RESUMO
The thymus is the site of T lymphocyte development and T cell education to recognize foreign, but not self, Ags. B cells also reside and develop in the thymus, although their functions are less clear. During "thymic involution," a process of lymphoid atrophy and adipose replacement linked to sexual maturation, thymocytes decline. However, thymic B cells decrease far less than T cells, such that B cells comprise â¼1% of human neonatal thymocytes but up to â¼10% in adults. All jawed vertebrates possess a thymus, and we and others have shown zebrafish (Danio rerio) also have thymic B cells. In this article, we investigated the precise identities of zebrafish thymic T and B cells and how they change with involution. We assessed the timing and specific details of zebrafish thymic involution using multiple lymphocyte-specific, fluorophore-labeled transgenic lines, quantifying the changes in thymic T- and B-lymphocytes pre- versus postinvolution. Our results prove that, as in humans, zebrafish thymic B cells increase relative to T cells postinvolution. We also performed RNA sequencing on D. rerio thymic and marrow lymphocytes of four novel double-transgenic lines, identifying distinct populations of immature T and B cells. Collectively, this is, to our knowledge, the first comprehensive analysis of zebrafish thymic involution, demonstrating its similarity to human involution and establishing the highly genetically manipulatable zebrafish model as a template for involution studies.
Assuntos
Linfócitos B , Timo , Peixe-Zebra , Animais , Peixe-Zebra/imunologia , Timo/imunologia , Timo/citologia , Linfócitos B/imunologia , Animais Geneticamente Modificados , Linfócitos T/imunologia , Humanos , Diferenciação Celular/imunologia , Modelos AnimaisRESUMO
OBJECTIVE: Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3±15.8 years, 38.0% males), and 63 children (age 8.8±4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in the LDLR. True HoFH due to LDLR variants had higher total (P=0.015) and LDL (low-density lipoprotein)-cholesterol (P=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (P=0.051) and had a greater frequency of xanthomas (P=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults with LDLR variants. Children who are true HoFH had higher frequency of major cardiovascular events (P=0.02), coronary heart (P=0.013), and aortic/supra-aortic valve diseases (P=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type of LDLR variant. From 118 subjects with LDLR variants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2 LDLR variants, those with at least one null allele were younger (P=0.003) and had a greater frequency of major cardiovascular events (P=0.038) occurring at an earlier age (P=0.001). CONCLUSIONS: There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.
Assuntos
Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Homozigoto , Hiperlipoproteinemia Tipo II/genética , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Fatores Etários , Apolipoproteína B-100/genética , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Criança , Pré-Escolar , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Estudos Retrospectivos , Fatores de Risco , América do Sul/epidemiologia , Adulto JovemRESUMO
The thymus is the site of T lymphocyte development and T cell education to recognize foreign, but not self, antigens. B cells also reside and develop in the thymus, although their functions are less clear. During 'thymic involution,' a process of lymphoid atrophy and adipose replacement linked to sexual maturation, thymocytes decline. However, thymic B cells decrease far less than T cells, such that B cells comprise ~1% of human neonatal thymocytes, but up to ~10% in adults. All jawed vertebrates possess a thymus, and we and others have shown zebrafish (Danio rerio) also have thymic B cells. Here, we investigated the precise identities of zebrafish thymic T and B cells and how they change with involution. We assessed the timing and specific details of zebrafish thymic involution using multiple lymphocyte-specific, fluorophore-labeled transgenic lines, quantifying the changes in thymic T- and B-lymphocytes pre- vs. post-involution. Our results prove that, as in humans, zebrafish thymic B cells increase relative to T cells post-involution. We also performed RNA sequencing (RNA-seq) on D. rerio thymic and marrow lymphocytes of four novel double-transgenic lines, identifying distinct populations of immature T and B cells. Collectively, this is the first comprehensive analysis of zebrafish thymic involution, demonstrating its similarity to human involution, and establishing the highly genetically-manipulatable zebrafish model as a template for involution studies.
RESUMO
AIM: Dyslipidemia is recognized as one of the major risk factors for cardiovascular diseases. This retrospective observational study was aimed to assess the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in dyslipidemic patients with a lipid profile not well controlled by maximally tolerated statin therapy or intolerant to these lipid-lowering drugs. We enrolled 151 patients, of whom, 119 were taking evolocumab and 32 alirocumab. RESULTS: Total cholesterol significantly decreased progressively until the fourth year; after 4âyears there was a significant reduction (-125.5âmg/dl, -51.5%, Pâ<â0.0001 vs baseline, and Pâ<â0.05 vs 1âyear and Pâ<â0.05 vs 2âyears) and -2.8âmg/dl (-2.3%) compared with the third year. Low-density lipoprotein-cholesterol (LDL-C) also decreased significantly until the fourth year. After 3âyears, there was a significant reduction (-117.8âmg/dl, -71.5%, Pâ<â0.0001 vs baseline, and Pâ<â0.05 vs 1âyear) and -13.9âmg/dl (-22.8%) compared with the second year; after 4âyears there was a significant reduction (-121.4âmg/dl, -73.7%, Pâ<â0.0001 vs baseline, and Pâ<â0.05 vs 1âyear and Pâ<â0.05 vs 2âyears) and -3.6âmg/dl (-7.7%) compared with the third year. High-density lipoprotein-cholesterol increased significantly only during the fourth year of detection. After 3âyears, there was a nonsignificant increase (4.9âmg/dl, 10.0%, Pâ=â0.061 vs baseline) and 1.6âmg/dl (3.1%) compared with the second year; after 4âyears, there was a significant increase (5.2âmg/dl, 10.6%, Pâ<â0.05 vs baseline) and 0.3âmg/dl (0.6%) compared with the third year. The value of Tg was significantly reduced progressively until the second year and then stabilized in the third and fourth years. After 3âyears, the value of Tg stabilized (-48.6âmg/dl, -32.4%, Pâ<â0.01 vs baseline, and Pâ<â0.05 vs 1âyear) and -4.8âmg/dl (-4.5%) compared with the second year; after 4âyears (-46.4âmg/dl, -31.0%, Pâ<â0.01 vs baseline, and Pâ<â0.05 vs 1âyear) there was a slight and nonsignificant increase of 2.2âmg/dl (2.2%) compared with the third year. Regarding adverse events, both drugs were well tolerated. CONCLUSIONS: We showed that PCSK9 inhibitors are well tolerated and provide long-term significant LDL-C lowering in individuals with hyperlipidemia.
Assuntos
Dislipidemias/tratamento farmacológico , Inibidores de PCSK9/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
AIMS: Type 1 diabetes (T1D) is a growing chronic disease. Evidence of whether the healthcare setting affects management and glycemic control is scarce. We evaluate outcomes in patients with T1D in private and public healthcare settings in Mexico, registered in the National T1D Registry in Mexico (RENACED-DT1). METHODS: Biochemical parameters, diabetes education, and treatment were analyzed considering the data registered in the last visit. Development of chronic complications was determined during follow-up. RESULTS: We included 1,603 patients; 71.5% (n = 1,146) registered in the public system, and 28.5% (n = 457) in a private institution. Patients in the public setting had higher HbA1c (8.6%, IQR: 7.3%-10.5% vs 7.7%, IQR: 7.0%-8.8%; p < 0.001). Indicators of diabetes education, glucose monitoring, and use of insulin-pumps were lower in the public setting. Patients in the public setting were at higher risk of diabetic chronic kidney disease, retinopathy, and neuropathy. Diabetes knowledge was a mediator between type of healthcare setting and the likelihood of achieving glycemic control. CONCLUSIONS: Patients registered in public healthcare settings have an adverse metabolic profile and higher risk of complications. Social factors need to be addressed in order to implement multidisciplinary measures focused on diabetes education for patients with T1D in Mexico.
Assuntos
Diabetes Mellitus Tipo 1 , Glicemia , Automonitorização da Glicemia , Atenção à Saúde , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Hemoglobinas Glicadas/análise , Controle Glicêmico , Humanos , México/epidemiologiaRESUMO
BACKGROUND: Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated. OBJECTIVE: Report the results of the first years (2017-2019) of the Mexican FH registry. METHODS: There are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations. RESULTS: To date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C <100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033). CONCLUSION: The results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.