There was no significant difference in the diagnostic pattern or in each elementary lesion between the biopsies performed at presentation and those performed during the follow-up. Lipogranuloma (significantly more numerous in the follow-up biopsies) and fibrosis (likewise significantly progressed in follow-up biopsies) were the only exceptions. CONCLUSIONS: Our data confirm the variability of the histological pattern in WD. However, the preferential localization of steatosis and balloon cells in periportal zone can be a useful clue for the diagnosis of WD.

6.
Eur Rev Med Pharmacol Sci ; 25(10): 3772-3790, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34109586

RESUMO

Multiple epidemiological studies have suggested that industrialization and progressive urbanization should be considered one of the main factors responsible for the rising of atherosclerosis in the developing world. In this scenario, the role of trace metals in the insurgence and progression of atherosclerosis has not been clarified yet. In this paper, the specific role of selected trace elements (magnesium, zinc, selenium, iron, copper, phosphorus, and calcium) is described by focusing on the atherosclerotic prevention and pathogenesis plaque. For each element, the following data are reported: daily intake, serum levels, intra/extracellular distribution, major roles in physiology, main effects of high and low levels, specific roles in atherosclerosis, possible interactions with other trace elements, and possible influences on plaque development. For each trace element, the correlations between its levels and clinical severity and outcome of COVID-19 are discussed. Moreover, the role of matrix metalloproteinases, a family of zinc-dependent endopeptidases, as a new medical therapeutical approach to atherosclerosis is discussed. Data suggest that trace element status may influence both atherosclerosis insurgence and plaque evolution toward a stable or an unstable status. However, significant variability in the action of these traces is evident: some - including magnesium, zinc, and selenium - may have a protective role, whereas others, including iron and copper, probably have a multi-faceted and more complex role in the pathogenesis of the atherosclerotic plaque. Finally, calcium and phosphorus are implicated in the calcification of atherosclerotic plaques and in the progression of the plaque toward rupture and severe clinical complications. In particular, the role of calcium is debated. Focusing on the COVID-19 pandemia, optimized magnesium and zinc levels are indicated as important protective tools against a severe clinical course of the disease, often related to the ability of SARS-CoV-2 to cause a systemic inflammatory response, able to transform a stable plaque into an unstable one, with severe clinical complications.


Assuntos
Aterosclerose/patologia , Oligoelementos/metabolismo , Aterosclerose/metabolismo , COVID-19/patologia , COVID-19/virologia , Cálcio/sangue , Cálcio/metabolismo , Cobre/sangue , Cobre/metabolismo , Humanos , Ferro/sangue , Ferro/metabolismo , Magnésio/sangue , Magnésio/metabolismo , Metaloproteinases da Matriz/metabolismo , Fósforo/sangue , Fósforo/metabolismo , Risco , SARS-CoV-2/isolamento & purificação , Selênio/sangue , Selênio/metabolismo , Índice de Gravidade de Doença , Oligoelementos/sangue , Zinco/sangue , Zinco/metabolismo
7.
Eur Rev Med Pharmacol Sci ; 25(10): 3886-3897, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34109597

RESUMO

OBJECTIVE: Platelets, blood coagulation along with fibrinolysis are greatly involved in the pathophysiology of infectious diseases induced by bacteria, parasites and virus. This phenomenon is not surprising since both the innate immunity and the hemostatic systems are two ancestral mechanisms which closely cooperate favoring host's defense against foreign invaders. However, the excessive response of these systems may be dangerous for the host itself. MATERIALS AND METHODS: We searched and retrieved the articles, using the following electronic database: MedLine and Embase. We limited our search to articles published in English, but no restrictions in terms of article type, publication year, and geography were adopted. RESULTS: The hemostatic phenotype of the infectious diseases is variable depending on the points of attack of the different involved pathogens. Infectious diseases which show a prothrombotic phenotype are bacterial sepsis, SARS-CoV-2 and malaria. However, among the bacterial sepsis, Yersinia Pestis is characterized by a profibrinolytic behavior. On the contrary, the hemorrhagic fevers, due to Dengue and Ebola virus, mainly exploit the activation of fibrinolysis secondary to a huge endothelial damage which can release a large amount of t-PA in the early phase of the diseases. CONCLUSIONS: Blood coagulation and fibrinolysis are greatly activated based on the strategy of the different infectious agents which exploit the excess of response of both systems to achieve the greatest possible virulence.


Assuntos
Coagulação Sanguínea , COVID-19/patologia , Fibrinólise , COVID-19/complicações , COVID-19/virologia , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais/virologia , Eritrócitos/citologia , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Humanos , Monócitos/citologia , Monócitos/metabolismo , Monócitos/virologia , SARS-CoV-2/isolamento & purificação , Tromboplastina/metabolismo , Vírus/patogenicidade
8.
Eur Rev Med Pharmacol Sci ; 25(11): 4064-4068, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34156684

RESUMO

OBJECTIVE: Atherosclerosis is one of the leading causes of disability and mortality worldwide. Inflammation, including monocytes, T and B cells, plays a key role in its pathogenesis. Our purpose was to evaluate plasma cells' presence in a large series of carotid artery plaques and the clinical association. PATIENTS AND METHODS: Forty-eight consecutive patients treated with carotid endarterectomy were retrospectively analyzed to assess plasma cells' presence inside the plaque. A semiquantitative grading score was applied, ranging from absence, scattered, clusters of 5-10, and sheets of >10 plasma cells. Plasma cell's location, as intraplaque, subendothelial or peri-adventitial, was also defined. RESULTS: In 75% of plaques analyzed, plasma cells were detected: scattered in 63.9%, in clusters in 22.2%, and in sheets in 13.9% of cases. In all cases, plasma cells were observed only inside the plaque. In 13.9% and in 11.1% of cases, plasma cells showed, respectively, a concomitant subendothelial or peri-adventitial distribution. In 5.6% of plaques, there was a simultaneous distribution in subendothelial, peri-adventitial layer, and intraplaque. Association between the presence of symptoms and plasma cells infiltrate was found. CONCLUSIONS: Our results suggest that plasma cells could be a key parameter linked to plaque instability. Some types of configurations are significantly associated with the occurrence of cerebrovascular symptoms.

9.
Eur Rev Med Pharmacol Sci ; 25(9): 3594-3606, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34002834

RESUMO

OBJECTIVE: Patients with 2019-nCoV infection have a high risk to develop venous thrombotic events. Several guidelines recommend the use of either unfractionated heparin or low molecular weight heparins in preventing thrombotic events in these patients. However, results from clinical studies, so far published, reached controversial conclusions on heparin efficacy in this kind of patients since the incidence of venous thromboembolism remains high despite prophylaxis. This narrative review aims to provide an overview of the antiviral and anti-inflammatory properties of heparins and their efficacy and safety in SARS-CoV-2 medical ward-patients. Moreover, anatomical findings and ongoing trials are also reported. Finally, this narrative review tries to explain why heparins fail to prevent venous thrombosis. MATERIALS AND METHODS: We searched for the most relevant published studies on heparins and 2019-nCoV infected patients using the MEDLINE electronic database in the period between January and December 2020. Articles were preliminarily defined as eligible if they: a) were in English language, b) enrolled 250 or more medical ward-patients and 100 or more ICU-patients, c) reported results on patients treated with heparins in a percentage of at least 70% and d) performed an objectively confirmed diagnosis of VTE. RESULTS: Data from medium to large scientific studies show that the incidence of venous thrombotic events in medical ward-patients with SARS-CoV-2 vary between 0% and 8.3%, while this rate is higher, from 6.2% to 49%, in Intensive Care Unit-patients. However, heparins reduce the mortality rate in these patients of about 50%. Histological findings show that thrombosis could affect capillaries, main and small-mid-sized vessels, and it is associated with diffuse alveolar damage. CONCLUSIONS: Heparins have anti-inflammatory and anti-viral properties, which may be of help in reducing mortality in SARS-CoV-2 patients. Failure of heparins at prophylactic dosages in preventing VTE, especially in ICU-patients, could be due to the severity of the disease. Data on the use of heparins in an early phase of the 2019-nCoV infection are still lacking.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/tratamento farmacológico , Heparina/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , Humanos , Mortalidade/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/imunologia
10.
Eur Rev Med Pharmacol Sci ; 25(4): 2146-2151, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33660834

RESUMO

OBJECTIVE: COVID-19, the newly emerging infectious disease, has been associated with acute liver injury, often related to progression to severe pneumonia. The association between moderate-severe liver injury and more severe clinical course of COVID-19 has suggested that liver injury is prevalent in severe than in mild cases of COVID-19, while no difference in liver involvement has been reported between survivors and non-survivors. The spectrum of liver involvement during COVID-19 ranges from an asymptomatic elevation of liver enzymes to severe hepatitis. Only rarely, cases with acute hepatitis have been reported in the absence of respiratory symptoms. Both epithelial and biliary cells possess the angiotensin-converting enzyme-2 receptors that SARS-CoV-2 uses to be internalized. However, to our knowledge, no ultrastructural identification of the virus in liver cells has been reported to date. Here we provide evidence of SARS-CoV-2 in the liver of two patients, a 34-year-old woman and a 60-year-old man with COVID-19. PATIENTS AND METHODS: We investigated two patients with COVID-19 showing several virions within cytoplasmic vacuoles of cholangiocytes and in endothelial cells of hepatic sinusoids. In both patients, we performed histological and ultrastructural examinations by liver biopsy. After two months, both patients were free of symptoms, and the SARS-CoV-2 infection had resolved. RESULTS: Liver biopsy histological and ultrastructural examination showed liver injury and several virions within cytoplasmic vacuoles of cholangiocytes and in endothelial cells of hepatic sinusoids. CONCLUSIONS: Although most studies in COVID-19 have been focused on the lungs, recently, cholestatic liver pathology has been introduced in the spectrum of pathological changes related to COVID-19. To the best of our knowledge, those presented in this paper are the first images of hepatic SARS-CoV-2 infected liver cells. Our findings suggest a role for cholangiocytes and biliary structures in the COVID-19.


Assuntos
COVID-19/complicações , Hepatopatias/complicações , Fígado/virologia , SARS-CoV-2/isolamento & purificação , Adulto , Biópsia , COVID-19/diagnóstico por imagem , COVID-19/virologia , Células Epiteliais/virologia , Feminino , Humanos , Fígado/diagnóstico por imagem , Hepatopatias/diagnóstico por imagem , Hepatopatias/virologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Vírion/isolamento & purificação
11.
Eur Rev Med Pharmacol Sci ; 25(1): 431-437, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33506933

RESUMO

OBJECTIVE: Thymosin beta 4 (TB4) is the most abundant member of the beta-thymosin family in humans. The main physiological role of TB4 is the regulation of actin polymerization. TB4 is also involved in angiogenesis, cell survival, cell migration and fetal development. The aim of this study was to evaluate the activity of TB4 as a fetal growth promoter when administered during pregnancy. MATERIALS AND METHODS: Our protocols have been carried out in full conformity with the rules and guidelines expected for this kind of trial. 10 pregnant mice received the same injection regimen. Only 6 of these 10 are part of this experiment because they were pregnant. At 10:00 a.m. on day E14 and E17 of gestation mice were weighed and treated with an intraperitoneal injection of TB4 (Regene RX, Rockville, MD, USA; 6 mg/kg in PBS). RESULTS: The mothers treated with TB4 for two days precisely E14 and E17, showed a higher cranio-caudal length when compared to control newborns. At histology, maternal TB4 treatment was associated with more advanced development of lungs, heart, kidney, cerebral cortex and notochord. CONCLUSIONS: Our study shows that TB4 administration during gestation may act as a powerful fetal growth promoter, by accelerating the development of newborn organs and tissues.


Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Nascimento Prematuro , Timosina/farmacologia , Animais , Feminino , Humanos , Recém-Nascido , Injeções Intraperitoneais , Camundongos , Gravidez , Timosina/administração & dosagem
12.
Eur Rev Med Pharmacol Sci ; 24(23): 12609-12622, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336781

RESUMO

OBJECTIVE: In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease. MATERIALS AND METHODS: PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm. RESULTS: The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed. CONCLUSIONS: The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.


Assuntos
Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Cardiomiopatias/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Endotélio Vascular/fisiopatologia , Cirrose Hepática/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Trombose/metabolismo , Angiotensina I/metabolismo , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Coagulação Sanguínea , COVID-19/patologia , COVID-19/fisiopatologia , Permeabilidade Capilar , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Miocardite/metabolismo , Miocardite/patologia , Miocardite/fisiopatologia , Receptores de Coronavírus/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Trombose/fisiopatologia , Internalização do Vírus
13.
J Inorg Biochem ; 193: 106-111, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30703747

RESUMO

Wilson's disease (WD) is a genetic metabolic disease strictly associated with liver cirrhosis. In this review, the genetic bases of the disease are discussed, with emphasis on the role of ATP7B (the Wilson disease protein) dysfunction as a determinant factor of systemic copper overload. Regarding the different multiple mutations described in WD patients, the peculiarity of Sardinian population is highlighted, Sardinians carrying a rare deletion in the promoter (5' UTR) of the WD gene. The role of epigenetic changes in the clinical presentation and evolution of liver disease in WD patients is also discussed, nutrition probably representing a relevantly risk factor in WD patients. The role of transmission electron microscopy in the diagnosis of WD-related liver disease is underlined. Mitochondrial changes, increased peroxisomes fat droplets, lipolysosomes and intranuclear glycogen inclusions are reported as the most frequent ultrastructural changes in the liver of WD carriers. The role of histochemical stains for copper is analyzed, and the Timm's method is suggested as the most sensitive one for revealing hepatic copper overload in all stage of WD. The marked variability of the histological liver changes occurring in WD is underlined simple steatosis may represent the only pathological changes, frequently associated with glycogenated nuclei. Mallory-Denk bodies lipogranulomas alcoholic and non-alcoholic fatty liver disease ending with bridging fibrosis and cirrhosis. Finally, the reversal of fibrosis as a possible therapeutic objective in WD is discussed.


Assuntos
Cobre/metabolismo , Degeneração Hepatolenticular/patologia , Fígado/patologia , ATPases Transportadoras de Cobre/genética , ATPases Transportadoras de Cobre/metabolismo , Epigênese Genética , Degeneração Hepatolenticular/tratamento farmacológico , Humanos , Cirrose Hepática/tratamento farmacológico , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mutação , Penicilamina/uso terapêutico
14.
J Matern Fetal Neonatal Med ; 31(6): 701-707, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28288550

RESUMO

The liver is a major hematopoietic organ during embryonic and fetal development in humans. Its hematopoietic activity starts during the first weeks of gestation and continues until birth. During this period the liver is colonized by undifferentiated hematopoietic stem cells (HSCs) that gradually differentiate and once mature, enter the circulatory system through the hepatic sinusoids, this process is called hepatic hematopoiesis. The morphology of hepatic hematopoiesis, has been studied in humans through the years, and led to a characterization of all the cell types that make up these phenomena. Studies on murine models also helped to describe the extent of hepatic hematopoiesis at different gestational ages. Using this knowledge, we attempted to describe how hepatic hematopoiesis morphologically evolves as gestation progresses, in human embryos and fetuses. Thus, we observed a total of 32 tissue specimens obtained from the livers of embryos and fetuses at different gestational ages. Basing our observations on the four stages of liver hematopoiesis identified by Sasaki and Sonoda in mice, we also described four consecutive stages of liver hematopoiesis in humans, which resulted to be highly similar to those described in murine models.


Assuntos
Eritropoese/fisiologia , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Fígado/embriologia , Animais , Antígenos CD34/análise , Modelos Animais de Doenças , Eritroblastos/citologia , Eritroblastos/metabolismo , Idade Gestacional , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Fígado/citologia , Macrófagos/citologia , Camundongos
15.
Int Urol Nephrol ; 49(9): 1621-1625, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28573487

RESUMO

CD31 reactivity is generally utilized as a marker of endothelial cells. CD31 immunoreactivity in the developing human kidney revealed that fetal glomerular capillary endothelial cells change their immunohistochemical phenotype during maturation. The aim of this study was to analyze CD31 reactivity in the fetal human kidney in the different stages of intrauterine development: We observed different distribution of CD31-reactive vascular progenitors in the different areas of the developing kidney. In particular, the nephrogenic zone and the renal capsule were characterized by a scarcity of CD31-reactive cells at all gestational ages. These data suggest the hypothesis that nephrogenesis does not need high oxygen levels and confirms a major role of hypoxia in nephrogenesis.


Assuntos
Rim/embriologia , Rim/metabolismo , Neovascularização Fisiológica , Organogênese/fisiologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Hipóxia Celular , Idade Gestacional , Humanos , Imuno-Histoquímica , Recém-Nascido , Rim/irrigação sanguínea
16.
Eur J Histochem ; 60(3): 2678, 2016 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-27734990

RESUMO

The surfactant complex, thanks to its multiple actions including decrease of surface- tension and antimicrobial activity, plays a fundamental role in newborn survival, lowering the risk of respiratory distress syndrome. The aim of this work was to determine if the synthesis of two surfactant proteins (SP), SPA and pro-SPB, shows some inter-individual variability during lung development in the intrauterine life. Immunoreactivity for SPA and pro-SPB was investigated in the lungs of  40 subjects, including 15 fetuses, ranging from 14 to 22 weeks of gestation, and 25 neonates, from 24 to 41 weeks. Lung samples were formalin fixed, paraffin-embedded and routinely processed. SPA and pro-SPB were detected utilizing commercial antibodies.  A semi-quantitative grading system (1 to 4) was applied, based on the number of reactive cells and the intensity of immunostaining. Surfactant protein immunostaining was found in  three compartments: bronchi, bronchioles and alveoli, starting from 14 weeks of gestation in the bronchial epithelium and from the 21st week in the alveolar spaces. Differences were found regarding SPA and pro-SPB expression in the vast majority of subjects: in some lungs, SPA was more expressed whereas in others pro-SPB showed an higher degree of immunoreactivity. The expression of both surfactant proteins was not strictly correlated with gestational age. Whereas the highest levels of reactivity were detected in at term neonates, on the other hand one case with grade 3 was detected at 22 weeks and one negative case for both proteins was observed at 31 weeks. Our data clearly show a marked inter-individual variability regarding the production of SPA and pro-SPB and suggest the existence of other epigenetic factors, acting during gestation, that might influence surfactant production and, consequently, the survival potential of  neonates at birth.


Assuntos
Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Pulmão/embriologia , Proteína A Associada a Surfactante Pulmonar/biossíntese , Proteína B Associada a Surfactante Pulmonar/biossíntese , Pré-Escolar , Feminino , Feto/citologia , Humanos , Lactente , Pulmão/citologia , Masculino
17.
Eur J Histochem ; 60(2): 2606, 2016 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-27349312

RESUMO

Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genótipo , Antígenos HLA-G/biossíntese , Doença de Hodgkin/metabolismo , Mutação INDEL , Proteínas de Neoplasias/biossíntese , Adolescente , Adulto , Feminino , Antígenos HLA-G/genética , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Tomografia por Emissão de Pósitrons
18.
Eur J Histochem ; 60(2): 2614, 2016 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-27349315

RESUMO

Hepatocellular carcinoma (HCC) represents a major global health problem, since more than 90% of primary liver cancers worldwide are HCC. Most cases of HCC are secondary to viral hepatitis infection (hepatitis B or C), alcoholism and cirrhosis. Sorafenib, an oral tyrosine kinase inhibitor that suppresses tumor proliferation and angiogenesis, emerged as the first effective systemic treatment for HCC after 30 years of research, and is currently the standard-of-care for patients with advanced HCC. Sorafenib is metabolized by cytochrome P450 (CYP450), particularly from the 3A4 isoform, producing two main metabolites: the N-oxide and the N-hydroxymethyl metabolite. We studied 11 HCC sample showing the presence of CYP3A4 and CYP3A7 in most of the samples analyzed. Specifically, the immunoreactivity of CYP3A4 was more strong and widespread than that of CYP3A7. The CYP3A4 immunoreactivity was observed in surrounding hepatocytes in 8 out of 11 cases; while the CYP3A7 immunostaining was found in normal liver cells, in 7 out of 11 cases. These results suggest the existence of a marked inter-individual variability regarding the presence of the isoforms of CYP3A. In addition, since sorafenib is metabolized by CYP3A4, but not by CYP3A7, an overexpression of CYP3A4 may lead to an increase in the degradation of the drug and then to clinical ineffectiveness. These results might implicate the necessity of an individualized approach in the treatment of HCC as positivity to CYP3A4 in HCC liver samples might predict a scarce response to sorafenib.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Citocromo P-450 CYP3A/metabolismo , Neoplasias Hepáticas/enzimologia , Proteínas de Neoplasias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/dietoterapia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade
19.
Ital J Pediatr ; 41: 78, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26472160

RESUMO

The preterm kidney cannot be simply considered as a kidney small in size: as compared to the adult kidney, the developing organ of the preterm infant is characterized by marked differences regarding the architecture and cell components. At macroscopy, fine linear demarcations indenting the renal surface characterize the fetal and preterm kidney. At microscopy, multiple major architectural changes differentiate the developing kidney from the adult one: a large capsule with a high cellularity; the branching ureteric bud, extending from the hilum towards the renal capsule; striking morphological differences among superficial (just born) and deep (more mature) glomeruli; persistence of remnants of the metanephric mesenchyme in the hylum; incomplete differentiation of developing proximal and distal tubules. At cellular level, kidneys of preterm infants are characterized by huge amounts of stem/precursor cells showing different degrees of differentiation, admixed with mature cell types. The most striking difference between the preterm and adult kidney is represented by the abundance of stem/progenitor cells in the former. Multiple stem cell niches may be identified in the preterm kidney, including the capsule, the sub-capsular nephrogenic zone, the cap mesenchyme embracing the ureteric bud tips, the cortical and medullary interstitium, and the hilar zone in proximity of the ureteric origin. The sub-capsular area represents the major stem cell niche in the prenatal kidney. It has been defined "blue strip", due to the scarcity of cytoplasm of the undifferentiated stem/progenitors, which appear as small cells arranged in a solid pattern. All these data taken together, the morphological approach to the analysis of the preterm kidney appears completely different from that typically utilized in kidney biopsies from adult subjects. Such a different structure should be taken into account when evaluating renal function in a preterm infant in clinical practice. Moreover, a better knowledge of molecular biology of the blue strip stem/progenitor cells could be at the basis of a new "endogenous" regenerative medicine, finalized to maintain and protect the nephrogenic potential of preterm infants till the 36th week of post-conceptional age, allowing them to escape oligonephronia and chronic kidney disease later in life.


Assuntos
Recém-Nascido Prematuro/fisiologia , Rim/citologia , Nicho de Células-Tronco/fisiologia , Diferenciação Celular/fisiologia , Humanos , Recém-Nascido
20.
Eur J Histochem ; 59(2): 2499, 2015 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-26150159

RESUMO

Wilms' Tumor 1 (WT1) is a transcription factor involved in the development of the urogenital system. The purpose of this study was to analyze the immunoreactivity for WT1 protein in different tissues and organs in human fetuses in early phases of gestation. To this end, samples from multiple organs were obtained from 4 human fetuses, ranging from 7 up to 12 weeks of gestation. Each sample was formalin-fixed, paraffin embedded and immunostained for WT1. Our data show that WT1 is involved in development of multiple human organs in a more vast series of cells types than previously reported. Immunostaining for WT1 was characterized by a predominant cytoplasmic reactivity in the vast majority of cell types. Mesenchimal progenitors in the fetal lung, ductal plate progenitors in fetal liver, cap mesenchimal cells in the developing kidney, fetal zone cells in adrenal glands, atrial and ventricular cardiomyocytes in the fetal heart, radial glial cells in the fetal cerebral cortex and skeletal muscle cell precursors showed the highest levels of WT1 immunoreactivity. Future studies will be needed to detect differences in the expression of WT1 in various organs at different gestational ages, in order to better evaluate the role of WT1 in cell proliferation and differentiation during intrauterine human development.


Assuntos
Desenvolvimento Fetal/fisiologia , Feto/metabolismo , Proteínas WT1/biossíntese , Adulto , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Idade Gestacional , Humanos , Imuno-Histoquímica , Masculino , Inclusão em Parafina , Gravidez , Distribuição Tecidual
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