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MOTIVATION: We present pyGOMoDo, a Python library to perform homology modeling and docking, specifically designed for human GPCRs. pyGOMoDo is a python wrap-up of the updated functionalities of GOMoDo web server (https://molsim.sci.univr.it/gomodo). It was developed having in mind its usage through Jupyter notebooks, where users can create their own protocols of modeling and docking of GPCRs. In this article, we focus on the internal structure and general capabilities of pyGOMoDO and on how it can be useful for carrying out structural biology studies of GPCRs. RESULTS: The source code is freely available at https://github.com/rribeiro-sci/pygomodo under the Apache 2.0 license. Tutorial notebooks containing minimal working examples can be found at https://github.com/rribeiro-sci/pygomodo/tree/main/examples.
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Biologia Computacional , Software , Humanos , Biologia Computacional/métodos , Simulação de Dinâmica Molecular , Biblioteca GênicaRESUMO
OBJECTIVE: To determine one or more indexes able to detect the presence of cardiac amyloidosis (CA) from planar scintigraphy images after injection of 99mTc-HMDP tracer and to identify the earliest acquisition time able to ensure an accurate diagnosis of amyloid transthyretin CA. METHODS AND RESULTS: A total of 38 patients were included: 18 subjects with a final diagnosis of ATTR-CA and 20 controls. Dynamic planar images of the anterior thorax were acquired, starting at intravenous injection of ≈ 700 MBq of 99mTc-HMDP. From time/activity curves (TAC) of regions of interest such as heart, vascular region, right ribcage, and soft tissues, several indices were considered. From the analysis, it resulted that both TACHeart/Bone(t) and RIheart-bone(t), for t > 6 minutes, well distinguish ATTR-CA patients from controls subjects. This is confirmed by the area under curves (AUC) analysis giving AUC values =.9 at t â 6 minutes and AUC â 1 for t > 10 minutes. CONCLUSIONS: The method proposed allows determining the presence of ATTR-CA, in an inexpensive manner both in terms of examination costs and time spent.
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Amiloidose , Difosfonatos , Amiloidose/diagnóstico por imagem , Osso e Ossos , Humanos , CintilografiaRESUMO
OBJECTIVE: To evaluate the feasibility of kinetic modeling-based approaches from [18F]-Flobetaben dynamic PET images as a non-invasive diagnostic method for cardiac amyloidosis (CA) and to identify the two AL- and ATTR-subtypes. METHODS AND RESULTS: Twenty-one patients with diagnoses of CA (11 patients with AL-subtype and 10 patients with ATTR-subtype of CA) and 15 Control patients with no-CA conditions underwent PET/CT imaging after [18F]Florbetaben bolus injection. A two-tissue-compartment (2TC) kinetic model was fitted to time-activity curves (TAC) obtained from left ventricle wall and left atrium cavity ROIs to estimate kinetic micro- and macro-parameters. Combinations of kinetic parameters were evaluated with the purpose of distinguishing Control subjects and CA patients, and to correctly label the last ones as AL- or ATTR-subtype. Resulting sensitivity, specificity, and accuracy for Control subjects were: 0.87, 0.9, 0.89; as far as CA patients, the sensitivity, specificity, and accuracy were respectively 0.9, 1, and 0.97 for AL-CA patients and 0.9, 0.92, 0.97 for ATTR-CA patients. CONCLUSION: Pharmacokinetic analysis based on a 2TC model allows cardiac amyloidosis characterization from dynamic [18F]Florbetaben PET images. Estimated model parameters allows to not only distinguish between Control subjects and patients, but also between AL- and ATTR-amyloid patients.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Estilbenos , Compostos de Anilina , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
Heterozygous loss-of-function mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (MODY) subtype GCK (GCK-MODY/MODY2). GCK sequencing revealed 16 distinct mutations (13 missense, 1 nonsense, 1 splice site, and 1 frameshift-deletion) co-segregating with hyperglycaemia in 23 GCK-MODY families. Four missense substitutions (c.718A>G/p.Asn240Asp, c.757G>T/p.Val253Phe, c.872A>C/p.Lys291Thr, and c.1151C>T/p.Ala384Val) were novel and a founder effect for the nonsense mutation (c.76C>T/p.Gln26*) was supposed. We tested whether an accurate bioinformatics approach could strengthen family-genetic evidence for missense variant pathogenicity in routine diagnostics, where wet-lab functional assays are generally unviable. In silico analyses of the novel missense variants, including orthologous sequence conservation, amino acid substitution (AAS)-pathogenicity predictors, structural modeling and splicing predictors, suggested that the AASs and/or the underlying nucleotide changes are likely to be pathogenic. This study shows how a careful bioinformatics analysis could provide effective suggestions to help molecular-genetic diagnosis in absence of wet-lab validations.
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Biologia Computacional , Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Mutação de Sentido Incorreto , Fenótipo , População Branca/genética , Adolescente , Sequência de Aminoácidos , Substituição de Aminoácidos , Criança , Pré-Escolar , Biologia Computacional/métodos , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Alinhamento de SequênciaRESUMO
INTRODUCTION: DTC patients having detectable Tg and negative post-therapeutic (131)I-WBS have to be investigated by different imaging techniques to detect metastases. PURPOSE: Comparison of neck US, CT and [18F]-FDG PET scan. METHODS: In 49 DTC patients with biochemical disease, neck was examined by US, CT and [18F]-FDG PET. FNA was performed and Tg was determined by FNA-Tg in selected cases of suspicious lymph nodes. Thorax was examined by CT and PET. Serum Tg was measured on LT4 therapy (basal Tg) and after the stimulation with recombinant human TSH (peak Tg). RESULTS: A thyroid remnant was seen by US, CT and PET in eight patients; recurrences were seen by US, CT and PET in six, five and five patients, respectively. Two metastatic nodes were identified by US and CT but not by PET. Lung micronodules were detected by CT in 7/49 (14.3 %) patients and by FDG PET in three of them. Basal Tg ranged from 0.5-1,725 ng/ml while peak Tg ranged from 0.5 to 2,135 ng/ml: the distribution between positive and negative patients was similar. Bone scan was negative in all cases. CONCLUSIONS: In DTC patients with detectable Tg and negative I-131 post-therapy WBS, imaging examination revealed remnant or metastases in 43 % of cases. Remnant and recurrences were equally detected by the three techniques; US was better than [18F]-FDG PET for lymph node metastases since this latter method can give false both positive and negative results; chest examination is best made by CT versus FDG PET due to its higher spatial resolution.
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Metástase Neoplásica , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Neoplasias da Glândula Tireoide , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Radiografia , Cintilografia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Ultrassonografia , Adulto JovemRESUMO
Although the negative effects of inorganic UV filters have been documented on several marine organisms, sunscreen products containing such filters are available in the market and proposed as eco-friendly substitutes for harmful, and already banned, organic UV filters (e.g. octinoxate and oxybenzone). In the present study, we investigated the effects of four sunscreen products, labelled by cosmetic companies as "eco-friendly", on the early developmental stages of the sea urchin Paracentrotus lividus, a keystone species occurring in vulnerable coastal habitats. Among sunscreens tested, those containing ZnO and TiO2 or their mix caused severe impacts on sea urchin embryos. We show that inorganic UV filters were incorporated by larvae during their development and, despite the activation of defence strategies (e.g. phagocytosis by coelomocytes), generated anomalies such as skeletal malformations and tissue necrosis. Conversely, the sunscreen product containing only new-generation organic UV filters (e.g. methylene bis-benzotriazolyl tetramethyl, ethylhexyl triazone, butylphenol diethylamino hydroxybenzoyl hexyl benzoate) did not affect sea urchins, thus resulting actually eco-compatible. Our findings expand information on the impact of inorganic UV filters on marine life, corroborate the need to improve the eco-friendliness assessment of sunscreen products and warn of the risk of bioaccumulation and potential biomagnification of inorganic UV filters along the marine food chain.
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Protetores Solares , Protetores Solares/toxicidade , Animais , Ouriços-do-Mar , Raios Ultravioleta , Titânio , Poluentes Químicos da Água/análise , Paracentrotus , Larva , Óxido de ZincoRESUMO
BACKGROUND: The aim of the treatment of radial head comminuted fractures is the restoration of anatomical normalcy to avoid the risk of several complications such as joint instability. Among the options for the treatment of such fractures, it is worth mentioning osteosynthesis, resection of the radial head or prosthetic replacement. In the presence of comminution or severe dislocation of the fracture's fragments, as in our patient's type III Mason fracture, prosthesis implantation is the treatment of choice. CASE REPORT: This clinical case reports a 22-year-old volleyball player, who during training suffered a comminuted fracture of the radial head, type III according to Mason's classification. A prosthesis was implanted. The post-operative course took place regularly. However, approximately three months after surgery, the patient experienced sudden pain and functional limitation following a normal elbow extension movement, so much so that he required medical attention in our emergency room. Following all the appropriate clinical-instrumental tests, a complete dissociation of the bipolar prosthesis of the radial head was found. CONCLUSIONS: Our clinical case shows the disassembly of a bipolar radial head prosthesis, a rather rare complication. From a medicolegal perspective, the patients should be aware of the increased risk of requiring further surgery after radial head replacement. When patients are thoroughly informed, they can cooperate and comply with indications more effectively, thus taking an active role in recovery management.
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Articulação do Cotovelo , Fraturas Cominutivas , Fraturas do Rádio , Humanos , Masculino , Adulto Jovem , Articulação do Cotovelo/cirurgia , Fixação Interna de Fraturas , Fraturas Cominutivas/cirurgia , Próteses e Implantes , Implantação de Prótese , Rádio (Anatomia)/cirurgia , Fraturas do Rádio/cirurgia , Amplitude de Movimento Articular , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Gamete failure-derived infertility affects millions of people worldwide; for many patients, gamete donation by unrelated donors is the only available treatment. Embryonic stem cells (ESCs) can differentiate in vitro into germ-like cells, but they are genetically unrelated to the patient. Using an in vitro protocol that aims at recapitulating development, we have achieved, for the first time, complete differentiation of human induced pluripotent stem cells (hiPSCs) to postmeiotic cells. Unlike previous reports using human ESCs, postmeiotic cells arose without the over-expression of germline related transcription factors. Moreover, we consistently obtained haploid cells from hiPSCs of different origin (keratinocytes and cord blood), produced with a different number of transcription factors, and of both genetic sexes, suggesting the independence of our approach from the epigenetic memory of the reprogrammed somatic cells. Our work brings us closer to the production of personalized human gametes in vitro.
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Células-Tronco Pluripotentes Induzidas/fisiologia , Meiose , 3-Hidroxiesteroide Desidrogenases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD/metabolismo , Benzotiazóis/farmacologia , Técnicas de Cultura de Células , Proteínas de Ciclo Celular , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Colforsina/farmacologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA , Fator 2 de Crescimento de Fibroblastos/farmacologia , Expressão Gênica , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Cariotipagem , Fator Inibidor de Leucemia/farmacologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Nestina , Proteínas Nucleares/metabolismo , Ploidias , Regiões Promotoras Genéticas , Proteínas/genética , Proteínas/metabolismo , Espermatogônias/citologia , Espermatogônias/metabolismo , Antígenos Embrionários Estágio-Específicos/metabolismo , Triazóis/farmacologia , Vimentina/metabolismoRESUMO
OBJECTIVE: The aim of this review was to explore recent pieces of evidence focused on the use of miRNAs for PMI estimation both in humans and animal experiments, with particular interest on the best miRNAs to use as reference/target markers in different tissues or biological fluids. MiRNAs are innovative biomarkers used in clinical and research field; they appear very attractive, being introduced in forensic research scenarios even for PMI estimation. MATERIALS AND METHODS: Data from PubMed and Scopus were analyzed from January 2013 to August 2020. Based on inclusion/exclusion criteria, high-quality articles have been selected to become the subject of this review. RESULTS: A total of 737 papers were found but, after titles/abstracts screening for inclusion criteria and a full-text careful selection, 33 papers were deeply studied. After the exclusion of 19 papers, 15 articles remained. Eight papers dealt with animals (mice/rats), two both with animals and humans (for method validation previously built), while 5 exclusively with humans. Myocardium (6/15) and brain (6/15) were the most studied tissues, respectively in mice/rats and humans. PMI considered was up to 7.5 days in mouse studies and less than 3 days in human models. CONCLUSIONS: Because of their significant stability in both early and long PMI, miRNAs are the cleverest reference markers to be used. Temperature and environmental conditions influence mostly mRNA, while miRNAs are less susceptible to them. The best miRNA to choose depends on its tissue specificity, i.e., miR-9 and miR-125 in brain or miR-1 and miR-133 in skeletal muscle/heart.
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MicroRNAs/genética , Mudanças Depois da Morte , Patologia Legal , Humanos , Reação em Cadeia da PolimeraseRESUMO
The idea that performing a proper succession of imaging tests and techniques allows an accurate and early diagnosis of cardiac amyloidosis, avoiding the need to perform the myocardial biopsy, is becoming increasingly popular. Furthermore, being imaging techniques non-invasive, it is possible to perform the follow-up of the pathology through repeated image acquisitions. In the present review, the various innovative imaging methodologies are presented, and it is discussed how they have been applied for early diagnosis of cardiac amyloidosis (CA), also to distinguish the two most frequent subtypes in CA: immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR); this allows to perform the therapy in a targeted and rapid manner.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Amiloidose de Cadeia Leve de Imunoglobulina , Biópsia , Cardiomiopatias/diagnóstico por imagem , Diagnóstico Precoce , HumanosRESUMO
Per- and polyfluoroalkyl substances (PFAS) are anthropogenic chemicals present in the environment and defined as persistent organic pollutants (POPs). The interest in these forms of contaminants is related to the toxic consequences for health derived from exposures and bioaccumulation processes. The present research aims at assessing differences in the exposure of PFAS in the Italian population by hair analyses. To this aim, 20 compounds of the PFAS family were investigated in hair of 86 Italian subjects distributed across the regions of Veneto, Emilia-Romagna, Lombardy and Marche. The applied method was ad hoc developed in a previous research and included SPE extraction and LC-QTOF analysis. In the analyzed population, 66.4 % had quantifiable amounts of one or more PFAS molecules (up to 4 compounds); mean PFAS content, expressed as sum of PFAS, was 0.1457 ng/g, ranging from "not detected" to 0.85 ng/g (SD 0.1867). PFOA and PFOS were the chemicals most frequently detected, with mean concentrations of 0.1402 ng/g and 0.1155 ng/g, respectively. PFBA was detected in 9.3 % of subjects with a mean concentration of 0.3760 ng/g; PFNA in 3.5 % of subjects with mean concentration 0.12 ng/g; PFDA was found in one subject at the concentration of 0.541 ng/g. PFUnA and PFHxS were detected below the limit of quantification. The overall results displayed differences in the presence and prevalence of PFAS in hair of the Italian population on a geographical base. On the contrary, no significatively differences in the amount of PFAS were observed when considering gender or age classes. On this base, hair can be considered a good diagnostic tool to assess PFAS exposure on a regional-scaled base. Of course, more studies are required to infer PFAS internal dose from hair results due to its peculiar detection window and to interpretative issues derived from external contamination.
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Monitoramento Ambiental/métodos , Fluorocarbonos/análise , Cabelo/química , Adolescente , Adulto , Idoso , Envelhecimento , Cromatografia Líquida de Alta Pressão , Poluentes Ambientais/análise , Feminino , Geografia , Humanos , Itália/epidemiologia , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Prevalência , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
The oligopeptide-binding protein, OppA, ushers oligopeptide substrates to the membrane-associated oligopeptide permease (Opp), a multi-component ABC-type transporter involved in the uptake of oligopeptides by several bacterial species. In the present study, we report a structural model and an oligopeptide docking analysis of the OppA protein expressed by Xanthomonas axonopodis pv. citri (X. citri), the etiological agent of citrus canker. The X. citri OppA structural model showed a conserved three-dimensional structure, irrespective of the low amino acid identities with previously defined structures of Bacillus subtilis and Salmonella typhimurium orthologs. Oligopeptide docking analysis carried out with the proposed model indicated that the X. citri OppA preferentially binds tri- and tetrapeptides. The present study represents the first structural analysis of an OppA ortholog expressed by a phytopathogen and contributes to the understanding of the physiology and nutritional strategies of X. citri.
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Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Lipoproteínas/química , Lipoproteínas/metabolismo , Oligopeptídeos/metabolismo , Xanthomonas axonopodis/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Sítios de Ligação , Proteínas de Transporte/genética , Ligantes , Lipoproteínas/genética , Modelos Moleculares , Dados de Sequência Molecular , Oligopeptídeos/química , Doenças das Plantas/microbiologia , Ligação Proteica , Conformação Proteica , Xanthomonas axonopodis/genética , Xanthomonas axonopodis/patogenicidadeRESUMO
Cells are extremely crowded environments, thus the use of diluted salted aqueous solutions containing a single protein is too simplistic to mimic the real situation. Macromolecular crowding might affect protein structure, folding, shape, conformational stability, binding of small molecules, enzymatic activity, interactions with cognate biomolecules, and pathological aggregation. The latter phenomenon typically leads to the formation of amyloid fibrils that are linked to several lethal neurodegenerative diseases, but that can also play a functional role in certain organisms. The majority of molecular simulations performed before the last few years were conducted in diluted solutions and were restricted both in the timescales and in the system dimensions by the available computational resources. In recent years, several computational solutions were developed to get close to physiological conditions. In this review we summarize the main computational techniques used to tackle the issue of protein aggregation both in a diluted and in a crowded environment.
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Simulação por Computador , Substâncias Macromoleculares/metabolismo , Agregados Proteicos , Algoritmos , Animais , Biologia Computacional , Humanos , Modelos MolecularesRESUMO
OBJECTIVE: Flutamide (FLU) is a non-steroidal antiandrogen drug approved for the treatment of advanced prostate cancer. While this indication limits the use to male patients, FLU is widely prescribed to women, off-label, for the treatment of polycystic ovary syndrome (POCS) related hirsutism and acne. According to the literature, its assumption is associated with a higher incidence of adverse events in women than in male patients. MATERIALS AND METHODS: A literature search was conducted in main databases targeting unwilling FLU effects in hepatic and reproductive function. References in the selected paper were also considered as an additional source of data. Human- and animal-based studies were separately considered. RESULTS: Twenty-three human-based studies were evaluated: ten were case reports, six were retrospective studies, four were prospective, two were surveillance studies, while the last was an observational study. Nine animal-based studies were also evaluated. CONCLUSIONS: Scientific contributions highlight that FLU is responsible for specific hepatotoxic profiles in the female gender. From the ethical point of view, off-label prescribing of FLU in women is not only substantially unlawful, but also, without major safeguards being granted, a potential source of liability for prescribers.
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Antagonistas de Androgênios/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Flutamida/efeitos adversos , Feminino , Humanos , Masculino , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Recurrent hepatitis C after orthotopic liver transplantation (OLT) is universal and can lead to graft failure and, consequently, reduced survival. Hepatitis C treatment can be used to prevent these detrimental outcomes. The aim of this study was to describe rates of hepatitis C recurrence and sustained virological response (SVR) to interferon-based treatment after OLT and its relationship to survival and progression of liver disease through retrospective analysis of medical records of 127 patients who underwent OLT due to cirrhosis or hepatocellular carcinoma secondary to chronic hepatitis C between January 2002 and December 2013. Fifty-six patients were diagnosed with recurrent disease, 42 started interferon-based therapy and 37 completed treatment. Demographic, treatment- and outcome-related variables were compared between SVR and non-responders (non-SVR). There was an overall 54.1% SVR rate with interferon-based therapies. SVR was associated with longer follow-up after treatment (median 66.5 vs 37 months for non-SVR, P=0.03) and after OLT (median 105 vs 72 months, P=0.074), and lower rates of disease progression (15 vs 64.7%, P=0.0028) and death (5 vs 35.3%, P=0.033). Regardless of the result of therapy (SVR or non-SVR), there was a significant difference between treated and untreated patients regarding the occurrence of death (P<0.001) and months of survival (P<0.001). Even with suboptimal interferon-based therapies (compared to the new direct-acting antivirals) there is a 54.1% SVR rate to treatment. SVR is associated with improved survival and reduced risks of clinical decompensation, loss of the liver graft and death.
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Antivirais/uso terapêutico , Carcinoma Hepatocelular/cirurgia , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Complicações Pós-Operatórias/tratamento farmacológico , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Progressão da Doença , Hepatite C Crônica/complicações , Hepatite C Crônica/mortalidade , Humanos , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
OBJECTIVES: We sought to elucidate the flow-function relation in chronic postischemic dysfunction during vasodilator stress. BACKGROUND: In patients with ischemia and regional dysfunction, stress echocardiography can elicit three responses in the dysfunctioning segments: no change, improvement or worsening. The physiology underlying these responses is unclear. METHODS: Seventeen patients with ischemia and left ventricular dysfunction underwent evaluation of regional function by two-dimensional echocardiography and myocardial blood flow by positron emission tomography and 13N-ammonia. Flow (ml/min per g) and function (regional wall motion score [RWMS] from 1 = normal to 4 = dyskinetic) were evaluated both at rest and after dipyridamole (0.56 mg/kg body weight over 4 min). RESULTS: In 45 normal segments, rest to dipyridamole flow increased from 0.83 +/- 0.22 (mean +/- 1 SD) to 1.87 +/- 0.90 (p < 0.01) with a hyperkinetic contraction pattern. Among dysfunctioning segments, responders (n = 11) showed an upsloping flow-function curve during stress (i.e., increased function [RWMS rest 2.5 +/- 0.5 vs. dipyridamole 1.2 +/- 0.4] and increased flow [rest 0.69 +/- 0.30 vs. dipyridamole 1.89 +/- 1.43, p < 0.01]); nonresponders (n = 20) had a flat flow-function curve during dipyridamole (i.e., fixed function [RWMS rest and dipyridamole 2.6 +/- 0.5] and no flow increase [rest 0.64 +/- 0.24 vs. dipyridamole 0.87 +/- 0.51, p = NS): Ischemic segments (n = 9) exhibited a downsloping flow-function curve during dipyridamole (i.e., worsened function [RWMS rest 2 +/- 0.5, dipyridamole 3.1 +/- 0.6] and no significant flow change [rest 0.67 +/- 0.29 vs. dipyridamole 0.79 +/- 0.23, p = NS]). CONCLUSIONS: Myocardial segments with rest dysfunction and a contractile reserve elicitable by a vasodilator stress more often exhibit residual flow reserve, whereas segments with a fixed or worsening mechanical response during stress show a flat flow response.
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Circulação Coronária , Doença das Coronárias/fisiopatologia , Dipiridamol , Ecocardiografia , Tomografia Computadorizada de Emissão , Vasodilatadores , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Fatores de Confusão Epidemiológicos , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico por imagem , Teste de Esforço/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologiaRESUMO
OBJECTIVES: The aim of this study was to determine whether the presence of residual coronary reserve can in itself identify viable segments. BACKGROUND: Experimental data suggest that despite hypoperfusion at rest, viable myocardium may exhibit persistence of coronary reserve. Preliminary observations in patients show that in basally dyssynergic areas, a residual vasodilator capability is present despite hypoperfusion at rest and that a flow-mediated increase in regional wall motion identifies residual viability. METHODS: Fourteen patients with evidence of previous myocardial infarction, infarct-related single-vessel coronary artery disease and impaired regional ventricular function at rest underwent positron emission viability imaging by fluorine-18 deoxyglucose. In addition, blood flow at rest and vasodilator capability were regionally evaluated in all patients by means of nitrogen-13 ammonia. RESULTS: Of a total of 252 segments, 133 were dyssynergic at rest. Of these 133 segments, 60 (group 1) showed normal metabolic activity and only mild reduction in myocardial blood flow. The other 73 segments showed a marked reduction in flow; of these, 25 (group 2, viable) had persistent metabolic activity, whereas 48 (group 3, necrotic) did not. Despite similar levels of hypoperfusion at rest, group 2 segments showed a preserved coronary reserve that was virtually absent in necrotic segments (2.6 +/- 1.3 vs. 1.3 +/- 0.5, p < 0.01). This value was similar to that observed in viable group 1 segments (2.5 +/- 1.6, p = NS). CONCLUSIONS: In addition to characterizing myocardium at risk, imaging of coronary flow at baseline and after dipyridamole by positron emission tomography provides helpful information on myocardial viability that may integrate the "static" viability information obtained with the baseline flow/metabolic approach.
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Circulação Coronária/fisiologia , Doença das Coronárias/diagnóstico , Coração/fisiopatologia , Idoso , Amônia , Angiografia Coronária , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/fisiopatologia , Desoxiglucose/análogos & derivados , Dipiridamol , Ecocardiografia , Feminino , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Radioisótopos de Nitrogênio , Tomografia Computadorizada de EmissãoRESUMO
OBJECTIVES: The aim of this study was to quantitatively measure regional and global myocardial blood flow and coronary reserve in hypertensive patients without coronary artery disease and to assess the correlation with left ventricular mass. BACKGROUND: The effect of left ventricular hypertrophy on regional vasodilating coronary capability in arterial hypertension is controversial, and no quantitative method has been applied to assess a possible correlation. METHODS: Positron emission tomography was performed in 50 untreated hypertensive patients and 13 normotensive subjects. Blood flow at baseline and after dipyridamole was globally and regionally measured by using nitrogen-13 ammonia; coronary reserve and resistance were calculated. Left ventricular mass was assessed by two-dimensional echocardiography. RESULTS: In hypertensive patients, flow at baseline was similar to that of normotensive subjects (p = 0.21), but values were reduced after pharmacologic vasodilation (p < 0.05). This impairment of maximal coronary flow was not correlated with left ventricular mass (p = 0.13). Among hypertensive patients, we identified a group with a homogeneous distribution of perfusion and a group with a heterogeneous flow pattern. Flow was globally reduced in the former group, but it was abnormal only at the site of perfusion defects in the latter. Patients with regional defects showed the highest likelihood of having an increased left ventricular mass. CONCLUSIONS: In arterial hypertension, left ventricular mass is not correlated with global myocardial blood flow. Nevertheless, patients with ventricular hypertrophy are likely to show a heterogeneous flow pattern with regional defects and almost normal blood flow in nonaffected regions. In hypertensive patients with a homogeneous perfusion pattern during stress, myocardial blood flow frequently shows a diffuse reduction.
Assuntos
Circulação Coronária , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Adulto , Idoso , Amônia , Análise de Variância , Distribuição de Qui-Quadrado , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Dipiridamol , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/patologia , Análise dos Mínimos Quadrados , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Radioisótopos de Nitrogênio , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Resistência Vascular/fisiologia , Vasodilatação/fisiologia , VasodilatadoresRESUMO
OBJECTIVES: The aim of this study was to evaluate myocardial blood flow regulation in collateral-dependent myocardium of patients with coronary artery disease. BACKGROUND: Despite great clinical relevance, perfusion correlates of collateral circulation in humans have rarely been estimated by quantitative methods at rest and during stress. METHODS: Nineteen patients with angina and isolated occlusion of the left anterior descending (n = 14) or left circumflex (n = 5) coronary artery were evaluated. Using positron emission tomography and nitrogen-13 ammonia, we obtained flow measurements at baseline, during atrial pacing-induced tachycardia and after intravenous administration of dipyridamole (0.56 mg/kg body weight over 4 min). Flow values in collateral-dependent and remote areas were compared with values in 13 normal subjects. RESULTS: Flow at rest was similar in collateralized and remote myocardium (0.61 +/- 0.11 vs. 0.63 +/- 0.17 ml/min per g, mean +/- 1 SD), and both values were lower than normal (1.00 +/- 0.20 ml/min per g, p < 0.01). During pacing, blood flow increased to 0.83 +/- 0.25 and 1.11 +/- 0.39 ml/min per g in collateral-dependent and remote areas, respectively (p < 0.05 vs. baseline); both values were lower than normal (1.86 +/- 0.61 ml/min per g, p < 0.01). Dipyridamole induced a further increase in perfusion in remote areas (1.36 +/- 0.57 ml/min per g, p < 0.01 vs. pacing) but not in collateral-dependent regions (0.93 +/- 0.37 ml/min per g, p = NS vs. pacing); again, both values were lower (p < 0.01) than normal (3.46 +/- 0.78 ml/min per g). Dipyridamole flow in collateral-dependent myocardium was slightly lower in patients with poorly developed than in those with well developed collateral channels (0.75 +/- 0.29 vs. 1.06 +/- 0.38 ml/min per g, respectively, p = 0.06); however, the former showed higher flow inhomogeneity (collateral/control flow ratio 0.58 +/- 0.10 vs. 0.81 +/- 0.22, respectively, p < 0.02). A linear direct correlation was observed between flow reserve of collateral-dependent and remote regions (r = 0.83, p < 0.01). CONCLUSIONS: Despite rest hypoperfusion, collateral-dependent myocardium maintains a vasodilator reserve that is almost fully utilized during increases in oxygen consumption. A global microvascular disorder might hamper adaptation to chronic coronary occlusion.
Assuntos
Circulação Colateral/fisiologia , Circulação Coronária/fisiologia , Adulto , Idoso , Aminofilina , Amônia , Análise de Variância , Angina Pectoris/diagnóstico , Angina Pectoris/fisiopatologia , Estimulação Cardíaca Artificial , Distribuição de Qui-Quadrado , Angiografia Coronária/estatística & dados numéricos , Doença das Coronárias/diagnóstico , Doença das Coronárias/fisiopatologia , Dipiridamol/antagonistas & inibidores , Eletrocardiografia/estatística & dados numéricos , Humanos , Modelos Lineares , Microcirculação/fisiopatologia , Pessoa de Meia-Idade , Radioisótopos de Nitrogênio , Valores de Referência , Tomografia Computadorizada de Emissão/estatística & dados numéricosRESUMO
Blockade of dopamine (DA) receptors by neuroleptics tends to produce sedation, as shown by increased sleeping time, reduction of the arousal response to sensory stimuli and slowing of the electrical (EEG) activity of the brain. The EEG and behavioural effects of the selective compounds, SCH 23390 and raclopride, which block either D1 or D2 receptor subtypes, respectively were evaluated. Groups of rabbits were prepared for the measurement of EEG activity (neocortex and hippocampus). The EEG was analyzed visually and by spectral power analysis. Gross behaviour was also observed. The D1 antagonist, SCH 23390, by itself (0.03-0.3 mg/kg i.v.) produced small changes in the EEG and no evidence of sedation. Periods of slow waves occurred sporadically. Computerized EEG analysis showed moderate increases of total power density. The D2 receptor blocker, raclopride, alone (1-3 mg/kg i.v.) produced changes of the activity of the EEG, mostly, short periods of slow waves and slight increases of total power. No sedation was noted. Although both selective antagonists were studied at larger doses than those minimally effective, they produced slight EEG and behavioural changes which were not comparable with the marked actions produced by classical neuroleptics, such as haloperidol. However, when raclopride (1 mg/kg) was given after treatment with SCH 23390 (0.03 mg/kg) there was a marked synchronized activity in the EEG, associated with a state of sedation and diminished responsiveness to sensory stimuli. The data indicate that EEG synchronization and sedation, classically associated with treatment with neuroleptics, do not depend upon the selective blockade of either D1 or D2 receptors but, instead, require concurrent blockade of both subtypes of receptor.