RESUMEN
INTRODUCTION: The alpha-1 antitrypsin deficiency (A1ATD) is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. There is no data regarding prevalence of main, clinically most important A1ATD alleles PI*Z and PI*S in patients with pulmonary Langerhans cell histiocytosis (PLCH). PLCH is not only strongly linked to the cigarette smoking, but is also characterised by polycystic lung lesions. The goal of the study was to assess the incidence of A1ATD alleles in patients with PLCH. MATERIAL AND METHODS: Blood samples were collected from 34 adult patients (14 women and 20 men), with histologically confirmed PLCH. AAT serum concentration was assessed by nephelometry and PI-phenotype, identified by isoelectrofocusing. The PI*S and PI*Z alleles were confirmed by genotyping usisng real-time PCR. RESULTS: Deficiency alleles PI*Z and PI*S were detected in 3 patients (one woman and 2 men), respectively in 5.88% and 2.94%. The estimated incidence of deficiency alleles was 29.4/1000 (95% CI; 10-69.5) for PI*Z and 14.7/1000(95%CI; 13.9-43.3) for PI*S. According to our previous reports, the expected prevalence of PI*Z and PI*S alleles in general Polish population was 13.7/1000 (95% CI 5.8-21.5), and 7,6/1000 (95% CI 1.7-13.5) respectively. CONCLUSIONS: The incidence of main A1AT deficiency alleles in patients with PLCH seems higher than in general Polish population. The study is on-going.
Asunto(s)
Histiocitosis de Células de Langerhans/genética , Población Blanca/genética , Deficiencia de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adulto , Femenino , Frecuencia de los Genes , Pruebas Genéticas , Histiocitosis de Células de Langerhans/sangre , Histiocitosis de Células de Langerhans/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Polonia/epidemiología , alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/sangreRESUMEN
The alpha-1 antitrypsin deficiency (AATD) targeted screening program, together with the National Registry, were established in Poland in 2010 soon after the AATD diagnostics became available. Between 2010 and 2014 a total of 2525 samples were collected from respiratory patients countrywide; 55 patients with severe AAT deficiency or rare mutations were identified and registered, including 36 PiZZ subjects (65%). The majority of AATD patients were diagnosed with COPD (40%) or emphysema (7%), but also with bronchial asthma (16%) and bronchiectasis (13%). Therefore, the registry has proved instrumental in setting-up the AATD-dedicated network of respiratory medical centres in Poland. Since augmentation therapy is not reimbursed in our country, the smoking cessation guidance, optimal pharmacotherapy of respiratory symptoms as well the early detection, and effective treatment of exacerbations is absolutely essential.
Asunto(s)
Tamizaje Masivo , Sistema de Registros , Deficiencia de alfa 1-Antitripsina/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Asma/diagnóstico , Asma/etiología , Bronquiectasia/diagnóstico , Bronquiectasia/etiología , Progresión de la Enfermedad , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Polonia , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/etiología , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/terapiaRESUMEN
INTRODUCTION: Inherited alpha-1 antitrypsin (AAT) deficiency is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. It has also been suggested that AAT deficiency might be instrumental vasculitis associated with the anti-neutrophil cytoplasm antibodies (cANCA) and subsequent lung tissue injury. MATERIAL AND METHODS: We present the results from a pilot study involving 51 patients with granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis (GPA), 43 of whom were cANCA positive. The control group consisted of 658 individuals. AAT blood concentration assessment by nephelometry, phenotyping by isoelectrofocusing and real-time PCR genotyping were performed. RESULTS: Deficiency alleles PI*Z and PI*S were detected in 3 (5.88%) and in 2 patients (3.92%) with GPA, respectively. All of them were cANCA positive. In the controls, PI*Z was observed in 2.8% while PI*S in 1.5% of cases. Accordingly, the increased incidence of main deficiency alleles was demonstrated in GPA, and particularly in cANCA+GPA patients, when compared to the controls. The estimated frequency for PI*Z in GPA, cANCA+GPA patients and controls was, respectively, 29.4/1000, 34.9/1000 and 13.7/1000, whereas for PI*S it was 19.2/1000, 23.2/10,00 and 7.6/1000. However, the observed differences did not reach statistical significance due to the considerable size disproportion between groups. CONSCLUSIONS: We believe that our preliminary data confirm the clinical importance of AAT deficiency in GPA patients and the need to screen for AAT deficiency alleles. The study is on-going.
Asunto(s)
Granulomatosis con Poliangitis/genética , Deficiencia de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Granulomatosis con Poliangitis/sangre , Granulomatosis con Poliangitis/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Polonia/epidemiología , Prevalencia , Adulto Joven , alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/epidemiologíaRESUMEN
INTRODUCTION: It is estimated that in about 1% of all liver transplant candidates liver cirrhosis is caused by hereditary homozygous α1antitrypsin (AAT) deficiency. OBJECTIVES: The aim of the study was to evaluate the role of heterozygous AAT deficiency in the development of liver cirrhosis leading to liver transplantation. PATIENTS AND METHODS: In the years 2009-2011, we conducted a prospective study of 304 consecutive patients (men, 57%) scheduled for orthotopic liver transplantation. AAT phenotyping and the clinical assessment of hepatic and cardiopulmonary functions were performed in all subjects. RESULTS: The most common causes of liver cirrhosis were viral hepatitis (21%) and alcohol abuse (12%). Normal protease inhibitor (Pi) MM phenotype was observed in 284 patients. The PiMZ phenotype was detected in 11 subjects (4%), which indicates its higher prevalence in patients with liver cirrhosis compared with the general population (2%). PiMS phenotype was found in 6 patients (2%), and this value was similar to that observed in the Polish population. In 3 patients, less common phenotypes were observed: MP, IM, and MX. CONCLUSIONS: The PiMZ phenotype may be an independent risk factor for the development of liver cirrhosis along with the most common causes, namely, viral hepatitis and alcohol abuse.
Asunto(s)
Alcoholismo/epidemiología , Hepatitis Viral Humana/epidemiología , Cirrosis Hepática/epidemiología , Cirrosis Hepática/terapia , Deficiencia de alfa 1-Antitripsina/epidemiología , Deficiencia de alfa 1-Antitripsina/genética , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Causalidad , Comorbilidad , Femenino , Heterocigoto , Humanos , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Polonia/epidemiología , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Adulto Joven , Deficiencia de alfa 1-Antitripsina/sangreRESUMEN
Inherited alpha-1 antitrypsin deficiency (A1ATD) is listed among the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. Data on the A1ATD prevalence in Poland are scarce, no studies with large enough groups representative for whole Polish population have been performed. Here, we present the preliminary data on the incidence of A1AT main deficiency alleles from the newborn screening in Mazovia (Central Poland) region. Real-time PCR genotyping and A1AT blood concentration measurement by nephelometry were performed from the dry blood spots (DBS) samples of 658 newborns. Deficiency alleles PI*Z i PI*S were present in 28 children, respectively in 2.8% and 1.5%. Their existence corresponded with significantly lower A1AT blood concentration. Estimated incidence of deficiency alleles was 13,7/1000 (95% CI 5.8-21.5) for PI∗Z and 7.6/1000 (95% CI 1.7- 13.5) for PI∗S. The calculated prevalence for the main deficiency genotype ZZ was 1/5345. The study is on-going.
Asunto(s)
Pruebas Genéticas , Tamizaje Neonatal , Población Blanca/genética , Deficiencia de alfa 1-Antitripsina/epidemiología , Deficiencia de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Frecuencia de los Genes , Humanos , Incidencia , Recién Nacido , Polonia/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética , alfa 1-Antitripsina/sangre , Deficiencia de alfa 1-Antitripsina/sangreRESUMEN
INTRODUCTION: Plasminogen inhibitor activator type 1 (PAI-1) is an important regulator of tumor growth and metastasis formation acting directly via specific urokinase complexing or indirectly due to its affinity to vitronectin. We have shown previously that PAI-1 modifies angiogenic activity of endothelial cells in a dose-dependent manner but also in close relationship to the cell phenotype. Present study aimed on evaluating the PAI-1 effect on the proliferative activity of lung cancer cells (A549), prostate cancer cells (DU145) as well as endothelial cells (HUVEC). RESULTS: Mutated PAI-1 (1, 10, 100 microg/mL) characterized by the prolonged antifibrinolytic activity (T1/2 approximately 7000 h) inhibited proliferation of lung cancer A549 cells in a dose-dependent (p < 0.001) and time-dependent (p < 0.001) manner. No significant effect on the DU145 prostate cancer cells has been observed except of the 72 h cultures with highest PAI-1 concentration (100 microg/ml) (p < 0.001). Proliferative activity of endothelial cells (HUVEC) was affected by 100 microg/ml PAI-1 only, and independent of the culture period (24, 48 and 72 h, p < 0.001). CONCLUSION: Plasminogen inhibitor activator type 1 modulates cell proliferation via antifibrynolitic mechanizm time- and dose-dependently, however final outcome is strongly affected by the cell phenotype.
Asunto(s)
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Inhibidores de Serina Proteinasa/metabolismo , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Fenotipo , Inhibidor 1 de Activador Plasminogénico/farmacología , Inhibidores de Serina Proteinasa/farmacología , Células Tumorales Cultivadas/clasificación , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/patología , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Patients with defective plasminogen activator inhibitor protein (PAI-1) or with PAI-1 deficiency can experience hemorrhage as a result of a hyperfibrinolysis. In these patients, a normal thrombus forms, but endogenous lysis is unchecked as tissue plasminogen activator is unopposed. Treatment includes anti-fibrinolytic agents, including oral tranexamic acid. Another treatment option is the administration of PAI-1, but this serpin rapidly inactivates itself. We have developed a mutant plasminogen activator inhibitor with a very long half life (VLHL PAI-1, t1/2>700 h). Here we investigate VLHL PAI-1 effects in the blood of PAI-1 deficient mice, as a model of human disease. Using a thrombelastograph, we found that blood clots of PAI-1 knockout mice were lysed much more quickly than wild type mice. Additionally, blood clots had less shear elastic modulus strength than clots of normal animals. VLHL PAI-1 treatment of PAI-1 deficient mice extended or prevented thrombus lysis and increased clot strength in a concentration dependent fashion. These two parameters determine the extent of thrombus growth and regression; thus, further testing is anticipated to confirm the effectiveness of plasminogen activator inhibitor with a very long half life in an in vivo model and we hope that this protein can be effective in human PAI-1 deficiency disorder.
Asunto(s)
Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/deficiencia , Terapia Trombolítica , Trombosis/sangre , Animales , Semivida , Humanos , Insectos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/uso terapéutico , Inactivadores Plasminogénicos/sangre , Inactivadores Plasminogénicos/deficiencia , Inactivadores Plasminogénicos/uso terapéutico , Terapia Trombolítica/métodos , Trombosis/tratamiento farmacológicoRESUMEN
Epigenetics, one of the widely investigated topics in human genetics, refers to phenotypic or gene expression changes caused by specific regulatory mechanisms (eg. DNA methylation, histone proteins modifications, antisense RNA or RNAi expression) that do not involve changes in DNA sequence. The disturbances in epigenetic gene expression regulatory mechanisms might lead to oncogenic transformation as well as monogenic or complex diseases. On the other side, better knowledge about epigenetic causes of certain diseases, gives an opportunity to potential therapies. One of the epigenetic research models in Angelman syndrome (AS). This neurologic disorder associated with improper central nervous system development and function, together with Prader-Willi syndrome are caused by the defects of epigenetic regulation. These disturbances are related to the defects of genomic imprinting, a phenomenon that contributes to allele specific, depending from parental origin, gene expression. In the majority of AS cases, the large deletion in chromosome 15 (15q11-13) of maternal origin (65-75%) or paternal disomy of chromosome 15 (3-7%) are observed. However, in a limited number of cases, other imprinting defects or mosaicism can be found and confirmed by new molecular biology techniques. Investigation of the etiology of the diseases caused by the defects in epigenetic regulation gives a basis to the development of epi-therapy that might be a promising alternative for their treatment. Moreover, knowledge about the epigenome gives an opportunity for prevention of human genetic disorders.
Asunto(s)
Síndrome de Angelman/genética , Regulación de la Expresión Génica/genética , Epigénesis Genética , Impresión Genómica/genética , Humanos , Mosaicismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Angelman Syndrome (AS) is a neurogenetic disorder associated with aberrant genomic imprinting. AS patients with an imprinting defect have only paternal genes expression pattern despite the normal bi-parental inheritance of chromosome 15. In 2-3% of AS cases, the altered gene expression is a consequence of an imprinting defect (ID) such as microdeletions in imprinting centre (IC). Statistically, one third of patients with an imprinting defect and no IC deletion have somatic mosaicism. OBJECTIVES: The objectives of this study were: identification of somatic mosaicism for an imprinting defect in the patients with clinical manifestation of AS and development of a procedure for the identification of IC microdeletion. MATERIAL AND METHODS: Twenty eight AS patients with an aberrant methylation pattern confirmed in methylation screening procedure (MS-PCR) were qualified for mosaicism analysis with quantitative real-time PCR technique. RESULTS: The quantitative analysis of methylated alleles did not confirm the presence of somatic mosaicism in any of the examined patients. CONCLUSIONS: The methods for somatic mosaicism and microdeletion in IC analyses based on quantitative real-time PCR technique can be used in the molecular diagnostic of Angelman syndrome.
Asunto(s)
Síndrome de Angelman/genética , Impresión Genómica , Reacción en Cadena de la Polimerasa/métodos , Metilación de ADN , Humanos , MosaicismoRESUMEN
The deficiency of serine protease inhibitor, alpha-1-antitrypsin (AATD), is genetically determined defect that increases the risk of lung and liver disease development. The results of recent epidemiological studies indicate the overwhelming majority of individuals with alpha-1-antitrypsin deficiency still remain undiagnosed. The complete laboratory diagnosis of AATD is based on combination of quantitative and qualitative methods. The measurement of plasma/serum AAT concentration is always the initial test performed in clinically suspected individuals. Nevertheless, only the AAT phenotype or genotype identification allows the full medical verification of the diagnosis. Among the various techniques of either AAT variant phenotyping or genotyping accepted by reference medical centers worldwide, the isoelectric focusing, real-time-PCR and restriction fragment-length polymorphism PCR (RFLP-PCR) are "considered the most effective" performed the most commonly. The AAT diagnostics in Poland still awaits for introduction into clinical routine. The aim of present review is to outline the major methods of AATD diagnosis and discuss with the special issuing of their potential benefits and disadvantages.