Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons.

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.

Dietary palmitic acid to oleic acid ratio modulates energy metabolism and biological rhythms in young healthy Japanese males.

The present study investigated the potential role of the composition of dietary fatty acids in the regulation of biological rhythms, such as the sleep architecture, core body temperature and leukocyte clock gene expression, in subjects fed meals rich in palmitic acid (PA) or oleic acid (OA). Eleven males participated in two sessions of indirect calorimetry in a whole-room metabolic chamber. In each session, subjects consumed three meals rich in PA (44·3 % of total fat as PA and 42·3 % as OA) or OA (11·7 % of total fat as PA and 59·3 % as OA) in the metabolic chamber. The ratio of PA to OA in plasma was significantly lower and fat oxidation was significantly higher during 24 h of indirect calorimetry in the session with meals rich in OA than in that with meals rich in PA. The duration of slow wave sleep (SWS) was shorter, the latency of SWS was longer and the nadir of core body temperature after bedtime was later in the session with meals rich in PA than in that with meals rich in OA. The peak in CRY1 gene expression was earlier and its amplitude was higher in the session with meals rich in PA than in that with meals rich in OA. In healthy young males, meals rich in PA decreased fat oxidation and disrupted biological rhythms, particularly the sleep architecture and core body temperature during sleep, more than meals rich in OA.

Protective Effect of Pemafibrate Treatment against Diabetic Retinopathy in Spontaneously Diabetic Torii Fatty Rats.

Diabetic retinopathy (DR) can cause visual impairment and blindness, and the increasing global prevalence of diabetes underscores the need for effective therapies to prevent and treat DR. Therefore, this study aimed to evaluate the protective effect of pemafibrate treatment against DR, using a Spontaneously Diabetic Torii (SDT) fatty rat model of obese type 2 diabetes. SDT fatty rats were fed either a diet supplemented with pemafibrate (0.3 mg/kg/d) for 16 weeks, starting at 8 weeks of age (Pf SDT fatty: study group), or normal chow (SDT fatty: controls). Normal chow was provided to Sprague-Dawley (SD) rats (SD: normal controls). Electroretinography (ERG) was performed at 8 and 24 weeks of age to evaluate the retinal neural function. After sacrifice, retinal thickness, number of retinal folds, and choroidal thickness were evaluated, and immunostaining was performed for aquaporin-4 (AQP4). No significant differences were noted in food consumption, body weight, or blood glucose level after pemafibrate administration. Triglyceride levels were reduced, and high-density lipoprotein cholesterol levels were increased. Extension of oscillatory potential (OP)1 and OP3 waves on ERG was suppressed in the Pf SDT fatty group. Retinal thickness at 1500 microns from the optic disc improved in the Pf SDT fatty group. No significant improvements were noted in choroidal thickness or number of retinal folds. Quantitative analyses showed that AQP4-positive regions in the retinas were significantly larger in the Pf SDT fatty group than in the SDT fatty group. The findings suggest that pemafibrate treatment can exert protective effects against DR.

Maternal GABAergic and GnRH/corazonin pathway modulates egg diapause phenotype of the silkworm Bombyx mori.

Diapause represents a major developmental switch in insects and is a seasonal adaptation that evolved as a specific subtype of dormancy in most insect species to ensure survival under unfavorable environmental conditions and synchronize populations. However, the hierarchical relationship of the molecular mechanisms involved in the perception of environmental signals to integration in morphological, physiological, behavioral, and reproductive responses remains unclear. In the bivoltine strain of the silkworm Bombyx mori, embryonic diapause is induced transgenerationally as a maternal effect. Progeny diapause is determined by the environmental temperature during embryonic development of the mother. Here, we show that the hierarchical pathway consists of a γ-aminobutyric acid (GABA)ergic and corazonin signaling system modulating progeny diapause induction via diapause hormone release, which may be finely tuned by the temperature-dependent expression of plasma membrane GABA transporter. Furthermore, this signaling pathway possesses similar features to the gonadotropin-releasing hormone (GnRH) signaling system for seasonal reproductive plasticity in vertebrates.

Factors associated with cavity formation after stereotactic body radiation therapy for peripheral early-stage lung cancer.

PURPOSE: This retrospective study aimed to identify the factors associated with cavity formation after SBRT in peripheral early-stage lung cancer patients. We analyzed the occurrence of cavity changes after SBRT. MATERIALS AND METHODS: We examined 99 cases with T1-T2aN0 peripheral non-small cell lung cancer treated with SBRT from 2004 to 2021. Patients underwent respiratory function tests, including diffusing capacity for carbon monoxide (DLco), before treatment. The median observation period was 35 months (IQR 18-47.5 months). Treatment involved fixed multi-portal irradiation in 67% of cases and VMAT in 33%. The total radiation doses ranged from 42 to 55 Gy, delivered over 4 to 5 fractions. RESULTS: Cavity formation occurred in 14 cases (14.1%), appearing a median of 8 months after SBRT. The cavity disappeared in a median of 4 months after formation. High DLco and total radiation dose were identified as factors significantly associated with cavity formation. There have been no confirmed recurrences to date, but one patient developed a lung abscess. CONCLUSION: Although cavity formation after SBRT for peripheral early-stage lung cancer is infrequent, it can occur. This study showed high DLco and total radiation dose to be factors significantly associated with cavity formation. These findings can be applied to optimizing radiation therapy (RT) and improving patient outcomes. Further research is needed to determine the optimal radiation dose for patients with near-normal DLco for whom surgery is an option. This study provides valuable insights into image changes after RT.

Characteristics of pleural effusion due to paradoxical response in patients with pulmonary tuberculosis.

BACKGROUND: Patients with pulmonary tuberculosis may present with deterioration of pleural effusion during anti-tuberculosis therapy, referred to as a paradoxical response (PR), with some patients requiring additional intervention. However, PR may be confused with other differential diagnoses, and the predictive factors for recommending additional therapies are unknown. Therefore, this study aimed to reveal useful information for the diagnosis and intervention of PR. METHODS: Data from human immunodeficiency virus-negative patients with tuberculous pleurisy (n = 210), including 184 patients with pre-existing pleural effusion and 26 patients with PR at Fukujuji Hospital, were retrospectively collected from January 2012 to December 2022 and compared. Furthermore, patients with PR were divided into the intervention group (n = 9) and the no intervention group (n = 17) and were compared. RESULTS: Patients in the PR group had lower pleural lactate dehydrogenase (LDH) (median 177 IU/L vs. 383 IU/L, p < 0.001) and higher pleural glucose (median 122 mg/dL vs. 93 mg/dL, p < 0.001) levels than those in the preexisting pleural effusion group. Other pleural fluid data were not significantly different. Patients in the intervention group had a shorter duration from the initiation of anti-tuberculosis therapy to the development of PR than patients in the no intervention group (median 19.0 days [interquartile range (IQR): 18.0-22.0] vs. median 37.0 days [IQR: 28.0-58.0], p = 0.012). CONCLUSION: This study demonstrates that, apart from lower pleural LDH and elevated pleural glucose levels, PR presents with similar features to preexisting pleural effusion and that patients who develop PR faster tend to require intervention.

Comparison of the thickness of the erector spinae muscles between aspiration pneumonia and bacterial pneumonia patients.

BACKGROUND AND AIMS: Aspiration pneumonia is generally associated with deterioration of skeletal muscle mass, which is usually evaluated by the erector spinae muscle cross-sectional area (ESMCSA); however, no report has assessed ESMCSA in patients with aspiration pneumonia. Furthermore, erector spinae muscle thickness (ESMT) was developed to be easier to measure than ESMCSA. Therefore, this study investigated the relationship between ESMT and ESMCSA in aspiration pneumonia patients compared to bacterial pneumonia patients. METHODS: We retrospectively collected data for 164 patients with aspiration pneumonia and 480 patients with bacterial pneumonia who were hospitalized at Fukujuji Hospital between September 2018 and May 2022. We assessed the correlations between ESMCSA and ESMT and compared the data between the two groups. RESULTS: ESMT had a strong, proportional relationship with ESMCSA in all patients (r = 0.908, p < 0.001) and those with aspiration pneumonia (r = 0.896, p < 0.001). ESMCSA (median 671.8 mm2 [range 164.0-1636.7] vs. median 1057.0 mm2 [range 161.3-2412.5], p < 0.001) and ESMT (median 17.1 mm [range 6.95-34.4] vs. median 23.8 mm [range 6.95-43.7], p < 0.001) were significantly lower in patients with aspiration pneumonia. A multivariate analysis of aspiration pneumonia diagnosis showed significant independent differences from bacterial pneumonia in ESMCSA (odds ratio 0.998 [95% CI: 0.996-0.999], p = 0.001) and ESMT (odds ratio 0.90 [95% CI: 0.84-0.96], p = 0.002). CONCLUSION: This study demonstrates a strong correlation between ESMCSA and ESMT. ESMT can be more easily used to evaluate skeletal muscle mass and can help in diagnosing aspiration pneumonia.

Genital mycobacteriosis caused by Mycobacterium marinum detected in two captive sharks by peptide nucleic acid-fluorescence in situ hybridization.

Mycobacterium marinum is a prevalent nontuberculous mycobacterium (NTM)-infecting teleosts. Conversely, little is known about mycobacteriosis in elasmobranchs, and M. marinum infection has never been reported from the subclass. This study investigated the histopathological characteristics and localization of this mycobacterium through molecular analysis of two captive sharks, a scalloped hammerhead Sphyrna lewini and a Japanese bullhead shark Heterodontus japonicus, exhibited in the same aquarium tank. We detected genital mycobacteriosis caused by M. marinum infection using molecular analyses, including polymerase chain reaction (PCR) and DNA sequencing targeting the 60 kDa heat-shock protein gene (hsp65), and peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH) targeting the 16S rRNA gene. Both sharks showed granulomas in connective tissues of the gonads without central necrosis or surrounding fibrous capsules, which is unlike the typical mycobacterial granulomas seen in teleosts. This study reveals that elasmobranchs can be aquatic hosts of M. marinum. Because M. marinum is a representative waterborne NTM and a potential zoonotic agent, cautious and intensive research is needed to overcome a lack of data on the relationship between NTM and the aquatic environment in association with this subclass of Chondrichthyes.

Core single nucleotide polymorphism analysis reveals transmission of Mycobacterium marinum between animal and environmental sources in two aquaria.

Mycobacterium marinum is a slow-growing, photochromogenic nontuberculous mycobacterium, which can cause mycobacteriosis in various animals, including humans. Several cases of fish mycobacteriosis have been reported to date. Mycobacterium marinum has also been isolated from aquatic environmental sources such as water, sand, biofilms, and plants in the natural environments. Hence, we hypothesized that a wide variety of sources could be involved in the transmission of M. marinum. In this study, we tested this hypothesis by isolating M. marinum from various sources such as fish, invertebrates, seagrass, periphytons, biofilms, sand, and/or water in two aquaria in Japan and conducting a phylogenetic analysis based on single-nucleotide polymorphisms (SNPs) using whole-genome sequences of the isolated strains. The analysis revealed that the strains from animal and environmental sources belonged to the same clusters. This molecular-based study epidemiologically confirmed that various sources, including fish, invertebrates, and environmental sources, could be involved in transmission of M. marinum in a closed-rearing environment. This is the first report where M. marinum was isolated from different sources, and various transmission routes were confirmed in actual cases, which provided essential information to improve the epidemiology of M. marinum.

New Oxyhalide Solid Electrolytes with High Lithium Ionic Conductivity >10†mS cm-1 for All-Solid-State Batteries.

All-solid-state batteries (ASSBs) with inorganic solid electrolytes (SEs) have attracted significant interest as next-generation energy storage. Halides such as Li3 YCl6 are promising candidates for SE because they combine high oxidation stability and deformability. However, the ionic conductivities of halide SEs are not as high as those of other SEs, especially sulfides. Here, we discover new lithium-metal-oxy-halide materials, LiMOCl4 (M=Nb, Ta). They exhibit extremely high ionic conductivities of 10.4 mS cm-1 for M=Nb and 12.4 mS cm-1 for M=Ta, respectively, even in cold-pressed powder forms at room temperature, which are comparable to or surpass those of organic liquid electrolytes used in lithium-ion batteries. Bulk-type ASSB cells using the oxyhalides as the cathode SE demonstrate an outstanding rate capability with a capacity retention of 80 % at 5 C/0.1 C. We believe that the proposed oxyhalides are promising SE candidates for the practical applications of ASSBs.

Engineering of human brain organoids with a functional vascular-like system.

Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.

Expression analysis of peptidergic enteroendocrine cells in the silkworm Bombyx mori.

Enteroendocrine cells (ECs) in the insect midgut respond to physiological changes in the intestine by releasing multiple peptides to control food intake, gastrointestinal activity and systemic metabolism. Here, we performed a comprehensive mapping of ECs producing different regulatory peptides in the larval midgut of Bombyx mori. In total, we identified 20 peptide genes expressed in different ECs in specific regions of the midgut. Transcript-specific in situ hybridisation combined with antibody staining revealed approximately 30 subsets of ECs, each producing a unique peptide or a combination of several different peptides. Functional significance of this diversity and specific roles of different enteroendocrine peptides are largely unknown. Results of this study highlight the importance of the midgut as a major endocrine/paracrine source of regulatory molecules in insects and provide important information to clarify functions of ECs during larval feeding and development.

The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.

Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infections, respectively. Jumonji domain containing-3 (Jmjd3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in the activation of macrophages. Here we show that Jmjd3 is essential for M2 macrophage polarization in response to helminth infection and chitin, though Jmjd3 is dispensable for M1 responses. Furthermore, Jmjd3 (also known as Kdm6b) is essential for proper bone marrow macrophage differentiation, and this function depends on demethylase activity of Jmjd3. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited number of genes. Among them, we identified Irf4 as encoding a key transcription factor that controls M2 macrophage polarization. Collectively, these results show that Jmjd3-mediated H3K27 demethylation is crucial for regulating M2 macrophage development leading to anti-helminth host responses.

Low-dosage ethambutol, less than 12.5 mg/kg/day, does not worsen the clinical outcomes of pulmonary Mycobacterium avium and Mycobacterium intracellulare disease: a retrospective cohort study.

OBJECTIVES: Multidrug chemotherapy is recommended for treating pulmonary Mycobacterium avium and Mycobacterium intracellulare disease. Although ethambutol has been demonstrated to inhibit macrolide resistance, the ethambutol dosage is sometimes decreased due to concerns about optic neuropathy. We aimed to assess whether lower ethambutol doses impact treatment outcomes. METHODS: Patients treated over 12 months between 2016 and 2020 were collected retrospectively. Clinical outcomes, including negative culture conversion, microbiological cure, adverse events, resistance to macrolides, and recurrence, were compared according to daily ethambutol dosage. RESULTS: Among 146 patients, 42 were treated with ethambutol dosages over 12.5 mg/kg/day, and 104 were treated with lower dosages. Negative culture conversion was achieved for 125 patients, and 90 patients achieved microbiological cure. Recurrence was identified in 16 patients who achieved microbiological cure. No macrolide resistance was observed, and no significant difference was observed in the percentage of negative culture conversion (P = 1.00) or microbiological cure (P = 0.67) between the high- and low-dosage ethambutol groups. Sputum smear positivity was associated with a lower adjusted odds ratio (aOR) of negative culture conversion (aOR: 0.48, 95% CI: 0.29-0.80). A lower aOR of microbiological cure was independently associated with sputum smear positivity (aOR: 0.52, 95% CI: 0.37-0.74) and with the use of an intermittent regimen (aOR: 0.60, 95% CI: 0.41-0.87). Daily ethambutol dosage was not identified as a prognostic factor for any of the outcomes. Optic neuropathy was observed in 7.1% of the high-dose ethambutol group and 1.0% of the low-dosage ethambutol group (P = 0.07). CONCLUSION: An ethambutol dosage of 12.5 mg/kg/day or less in guideline-based chemotherapy may reduce optic neuropathy without worsening clinical outcomes.

Usefulness of gastric aspirate for the diagnosis of smear-negative pulmonary tuberculosis.

INTRODUCTION: Gastric aspirate can be useful for the diagnosis of pulmonary tuberculosis (TB) in patients with smear-negative pulmonary TB or without sputum production. The gastric aspirate smear technique has low sensitivity, and a previous report demonstrated that no patient was diagnosed by only gastric aspirate analysis. However, some patients with TB have been negative on sputum examination but positive on gastric aspirate examination, and the incidence of such cases is uncertain. Therefore, this study investigated the usefulness of gastric aspirate in the diagnosis of pulmonary TB. METHODS: To analyze the diagnostic accuracy of gastric aspirate examination, the data of 513 patients with negative sputum smears or a lack of sputum production, including 203 patients with pulmonary TB (39.6%) and 93 patients with nontuberculous mycobacteriosis who underwent gastric aspiration at Fukujuji Hospital from January 2016 to March 2021, were collected retrospectively. RESULTS: The accuracy rates of gastric aspirate examination for the diagnosis of pulmonary TB were as follows: 21.2% sensitivity and 91.9% specificity for smear positivity, 55.8% sensitivity and 99.6% specificity for nucleic acid amplification test positivity, and 71.4% sensitivity and 100% specificity for culture positivity. Twenty-three patients (11.2%) were diagnosed by gastric aspirate examination alone. Among the 356 patients who underwent three repeated sputum examinations in addition to gastric aspirate examination, the cumulative diagnostic rate for the 3 mycobacterial examinations plus gastric aspirate examination was higher than that for only three sputum examinations. CONCLUSIONS: Gastric aspirate is useful for the diagnosis of TB in patients with smear-negative pulmonary TB or without sputum production.

Characteristics of pleural effusion with a high adenosine deaminase level: a case-control study.

BACKGROUND: Increased pleural fluid adenosine deaminase (ADA) is useful for diagnosing tuberculous pleurisy (TB), but high ADA levels are associated with other diseases. In this study, we compare various disease characteristics in patients with high-ADA pleural effusion. METHODS: We retrospectively collected data for 456 patients with pleural fluid ADA levels of ≥ 40 U/L from January 2012 to October 2021. Cases were classified as TB (n = 203), pleural infection (n = 112), malignant pleural effusion (n = 63), nontuberculous mycobacteria (n = 22), malignant lymphoma (ML) (n = 18), autoimmune diseases (n = 11), and other diseases (n = 27), and data were compared among those diseases. Predictive factors were identified by comparing data for a target disease to those for all other diseases. A diagnostic flowchart for TB was developed based on those factors. RESULTS: The most frequent disease was TB, though 60.0% of patients were diagnosed with other diseases. Median ADA levels in patients with TB were 83.1 U/L (interquartile range [IQR] 67.2-104.1), higher than those of patients with pleural infection (median 60.9 [IQR 45.3-108.0], p = 0.004), malignant pleural effusion (median 54.1 [IQR 44.8-66.7], p < 0.001), or autoimmune diseases (median 48.5 [IQR 45.9-58.2], p = 0.008), with no significant difference from NTM (p = 1.000) or ML (p = 1.000). Pleural fluid lactate dehydrogenase (LDH) levels of < 825 IU/L were beneficial for the diagnosis of TB. Neutrophil predominance or cell degeneration, white blood cell count of ≥ 9200/µL or C-reactive protein levels of ≥ 12 mg/dL helped in diagnosing pleural infection. Pleural fluid amylase levels of ≥ 75 U/L and a pleural fluid ADA/total protein (TP) ratio of < 14 helped in diagnosing malignant pleural effusion. High serum LDH and high serum/pleural fluid eosinophils helped in diagnosing ML and autoimmune diseases, respectively. The flowchart was comprised of the following three factors: pleural fluid LDH < 825 IU/L, pleural fluid ADA/TP of < 14, and neutrophil predominance or cell degeneration, which were decided by a decision tree. The diagnostic accuracy rate, sensitivity, and specificity for the diagnosis of TB were 80.9%, 78.8%, and 82.6%, respectively. CONCLUSION: Cases involving high pleural fluid ADA levels should be investigated using several factors to distinguish TB from other diseases.

Quality of life of caregivers supporting neurologically impaired patients who underwent surgery.

BACKGROUND: A questionnaire survey was conducted to clarify whether surgical treatments performed by a pediatric surgeon improve the quality of life (QOL) of caregivers (medical doctors, nurses, physical therapists, and nursery teachers) supporting neurologically impaired (NI) patients who work at specialized institutions. METHODS: The questionnaire survey was conducted with caregivers who cared for NI patients who underwent an operation at the Department of Pediatric Surgery, Kurume University Hospital. Quality-of-life related responses concerning the change of care after surgical procedures in NI patients were collected in addition to the background data related to caregivers and the surgical procedures performed for them. Degrees of difficulty in caring for NI patients and of the caregivers' own QOL postoperatively were also compared. RESULTS: There were 192 valid responses. The majority of responses were from females and nurses aged in their 40s and 50s. The surgical procedure performed most often in the NI patients was gastrostomy. Of the respondents, 77% answered that the postoperative care became easier. The degrees of difficulty in caring for NI patients and the caregivers' own QOL were significantly higher and lower, respectively, among physical therapists compared with caregivers in other occupations. Moreover, the QOL in respondents with factors related to a longstanding relationship with NI patients was significantly higher compared with the respondents without them. CONCLUSION: This survey indicated that surgical procedures for NI patients might contribute to improved QOL for the caregiver by reducing the difficulty of caring for NI patients.

Influence of laparoscopy-aided gastrostomy on gastroesophageal reflux in neurologically impaired patients using multichannel intraluminal impedance pH measurements.

BACKGROUND: Development of gastroesophageal reflux disease (GERD) after gastrostomy remains debatable. Therefore, this study aimed to evaluate whether laparoscopy-aided gastrostomy (LAG) influence on the occurrence of GERD in neurologically impaired (NI) patients. Furthermore, we investigated whether preoperatively excluding NI patients with GERD can reduce the number of patients requiring subsequent anti-reflux surgery (ARS) after LAG. METHODS: This retrospective study included 35 NI patients (median age: 11.0; interquartile range 5.0-23.5 years) who underwent LAG according to our criterion from October 2012 to June 2020 and MII-pH before and after LAG. MII-pH parameters were compared in all patients and among three age groups between before and after LAG. RESULTS: There were no significant differences in MII-pH parameters before and 1 year after LAG in all patients, and no patient underwent subsequent ARS. Only one paediatric patient with 64 number of reflux episodes before LAG required subsequent ARS 3 years after LAG. CONCLUSIONS: Generally, LAG did not influence the postoperative GERD at 1 year after LAG, and our criteria could reduce the number of patients requiring subsequent ARS. However, paediatric NI patients with higher number of reflux episodes in preoperative MII-pH study may need careful long-term follow-up after LAG.

Posttreatment Lymphopenia Is Associated With an Increased Risk of Redeveloping Nontuberculous Lung Disease in Patients With Mycobacterium avium Complex Lung Disease.

BACKGROUND: Lymphopenia has been reported as a risk factor for poor prognosis in various infectious diseases, including Mycobacterium avium complex lung disease (MAC-LD), and recurrence in several infectious diseases. However, the association between lymphopenia and the risk of redeveloping nontuberculous lung disease (NTM-LD) after completed treatment for MAC-LD is unknown. METHODS: We performed a retrospective cohort study with 147 patients with MAC-LD who successfully completed guideline-based therapy. Lymphopenia was defined as an absolute lymphocyte count (ALC) <1000 cells/µL based on commonly accepted reference values. RESULTS: During the median follow-up period of 41.9 months after treatment completion, 59 (40.1%) patients redeveloped NTM-LD. Patients with NTM-LD redevelopment had significantly lower posttreatment ALCs (median, 1260 vs 1420 cells/µL) than those without, and the univariate Cox proportional hazard analysis identified posttreatment ALC as a predictive factor for redevelopment (hazard ratio, .94 [95% confidence interval, .89-.99] for every increase of 100 cells/µL; P = .04). In the multivariate analysis, posttreatment ALC and the extent of bronchiectasis were independently associated with NTM-LD redevelopment. The cumulative rate of NTM-LD redevelopment was significantly higher in patients with posttreatment lymphopenia than in those without (P = .008). CONCLUSIONS: Posttreatment lymphopenia could predict an increased risk of NTM-LD redevelopment after completed treatment for MAC-LD.

T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development.

The transcription factor Foxp3 is essential for the development of regulatory T (Treg) cells, yet its expression is insufficient for establishing the Treg cell lineage. Here we showed that Treg cell development was achieved by the combination of two independent processes, i.e., the expression of Foxp3 and the establishment of Treg cell-specific CpG hypomethylation pattern. Both events were induced by T cell receptor stimulation. The Treg cell-type CpG hypomethylation began in the thymus and continued to proceed in the periphery and could be fully established without Foxp3. The hypomethylation was required for Foxp3(+) T cells to acquire Treg cell-type gene expression, lineage stability, and full suppressive activity. Thus, those T cells in which the two events have concurrently occurred are developmentally set into the Treg cell lineage. This model explains how Treg cell fate and plasticity is controlled and can be exploited to generate functionally stable Treg cells.