The Contribution of Genetic Variants of the Peroxisome Proliferator-Activated Receptor-Alpha Gene to High-Altitude Hypoxia Adaptation in Sherpa Highlanders.

Kinota, Fumiya, Yunden Droma, Nobumitsu Kobayashi, Toshimichi Horiuchi, Yoshiaki Kitaguchi, Masanori Yasuo, Masao Ota, and Masayuki Hanaoka. The contribution of genetic variants of the gene encoding peroxisome proliferator-activated receptor-alpha gene (PPARA) to high-altitude hypoxia adaptation in Sherpa highlanders. High Alt Med Biol. 24:186-192, 2023.-Sherpa highlanders, who play invaluable roles in the exploration of Mount Everest, have exceptional tolerance to hypobaric hypoxia. Sherpa people are well known to possess the traits determined by genetic background for high-altitude adaptation. The metabolic adaptation mechanism is one of the biological ways for Sherpa highlanders in protecting them from hypoxia stress at high altitude. Studies have suggested that the gene encoding PPARA is associated with metabolic adaptation in the Himalayan population of Tibetans. This study attempts to investigate the genetic variants of the PPARA in Sherpa highlanders and the association with high-altitude hypoxia adaptation. Seven single-nucleotide polymorphisms (SNPs; rs135547, rs5769178, rs881740, rs4253712, rs5766741, and rs5767700 in introns and rs1800234 in exon 6) in the PPARA were genotyped in 105 Sherpa highlanders who lived in the Khumbu region (3440 m above sea level) and 111 non-Sherpa lowlanders who resided in Kathmandu (1300 m) in Nepal. By means of analyses of genetic distances, genotype distributions, allele frequencies, linkage disequilibrium, and haplotype constructions of the seven SNPs in the Sherpa highlanders versus the non-Sherpa lowlanders, it was revealed that the frequencies of minor alleles of rs4253712, rs5766741, rs5767700, and rs1800234 SNPs, as well as the frequency of haplotype constructed by the minor alleles of rs5766741-rs5767700-rs1800234, were significantly overrepresented in the Sherpa highlanders in comparison with the non-Sherpa lowlanders. The results strongly suggest that the genetic variants of the PPARA are likely to contribute to the high-altitude adaptation in Sherpa highlanders.

Serial Cancer Development Three Times in a Patient with Fanconi Anemia.

Fanconi anemia (FA) is characterized clinically by bone marrow failure, congenital malformations, sensitivity to DNA cross-linking agents, and increased risk of malignancy. Hematological cancer is the best-described malignancy in patients with FA, but the susceptibility to the development of solid tumors is also well documented, especially after hematopoietic stem cell transplantation (HSCT). With regard to the development of solid tumors in patients with FA, head and neck, esophageal, and anal squamous cell carcinoma are well known, but reports of lung cancer are extremely rare. Here, we describe an FA patient with a history of HSCT that developed 3 serial cancers - oral, esophageal, and nonsmall cell lung cancer - over a period of 6 years. The third lesion was nonsmall cell lung cancer and its location corresponded closely to the field of irradiation treatment for prior esophageal cancer. The occurrence of lung cancer in patients with FA is uncommon, but FA patients should be screened regularly and serially. Our case also indicated the importance of the irradiated field as a location for subsequent cancer development.

Computed tomography-guided bronchoscopy in the diagnosis of small peripheral pulmonary lesions: A retrospective study of 240 examinations in a single academic center.

BACKGROUND: Factors that affect the diagnostic yield in computed tomography (CT)-guided bronchoscopy have not yet been fully evaluated. To improve the diagnostic yield of peripheral pulmonary lesions (PPLs) by CT-guided bronchoscopy, we quantitatively analyzed factors affecting the diagnostic yield. METHODS: The data were collected for 240 PPLs in 237 patients examined by using CT-guided bronchoscopy between October 2003 and November 2011 in our respiratory center. The association of diagnostic yield with the CT bronchus sign (CT-BS), lesion size, location, number of tissue specimens, and type of bronchoscope was retrospectively assessed. RESULTS: The diagnostic yield of PPLs with negative CT-BS was significantly lower (2.9%) than that for PPLs with positive CT-BS (52.2%; p<0.01). Among the PPLs with positive CT-BS, the yield was significantly higher in those in the left S(3) than for lesions in other bronchial segments (83.3% vs. 50.3%; p<0.05). Lesion size was not significantly associated with diagnostic yield. The yield was significantly lower in PPLs without lung tissue specimens than in lesions with biopsy specimens (p<0.01). Moreover, a thin bronchoscope produced a higher yield in comparison with other bronchoscope types (66.0% vs. 47.6%; p<0.05). Multivariate analysis revealed that the number of biopsy specimens was an independent factor affecting diagnostic yield. CONCLUSIONS: CT-guided bronchoscopy is valuable in the diagnosis of PPLs with positive CT-BS regardless of lesion size; however, PPLs with negative CT-BS are not good candidates for CT-guided bronchoscopy. Obtaining tissue specimens by biopsy is a critical factor in diagnosing PPLs.

Combination of virtual bronchoscopic navigation with conventional transbronchial needle aspiration in the diagnosis of peribronchial pulmonary lesions located in the middle third of the lungs.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is frequently applied to the diagnosis of central airway lesions, and endobronchial ultrasound with a guide sheath (EBUS-GS) is mainly used for the diagnosis of peripheral pulmonary lesions. However, there remains an unmet need to improve the diagnostic yields for peribronchial pulmonary lesions located along the secondary/tertiary and fourth/fifth bronchi (the "middle third zone" of the lungs), which neither EBUS-TBNA nor EBUS-GS can easily approach. METHODS: A combination of virtual bronchoscopic navigation (VBN) with conventional TBNA was utilized for the cytological diagnosis of 15 patients with small pulmonary lesions (less than 20mm in diameter) in the middle third zone between March 2012 and January 2015 in our respiratory institute. The lesions were traced using the VBN system, and then the VBN was operated and guided by the vision of actual bronchoscopy. The TBNA site was determined by VBN, and the specimens were obtained using conventional TBNA under X-ray fluoroscopy. The diagnosis was made based on the cytological findings of the specimens. RESULTS: Adequate specimens were obtained in 12 (80.0%) of the cases through the novel technique of combining TBNA with VBN in bronchoscopic examinations. Seven out of the ten malignant cases (70.0%) were definitely diagnosed by this procedure. No adverse effects were experienced, except for an acceptable amount of bleeding. CONCLUSIONS: The combination of VBN with conventional TBNA was advantageous and safe for the cytological diagnosis of small peribronchial pulmonary lesions in the middle third zone of the lungs.

Hydrogen peroxide content and pH of expired breath condensate from patients with asthma and COPD.

BACKGROUND: Oxidative stress is implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Analysis of the expired breath condensate (EBC) has been suggested to provide non-invasive inflammatory markers that reflect oxidative stress in the airways. OBJECTIVE: The present study attempts to elucidate whether the hydrogen peroxide (H2O2) levels and pH values in EBC may be useful as biomarkers of the activity or severity of asthma and COPD. METHODS: We measured the H2O2 levels and pH values using a derivatives of reactive oxygen metabolites exhalation test kit (Diacron) and a pH analyser, respectively, in EBC obtained using an EcoScreen from 29 patients with asthma, 33 with COPD, and 33 healthy individuals (all non-smokers). We then examined the relationships among oxidative stress and the asthma control test (ACT) or COPD assessment test (CAT) scores, pulmonary function, fractional exhaled nitric oxide (FeNO), and the extent of low attenuation areas on HRCT. RESULTS: The H2O2 levels were elevated and pH was lower in both asthma (H2O2; 8.75 ± 0.88 µM, p < 0.01, pH; 7.14 ± 0.07, p < 0.05) and COPD (H2O2; 7.44 ± 0.89 µM, p < 0.01, pH; 6.87 ± 0.10, p < 0.01) compared with control subjects (H2O2; 3.42 ± 0.66 µM, pH; 7.35 ± 0.04). Neither the H2O2 levels nor pH correlated with the ACT scores and FeNO in asthma patients. Neither the H2O2 levels nor pH significantly correlated with the pulmonary function in asthma and COPD. However, the CAT scores significantly correlated with the H2O2 levels in patients with COPD (r = 0.52, p < 0.01). CONCLUSIONS: These findings suggest that oxidative stress is involved in the pathogenesis of asthma and COPD and that the H2O2 levels in EBC might reflect the health status in COPD.

The association of Toll-like receptor 4 gene polymorphisms with the development of emphysema in Japanese subjects: a case control study.

BACKGROUND: The principal role of Toll-like receptor 4 (TLR4) is the induction of immune responses to lipopolysaccharides. Previously, mice deficient in the TLR4 gene exhibited up-regulation of the NADPH oxidase system in the lungs. This resulted in increased oxidant generation and elastolytic activity, which led to pulmonary emphysema. It was suggested that TLR4 might maintain constitutive lung integrity by modulating oxidant generation. We investigated whether single nucleotide polymorphisms (SNPs) in the TLR4 gene were associated with the emphysema phenotype in Japanese subjects with chronic obstructive pulmonary disease (COPD). RESULTS: Seven SNPs in the TLR4 gene (rs10759930, rs1927914, rs12377632, rs2149356, rs11536889, rs7037117, and rs7045953) were genotyped with allelic discrimination assays. The frequencies of SNPs were compared between 106 patients with the emphysema phenotype of COPD and 137 healthy smokers. We found that the positivity of the individuals with the major G allele of rs11536889 was significantly less in the emphysema group than the control group (p = 0.019). The frequencies of the minor C allele and the distribution of the CC genotype as well as the frequency of the major haplotype that carried the minor C allele of rs11536889 were all significantly higher in the emphysema group than the control group (p = 0.0083, 0.019, and 0.004, respectively). Furthermore, the strength of the association of the CC genotype with the emphysema phenotype was in an odds ratio of 2.60 with 95% confidence intervals from 1.17 to 5.78. However, these significances were not apparent after adjust for age and smoking history by logistic regression. No associations were observed between the rs11536889 and the low attenuation area score, the forced expiratory volume, and the carbon monoxide diffusion capacity in the emphysema group. CONCLUSIONS: The minor C allele of the rs11536889 SNP in the TLR4 gene is likely associated with the risk of developing emphysema in the Japanese population.

Successful Retreatment With ADOC Chemotherapy in Relapsed Thymic Carcinoma: Experiences in Two Cases.

The optimal second-line chemotherapeutic regimen for thymic carcinoma remains uncertain and predictive factors for the response have not been identified. We encountered two cases of relapsed thymic carcinoma with recurrence 1.5 and 8 years after initial response to cisplatin/doxorubicin/vincristine/cyclophosphamide (ADOC) chemotherapy. Both cases were successfully retreated with ADOC. Our observations suggest that relapsed thymic carcinoma occurring a long treatment-free time from the initial response may be sensitive to the previous chemotherapy. We described two cases of relapsed thymic carcinoma successfully retreated with ADOC chemotherapy. Both patients had partial response to initial ADOC and long disease free times.

[Two familial cases of psittacosis].

We report here 2 cases of psittacosis in a family. In the first case, a 51-year-old woman was admitted with fever, dry cough, and a chest radiograph showed increased opacity in the right upper lung field. On a diagnosis of atypical pneumonia, minocycline was given and her clinical symptoms and abnormal laboratory data were improved. The second case was her husband, a 58-year-old man who presented with fever 4 days after his wife's admission. His chest radiograph revealed increased opacity in the left lower lung field. The administration of azithromycin for 3 days attenuated his clinical symptoms and his abnormal laboratory data improved. The serum titer of complement fixation (CF) test and ELISA test against Chlamydophila psittaci were elevated in both cases on analysis of paired acute- and convalescent-phase serum speciments. The antigen of Chlamydophila was revealed from these parrots, which had been raised in their family. Therefore, we concluded that the psittacosis had originated from the parrots.

[A case of multiple lung abscesses successfully treated with computed tomography guided percutaneous thoracic drainage].

A 48-year-old woman who had abused alcohol admitted to our hospital because of fever and chest pain. Laboratory data presented inflammation and liver dysfunction. Chest X-ray films revealed multiple mass lesions with air fluid levels. We diagnosed multiple lung abscesses and started treatment with antibiotics. However, her fever did not improve and mass lesions increased. On day 6 of hospitalization, three drainage tubes were inserted percutaneously into the mass lesions under computed tomography (CT) guidance, and alpha-hemolytic streptococcus, peptostreptococcus sp. and neutrophils were isolated from the drainage fluid. Abcesses and inflammation were improved by administration of the antibiotics selected according to the result of fluid culture. Because all multiple abcesses were located near the pleura, we successfully treated them with simultaneous percutaneus thoracic drainage.