RESUMO
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
BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by an increased LDL-cholesterol (LDLc) serum concentration and premature cardiovascular disease. Screening of small populations where at least one homozygous (HoFH) patient has been identified may be a proper approach for detecting FH patients. Previously, we reported an HoFH patient carrying the mutation p.Asp360His LDLR, who was born in the Mexican community El Triunfo (Quimixtlan, Puebla). AIM OF THE STUDY: To identify patients with familial hypercholesterolemia in the community El Triunfo and to describe their clinical and biochemical characteristics. METHODS: We studied 308 individuals by quantifying lipid levels and by DNA sequencing. RESULTS: Sixteen of 308 individuals presented an LDLc level >170 mg/dL and all of them turned out to be heterozygous for the LDLR p.Asp360His variant. Subsequently, 34 of their first-degree relatives (mainly siblings and parents) were genotyped rendering six additional HeFH patients, which resulted in 22 carriers of the mutated allele. The study of six LDLR polymorphisms in four unrelated individuals from the community (one HoFH and three HeFH) showed the same haplotype combination, suggesting a unique ancestral origin of the mutation. CONCLUSIONS: The community El Triunfo, has the highest worldwide frequency ever reported of HeFH, with 7.14% (22/308, equivalent to 1/14 inhabitants). Since the HeFH patients showed variable biochemical expression, we suggest looking for factors with the potential to modify the phenotype. Finally, we stress the importance of establishing accurate LDLc cut-off points applicable to Mexican population for the diagnosis of FH.
Assuntos
LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Mutação , Adulto JovemRESUMO
We report on the case of an 8-year-old Mexican male, with a 3-year-old clinical diagnosis of familial hypercholesterolemia, and the difficulties encountered in his treatment while in our care. His treatment started with a regimen consisting of ezetimibe/simvastatin, cholestyramine, and a dietary plan of 1600 calories, with a limited intake of 200 mg of cholesterol per day. Problems arose when the patient's low-density lipoprotein cholesterol (LDL) levels did not meet ideal targets, which prompted the use of LDL cholesterol apheresis (not available in Mexico) for 6 months. As a last resort, PCSK9 inhibitors were administered but the LDL levels remained in the 600 mg/dL range. AmbryGenetics conducted a genetic test employing the Sanger method. The results suggested that there were 2 different mutations for each allele of the same LDL receptor gene (c.249delTinsGG and p.(Cys109Arg)), located in exons 3 and 4, respectively. We identified compound heterozygous mutations in our index case, with him having both the p.C109R mutation (from the maternal lineage), as well as a c.249delTinsGG mutation (from the paternal lineage). The p.C109R mutation has been previously reported, not only in Mexico, but in European regions (Germany, Czech Republic, Ireland, Italy) as well. Functional studies indicated a residual enzymatic activity of 15% to 30% for heterozygotes. To date, the variant c.249delTinsGG has not been reported. This case study illustrates the fact that in Mexico there are limited options available for treatment in such a scenario. As medical professionals, we are limited by the tools at our disposal.
RESUMO
BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes accumulation of serum low-density lipoprotein cholesterol and premature cardiovascular disease. It is mainly related to mutations in the LDLR gene. Homozygous FH (HoFH) patients have the most severe form of the disease accounting for a worldwide prevalence of 1:1,000,000. In Mexico, at least 5 cases of HoFH have been reported. OBJECTIVE: The aim of this study was to describe the clinical, biochemical, and molecular data observed in patients with HoFH phenotype. METHODS: We included 13 patients, belonging to 11 families, with clinical and biochemical diagnoses suggestive of HoFH. Molecular analyses of the LDLR and APOB genes were performed by means of polymerase chain reaction followed by Sanger sequencing. RESULTS: The causal mutation of HoFH was found in 8 of 11 unrelated patients. Excepting 1, all were true homozygotes. Six different variants in LDLR were identified: c.-139delCTCCCCCTGC, p.Glu140Lys, p.Asp360His, p.Asn405Lys, p.Ala755Glyfs*7, and p.Leu759Serfs*6. Of these, p.Asp360His and p.Asn405Lys were detected for the first time in Mexico; p.Leu759Serfs*6 showed to be the most frequent (43.7% of the alleles 7/16), and c.-139delCTCCCCCTGC is a new variant located in the promoter region. CONCLUSIONS: This work increases knowledge of biochemical and genetic features in Mexican patients with HoFH. A novel mutation in the LDLR gene promoter was detected: c.-139delCTCCCCCTGC, which possibly inhibits its expression.
Assuntos
Apolipoproteínas B/genética , Homozigoto , Hiperlipoproteinemia Tipo II/genética , Mutação , Receptores de LDL/genética , Adolescente , Adulto , Criança , Pré-Escolar , Simulação por Computador , Feminino , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , México , Linhagem , Fenótipo , Adulto JovemRESUMO
To address inequitable access to health services of indigenous communities in the Bolivian highlands, the Bolivian Ministry of Health, with the support of Save the Children-Saving Newborn Lives, conducted operational research to identify, implement and test a package of maternal and newborn interventions using locally recruited, volunteer Community Health Workers (vCHW) between 2008 and 2010. The additional annual economic and financial costs of the intervention were estimated from the perspective of the Bolivian Ministry of Health in two municipalities. The cost of intervention-stimulated increases in facility attendance was estimated with national surveillance data using a pre-post comparison, adjusted for secular trends in facility attendance. Three scale-up scenarios were modelled by varying the levels of coverage and the number (per mother and child pair) and frequency of home visits. Average cost per mother and average cost per home visit are presented in constant 2015 US$. Eighteen per cent of expectant mothers in the catchment area were visited at least once. The annualized additional financial cost of the community-based intervention across both municipalities was $43 449 of which 3% ($1324) was intervention design, 20% ($8474) set-up and 77% ($33 651) implementation. Drivers of additional costs were additional paid staff (68%), 81% of which was for management and support by local implementing partner and 19% of which was for vCHW supervision. The annual financial cost per vCHW was $595. Modelled scale-up scenarios highlight potential efficiency gains. Recognizing local imperatives to reduce inequalities by targeting underserved populations, the observed low coverage by vCHWs resulted in a high cost per mother and child pair ($296). This evaluation raises important questions about this model's ability to achieve its ultimate goals of reducing neonatal mortality and inequalities through behaviour change and increased care seeking and has served to inform innovative alternative models, better equipped to tackle stagnant inequitable access to care.
Assuntos
Serviços de Saúde da Criança/economia , Serviços de Saúde Comunitária/economia , Análise Custo-Benefício , Visita Domiciliar , Serviços de Saúde Materna/economia , Bolívia , Serviços de Saúde da Criança/organização & administração , Serviços de Saúde Comunitária/organização & administração , Agentes Comunitários de Saúde/economia , Feminino , Humanos , Recém-Nascido , Serviços de Saúde Materna/organização & administração , Gravidez , Avaliação de Programas e Projetos de Saúde , Voluntários , Populações VulneráveisRESUMO
BACKGROUND: There is little information about familial hypercholesterolemia (FH) epidemiology and care in Ibero-American countries. The Ibero-American FH network aims at reducing the gap on diagnosis and treatment of this disease in the region. OBJECTIVE: To describe clinical, molecular, and organizational characteristics of FH diagnosis in Argentina, Brazil, Chile, Colombia, Mexico, Portugal, Spain, and Uruguay. METHODS: Descriptive analysis of country data related to FH cascade screening, molecular diagnosis, clinical practice guidelines, and patient organization presence in Ibero-America. RESULTS: From a conservative estimation of an FH prevalence of 1 of 500 individuals, there should be 1.2 million heterozygous FH individuals in Ibero-America and roughly 27,400 were diagnosed so far. Only Spain, Brazil, Portugal, and Uruguay have active cascade screening programs. The prevalence of cardiovascular disease ranged from 10% to 42% in member countries, and the highest molecular identification rates are seen in Spain, 8.3%, followed by Portugal, 3.8%, and Uruguay with 2.5%. In the 3 countries with more FH patients identified (Spain, Portugal, and Brazil) between 10 and 15 mutations are responsible for 30% to 47% of all FH cases. Spain and Portugal share 5 of the 10 most common mutations (4 in low density lipoprotein receptor [LDLR] and the APOB3527). Spain and Spanish-speaking Latin American countries share 6 of the most common LDLR mutations and the APOB3527. LDL apheresis is available only in Spain and Portugal and not all countries have specific FH diagnostic and treatment guidelines as well as patient organizations. CONCLUSIONS: Ibero-American countries share similar mutations and gaps in FH care.
Assuntos
Hiperlipoproteinemia Tipo II/epidemiologia , Doenças Cardiovasculares/complicações , Humanos , Hiperlipoproteinemia Tipo II/complicações , Portugal/epidemiologia , América do Sul/epidemiologia , Espanha/epidemiologiaRESUMO
Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 and matrix metalloproteinase 2, tissue inhibitor of metalloproteinases 1, myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid naïve patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p < 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression.
Assuntos
Heterozigoto , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas da Matriz Extracelular/sangue , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/diagnóstico , Sensibilidade e EspecificidadeRESUMO
Duchenne muscular dystrophy is a severe, debilitating and progressive disease that affects 1 in 3,500 live male births in the world. The diagnosis should be confirmed by genetic testing to identify the mutation in the DMD gene or muscle biopsy and immunostaining to demonstrate the absence of dystrophin. Although up to now continues to be an incurable disease, this does not mean it has no treatment. Treatment should be multidisciplinary, looking for the functionality of the patient and avoiding or correcting complications, mainly cardio-respiratory and skeletal. Many proposals have been evaluated and implemented with the aim of improving the quality of life for these patients. The long-term steroids have shown significant benefits, such as prolonging ambulation, reduce the need for spinal surgery, improve cardiorespiratory function and increase survival and the quality of life. This document presents the recommendations based on the experience of the working group and experts worldwide on the diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy.
TITLE: Diagnostico y tratamiento con esteroides de pacientes con distrofia muscular de Duchenne: experiencia y recomendaciones para Mexico.La distrofia muscular de Duchenne es una enfermedad grave, incapacitante y progresiva que afecta a 1 de cada 3.500 recien nacidos varones alrededor del mundo. El diagnostico debera confirmarse mediante pruebas geneticas para identificar la mutacion en el gen DMD, o bien por biopsia muscular e inmunotincion para demostrar la ausencia de distrofina. Aunque actualmente continua siendo una enfermedad incurable, no significa que no tenga tratamiento. Este debe ser multidisciplinario, buscando la funcionalidad del paciente y evitando o corrigiendo las complicaciones, principalmente cardiorrespiratorias y esqueleticas. Se han evaluado e implementado multiples propuestas con la finalidad de mejorar la calidad de vida en estos pacientes. Los esteroides a largo plazo han demostrado importantes beneficios para los pacientes, prolongan la deambulacion, reducen la necesidad de cirugia de columna, mejoran la funcion cardiorrespiratoria, y aumentan la supervivencia y la calidad de vida. En este documento se presentan las recomendaciones con base en la experiencia del grupo de trabajo y de los expertos de ambito mundial sobre el diagnostico y el tratamiento con esteroides para los pacientes con distrofia muscular de Duchenne.
Assuntos
Corticosteroides/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Cuidadores/educação , Terapia Combinada , Diagnóstico Diferencial , Distrofina/genética , Cardiopatias/etiologia , Cardiopatias/prevenção & controle , Humanos , Hiperglicemia/induzido quimicamente , Terapia de Imunossupressão , Incidência , Masculino , México/epidemiologia , Técnicas de Diagnóstico Molecular , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/epidemiologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/reabilitação , Obesidade/induzido quimicamente , Equipe de Assistência ao Paciente , Modalidades de Fisioterapia , Qualidade de Vida , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/prevenção & controle , Terapia RespiratóriaRESUMO
The Casimiroa pringlei essential oil was analyzed to determine its chemical composition. Its effect on rat uterine smooth muscle was studied and compared with verapamil. Pure commercial piperitone, eucalyptol, and alpha-terpineol, the major constituents of C. pringlei essential oil, were tested on the uterine tonic contraction induced by high-potassium depolarizing solution (KCl 60 mM).
Assuntos
Casimiroa , Óleos Voláteis/farmacologia , Parassimpatolíticos/farmacologia , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Análise de Variância , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Casimiroa/química , Cromatografia Gasosa , Feminino , Espectrometria de Massas , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Parassimpatolíticos/química , Parassimpatolíticos/isolamento & purificação , Extratos Vegetais , Óleos de Plantas/química , Óleos de Plantas/isolamento & purificação , Óleos de Plantas/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Verapamil/farmacologiaRESUMO
Se realizó un estudio de intervención en la Escuela Primaria 1ro. de Mayo perteneciente a la comunidad de Los Sirios, en Santa Clara, para determinar la influencia de la labor educativa en las prácticas higiénicas y la prevalencia de parasitismo en los escolares. Se visitaron las viviendas y se aplicaron encuestas a los padres de los niños para conocer las prácticas higiénicas de la población y las condiciones higiénico-epidemiológicas de la comunidad. A partir de eso se diseñó la labor educativa dirigida a los padres, y se transitó de la investigación a la acción con participación comunitaria. Se estudiaron 133 escolares a quienes se recogió muestra de heces fecales y región anal por el método de Graham. La prevalencia de parasitismo fue de 69,9 por ciento y fue el Enterobius vermicularis el más frecuente. Los síntomas que predominaron fueron, el prurito anal y la irritabilidad, para lo que se aplicó tratamiento. Pasados 6 meses de la intervención se repitieron los exámenes coproparasitológicos a los niños y la encuesta a los padres y se encontró una disminución significativa del parasitismo, así como modificaciones positivas en las prácticas higiénicas de la población
Assuntos
Humanos , Enteropatias Parasitárias , Serviços de Saúde EscolarRESUMO
El parasitismo intestinal representa un significativo problema en la salud mundial. Se realiza un estudio epidemiológico descriptivo en manipuladores de alimentos de los principales centros de elaboración de la ciudad de Santa Clara, provincia Villa Clara, durante 1998. Los enteroparásitos patógenos encontrados por orden de frecuencia fueron la Giardia lamblia y la Entamoeba hitolytica; detectados por método directo y de ritchie para dichos parásitos. La técnica de kato katz fue más eficaz para el diagnóstico de los geohelmintos. Se resalta la función del personal médico en centros de trabajo
Assuntos
Humanos , Adolescente , Adulto , Pessoa de Meia-Idade , Masculino , Feminino , Entamebíase , Fezes , Manipulação de Alimentos , GiardíaseRESUMO
Se realiza una exposición de los casos notificados como parasitismo exótico en becarios extranjeros, radicados en la provincia de Villa Clara, en el período comprendido entre 1992 y 1997. Los casos positivos son varones en su mayoría; los parásitos más frecuentes fueron el Schistosoma haematobium, el Schistosoma mansoni y la Filaria loa-loa. Se mantiene el pesquisaje de estas afecciones y otras que pudieran presentarse para evitar su propagación en el país