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1.
Cardiovasc Diabetol ; 19(1): 7, 2020 01 10.
Article in English | MEDLINE | ID: mdl-31924211

ABSTRACT

BACKGROUND: Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. METHODS: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. RESULTS: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. CONCLUSION: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.


Subject(s)
Benzhydryl Compounds/pharmacology , Blood Glucose/drug effects , Diabetes Mellitus/drug therapy , Diabetic Cardiomyopathies/prevention & control , Glucosides/pharmacology , Myocytes, Cardiac/drug effects , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Ventricular Function, Left/drug effects , Angiotensin II , Animals , Biomarkers/blood , Blood Glucose/metabolism , Calcium Channels, L-Type/metabolism , Calcium Signaling/drug effects , Cells, Cultured , Diabetes Mellitus/blood , Diabetic Cardiomyopathies/chemically induced , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/physiopathology , Disease Models, Animal , Fibrosis , Inflammation Mediators/metabolism , Male , Mice, Inbred C57BL , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats, Sprague-Dawley , Sodium-Calcium Exchanger/metabolism , Sodium-Hydrogen Exchanger 1/metabolism
2.
Allergol. immunopatol ; 43(3): 272-278, mayo-jun. 2015. tab
Article in Spanish | IBECS | ID: ibc-136334

ABSTRACT

BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs


No disponible


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Desensitization, Immunologic/methods , Desensitization, Immunologic/statistics & numerical data , Desensitization, Immunologic , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/prevention & control , Health Knowledge, Attitudes, Practice , Surveys and Questionnaires , Allergy and Immunology/education , Allergy and Immunology , Allergy and Immunology/statistics & numerical data , Immunologic Techniques/methods , Immunologic Techniques/standards , Immunologic Techniques
3.
Allergol Immunopathol (Madr) ; 43(3): 272-8, 2015.
Article in English | MEDLINE | ID: mdl-25796303

ABSTRACT

BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs.


Subject(s)
Clinical Competence/statistics & numerical data , Immunologic Deficiency Syndromes/epidemiology , Physicians/statistics & numerical data , Brazil , Cross-Sectional Studies , General Surgery , Hospitals, General , Humans , Immunologic Deficiency Syndromes/diagnosis , Internal Medicine , Pediatrics , Physician's Role , Professional Practice , Surveys and Questionnaires
4.
J Investig Allergol Clin Immunol ; 24(3): 184-91, 2014.
Article in English | MEDLINE | ID: mdl-25011356

ABSTRACT

BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. METHODS: We actively searched for cases by contacting all Brazilian referral centers. RESULTS: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). CONCLUSIONS: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.


Subject(s)
BCG Vaccine/adverse effects , Severe Combined Immunodeficiency/therapy , Adolescent , Brazil/epidemiology , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Prognosis , Severe Combined Immunodeficiency/complications , Severe Combined Immunodeficiency/epidemiology
5.
J. investig. allergol. clin. immunol ; 24(3): 184-191, mayo.-jun. 2014. ilus
Article in English | IBECS | ID: ibc-127232

ABSTRACT

Background: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. Methods: We actively searched for cases by contacting all Brazilian referral centers. Results: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months ( P= .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months ( P= .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). Conclusions: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression (AU)


Antecedentes: La inmunodeficiencia severa combinada (IDSC) es una de las formas más graves de la inmunodeficiencia primaria. El objetivo de este estudio fue analizar el estado del diagnóstico, tratamiento y pronóstico de esta enfermedad en Brasil y documentar el impacto de la vacunación con BCG (bacillus Calmette-Guérin). Métodos: Los casos fueron seleccionados tras contactar con los centros de referencia de Brasil. Resultados: Se contactaron 23 centros en total, que permitieron recopilar a 70 pacientes entre los años 1996 y 2011 procedentes de 65 familias, 49 de ellos (70%) varones. En más de la mitad de ellos (39), el diagnóstico fue realizado con posteriridad al año 2006. La edad media en el diagnóstico varió entre los 9,7 a los 6,1 meses (p=0.058), antes y después del año 2000, respectivamente, y el tiempo en que se realizó el diagnóstico disminuyó de los 7,9 a los 4,2 meses (p=0.009). La mayoría de ellos (60/70) se habían vacunado con BCG antes del diagnóstico, 39/60 (65%) tuvieron complicaciones con la BCG y en 29/39 (74.3%) la enfermedad se diseminó. En menos de la mitad de los pacientes (30/70, 42,9%) se realizó un trasplate de células madre (HSCT). La mitad de los pacientes (35/70, 50%) murieron; 23/35 de ellos sin HSCT. La diseminación del BCG fue la causa de la muerte, sola o asociada con otras causas, en 9/31 casos (29%, en 4 casos sin datos). Conclusiones: En conclusión, el diagnóstico de IDSC en Brasil ha mejorado en la última década, tanto en términos numéricos, cómo respecto a la edad de detección de la enfermedad. La mortalidad es alta en comparación con los países desarrollados. La vacuna con BCG provoca complicaciones importantes en estos pacientes, lo cual alerta sobre el posible diagnóstico y progresión de esta enfermedad (AU)


Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , BCG Vaccine/adverse effects , Severe Combined Immunodeficiency/epidemiology , Severe Combined Immunodeficiency/therapy , Brazil/epidemiology , Prognosis , Severe Combined Immunodeficiency/complications , Severe Combined Immunodeficiency/immunology
6.
Eur J Pharm Sci ; 45(5): 592-9, 2012 Apr 11.
Article in English | MEDLINE | ID: mdl-22234377

ABSTRACT

Butyroyloxymethyl diethylphosphate (AN-7) is a prodrug of butyric acid effective in reducing cardiotoxicity caused by chemotherapy. In this study, we tested whether AN-7 protects the heart and cardiomyocytes against ischemia injury. A single oral dose of AN-7 was given to mice or rats. Animals were sacrificed 1.5 or 24 h later and the hearts were subjected to ischemia and reperfusion ex-vivo (Langendorff). The mechanical performance was recorded throughout and the infarct size was measured at the end of reperfusion. Neonatal rat cardiomyocytes were subjected to 24-48 h hypoxia (1% O(2)) in the absence or presence of AN-7 and mitochondria damage and cell death were assessed. Proteins were analyzed by Western immunoblotting. In the two rodents, a single dose of AN-7 given in vivo preconditioned the hearts for improved functional recovery from ischemia and reperfusion performed ex-vivo. Both 1.5 h and 24 h treatments improved the pressure-related parameters whereas the coronary flow was ameliorated in the 24 h treatment only. Infarct size was smaller in the AN-7 treated hearts. In cardiomyocytes, AN-7 diminished the hypoxia induced dissipation of mitochondria membrane potential and cell death. Compared with untreated controls, AN-7-treated hearts recovering from global ischemia and cardiomyocytes undergoing hypoxia, displayed significantly higher levels of the cytoprotective heme oxygenase-1. Our findings indicate that AN-7 imparts cardioprotection against ischemia both in vivo and in vitro and emerges as a potential treatment modality for cardiac injury.


Subject(s)
Heart/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/drug effects , Organophosphates/pharmacology , Prodrugs/pharmacology , Animals , Butyrates/pharmacology , Cell Death/drug effects , Heart/physiopathology , Heme Oxygenase-1/metabolism , Hypoxia/drug therapy , Hypoxia/metabolism , Hypoxia/physiopathology , Male , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Organophosphorus Compounds/pharmacology , Rats , Rats, Wistar , Regional Blood Flow , Reperfusion
7.
Scand J Immunol ; 58(5): 572-7, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14629629

ABSTRACT

Previous studies of human in vivo complement protein levels have only compared data for neonates with that from adult sera. Here, we establish the normal concentration ranges of the following complement regulatory proteins in healthy Brazilian children of different age groups (neonates: 1 month-1 year, 1-6 years and 6-13 years) and in adults: factor H (fH), factor I (fI), C4b-binding protein (C4 BP), properdin and vitronectin. We found that the concentrations of fH, fI, properdin and vitronectin in neonates are significantly lower than in adults. Remarkably, the concentration of C4 BP is below the method resolution (<50 micro g/ml) in 76% of the sera from neonates, while adults presented 199-532 microg/ml of C4 BP in their sera. The concentration of properdin in the sera from neonates and up to 1-year-old children was less than that observed in older children. Adults presented vitronectin levels significantly higher than all the other age groups in the study. No significant sex differences in the concentrations of all the studied regulatory proteins were detected. This study reveals the ontogeny of complement system in greater detail than previously available and may point to the reasons why neonates have higher susceptibility to develop life-threatening pyogenic infections. These reference values will be of use in clinical and laboratory investigations of disorders associated with low levels of these regulatory proteins.


Subject(s)
Complement Factor H/analysis , Complement Inactivator Proteins , Fibrinogen/analysis , Glycoproteins/analysis , Properdin/analysis , Vitronectin/analysis , Adolescent , Adult , Age Factors , Child , Child, Preschool , Humans , Infant , Reference Values
8.
Clin Exp Immunol ; 131(2): 280-6, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12562389

ABSTRACT

We have studied the molecular basis of factor I (fI) deficiency in two Brazilian sisters from a consanguineous family. By reverse transcription-polymerase chain reaction we observed that all fI cDNA amplified products from one sister had the same size as those of normal cDNA, however, they were significantly less intense. Sequencing analysis of subcloned cDNA revealed a dinucleotide insertion (AT) between positions 1204 and 1205 in the 11th exon that creates a stop codon 13 bp downstream of the insertion site. Genomic DNA sequencing and heteroduplex analysis confirmed that both probands are homozygous for this mutation, whereas their parents are heterozygous. The stop codon and the diminished amounts of fI cDNA could indicate increased fI mRNA instability, perhaps due to a mechanism of nonsense-mediated decay. This hypothesis is consistent with our observation that treatment with the translation inhibitor cycloheximide stabilized fI mRNA expression in proband's fibroblasts.


Subject(s)
Afibrinogenemia/genetics , Codon, Nonsense/genetics , Fibrinogen/genetics , Homozygote , Adult , Base Sequence , Child, Preschool , DNA, Complementary/genetics , Female , Humans , Molecular Sequence Data , Pedigree , Reverse Transcriptase Polymerase Chain Reaction
9.
Scand J Immunol ; 53(6): 615-21, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11422911

ABSTRACT

Here we describe two new cases of complete deficiency of factor I (fI) in two sisters from a consanguineous Brazilian family. The eldest sibling (20-year-old) developed systemic lupus erythematosus (SLE) early during childhood while the youngest had been committed on several occasions owing to repeated infections although she was asymptomatic for auto-immune diseases. We also detected lower concentrations of C3 and factor B in both sisters. Biological functions dependent on complement activation such as the production of opsonins and killing of phagocytozed micro-organisms, chemotactic factors and haemolytic activity were all significantly reduced in both probands. Consistent with the absence of fI and low levels of fH, a deregulated production of C3b was observed by bidimensional electrophoresis in sera of both the probands.


Subject(s)
Bacterial Infections/complications , Coagulation Protein Disorders/genetics , Coagulation Protein Disorders/immunology , Complement Factor H/metabolism , Fibrinogen/genetics , Lupus Erythematosus, Systemic/complications , Adult , Cell Migration Inhibition , Cells, Cultured , Child, Preschool , Coagulation Protein Disorders/complications , Complement Activation , Complement C3/metabolism , Complement C3b/metabolism , Family Health , Female , Fibrinogen/metabolism , Genetic Predisposition to Disease , Humans , Immunoelectrophoresis, Two-Dimensional , Phagocytosis
10.
Scand J Immunol ; 53(6): 622-6, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11422912

ABSTRACT

An 8-year-old son (L.A.S.) of consanguineous parents, presented recurrent bacterial infections, vasculitis and extremely low levels of serum C3 (0.15 microg/ml). The classical and alternative pathway haemolytic activities and the generation of opsonins and chemotactic factors derived from the activation of the complement system were markedly affected in the proband's serum. An in vitro addition of purified C3 restored the classical pathway-dependent haemolytic activity of his serum. Autoradiographs of the proband's lipopolysaccharide (LPS)-stimulated and 35S-labelled fibroblast supernatants after that the SDS-PAGE revealed no C3 alpha or beta chains. The amount of C3 mRNA synthesized by the proband's fibroblasts, as evaluated by reverse transcription-polymerase chain reaction (RT-PCR) assays, was greatly reduced.


Subject(s)
Coagulation Protein Disorders/genetics , Complement C3/deficiency , Complement C3/genetics , Cell Migration Inhibition , Cells, Cultured , Child , Coagulation Protein Disorders/immunology , Complement C3/biosynthesis , Fibroblasts/metabolism , Hemolysis , Humans , Male , Pedigree , Phagocytosis , RNA, Messenger/biosynthesis
11.
J Pediatr (Rio J) ; 77(4): 331-6, 2001.
Article in Portuguese | MEDLINE | ID: mdl-14647867

ABSTRACT

OBJECTIVE: To report a case of rare neutrophil functional disorder with clinical and laboratory findings similar to those of chronic granulomatous disease. METHODS: Patient with extremely reduced level of glucose-6-phosphate dehydrogenase and recurrent infections that improved after continuous use of cotrimoxazole. The patient presented leukocytes with defective respiratory burst, similar to what occurs in chronic granulomatous disease. COMMENTS: The diagnosis of glucose-6-phosphate dehydrogenase deficiency in neutrophils should be considered in any patient with hemolytic anemia whose level of G6PD is extremely low or in any patient that presents recurrent infections as differential diagnosis of chronic granulomatous disease.

12.
J Pediatr (Rio J) ; 74 Suppl 1: S3-S11, 1998 Jul.
Article in Portuguese | MEDLINE | ID: mdl-14685569

ABSTRACT

OBJECTIVE: The aim of this review is to present some aspects of the immune system.METHOD: Review of the literature, covering some of the most important aspects to the pediatrician.RESULTS: We describe characteristics of the immune system when presented to different antigens, and cells and cytokines effector functions. We also discuss aspects of immaturity of the immune system observed in the pediatric group.CONCLUSION: It is very important that the pediatrician understands how the immune system works.

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