Pseudo-Gitelman Syndrome Presenting with Hypokalemic Metabolic Alkalosis and Hypocalciuria.

Pseudo-Bartter syndrome is a well-known differential diagnosis that needs to be excluded in cases of normotensive hypokalemic metabolic alkalosis. Pseudo-Bartter syndrome and pseudo-Gitelman syndrome are often collectively referred to as pseudo-Bartter/Gitelman syndrome; however, pseudo-Gitelman syndrome should be considered as a separate entity because Gitelman syndrome is characterized by hypocalciuria and hypomagnesemia, while Bartter syndrome is usually associated with hypercalciuria. Herein, we report the cases of two young adult female patients who presented with severe hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Diuretic or laxative abuse and self-induced vomiting were absent, and a chloride deficit and remarkable bicarbonaturia were observed. Initial sequencing studies for SLC12A3, CLCKNB, and KCNJ10 revealed no mutations, and whole-exome sequencing revealed no pathogenic variants. The metabolic alkalosis was saline-responsive in one case, and steroid therapy was necessary in the other to relieve chronic tubulointerstitial nephritis, which was diagnosed with kidney biopsy. A new category of pseudo-Gitelman syndrome should be defined, and various etiologies should be investigated.

Adenylyl-Sulfate Kinase (Met14)-Dependent Cysteine and Methionine Biosynthesis Pathways Contribute Distinctively to Pathobiological Processes in Cryptococcus neoformans.

Blocking of nutrient uptake and amino acid biosynthesis are considered potential targets for next-generation antifungal drugs against pathogenic fungi, including Cryptococcus neoformans. In this regard, the sulfate assimilation pathway is particularly attractive, as it is only present in eukaryotes such as plants and fungi, yet not in mammals. Here, we demonstrated that the adenylyl sulfate kinase (Met14) in the sulfate assimilation pathway is not essential yet is required for the viability of C. neoformans due to its involvement in biosynthesis of two sulfur-containing amino acids, cysteine and methionine. Met14-dependent cysteine and methionine biosynthesis was found to significantly contribute to a diverse range of pathobiological processes in C. neoformans. Met14-dependent cysteine rather than methionine biosynthesis was also found to play pivotal roles in cell growth and tolerance to environmental stresses and antifungal drugs. In contrast, the Met14-dependent methionine biosynthesis was found to be more important than cysteine biosynthesis for the production of major cryptococcal virulence factors of melanin pigments and polysaccharide capsules. Finally, we also found that despite its attenuated virulence in an insect model, Galleria mellonella, the met14Δ mutant yielded no difference in virulence in a murine model of systemic cryptococcosis. Hence, clinical inhibition of Met14-dependent amino acid biosynthetic pathways may not be advantageous for the treatment of systemic cryptococcosis. IMPORTANCE Current antifungal drugs have several limitations, such as drug resistance, severe side effects, and a narrow spectrum. Therefore, novel antifungal targets are urgently needed. To this end, fungal sulfur amino acid biosynthetic pathways are considered potential targets for development of new antifungal agents. Here, we demonstrated that Met14 in the sulfate assimilation pathway promotes growth, stress response, and virulence factor production in C. neoformans via synthesis of sulfur-containing amino acids methionine and cysteine. Met14-dependent cysteine rather than methionine synthesis was found to be critical for growth and stress responses, whereas Met14-dependent methionine synthesis was more important for the production of antiphagocytic capsules and antioxidant melanin in C. neoformans. Surprisingly, deletion of the MET14 gene was found to attenuate cryptococcal virulence in an insect model, yet not in a murine model. Collectively, our results showed that Met14-dependent cysteine and methionine biosynthesis play roles that are distinct from each other in C. neoformans. Moreover, Met14 is unlikely to be a suitable anticryptococcal drug target.

Dysregulating PHO Signaling via the CDK Machinery Differentially Impacts Energy Metabolism, Calcineurin Signaling, and Virulence in Cryptococcus neoformans.

Fungal pathogens uniquely regulate phosphate homeostasis via the cyclin-dependent kinase (CDK) signaling machinery of the phosphate acquisition (PHO) pathway (Pho85 kinase-Pho80 cyclin-CDK inhibitor Pho81), providing drug-targeting opportunities. Here, we investigate the impact of a PHO pathway activation-defective Cryptococcus neoformans mutant (pho81Δ) and a constitutively activated PHO pathway mutant (pho80Δ) on fungal virulence. Irrespective of phosphate availability, the PHO pathway was derepressed in pho80Δ with all phosphate acquisition pathways upregulated and much of the excess phosphate stored as polyphosphate (polyP). Elevated phosphate in pho80Δ coincided with elevated metal ions, metal stress sensitivity, and a muted calcineurin response, all of which were ameliorated by phosphate depletion. In contrast, metal ion homeostasis was largely unaffected in the pho81Δ mutant, and Pi, polyP, ATP, and energy metabolism were reduced, even under phosphate-replete conditions. A similar decline in polyP and ATP suggests that polyP supplies phosphate for energy production even when phosphate is available. Using calcineurin reporter strains in the wild-type, pho80Δ, and pho81Δ background, we also demonstrate that phosphate deprivation stimulates calcineurin activation, most likely by increasing the bioavailability of calcium. Finally, we show that blocking, as opposed to permanently activating, the PHO pathway reduced fungal virulence in mouse infection models to a greater extent and that this is most likely attributable to depleted phosphate stores and ATP, and compromised cellular bioenergetics, irrespective of phosphate availability. IMPORTANCE Invasive fungal diseases cause more than 1.5 million deaths per year, with an estimated 181,000 of these deaths attributable to Cryptococcal meningitis. Despite the high mortality, treatment options are limited. In contrast to humans, fungal cells maintain phosphate homeostasis via a CDK complex, providing drug-targeting opportunities. To investigate which CDK components are the best targets for potential antifungal therapy, we used strains with a constitutively active (pho80Δ) and an activation-defective (pho81Δ) PHO pathway, to investigate the impact of dysregulated phosphate homeostasis on cellular function and virulence. Our studies suggest that inhibiting the function of Pho81, which has no human homologue, would have the most detrimental impact on fungal growth in the host due to depletion of phosphate stores and ATP, irrespective of phosphate availability in the host.

Comparison of active tuberculosis case finding strategies for immigrants in South Korea: Epidemiology and cost-effectiveness analysis.

BACKGROUND: Tuberculosis (TB) is one of the serious infectious diseases in South Korea, with 49 new cases per 100,000 people and 629 multi-drug resistant (MDR) cases reported in 2020. TB is increasing among immigrants in S. Korea, and various TB case finding strategies are being performed for screening. We compared active case finding (ACF) with passive case finding (semi-PCF) across epidemiological characteristics and investigated a cost-effective strategy for screening immigrants for TB. METHODS: ACF driven by non-governmental organizations and semi-PCF as part of the government's visa renewal process using CXR with additional acid-fast bacilli (AFB) smear and cultures were performed. Epidemiological parameters were compared between the two TB screening projects, and costs were collected. Cost-effectiveness was evaluated using a decision analysis model from the health system perspective. The primary outcome was incremental cost-effectiveness ratio (ICER) per averted TB case. Additional probabilistic sensitivity analysis was conducted. RESULTS: ACF (2.02%) showed a higher TB prevalence rate than semi-PCF (0.67%) on CXR. For subjects older than 60 years, the suspected TB rate on CXR was significantly higher in ACF (36.6%) than in semi-PCF (12.2%) (P<0.01). TB incidence among the family visa type was significantly higher in ACF (1.96%) than in semi-PCF (0.88%) (P < 0.0012). Costs for ACF ($666.92) were $20.784 higher than for semi-PCF ($646.13), but TB progression decreased by 0.02, resulting in an ICER of $948.18 per averted TB case. In sensitivity analysis, the indirect costs of ACF and semi-PCF had the highest impact on ICER. CONCLUSION: ACF found more TB cases than semi-PCF through CXR screening, and suspect cases with old age and family visa type were more common in ACF than in semi-PCF. ACF is cost-effective as a TB screening strategy for immigrants.

A prospective patient registry to monitor safety, effectiveness, and utilisation of bedaquiline in patients with multidrug-resistant tuberculosis in South Korea.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) represents a major public health concern, with an ongoing need for new effective treatments. Bedaquiline is an oral diarylquinoline that has shown encouraging treatment success and culture conversion rates in MDR-TB. METHODS: A South Korean patient registry was set up across 19 centres between 2016 and 2018 for the prospective collection of data from patients with MDR-TB who received either a bedaquiline-containing or a non-bedaquiline-containing regimen. Treatment was at the physician's discretion (bedaquiline use requiring approval by special committee) and was based on patient characteristics, disease status, and local treatment guidelines. RESULTS: The safety population included 172 patients (88 bedaquiline and 84 non-bedaquiline). The mean (standard deviation, SD) duration of follow-up was 24.3 (9.5) months. Mean (SD) durations of treatment were 5.4 (1.8) months in bedaquiline-treated patients and 15.7 (6.7) months in the non-bedaquiline group. Treatment success (cured and treatment completed according to WHO 2013 treatment outcome definitions) was achieved by 56.3% of bedaquiline-treated and 45.2% of non-bedaquiline-treated patients. Sputum culture conversion rates were 90.4% and 83.7% with and without bedaquiline, respectively. Diarrhoea and nausea were the most frequently reported treatment-emergent adverse events (TEAEs) in the bedaquiline group (27.3% [24/88] and 22.7% [20/88], respectively). The most frequent bedaquiline-related TEAEs were prolonged QT interval (10.2%; 9/88), and diarrhoea and nausea (9.1% each; 8/88). QT interval prolongation was reported in 19.3% (17/88) of bedaquiline-treated and 2.4% (2/84) of non-bedaquiline-treated patients, but bedaquiline was not discontinued for any patient for this reason. There were 13 (14.7%) and three (3.6%) deaths in the bedaquiline-treated and non-bedaquiline groups, respectively. Review of fatal cases revealed no unexpected safety findings, and no deaths were bedaquiline-related. The most common cause of death was worsening cancer (three patients). Patients in the bedaquiline group tended to have poorer baseline risk profiles than non-bedaquiline patients and were more likely to have relapsed or already failed second-line treatment. Interpretation of mortality data was complicated by high rates of loss to follow-up in both groups. CONCLUSIONS: The South Korean registry findings support previous risk/benefit observations and the continued use of bedaquiline as part of combination therapy in patients with MDR-TB.

Comparison of Macrophage Immune Responses and Metabolic Reprogramming in Smooth and Rough Variant Infections of Mycobacterium mucogenicum.

Mycobacterium mucogenicum (Mmuc), a rapidly growing nontuberculous mycobacterium (NTM), can infect humans (posttraumatic wound infections and catheter-related sepsis). Similar to other NTM species, Mmuc exhibits colony morphologies of rough (Mmuc-R) and smooth (Mmuc-S) types. Although there are several case reports on Mmuc infection, no experimental evidence supports that the R-type is more virulent. In addition, the immune response and metabolic reprogramming of Mmuc have not been studied on the basis of morphological characteristics. Thus, a standard ATCC Mmuc strain and two clinical strains were analyzed, and macrophages were generated from mouse bone marrow. Cytokines and cell death were measured by ELISA and FACS, respectively. Mitochondrial respiration and glycolytic changes were measured by XF seahorse. Higher numbers of intracellular bacteria were found in Mmuc-R-infected macrophages than in Mmuc-S-infected macrophages. Additionally, Mmuc-R induced higher levels of the cytokines TNF-α, IL-6, IL-12p40, and IL-10 and induced more BMDM necrotic death. Furthermore, our metabolic data showed marked glycolytic and respiratory differences between the control and each type of Mmuc infection, and changes in these parameters significantly promoted glucose metabolism, extracellular acidification, and oxygen consumption in BMDMs. In conclusion, at least in the strains we tested, Mmuc-R is more virulent, induces a stronger immune response, and shifts bioenergetic metabolism more extensively than the S-type. This study is the first to report differential immune responses and metabolic reprogramming after Mmuc infection and might provide a fundamental basis for additional studies on Mmuc pathogenesis.

Predictive Role of Lung Injury Prediction Score in the Development of Acute Respiratory Distress Syndrome in Korea.

PURPOSE: Early recognition and therapeutic intervention are important in patients at high risk of acute respiratory distress syndrome (ARDS). The lung injury prediction score (LIPS) has been used to predict ARDS development; however, it was developed based on the previous definition of ARDS. We investigated the predictive role of LIPS in ARDS development according to its Berlin definition in the Korean population. MATERIALS AND METHODS: This was a retrospective study that enrolled adult patients admitted to the intensive care unit (ICU) at a single university-affiliated hospital in Korea from September 1, 2018, to August 31, 2019. LIPS at the time of ICU admission and the development of ARDS were evaluated. RESULTS: Of the 548 enrolled patients, 33 (6.0%) fulfilled the Berlin ARDS definition. The LIPS for non-ARDS and ARDS groups were 4.96±3.05 and 8.53±2.45, respectively (p<0.001); it was significantly associated with ARDS development (odds ratio 1.48, 95% confidence interval, 1.29-1.69; p<0.001). LIPS >6 predicted the development of ARDS with a sensitivity of 84.8% and a specificity of 67.2% [area under the curve (AUC)=0.82]. A modified LIPS model adjusted for age and severity at ICU admission predicted ICU mortality in patients with ARDS (AUC=0.80), but not in those without ARDS (AUC=0.54). CONCLUSION: LIPS predicted the development of ARDS as diagnosed by the Berlin definition in the Korean population. LIPS provides useful information for managing patients with ARDS.

Sub-nanosecond terahertz radiation obtained with an aperiodically poled lithium niobate and organic HMQ-TMS.

We report a compact, simple source of terahertz radiation that can be tuned to well-defined frequencies spanning ∼1.4 to 10 THz, based on difference-frequency generation in an HMQ-TMS crystal. The pair of pump pulses required for this process is obtained by optical parametric generation in an aperiodically-poled lithium niobate crystal; the center wavelength of this pair of pulses is around 1.45 µm. We obtained 40 nJ THz pulses using 38 µJ, 0.85 ns pump pulses.

The interference effect of maternally-derived antibodies on the serological performance of pigs immunized with a foot-and-mouth disease oil emulsion vaccine.

To control foot-and-mouth disease (FMD) outbreaks that originated in Jincheon County in South Korea between 2014 and 2015, several commercial vaccines were studied for their efficacy and serological performance in the field. In this study, the efficacy of the O SKR 7/10 vaccine was evaluated by challenge with the FMD virus (FMDV) O/Jincheon/SKR/2014 (O Jincheon), which has the same O/SEA/Mya-98 lineage as the O/SKR/7/10 strain that was isolated in 2010 in South Korea, in FMD-seronegative pigs. Full protection against the O Jincheon virus was demonstrated as early as 14 days postvaccination, which was explained by the strong serological relationship (r1 value: ≥ 0.92) between the O Jincheon and O SKR 2010 viruses. However, in the field trial, no satisfactory serological elevations against FMDV were observed, even in the double-vaccinated groups. Therefore, it can be concluded that the O SKR 7/10 vaccine may need to be improved to overcome the interference effects from the high levels of maternally-derived antibodies generated due to the mandatory nationwide vaccination of sows in South Korea.

Gas-Induced Ion-Free Stable Radical Anion Formation of Organic Semiconducting Solids as Highly Gas-Selective Probes.

The formation of stabilized radical anions on organic materials in the solid state is an important issue in radical-based fundamental research and various applications. Herein, for the first time, we report on gas-induced ion-free stable radical anion formation (SRAF) of organic semiconducting solids with high gas selectivities through the use of organic field-effect transistor (OFET) gas sensors and electron spin resonance spectroscopy. In contrast to the previously reported SRAF, which requires either anionic analytes in solution and/or cationic substituents on π-electron-deficient aromatic cores, NDI-EWGs consist of an n-type semiconducting naphthalene diimide (NDI) and various electron-withdrawing groups (EWGs) that exhibit non-ion-involved, gas-selective SRAF in the solid state. In the presence of hard Lewis base gases, NDI-EWG-based OFETs exhibit enhanced conductivity (Current-ON mode) through the formation of an SRAF NDI/gas complex, while in the presence of borderline and soft Lewis base gases, NDI-EWG-based OFETs show decreased conductivity (Current-OFF mode) by the formation of a resistive NDI/gas complex. Organic semiconducting solids with EWGs exhibiting highly gas-selective solid-SRAF constitute a very promising platform for radical-based chemistry and can be used in various applications, such as highly gas-selective probes.

Comparison of DNA extraction methods for drug susceptibility testing by allele-specific primer extension on a microsphere-based platform: Chelex-100 (in-house and commercialized) and MagPurix TB DNA Extraction Kit.

Tuberculosis (TB), caused by infections of the Mycobacterium tuberculosis (MTB) complex, is the ninth leading cause of death worldwide, and several molecular approaches for MTB species identification and the detection of mutations associated with drug resistance have been developed to date. We previously developed a diagnostic assay for drug susceptibility testing that can detect mutations conferring resistance to anti-TB drugs using allele-specific primer extension on a microsphere-based platform for multiplex polymerase chain reaction. The aim of the present study was to optimize this diagnostic assay based on the evaluation of three methods for extracting mycobacterial DNA from clinical samples. Mycobacterial DNA of 81 samples was digested and decontaminated by N-acetyl-l-cysteine-2% NaOH and then extracted using three methods: "in-house" 5% Chelex-100 chelating resin, InstaGene Matrix, and MagPurix TB DNA Extraction Kit. The former two methods are manual extraction methods, whereas the MagPurix TB DNA Extraction Kit is an automated extraction method used with the MagPurix 12 s automated nucleic acid purification system. The extracted DNA was then subjected to our diagnostic assay, and the results were compared among methods. The magnetic bead method exhibited a higher extraction efficiency and resulted in greater diagnostic efficacy than the two resin-based methods with respect to both target gene detection and acid-fast bacilli smear grades. Therefore, the MagPurix TB DNA Extraction Kit is the optimal MTB DNA extraction method for our diagnostic assay of TB drug susceptibility testing.

Clinical and molecular characteristics of pulmonary sarcomatoid carcinoma.

Background/Aims: Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) that contains components of spindle or giant cells. Owing to its low prevalence, there are insufficient data regarding its clinical features, therapeutic strategies and prognosis. METHODS: The medical records of 26 patients diagnosed with PSC from January 2009 to June 2015 were reviewed and analyzed for clinicopathological characteristics, treatment modality, and outcomes. RESULTS: The median age was 69.5 years. Twenty-three patients (88%) were male. Twenty-four patients (92%) were smokers. The median time from symptom onset to diagnosis was one month. Eighteen patients (69%) were diagnosed at an advanced stage. Pleomorphic carcinoma was the most common subtype, and epidermal growth factor receptor (EGFR) mutation was positive in two of 11 patients. Among 13 patients tested for programmed death ligand 1 (PD-L1) immunohistochemistry assay, eight showed high expression of PD-L1. The median overall survival (OS) of all patients was 9.5 months. In total, 12 patients were treated with chemotherapy: nine with platinum-based doublet therapy, two with tyrosine kinase inhibitor, and one with docetaxel. Seven patients showed partial response or stable disease. The median OS and progression-free survival of patients who received chemotherapy were 8.7 and 2.8 months, respectively. Conclusions: PSC was more common in males, smokers, and the elderly, with worse prognosis than ordinary NSCLC; chemotherapy response was favorable, and EGFR mutation status and PD-L1 expression may offer more therapeutic options.

Description of Mycobacterium chelonae subsp. bovis subsp. nov., isolated from cattle (Bos taurus coreanae), emended description of Mycobacterium chelonae and creation of Mycobacterium chelonae subsp. chelonae subsp. nov.

Three rapidly growing mycobacterial strains, QIA-37T, QIA-40 and QIA-41, were isolated from the lymph nodes of three separate Korean native cattle, Hanwoo (Bos taurus coreanae). These strains were previously shown to be phylogenetically distinct but closely related to Mycobacterium chelonae ATCC 35752T by taxonomic approaches targeting three genes (16S rRNA, hsp6 and rpoB) and were further characterized using a polyphasic approach in this study. The 16S rRNA gene sequences of all three strains showed 99.7 % sequence similarity with that of the M. chelonae type strain. A multilocus sequence typing analysis targeting 10 housekeeping genes, including hsp65 and rpoB, revealed a phylogenetic cluster of these strains with M. chelonae. DNA-DNA hybridization values of 78.2 % between QIA-37T and M. chelonae indicated that it belongs to M. chelonae but is a novel subspecies distinct from M. chelonae. Phylogenetic analysis based on whole-genome sequences revealed a 95.44±0.06 % average nucleotide identity (ANI) value with M. chelonae, slightly higher than the 95.0 % ANI criterion for determining a novel species. In addition, distinct phenotypic characteristics such as positive growth at 37 °C, at which temperature M. chelonae does not grow, further support the taxonomic status of these strains as representatives of a novel subspecies of M. chelonae. Therefore, we propose an emended description of Mycobacterium chelonae, and descriptions of M. chelonae subsp. chelonae subsp. nov. and M. chelonae subsp. bovis subsp. nov. are presented; strains ATCC 35752T(=CCUG 47445T=CIP 104535T=DSM 43804T=JCM 6388T=NCTC 946T) and QIA-37T (=KCTC 39630T=JCM 30986T) are the type strains of the two novel subspecies.

Clinical Characteristics and Treatment Outcomes of Patients with Acquired Macrolide-Resistant Mycobacterium abscessus Lung Disease.

Macrolide antibiotics are mainstays in the treatment of lung disease due to the Mycobacterium abscessus complex. Although previous studies have reported development of acquired macrolide resistance in this species, limited data are available on the outcomes of lung disease due to macrolide-resistant Mycobacterium abscessus subsp. abscessus This study evaluated the clinical features, treatment outcomes, and molecular characteristics of macrolide-resistant isolates of M. abscessus subsp. abscessus We performed a retrospective review of medical records and genetic analysis of clinical isolates from 13 patients who had acquired macrolide-resistant M. abscessus subsp. abscessus lung disease between November 2006 and March 2016. Eleven (85%) patients had the nodular bronchiectatic form of the disease, and two (15%) patients had the fibrocavitary form. When acquired macrolide resistance was detected, 10 (77%) patients were on antibiotic therapy for M. abscessus subsp. abscessus, and three (23%) patients were on therapy for lung disease due to other nontuberculous mycobacteria. The median treatment duration after detecting resistance was 24.0 months (interquartile range, 16.0 to 43.0 months). Treatment outcomes were poor, and final sputum culture conversion was achieved in only one (8%) patient, after resectional surgery. All 13 clinical isolates demonstrated point mutations at position 2058 (n = 10) or 2059 (n = 3) of the 23S rRNA gene, which resulted in acquired macrolide resistance. This study indicates that treatment outcomes are very poor after the development of acquired macrolide resistance in patients with M. abscessus subsp. abscessus lung disease. Thus, more effective measures are needed to prevent development and effectively treat macrolide-resistant M. abscessus subsp. abscessus lung disease.

Social and Clinical Characteristics of Immigrants with Tuberculosis in South Korea.

PURPOSE: To determine the social and clinical characteristics of immigrants with tuberculosis (TB) in South Korea. MATERIALS AND METHODS: The registered adult TB patients who were diagnosed and treated in Korea Medical Centers from January 2013 to December 2015 were analyzed retrospectively. A total of 105 immigrants with TB were compared to 932 native Korean TB patients. RESULTS: Among these 105 immigrants with TB, 86 (82%) were Korean-Chinese. The rate of drug-susceptible TB were lower in the immigrants group than in the native Korean group [odds ratio (OR): 0.46; 95% confidence interval (CI): 0.22-0.96, p=0.035]. Cure rate was higher in the immigrant group than in the native Korean group (OR: 2.03; 95% CI: 1.26-3.28, p=0.003). Treatment completion rate was lower in the immigrant group than in the native Korean group (OR: 0.50; 95% CI: 0.33-0.74, p=0.001). However, treatment success rate showed no significant difference between two groups (p=0.141). Lost to follow up (default) rate was higher in the immigrant group than in the native Korean group after adjusting for age and drug resistance (OR: 3.61; 95% CI: 1.36-9.61, p=0.010). There was no difference between defaulter and non-defaulter in clinical characteristics or types of visa among these immigrants (null p value). However, 43 TB patients with recent immigration were diagnosed as TB even though they had been screened as normal at the time of immigration. CONCLUSION: Endeavor to reduce the default rate of immigrants with TB and reinforce TB screening during the immigration process must be performed for TB infection control in South Korea.

Clinical Characteristics and Treatment Outcomes of Patients with Macrolide-Resistant Mycobacterium massiliense Lung Disease.

Macrolide antibiotics are cornerstones in the treatment of Mycobacterium massiliense lung disease. Despite the emergence of resistance, limited data on macrolide-resistant M massiliense lung disease are available. This study evaluated the clinical features and treatment outcomes of patients and the molecular characteristics of macrolide-resistant M massiliense isolates. We performed a retrospective review of medical records and genetic analyses of clinical isolates from 15 patients who had macrolide-resistant M massiliense lung disease between September 2005 and February 2015. Nine patients (60%) had the nodular bronchiectatic form of the disease, and six (40%) had the fibrocavitary form. Before the detection of macrolide resistance, three patients (20%) were treated with macrolide monotherapy, four (27%) with therapy for presumed Mycobacterium avium complex infections, and eight (53%) with combination antibiotic therapy for M massiliense lung disease. The median treatment duration after the detection of resistance was 18.7 months (interquartile range, 11.2 to 39.8 months). Treatment outcomes were poor, with a favorable outcome being achieved for only one patient (7%), who underwent surgery in addition to antibiotic therapy. The 1-, 3-, and 5-year mortality rates were 7, 13, and 33%, respectively. Of the 15 clinical isolates, 14 (93%) had point mutations at position 2058 (n = 9) or 2059 (n = 5) of the 23S rRNA gene, resulting in macrolide resistance. Our study indicates that treatment outcomes are poor and mortality rates are high after the development of macrolide resistance in patients with M massiliense lung disease. Thus, preventing the development of macrolide resistance should be a key consideration during treatment.

Inadequate Bowel Cleansing Efficacy of Split-dose Polyethylene Glycol for Colonoscopy in Type 2 Diabetic Patients: A Prospective and Blinded Study.

BACKGROUND/AIMS: Split-dose polyethylene glycol (PEG) is considered a standard bowel preparation regimen for colonoscopy in the general population. However, it is not clear whether the regimen is optimal for colonoscopy in diabetic patients. The aim of this study was to compare the efficacy and tolerability of split-dose PEG for diabetic versus nondiabetic patients. METHODS: This is a single-center, prospective, investigator-blinded study. A total of 55 consecutive nondiabetic and 50 diabetic patients ingested 2 L PEG solution on the day before the procedure and then 2 L of the solution on the day of colonoscopy. The quality of bowel preparation was graded using the Ottawa scale. RESULTS: There was a significant difference in bowel preparation quality, with a worse preparation except for mid colon in diabetic group (total score: 7.06±1.69 vs. 5.54±1.97, P<0.001; right colon: 2.28±0.57 vs. 1.81±0.72, P<0.001; mid colon: 1.70±0.54 vs. 1.56±0.66, P=0.253; rectosigmoid colon: 1.70±0.76 vs. 1.14±0.62, P<0.001; fluid volume: 1.38±0.53 vs. 1.01±0.59, P=0.001). About 70% of nondiabetic patients had an adequate preparation compared with only 40% of diabetic patients (P=0.003). Diabetic group had longer cecal intubation time (6.4±3.6 vs. 4.5±2.4, P=0.002) and total procedure time (22.1±7.6 vs. 18.1±8.5, P=0.015). Compliance and adverse events were not significantly different. In diabetic group, inadequate bowel preparation had a significant association with higher fasting plasma glucose (136.9±21.8 vs. 121.8±19.4 mg/dL, P=0.016). CONCLUSIONS: Diabetic patients had a worse preparation quality and longer cecal intubation and total procedure time compared with nondiabetic patients. These data suggest that split-dose PEG preparation regimen is not sufficient for optimal bowel preparation in diabetic patients undergoing colonoscopy.

Reactive Oxygen Species Modulator 1 (Romo1) Predicts Poor Outcomes in Advanced Non-small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

PURPOSE: Reactive oxygen species modulator 1 (Romo1) is a key mediator of intracellular reactive oxygen species production. However, examination of the clinical usefulness of Romo1 in cancers has been limited. We evaluated the association of Romo1 expression with clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. MATERIALS AND METHODS: Romo1 expression in tumor tissue was examined by immunohistochemistry and evaluated by histological score. Survival analyses were performed according to Romo1 expression and the association between Romo1 expression and clinical parameters was evaluated. RESULTS: A total of 88 tumor specimens were analyzed. Significantly shorter median progression-free survival (PFS) was observed in the high Romo1 group compared with the low Romo1 group (4.5 months vs. 9.8 months, p < 0.001), and the median overall survival (OS) of the high Romo1 group was also significantly shorter than that of the low Romo1 group (8.4 months vs. 15.5 months, p < 0.001). Results of multivariate analyses showed significant association of high Romo1 expression with both poor PFS (hazard ratio [HR], 2.75; 95% confidence interval [CI], 1.71 to 4.44) and poor OS (HR, 3.99; 95% CI, 2.36 to 6.74). Results of the subgroup analysis showed a similar association regardless of tumor histology. Romo1 expression showed no association with any clinical parameter including age, sex, smoking status, stage, differentiation, or tumor histology. CONCLUSION: Romo1 overexpression was associated with poor response to treatment and shorter survival in advanced NSCLC patients treated with platinum-based chemotherapy. Romo1 could be a potential adverse predictive marker in this setting.

Longitudinal Lung Function Decrease in Subjects with Spontaneous Healed Pulmonary Tuberculosis.

OBJECTIVE: We compared the longitudinal course of post-bronchodilator Forced Expiratory Volume in 1 second (pFEV1) over a 10-year period in subjects with spontaneous healed pulmonary tuberculosis (SHPTB) with that in normal subjects. METHODS: We prospectively investigated 339 subjects with SHPTB and 3211 normal subjects. pFEV1 values measured biannually over 10 years were analyzed using mixed effects model. RESULTS: At baseline, there were no differences in gender, smoking amount, and mean height, except mean age (50.0 ± 8.1 VS. 48.1 ± 7.3, P< 0.001) between the SHPTB and normal group. 52% of the 339 participants with SHPTB and 56% of the 3211 normal participants participated till the end of study. According to the final model, the SHPTB group showed significantly larger decrease in the average pFEV1 over the time than the normal group (P< 0.001) adjusted for gender, age, height, smoking pack years, and time effects. Especially, the interaction effect between time and group was statistically significant (P = 0.036). CONCLUSION: The average lung function in terms of pFEV1 decreases faster in subjects with SHPTB than in normal individuals over time.

The effect of an IκB-kinase-ß(IKKß) inhibitor on tobacco smoke-induced pulmonary inflammation.

PURPOSE OF THE STUDY: Inactivation of NF-κB with IKKß knockout mice reduces tobacco smoke-induced pulmonary inflammation. In this study, we investigated whether the IKKß inhibitor PS-1145 could attenuate the pulmonary inflammation induced by tobacco smoke. MATERIALS AND METHODS: We divided 30 mice into three groups: a control group, a smoking group, and a PS-1145 group. Mice from the smoking and PS-1145 groups were exposed for 2 weeks to tobacco smoke. PS-1145 was injected intraperitoneally before every tobacco smoke exposure. After 2 weeks, bronchoalveolar lavage (BAL) was performed for cell counting and measuring of inflammatory chemokines. We analyzed the correlation between NF-κB and NF-κB-regulated chemokines in BAL fluid and measured the neutrophils and macrophages by immunostaining in lung tissues. RESULTS: The PS-1145 group showed a significant reduction in the number of total cells, neutrophils, and macrophages, as well as the KC and MCP-1 level, in the BAL fluid compared to the smoking group. There was no significant difference in the level of MIP-1α. The level of NF-κB in BAL fluid was significantly positively correlated with KC and MCP-1 levels, but not with MIP-1α level. The PS-1145 group also showed a significant fewer neutrophils and macrophages in the lung tissue. CONCLUSIONS: We conclude that the IKKß inhibitor PS-1145 suppressed the NF-κB signaling pathway and reduced the recruitment of inflammatory cells and chemokines in pulmonary inflammation induced by tobacco smoke. IKKß inhibition offers a potential therapeutic target for tobacco smoke-induced pulmonary inflammation.