Inhabitants of the Metsovo area, north-west Greece have been exposed since childhood to inhalation of asbestos, from a material containing tremolite, used for whitewashing ("luto soil"). This has resulted in endemic pleural calcifications (47% of adult population) and increased incidence of malignant pleural mesothelioma (MPM). In 1987, we reported that the incidence of MPM between 1981-1985 was around 300 times higher than expected in a nonasbestos exposed population (seven cases in 5 yrs in a population of 4,000-5,000).The present study is an updated report regarding this "mesothelioma epidemic", in conjunction with the diminished use and final abandonment of "luto soil" in the early 1980s.It appears that the incidence of MPM in Metsovo has dropped considerably since our first report. Between 1985-1994, we diagnosed six such cases (incidence rate=1.4 cases per 10,000 person-years), whilst between 1980-1984 eight cases had been diagnosed (incidence rate = 3.7 cases per 10,000 person-years). Although, because of the small number of cases, this did not reach statistical significance (p=0.08), we note that the incidence is now considerably lower than before. Had it remained unchanged, we would have expected 17 cases of MPM instead of six.This drop follows the diminished use of "luto" whitewash (by 92% of the population in 1950 and only 18% in 1980). If we take into account a 30-40 year latency period for mesothelioma, we expect that the "Metsovo mesothelioma epidemic" will fade away by the year 2020-2030, since the material has not been used since 1985.
Germline telomere-related gene mutations are associated with familial pulmonary fibrosis and lead to short telomere syndrome [1,2]. Most of the short telomere syndrome-related genes, such as TERT, TERC, DKC1, TINF2, NHP2 and NOP10, were identified in dyskeratosis congenita patients with early onset mucocutaneous manifestations and/or bone marrow failure [3]. The telomerase complex includes TERT, the TERC RNA and DKC1. NOP10, along with DKC1, NHP2 and GAR1, is essential for TERC stability and telomere maintenance [4]. Homozygous NOP10 mutation (c.100C>T, p.Arg34Trp) has been reported only once in a consanguineous family with autosomic recessive dyskeratosis congenita without pulmonary fibrosis [5]. Moreover, the p.Arg34Trp NOP10 mutation caused telomere shortening in homozygous and heterozygous carriers [5]. Here we provide evidence that a heterozygous NOP10 mutation (c.17A>G,p. Tyr6Cys) identified in a large family co-segregates with adult-onset familial pulmonary fibrosis.The proband (II.1), a 68-year-old non-smoker female, was diagnosed with pulmonary fibrosis at the age of 66 years (figure 1a and b). Two deceased, a brother (II.2) and sister (II.6), and one alive sister (II.7) were also diagnosed with pulmonary fibrosis (figure 1c). Another brother (II.4) and his son (III.5) died from leukaemia while one of the sons of the proband (III.2) had long-term leukopenia. The deceased father of the proband (I.1) was diagnosed with non-alcoholic liver cirrhosis (figure 1a). Mucocutaneous manifestations were not observed upon examination in this family.We identified by whole exome sequencing in the proband (II.1) a heterozygous pathogenic missense mutation in NOP10 (NM_ 018648) c.17A>G,p.Tyr6Cys according to international recommendations (figure 1a) [6]. No other rare variants predicted to be deleterious were found in whole exome data from the proband in the other genes linked to short telomere syndrome (TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2, WRAP53, SHQ1 and ZCCHC8) [7-9]. The variation is absent in 140 000 individuals from the gnomAD database. The mutated adenine is conserved at a genomic level (GERP=5). The in silico tools Polyphen 2 and CADD predicted a deleterious impact of the amino acid change p. Tyr6Cys with scores of 1 and 24, respectively, reflecting high conservation at a protein level. Flow cytometry and FISH (flowFISH) revealed that telomere length of the proband were shorter than the first percentile [6]. It was not possible to organise flowFISH analysis for all individuals of this family. Thus, telomere length for the individuals II.1, II.7, III.1 and III.2 was also measured through telomeric restriction fragment assay [9] at 7.4 kb, 6.3 kb, 8.5 kb and 8.6 kb, respectively. Telomere length for the individuals III.1 and III.2 were found to be shorter relative to the mother's telomere length [2]. The fact that non-carrier (III.1) and carrier (III.2) brother were found to have the same range of telomere length could be attributed to the "heritability" of telomere length and evocates epigeneti...
<b><i>Background:</i></b> Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of <i>MUC5B</i> gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients’ characteristics in the Greek national IPF cohort with suspected heritability. <b><i>Patients and Methods:</i></b> 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. <b><i>Results:</i></b> <i>MUC5B</i> rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 <i>TERT</i>, 5 <i>TERC</i>, 2 <i>RTEL1</i>, 2 <i>PARN</i>, 1 <i>NOP10</i>, and 1 <i>NHP2</i>), and biallelic <i>ABCA3</i> pathogenic variations in 3. Overlapping <i>MUC5B rs35705950</i> T risk allele and TRG pathogenic variations were shown in 11 patients (5 <i>TERT</i>, 3 <i>TERC</i>, 1 <i>PARN</i>, 1 <i>NOP10</i>, and 1 <i>NHP2</i>), <i>MUC5B</i> rs35705950 T risk allele, and biallelic <i>ABCA3</i> pathogenic variations in 2. In 38 patients, neither <i>MUC5B</i> rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (<i>p</i> = 0.025) where patients with <i>MUC5B</i> rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. <b><i>Conclusion:</i></b> The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease’s genetic “richesse,” complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating “personalized” medical care driven by genotypes in the near future.
Brucella melitensis (BM) is a rare respiratory pathogen. The lungs are usually affected in the subacute and chronic course of the disease, when pleurisy, empyema, hilar adenopathy, pneumonia and lung abscess have been described. We present a patient with BM haemorrhagic pleural effusion, with low pH, low glucose and positive pleural fluid cultures. Brucellosis should be considered in the differential diagnosis of patients with long-standing pleural effusions of unknown aetiology.
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