GOLM1 Promotes Pulmonary Fibrosis through Upregulation of NEAT1.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.

Effectiveness of azvudine in reducing mortality of COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: Azvudine has been approved for the treatment of coronavirus disease 2019 (COVID-19) patients in China, and this meta-analysis aims to illustrate the safety of azvudine and its effectiveness in reducing mortality. METHODS: PubMed, Embase, Web of science, Cochrane Library and the Epistemonikos COVID-19 Living Overview of Evidence database (L.OVE) were searched to aggregate currently published studies. Cochrane risk of bias tool and ROBINS-I tool were used to assess the risk of bias of randomized controlled study and cohort study respectively. Odds radios (ORs) with 95% confidence interval (CIs) were combined for dichotomous variables. Publication bias was assessed by Egger's test and funnel plots. RESULTS: A total of 184 articles were retrieved from the included databases and 17 studies were included into the final analysis. Pooled analysis showed that azvudine significantly reduced mortality risk in COVID-19 patients compared with controls (OR: 0.41, 95%CI 0.31-0.54, p < 0.001). Besides, either mild to moderate or severe COVID-19 patients could benefit from azvudine administration. There was no significant difference in the incidence of ICU admission (OR: 0.90, 95%CI 0.47-1.72, p = 0.74) and invasive ventilation (OR: 0.94, 95%CI 0.54-1.62, p = 0.82) between azvudine and control group. The incidence of adverse events was similar between azvudine and control (OR: 1.26, 95%CI 0.59-2.70, p = 0.56). CONCLUSIONS: This meta-analysis suggests that azvudine could reduce the mortality risk of COVID-19 patients, and the safety of administration is acceptable. TRIAL REGISTRATION: PROSPERO; No.: CRD42023462988; URL: https://www.crd.york.ac.uk/prospero/ .

Burnout among radiology residents: a systematic review and meta-analysis.

OBJECTIVE: To analyze the prevalence of burnout among radiology residents. METHOD: Five databases (PubMed, Web of Science, Embase, PsycINFO, and Scopus) were searched for studies reporting burnout in radiology residents for the period up to November 7, 2022. RESULTS: A total of 423 studies were identified, and eventually, 16 studies were selected for the qualitative analysis, of which 11 studies were used in the meta-analysis. There was a total of 2164 radiology residents. Six studies reported the prevalence of burnout but the data could not be pooled due to their inconsistent definitions of burnout. The mean scores of three burnout subscales indicated a moderate to high degree of severity: emotional exhaustion = 25.2 (95% CI, 22.1-28.3; I2 = 94.4%), depersonalization = 10.2 (95% CI, 8.5-11.9; I2 = 93.0%), and low perception of personal accomplishment = 32.9 (95% CI, 30.5-35.4; I2 = 94.4%). The pooled prevalence of high-degree emotional exhaustion was 49.9% (95% CI, 43.6-56.1%; I2 = 55.7%), high-degree depersonalization was 45.1% (95% CI, 38.3-52.0%; I2 = 63.2%), and high-degree diminished personal accomplishment was 58.2% (95% CI, 36.0-77.6%; I2 = 84.9%). The impact of the COVID-19 pandemic on radiology residents was not investigated. In addition, there are inconsistent findings on the effects of female sex, seniority, and social support on burnout. CONCLUSIONS: About half of the radiology residents showed at least one of the three burnout manifestations (emotional exhaustion, depersonalization, and personal accomplishment), with a moderate to high degree of severity. CLINICAL RELEVANCE STATEMENT: Such a high prevalence and severity of burnout among radiology residents warrant the attention of residency program directors. KEY POINTS: • Burnout, not uncommon among radiology residents, has not been effectively analyzed. • Nearly half of the radiology residents experience at least one of the three manifestations of burnout to a moderate to high degree. • The high prevalence and severe degree of burnout among radiology residents warrant the attention of residency program directors.

Gene mutations in sporadic lymphangioleiomyomatosis and genotype-phenotype correlation analysis.

BACKGROUND: Sporadic lymphangioleiomyomatosis (S-LAM) is a rare neoplasm with heterogeneous clinical features that is conventionally considered to be related to TSC2. This study serves to elucidate the mutation landscape and potential correlation between S-LAM genomic profiles and clinical phenotypes. METHODS: Genomic profiles of 22 S-LAM patients were obtained by sequencing genomic DNA and cell-free DNA from various specimens using an NGS (next-generation sequencing)-based tumor-driver gene panel. Detected mutations were summarized. Symptoms, serum vascular endothelial growth factor D (VEGF-D) values, pulmonary function, and six-minute walk distance (6MWD) were compared among groups with different TSC2 status and genotypes to analyze genotype-phenotype correlations. RESULTS: 67 Variants in 43 genes were detected, with a TSC2 mutation detection rate of 68.2%. The TSC2 detection rate was similar in specimens obtained either through transbronchial lung biopsy (TBLB) or surgical lung biopsy (70.0% vs. 69.2%, p > 0.05). A novel mutation in VEZF1 (c.A659G) was detected in four participants and may represent a mild disease state. TSC2 mutation was significantly related to a shorter 6MWD (p < 0.05), and a higher percentage of VEGF-D over 800 pg/mL (p < 0.05); stop-gain mutation was significantly related to a higher prevalence of pneumothorax. CONCLUSIONS: Tumor-driver mutations in genes other than TSC2 may have a role in S-LAM, and TBLB specimens are practical alternatives for genomic analysis. TSC2 mutation detectability and types are related to the disease severity and phenotypes of S-LAM.

[Clinical analysis of pulmonary nocardiosis associated with bronchiectasis].

Objective: To better understand the clinical characteristics of pulmonary nocardiosis associated with bronchiectasis. Methods: Patients diagnosed as bronchiectasis complicated with pulmonary nocardiosis in 9 tertiary general hospitals in China were enrolled from March 2016 to March 2020, with the record of general data, imaging performance and pathogen. The literature was reviewed. Results: Totally 17 patients were included. There were 12 females and 5 males. The ages ranged from 45 to 79 years, with an average of (63±9) years. There were 15 nonsmokers and 2 smokers, all of whom with chronic course. The clinical manifestations were mostly cough, expectoration, hemoptysis, fever, and dyspnea. The imaging manifestation was bronchiectasis in both lungs, with the most common involvement in the left lower lung, right middle lobe and left lingual lobe. Sputum cultures were positive in 10 cases, bronchoalveolar lavage fluid (BALF) cultures were positive in 6 cases, and next generation gene sequencings were positive in 4 cases, including 2 cases of Nocardia gelsenkii, 2 cases of Nocardia abscess, 2 cases of Nocardia stellate, 1 case of Nocardia mexicana, 1 case of Nocardia otitis caviae, and 9 cases of undetermined Nocardia. There were 3 cases of Klebsiella pneumoniae, 2 cases of Pseudomonas aeruginosa and 2 cases of Aspergillus. The symptoms and imaging of all patients were improved after anti Nocardia therapy. Conclusions: Bronchiectasis combined with nocardiosis is more common in middle-aged and elderly women without smoking, which is similar to the clinical manifestations of Lady Windermere syndrome. Bronchiectasis often involves the left lower lobe, right middle lobe and left lingual lobe. Nocardia infection might further precipitate the initiation and progression of bronchiectasis.

Pulmonary manifestations of Erdheim-Chester disease: clinical characteristics, outcomes and comparison with Langerhans cell histiocytosis.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis that typically affects many organs, including the lung and pleura. However, there are few studies concerning pulmonary involvement in ECD patients, as well as the difference of pulmonary involvement between ECD and Langerhans cell histiocytosis (LCH). We performed a retrospective study of 54 ECD patients, and compared the pulmonary manifestations with those of adult LCH patients in our centre. The median age of diagnosis of the 54 ECD patients was 48 years (range 9-66 years). Chest computed tomography (CT) scans revealed lung involvement in 49 (91%) patients and pleural involvement in 34 (63%). Thirty-three (61%) patients had interstitial lung disease (ILD) with varying degrees of interlobular septal thickening, micronodules, and ground-glass opacities. ECD and LCH patients with pulmonary involvement showed significant differences in smoking status (P < 0·001), respiratory symptoms (P = 0·001) such as cough and pneumothorax (P < 0·001), and radiological findings, including cysts (P < 0·001), opacities (P < 0·001), and pleural thickening (P < 0·001). With a median follow-up duration of 24 months (range, 1-84 months), the estimated three-year overall survival (OS) of this entire ECD cohort was 90·2%. Patients with ILD tended to have worse progression-free survival (PFS) than those with no ILD (P = 0·29).

Ga-68 EDTA aerosols in evaluation of inhaled-particle deposition and clearance of obstructive pulmonary diseases: A pilot prospective study compared with Galligas.

PURPOSE: 68-gallium (Ga-68) ethylenediaminetetraacetic acid (EDTA) aerosols and Galligas were compared in evaluation of inhaled-particle deposition and clearance in volunteers with or without obstructive pulmonary diseases. METHODS: Nonsmoking healthy volunteers, healthy smokers, asthma patients and patients with chronic obstructive pulmonary disease (COPD) were recruited to undergo the dynamic lung ventilation positron emission tomography/computerized tomography (PET/CT) scans within two consecutive days. The inhaled particles were Ga-68-labelled carbon nanoparticles (Galligas, 30-60 nm in size) and Ga-68-labelled EDTA aerosols (1-2 µm in size), respectively. The volunteers' lung function parameters were measured for comparison. RESULTS: Central deposition and inhomogeneity of both tracers were negatively correlated with lung function parameters, including the ratio of forced expiratory volume at 1 second to forced vital capacity (FEV1 /FVC). The central or hilum deposition of Galligas, but not 68-gallium (Ga-68) EDTA, was negatively correlated with the maximal expiratory flow at 25%, 50% and 75% of the forced vital capacity. Compared with Galligas, Ga-68 EDTA aerosols were more concentrated in the central region in all groups except for the healthy nonsmokers. Ventilation inhomogeneity was more evident when using Ga-68 EDTA aerosols, especially in patients with COPD and asthma patients. In the healthy smokers, the central region accumulated more Ga-68 EDTA at 30 minutes after inhalation than immediately after inhalation. Ga-68 EDTA cleared faster in lungs than Galligas. CONCLUSIONS: Both Galligas and Ga-68 EDTA aerosols can be used for PET/CT lung ventilation scan. However, Ga-68 EDTA aerosols showed more advantages in diagnosis and evaluation of obstructive airway diseases by revealing the inhaled-particle deposition and clearance.

The value of transbronchial lung biopsy in the diagnosis of lymphangioleiomyomatosis.

BACKGROUND: Transbronchial lung biopsy (TBLB) in the diagnosis of lymphangioleiomyomatosis (LAM) is not a common approach, although TBLB is often performed in diffuse lung diseases. We aimed to examine the diagnostic value and safety of TBLB in LAM patients based on the data collected in our center. METHODS: We reviewed LAM patients registered in our LAM Clinic from December 8, 2006, to December 31, 2019. All patients with definite or probable diagnosis of LAM who had been examined using TBLB were included. All available pathology slides were reviewed by an experienced LAM pathologist. All complications were reviewed by the medical records and confirmed using telephone interviews. RESULTS: The pathology results of 86 patients (including 74 definite LAM and 12 probable LAM) were available. The positive rate of TBLB in LAM patients was 49/86 (57.0%). The positive rates of SMA, HMB-45, ER, and PR in LAM patients were 97.6%, 93%, 84.6%, and 78.4% respectively. The positive rate of TBLB was 40%, 60% and 60.8% in patients with CT Grade I, Grade II, and Grade III respectively, and the difference was not significant. Patients who had 3-4 or 5-6 biopsied specimens had a higher rate of diagnosis than those with 1-2 biopsied specimens. Four patients (5.6%) reported pneumothorax. No major hemoptysis was reported. CONCLUSIONS: TBLB is a feasible and safe procedure for obtaining a pathological diagnosis of LAM. Taking more than 2 samples during the biopsy procedure increased the rate of diagnosis.

Airway-invasion-associated pulmonary computed tomography presentations characteristic of invasive pulmonary Aspergillosis in non-immunocompromised adults: a National Multicenter Retrospective Survey in China.

BACKGROUND: The European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria are widely used in the diagnosis of invasive pulmonary aspergillosis (IPA), but they only apply to immunocompromised patients. We here aimed to identify clinical characteristics helpful to the diagnosis of IPA in non-immunocompromised patients. METHODS: This is a multicenter retrospective study. Data were collected from adult patients with IPA admitted to 15 tertiary hospitals in China from 2010 to 2016. RESULTS: We included 254 patients in the study, of whom 66 (26.0%) were immunocompromised, and 188 (74.0%) were not. Airway-invasion-associated computed tomography (CT) signs including patchy exudation along the airway (67.6% vs. 45.5%, P = 0.001) and thickened airway wall (42.0% vs. 16.7%, P < 0.001) were more common in non-immunocompromised patients than in immunocompromised ones, and angio-invasive CT signs were more common in immunocompromised patients (55.3% vs.72.7%, P = 0.013). Typical angio-invasive CT signs were delayed in non-immunocompromised IPA patients, whereas airway-invasive signs appear earlier. Host immunocompromised condition was associated with ICU admission and/or intubation (OR 1.095; 95% CI 1.461-6.122; P = 0.003). Poor prognosis (35.5% vs. 21.1%, P = 0.005) was more common in immunocompromised patients. CONCLUSION: Airway-invasion-associated CT presentations at early stages of the disease are characteristic of IPA in non-immunocompromised hosts.

Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a slow albeit progressive rare neoplastic disease featured with diffuse thin-walled cysts in lungs and angiomyolipomas in kidneys. LAM affects almost exclusively women and has one of the strongest gender predispositions of any extragenital human disease. Two forms of LAM present clinically, sporadic (S-LAM) and tuberous sclerosis complex-associated (TSC-LAM). TSC is an autosomal dominant genetic multisystems neoplastic disease. A high prevalence of LAM can be detected in adult female TSC patients. Tremendous progress has been made in our understanding and management of this rare disease. Both LAM and TSC are TSC2 or TSC1 mutated diseases that result in overactivation of the mechanistic target of rapamycin (mTOR) pathway. Sirolimus, an mTOR inhibitor, has been approved for LAM treatment in the United States and many other countries. Therapies targeting female sex hormones have shown preclinical efficacy in animal and cell culture-based experiments, but have not been properly investigated clinically. In this review, we summarize current recommendations in the diagnosis and treatment of LAM.

Lung function and systemic inflammation associated with short-term air pollution exposure in chronic obstructive pulmonary disease patients in Beijing, China.

BACKGROUND: Exposure to air pollution is associated with chronic obstructive pulmonary disease (COPD). However, findings on the effects of air pollution on lung function and systemic inflammation in Chinese COPD patients are inconsistent and scarce. This study aims to evaluate the effects of ambient air pollution on lung function parameters and serum cytokine levels in a COPD cohort in Beijing, China. METHODS: We enrolled COPD participants on a rolling basis from December 2015 to September 2017 in Beijing, China. Follow-ups were performed every 3 months for each participant. Serum levels of 20 cytokines were detected every 6 months. Hourly ambient pollutant levels over the same periods were obtained from 35 monitoring stations across Beijing. Geocoded residential addresses of the participants were used to estimate daily mean pollution exposures. A linear mixed-effect model was applied to explore the effects of air pollutants on health in the first-year of follow-up. RESULTS: A total of 84 COPD patients were enrolled at baseline. Of those, 75 COPD patients completed the first-year of follow-up. We found adverse cumulative effects of particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO) on the forced vital capacity % predicted (FVC % pred) in patients with COPD. Further analyses illustrated that among COPD patients, air pollution exposure was associated with reduced levels of serum eotaxin, interleukin 4 (IL-4) and IL-13 and was correlated with increased serum IL-2, IL-12, IL-17A, interferon γ (IFNγ), monocyte displacing protein 1 (MCP-1) and soluble CD40 ligand (sCD40L). CONCLUSION: Acute exposures to PM2.5, NO2, SO2 and CO were associated with a reduction in FVC % pred in COPD patients. Furthermore, short-term exposure to air pollutants increased systemic inflammation in COPD patients; this may be attributed to increased Th1 and Th17 cytokines and decreased Th2 cytokines.

Fatal myositis and spontaneous haematoma induced by combined immune checkpoint inhibitor treatment in a patient with pancreatic adenocarcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have achieved unprecedented success in cancer treatment over the past decade. The application of ICIs hasled to the discovery of various types of immune-related adverse events (irAEs). Here, we report a case of fatal myositis and spontaneous haematoma following concurrent treatment of nivolumab and ipilimumab for pancreatic adenocarcinoma. CASE PRESENTATION: A 71-year-old gentleman with pancreatic adenocarcinoma underwent the Whipple procedure in September 2014. The patient received 8 cycles of adjuvant chemotherapy with gemcitabineand achieved a complete responsein April 2015. Treatment with the PD-1 inhibitor nivolumab was started due to suspected tumour recurrence in November 2015. In August 2016, the CTLA-4 inhibitor ipilimumab was added to nivolumab for 2 cycles. Eight weeks after the last dose, the patient developed severe myositis complicated with spontaneous haematomain skeletalmuscle. Pathology of the skeletal muscle autopsy revealed lymphocytic infiltration. Intense immunosuppressive therapy, including high-dose corticosteroids and methotrexate, resulted in clinical success in the treatment of myositis. However, the patient died of cancer recurrence. CONCLUSION: Myositis due to immunotherapy can be a fatal adverse event of ICIs, which requires close monitoring and cautious management.

Global lung function initiative 2012 reference values for spirometry in Asian Americans.

BACKGROUND: Spirometry reference values specifically designed for Asian Americans are currently unavailable. The performance of Global Lung Function Initiative 2012 (GLI-2012) equations on assessing spirometry in Asian Americans has not been evaluated. This study aimed to assess the fitness of relevant GLI-2012 equations for spirometry in Asian Americans. METHODS: Asian subjects who never smoked and had qualified spirometry data were extracted from the National Health and Nutrition Examination Survey (NHANES) 2011-2012. Z-scores of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC were separately constructed with GLI-2012 equations for North East (NE) Asians, South East (SE) Asians, and individuals of mixed ethnic origin (Mixed). In addition, Proportions of subjects with observed spirometry data below the lower limit of normal (LLN) were also evaluated on each GLI-2012 equation of interest. RESULTS: This study included 567 subjects (250 men and 317 women) aged 6-79 years. Spirometry z-scores (z-FEV1, z-FVC, and z-FEV1/FVC) based on GLI-2012 Mixed equations had mean values close to zero (- 0.278 to - 0.057) and standard deviations close to one (1.001 to 1.128); additionally, 6.0% (95% confidence interval (CI) 3.1-8.9%) and 6.4% (95% CI 3.7-9.1%) of subjects were with observed data below LLN for FEV1/FVC in men and women, respectively. In contrast, for NE Asian equations, all mean values of z-FEV1 and z-FVC were smaller than - 0.5; for SE Asian equations, mean values of z-FEV1/FVC were significantly smaller than zero in men (- 0.333) and women (- 0.440). CONCLUSIONS: GLI-2012 equations for individuals of mixed ethnic origin adequately fitted spirometry data in this sample of Asian Americans. Future studies with larger sample sizes are needed to confirm these findings.

Secondary pulmonary alveolar proteinosis: a single-center retrospective study (a case series and literature review).

BACKGROUND: Secondary pulmonary alveolar proteinosis (sPAP) is an extremely rare disease. The clinical features of sPAP patients remain to be summarizeds. METHODS: Patients pathologically diagnosed with PAP and with negative results for anti-granulocyte macrophage colony stimulating factor (GM-CSF) autoantibodies from Peking Union Medical College Hospital between January 2000 and July 2016 were retrospectively studied. The PubMed database was also searched for literature to collect published cases. RESULTS: In our center, nine patients were diagnosed as sPAP with a median age of 37 years. Hematological disorders, including myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and pulmonary tuberculosis (TB) infection were the underlying diseases. Cases secondary to MDS had very poor prognosis as all of them survived less than 2 years after their diagnosis, while those secondary to TB had favorable prognosis. Only 33.3% of cases showed interlobular septal thickening in our sPAP group. Through literature review, 164 sPAP cases were collected. The age at diagnosis was 45.0 ± 14.8 years old and the gender radio was 1.20:1 (M:F). 61.9% of cases were diagnosed by bronchoscopy. MDS and CML were common underlying diseases in 34.1% and 15.2% of patients, respectively. Patients with sPAP secondary to hematological diseases had a short survival time and half of them died within 14.95 months after diagnosis. CONCLUSIONS: MDS and TB infection were the most frequent underlying causes of sPAP in this single-center research in China, with cases secondary to MDS having a poor survival rate. sPAP was more likely to be secondary to hematological disorders, especially MDS and CML and had a fairly poor prognosis in published cases. sPAP should be suspected in PAP patients whose CT scan presents only ground-glass opacities without interlobular septal thickening.

A novel homozygous complex deletion in CFTR caused cystic fibrosis in a Chinese patient.

Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians, but is considered to be a very rare disease in Chinese population. Here, we present an 11-year-old Chinese CF patient with disseminated bronchiectasis and salty sweat, for whom exon sequencing followed by multiplex ligation-dependent probe amplification analysis of the CFTR gene was applied for mutation screening. A homozygous deletion involving exon 20 of CFTR was observed in the patient's genome. Molecular characterization of the breakpoints indicated that both alleles of this locus had an identical novel complex rearrangement (c.3140-454_c.3367+249del931ins13, p.R1048_G1123del), leading to an in-frame removal of 76 amino acid residues in the second transmembrane domains of the CFTR protein. Although a same haplotype containing this complex rearrangement was observed on both of the maternal and paternal alleles, the parents denied any blood relationship as far as they know. Genome-wide homozygosity mapping was performed through SNP microarray and only a single homozygous interval of ~14.1 Mb at chromosome 7 containing the CFTR gene was observed, indicating the possible origin of the deletion from a common ancestor many generations ago. This study expands the mutation spectrum of CFTR in patients of Chinese origin and further emphasizes the necessity of MLPA analysis in mutation screening for CF patients.

Tsc1 deficiency-mediated mTOR hyperactivation in vascular endothelial cells causes angiogenesis defects and embryonic lethality.

This is a study on the role of tuberous sclerosis complex1 (TSC1) mutation and mTOR activation in endothelial cells during angiogenic and embryonic development. Past studies had shown that Tsc1/Tsc2 mutant genes lead to overactivation of mTOR in the regulating pathways in developing fetus. We used conditional Cre-loxp gene knockout approach to delete Tsc1 in mice's endothelial cells in our experimental models. Similarly, activation of mTOR signaling in endothelial cells of these embryos (Tie2-Cre/Tsc1(-/-)) was found. Majority of Tie2-Cre/Tsc1(-/-) embryos died at embryonic day 14.5 in utero. Cardiovascular defects, subcutaneous edema and hemorrhage were present among them. Whole-mount immunostaining in these embryos revealed a disorganized vascular network, defective sprouting of vessels in yolk sac and thickening of the labyrinth layer in the placenta. A thinner ventricular wall with disorganized trabeculae was present in the hearts of Tie2-Cre/Tsc1(-/-) embryos. Endothelial cells in Tsc1-deficient mice showed defective mitochondrial and endoplasmic reticular morphology, but no significant change was observed in cell junctions. The mutant embryos displayed significantly reduced cell proliferation, increased apoptosis and disturbed expression of angiogenic factors. A cohort of mice was treated prenatally with mTOR inhibitor rapamycin. The offspring of these mutant mice survived up to 22 days after birth. It was concluded that physiological TSC1-mTOR signaling in endothelial cells is crucial for vascular development and embryogenesis. We postulated that disruption of normal angiogenic pathways through hyperactive mTOR signaling maybe the mechanism that lead to deranged vascular pathogenesis in the tuberous sclerosis complex.

Diffuse Cystic Lung Diseases: Diagnostic Considerations.

Diffuse cystic lung disease (DCLD) is a group of heterogeneous diseases that present as diffuse cystic changes in the lung on computed tomography of the chest. Most DCLD diseases are rare, although they might resemble common diseases such as emphysema and bronchiectasis. Main causes of DCLD include lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, pulmonary Langerhans cell histiocytosis, lymphoid interstitial pneumonia, amyloidosis, light-chain deposition disease, Sjögren syndrome, and primary or metastatic neoplasm. We discuss clinical factors that are helpful in the differential diagnosis of DCLDsuch as sex and age, symptoms and signs, extrapulmonary presentations, cigarette smoking, and family history. Investigations for DCLD include high-resolution computed tomography, biochemical and histopathological studies, genetic tests, pulmonary function tests, and bronchoscopic and video-assisted thoracoscopic biopsies. A proposed diagnostic algorithm would enhance ease of diagnosing most cases of DCLD.

Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients.

BACKGROUND AND OBJECTIVE: Cystic fibrosis (CF) is a relatively common autosomal recessive disorder in Caucasians. CF is considered a very rare disease in Asians, and fewer than 30 Chinese CF patients are reported in the literature. We enrolled seven patients of Chinese Han origin diagnosed with CF at the Peking Union Medical College Hospital, to characterize gene mutations and phenotypes of CF in Chinese patients. METHODS: We analysed the clinical presentation and screened the coding region of the CFTR gene for each patient. RESULTS: Patients were 0-6 years old at onset of symptoms and were 10-28 years old at the time of diagnosis with CF. None of the seven patients had a family history of CF, and only one patient had parents who were consanguineous. Two patients had gastrointestinal symptoms but stool Sudan III results were normal. Four of the seven CF patients also had allergic bronchopulmonary aspergillosis. The concentration of chloride in patients' sweat ranged from 66 mmol/l to 154 mmol/l. In total, we identified 11 different mutations in seven CF patients, including one novel mutation (△E7-E11). Only one of these mutations (R553X) is present in the Caucasian CFTR common mutation-screening panel; and none of the 11 mutations are common in Caucasian CF patients. CONCLUSIONS: CF in China is difficult to diagnose because of a combination of low awareness, atypical clinical symptoms, and a lack of sweat and genetic testing facilities in most hospitals. The mutations identified in Chinese CF patients are different from the common Caucasian gene mutations.

Characteristics of serum lipid metabolism in patients with autoimmune pulmonary alveolar proteinosis.

OBJECTIVE: To study the serum lipid panels in consecutive autoimmune pulmonary alveolar proteinosis(APAP)patients and analyze their relationship with anti-granulocyte macrophage-colony stimulating factor(GM-CSF)antibody and other markers. METHODS: Thirty-two non-diabetic APAP patients were enrolled in the study. Serum lipids of these patients and 100 healthy volunteers were tested after an overnight fasting. Anti-GM-CSF antibody levels were measured with enzyme-linked immunosorbent assay. The correlation of serum lipids with lactate dehydrogenase,carcinoembryonic antigen,pulmonary function,and artery blood gas parameters were analyzed. RESULTS: Total cholesterol and low-density lipoprotein cholesterol levels [(5.54±0.99)and(3.73±0.83)mmol/L respectively] were significantly higher in APAP patients than in healthy volunteers [(5.05±0.97)and(3.17±0.89)mmol/L respectively](all P<0.05). High-density lipoprotein cholesterol(HDL-C)level of the APAP group [(1.10±0.18)mmol/L ]was significantly lower than that of the healthy group(P<0.05). Low-density lipoprotein/HDL and total cholesterol/HDL ratios in the APAP group(3.47±0.90 and 5.14±1.12 respectively)were significantly higher than those in the healthy group[(2.63±0.87)and(4.18±1.12)](all P<0.05). There was no significant difference in triglyceride level between the two groups(P>0.05). HDL-C level was negatively correlated with alveolar-arterial oxygen pressure difference(r=-0.436,P<0.05)and positively correlated with arterial oxygen saturation(r=0.459,P<0.05). None of the lipid markers correlated with serum anti-GM-CSF antibody levels(all P>0.05). CONCLUSIONS: APAP patients were likely to suffer from disturbed lipid metabolism,which was correlated with disease severity to some degree. Lipid markers deserved more attention in the management of APAP patients.