ABSTRACT
Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating lymphocytes. The present study investigated whether this effect was further amplified in smokers who develop chronic obstructive pulmonary disease. Telomere length was determined by fluorescence in situ hybridisation in circulating lymphocytes harvested from 26 never-smokers, 24 smokers with normal lung function and 26 smokers with moderate-to-severe airflow obstruction (forced expiratory flow in one second 48+/-4% predicted). In contrast to never-smokers, telomere length significantly decreased with age in smokers. There was also a dose-effect relationship between the cumulative long-life exposure to tobacco smoking (pack-yrs) and telomere length. The presence and/or severity of chronic airflow obstruction did not modify this relationship. The results of the current study confirm that smoking exposure enhances telomere shortening in circulating lymphocytes. It also demonstrates a dose-effect relationship between exposure to tobacco smoking and telomere length, but failed to show that this effect is amplified in smokers who develop chronic obstructive pulmonary disease.
Subject(s)
Lymphocytes , Pulmonary Disease, Chronic Obstructive/genetics , Smoking/genetics , Telomere/ultrastructure , Adult , Age Factors , Aged , Female , Humans , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/blood , Smoking/bloodABSTRACT
BACKGROUND: Weight loss, mostly due to skeletal muscle atrophy, is a frequent and clinically relevant problem in patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying this phenomenon are unclear. This study sought to investigate whether activation of the nuclear transcription factor NF-kappaB and upregulation of the inducible form of nitric oxide synthase (iNOS) occur in the skeletal muscle of patients with COPD and low body weight as potential molecular mechanisms leading to cachexia METHODS: NF-kappaB DNA binding activity was determined by electromobility shift assay and the immunoreactivity of its inhibitory subunit IkappaB-kappa and that of iNOS by Western blot analysis in biopsy specimens of the quadriceps femoris muscle of seven COPD patients with normal body mass index (BMI, 27.5 (1) kg/m(2)) and seven patients with low BMI (18.5 (1) kg/m(2)). RESULTS: Compared with patients with normal body weight, those with low BMI showed a 30% increase in NF-kappaB DNA binding activity, a lower expression of IkappaB-alpha (3.37 (0.47) IOD v 5.96 (0.75) IOD, p<0.05; mean difference 2.59; 95% CI -4.53 to -0.65) and higher iNOS expression (1.51 (0.29) IOD v 0.78 (0.11) IOD, p<0.05; mean difference 0.74; 95% CI 0.04 to 1.42). CONCLUSIONS: NF-kappaB activation and iNOS induction occur in skeletal muscle of COPD patients with low body weight. These changes might contribute to the molecular pathogenesis of cachexia in COPD.
Subject(s)
Muscle, Skeletal/metabolism , NF-kappa B/metabolism , Nitric Oxide Synthase/metabolism , Pulmonary Disease, Chronic Obstructive/metabolism , Body Mass Index , Body Weight , Humans , Middle Aged , Nitric Oxide Synthase Type II , Up-RegulationABSTRACT
Fragile X syndrome is the most common form of inherited mental retardation. It is caused by the increase in length of a stretch of CGG triplet repeats within the FMR1 gene. A full mutation (> 200 repeats) leads to methylation of the CpG island and silencing of the FMR1 gene. We present here two sisters that are compound heterozygotes for a full mutation and a 53 repeat intermediate allele, one of them showing mental retardation and clinical features of an affected male (speech delay, hyperactivity, large ears, prominent jaw, gaze aversion), while the other is borderline normal (mild delay). Southern blot and FMRP expression analysis showed that the sister with mental retardation had the normal FMR1 gene totally methylated and no detectable protein, while her sister had 70% of her cells with the normal FMR1 gene unmethylated and normal FMRP levels. We found that the observed phenotypic differences between both sisters who are cytogenetically normal, are caused by extreme skewed X-chromosome inactivation. Analysis of the extended family showed that most of the other female family members that carry a pre-mutation or a full mutation showed some degree of skewing in their X-chromosome inactivation. The presence of several family members with skewed X inactivation and the direction and degree of skewing is inconsistent with a mere selection during development, and suggests a genetic origin for this phenomenon.
Subject(s)
Dosage Compensation, Genetic , Fragile X Syndrome/genetics , RNA-Binding Proteins , Adolescent , Child , Family Health , Female , Fragile X Mental Retardation Protein , Heterozygote , Humans , Intellectual Disability/genetics , Mutation , Nerve Tissue Proteins/genetics , Pedigree , Phenotype , Trinucleotide RepeatsABSTRACT
Cardiovascular diseases are frequent among patients with the obstructive sleep apnoea syndrome (OSAS), The aetiopathogenesis of this association is unclear. Type 1 plasminogen activator inhibitor (PAI-1) is one of the primary regulators of the fibrinolytic system. A reported association between PAI-1 activity and an insertion/deletion polymorphism (4G/5G) in the promoter region of the PAI-1 gene suggests a critical role for this genomic region in the pathogenesis of several cardiovascular diseases. In this study, we determined the prevalence of this polymorphism in patients with OSAS and in healthy control subjects. The 4G/5G polymorphism in the promoter region of the PAI-1 gene was determined in 78 male patients with severe OSAS (56 +/- 2 apnoeas per hour) and in 70 healthy male, non-smoker volunteers of similar age, without personal or familial history of cardiovascular disease. The frequency ofthe 4G/4G, 4G/5G and 5G/5G genotypes in patients with OSAS (18%, 62%, 19%, respectively) was not significantly different from that seen in healthy subjects (16%, 60%, 24% P=NS). These results show that the distribution of the 4G/5G polymorphism in the promoter region ofthe PAI-1 gene in patients with OSAS is similar to that observed in healthy subjects. This observation suggests that the PAI-1 polymorphism has no relationship with the increased risk of cardiovascular diseases seen in patients with OSAS.
Subject(s)
Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Genetic , Promoter Regions, Genetic/genetics , Sleep Apnea Syndromes/genetics , Case-Control Studies , Fibrinolysis , Gene Frequency , Genotype , Humans , Male , Middle Aged , Sleep Apnea Syndromes/bloodSubject(s)
Lung Diseases, Obstructive/physiopathology , Muscle, Skeletal/physiopathology , Apoptosis , Cachexia/etiology , Cell Hypoxia , Genetic Predisposition to Disease , Humans , Inflammation/etiology , Leptin/metabolism , Life Style , Lung Diseases, Obstructive/metabolism , Muscle Contraction , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Nitric Oxide/metabolism , Nutrition Disorders/etiology , Oxidative StressABSTRACT
Determinamos las concentraciones de colesterol y trigliceridos en un grupo de 50 ninos con diabetes insulino dependiente y en 30 ninos controles sin diabetes. Las concentraciones media de colesterol en los diabeticos fue de 180 +/- 62 mg/dl con relacion a los diabeticos de 168 +/- 18 mg/dl, p=NS. La concentracion media de trigliceridos es menor en los diabeticos con relacion al grupo control, 58.5 +/- 38 vs 62 +/- 14 mg/dl, p=0.05. Cinco de los ninos diabeticos presentaron colesterol elevado por encima de 250 mg/dl. Tres tenian trigliceridos elevado por encima de 140 mg/dl. Solo dos diabeticos presentaron colesterol y trigliceridos elevados a la vez. Los diabeticos con mayor deterioro de su enfermedad presentaron hiperlipidemia
