Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study.

BACKGROUND: 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 MUC5B 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. PATIENTS AND METHODS: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. RESULTS: MUC5B 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 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. CONCLUSION: 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.

Acute Respiratory Events in Connective Tissue Disorders.

Subacute-acute, hyperacute, or even catastrophic and fulminant respiratory events occur in almost all classic connective tissue disorders (CTDs); they may share systemic life-threatening manifestations, may precipitously lead to respiratory failure requiring ventilatory support as well as a combination of specific therapeutic measures, and in most affected patients constitute the devastating end-of-life event. In CTDs, acute respiratory events may be related to any respiratory compartment including the airways, lung parenchyma, alveolar capillaries, lung vessels, pleura, and ventilatory muscles. Acute respiratory events may also precipitate disease-specific extrapulmonary organ involvement such as aspiration pneumonia and lead to digestive tract involvement and heart-related respiratory events. Finally, antirheumatic drug-related acute respiratory toxicity as well as lung infections related to the rheumatic disease and/or to immunosuppression complete the spectrum of acute respiratory events. Overall, in CTDs the lungs significantly contribute to morbidity and mortality, since they constitute a common site of disease involvement; a major site of infections related to the 'mater' disease; a major site of drug-related toxicity, and a common site of treatment-related infectious complications. The extreme spectrum of the abovementioned events, as well as the 'vicious' coexistence of most of the aforementioned manifestations, requires skills, specific diagnostic and therapeutic means, and most of all a multidisciplinary approach of adequately prepared and expert scientists. Avoiding lung disease might represent a major concern for future advancements in the treatment of autoimmune disorders.

Investigation of Lung Involvement in Connective Tissue Disorders.

Lung involvement in connective tissue disorders (CTDs) may present as pleomorphic since any lung compartment may be involved such as airways, exocrine secretory and alveolar epithelia, interstitial lung structure, pulmonary vasculature and pleura as well as, in specific disorders, several tissues of the thoracoabdominal ventilator pump. Any combination of the above anatomic structures may be involved concomitantly although some specific combinations may include a determinant of rheumatic disorders. The diagnosis of a specific CTD requires the fulfilment of clearly defined clinical and laboratory criteria including in most cases positivity for autoantibodies, mostly specific serologic combinations. In this setting, serologic investigation targets mainly, although not exclusively, the detection of antinuclear antibodies. A specific serologic positivity or a combination of autoantibodies constitutes not only a diagnostic criterion for a specific CTD, but may also characterize the pattern of respiratory manifestation in a determinant rheumatic disorder. Therefore, the investigation of lung involvement in CTDs requires adequate skills in the ambit of a multidisciplinary approach and an extended spectrum of diagnostic tools and modalities able to detect both early clinical clues and serologic conversion as well as any pathophysiologic alteration that regards the complexity of respiratory functional status. Although many patients with CTDs suffer from a 'vicious' combination of lung involvement, lung drug toxicity and infections related to the above two as well as to the 'mater' disease, for space reasons this review will focus on the established lung manifestations that regard the 7 major CTDs.

Evaluation of the fully automated Bactec MGIT 960 system for the susceptibility testing of Mycobacterium tuberculosis to first-line drugs: a multicenter study.

The accuracy of the Bactec MGIT 960 system for susceptibility testing of 177 clinical isolates of Mycobacterium tuberculosis to first line drugs (isoniazid, rifampicin, ethambutol and streptomycin) was compared with the agar reference method. The sensitivity, the ability to detect resistance, of the MGIT system was 100%, while the specificity, the ability to detect susceptibility, ranged from 98.6% to 100% for all drugs tested.

Multicenter evaluation of the fully automated Bactec MGIT 960 system for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide: comparison with the radiometric Bactec 460TB system.

One hundred and fifty clinical isolates of Mycobacterium tuberculosis were tested for susceptibility to pyrazinamide using the fully automated Bactec MGIT 960 system and the radiometric Bactec 460TB system. The overall concordance rate between MGIT 960 and radiometric system was 100% and the mean turnaround times to report the susceptibility test results were almost identical (6.37 and 6.8 days, respectively).

Secular growth changes in the Hellenic population in the twentieth century.

Statural growth is dependent on hereditary and environmental factors, i.e disease, nutrition. The improvement of socioeconomic conditions that took place during the 20th century resulted in a secular trend towards greater height and earlier sexual maturation. Greek society has changed dramatically from a mainly agricultural society at the beginning of the 20th century to a mainly urban one in the second half of the century, and during this period Greece became a developed country. The various studies examining the height of children living in Athens during this period show a gradual increase in the height of children, the difference of the mean height between 2001 and 1928 being 11.8 cm and 7.3 cm for 17 year old boys and girls, respectively. The difference in mean height was present at all ages. The difference in final height was mainly due to prepubertal growth. Girls at the age of 10 and boys at 11 years were about 8 cm taller in 2001 than in 1928. A growth study carried out on conscripts in 1990 found no significant difference in the height of males coming from urban or rural areas of the country, whereas such a difference was detected in 1968, rural men being significantly shorter than urban ones in 1968. There are only a few studies on the sexual maturation of Greek children. The available data suggest a secular trend towards earlier puberty in females; however, this can not be substantiated for males. Menarcheal age in Greek girls showed a positive secular change that is in agreement with the observed trend for earlier pubertal maturation in girls. In conclusion, Greek children in the 20th century experienced a positive secular trend in stature which also includes final height. A secular trend for earlier sexual maturation can be shown only for girls.

A highly carbapenem-resistant Pseudomonas aeruginosa isolate with a novel blaVIM-4/blaP1b integron overexpresses two efflux pumps and lacks OprD.

OBJECTIVES: A Pseudomonas aeruginosa clinical isolate that exhibited high-level carbapenem resistance and produced metallo-beta-lactamase (MBL) was recovered from a Greek patient. This study was conducted to determine the underlying mechanisms that conferred the carbapenem resistance phenotype. METHODS: MICs were determined by Etest and Etest MBL. PCR assays were performed for identification of bla(VIM-type), other antibiotic resistance and efflux pump genes and mapping of class 1 integrons. Expression of efflux pump genes was quantified by real-time PCR. Nucleotide sequencing was used to determine the bla(VIM) allele. The location of the MBL allele was investigated by mating experiments, plasmid analysis and hybridization studies. RESULTS: The isolate was highly carbapenem-resistant (MICs of imipenem and meropenem were 512 and 128 mg/L, respectively) and multidrug-resistant. It harboured the beta-lactamase genes bla(VIM-4) and bla(P1b) in a novel class 1 integron named InV4P1, and a second integron with aac(6')-Ib and bla(OXA-35) gene cassettes. The isolate was deficient in porin OprD and overexpressed efflux pumps MexAB-OprM and MexXY-OprM. Conjugation experiments failed to detect transferable MBL determinants, plasmids were not visualized and bla(VIM) was detected by PCR in the chromosomal band. CONCLUSIONS: Multiple carbapenem resistance mechanisms are demonstrated to coexist in a single P. aeruginosa isolate and might confer the high-level carbapenem resistance.

Novel variant (bla(VIM-4)) of the metallo-beta-lactamase gene bla(VIM-1) in a clinical strain of Pseudomonas aeruginosa.

A Pseudomonas aeruginosa isolate highly resistant to carbapenems was collected from a patient with postsurgical cerebrospinal infection in Greece. The isolate carried a class 1 integron that contained as a sole cassette the gene bla(VIM-4), a novel variant of bla(VIM-1), with one nucleotide difference resulting in a Ser-to-Arg change at amino acid position 175 of the VIM-1 enzyme. This is the first detection of a VIM-1 variant after its appearance in Italy.

Persistence of a clone of glycopeptide-resistant Enterococcus faecalis among patients in an intensive care unit of a Greek hospital.

OBJECTIVES: To investigate an outbreak of glycopeptide-resistant Enterococcus faecalis (GREF) in the intensive care unit (ICU) of 'G. Gennimatas' General Hospital, Athens, Greece. MATERIALS AND METHODS: Between August 2000 and November 2001, 20 highly GREF isolates were recovered from severe infections of separate patients in the ICU. The isolates were tested by PCR, PFGE, mating experiments and plasmid analysis. RESULTS: All isolates carried the vanA gene. Nineteen isolates fitted to one clone by macrorestriction analysis with four subclones being consecutively detected. Each subclone seemed to predominate for a specific time period. Additionally, four GREF isolates related to the ICU clone were recovered from other wards of the hospital. CONCLUSIONS: Our findings indicate that a monoclonal GREF outbreak persisted for more than 1 year in a large Greek hospital. The rate of GREF isolation declined after the application of infection control measures.