Hyperglycemia induced cathepsin L maturation linked to diabetic comorbidities and COVID-19 mortality.

Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Leprdb/dbmice and Leprdb/+mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications.

People with diabetes are at greater risk of developing severe COVID-19 and dying from the illness, which is caused by a virus known as SARS-CoV-2. The high blood sugar levels associated with diabetes appear to be a contributing factor to this heightened risk. However, diabetes is a complex condition encompassing a range of metabolic disorders, and it is therefore likely that other factors may contribute. Previous research identified a link between an enzyme called cathepsin L and more severe COVID-19 in people with diabetes. Elevated cathepsin L levels are known to contribute to diabetes complications, such as kidney damage and vision loss. It has also been shown that cathepsin L helps SARS-CoV-2 to enter and infect cells. This raised the question of whether elevated cathepsin L is responsible for the increased COVID-19 vulnerability in patients with diabetes. To investigate, He, Zhao et al. monitored disease severity and cathepsin L levels in patients with COVID-19. This confirmed that people with diabetes had more severe COVID-19 and that higher levels of cathepsin L are linked to more severe disease. Analysis also revealed that cathepsin L activity increases as blood glucose levels increase. In laboratory experiments, cells exposed to glucose or fluid from the blood of people with diabetes were more easily infected with SARS-CoV-2, with cells genetically modified to lack cathepsin L being more resistant to infection. Further experiments revealed this was due to glucose promoting maturation and migration of cathepsin L in the cells. The findings of He, Zhao et al. help to explain why people with diabetes are more likely to develop severe or fatal COVID-19. Therefore, controlling blood glucose levels in people with diabetes may help to prevent or reduce the severity of the disease. Additionally, therapies targeting cathepsin L could also potentially help to treat COVID-19, especially in patients with diabetes, although more research is needed to develop and test these treatments.

[Allergic bronchopulmonary aspergillosis in patients with chronic obstructive pulmonary disease: report of 3 cases].

OBJECTIVE: To improve the clinical knowledge on allergic bronchopulmonary aspergillosis (ABPA) combined with COPD by report of cases. METHODS: We retrospectively analyzed the clinical information of 3 cases of ABPA combined with COPD diagnosed in our hospital from Jan. 2009 to Dec. 2012. RESULTS: The 3 patients were all males, and aged from 68 to 82 years. The main complaints of all the patients were exertional dyspnea, cough and sputum production, with episodes of wheezing. All patients denied the history of allergic diseases, e.g., asthma, rhinitis, sinusitis, eczema, and family history of asthma. They all had a history of heavy smoking. The pulmonary function tests indicated obstructive impairment, and the ratio of FEV1 to FVC (FEV1/FVC) after bronchodilators were 30%, 33% and 43%, respectively, with no significant bronchodilator reversibility, which were consistent with the diagnostic criteria for COPD, with 1 case in GOLD grade III and 2 cases in GOLD grade IV based on the GOLD spirometric criteria for COPD severity. Lung HRCT showed emphysema with or without bulla formation. All cases showed immediate positive response to Aspergillus antigen by skin prick test (SPT), increased serum total IgE > 1000 kU/L, increased serum level of Aspergillus specific IgE (>0.35 kU/L) and IgG (>40 mg/L). Central bronchiectasis was also evident on HRCT scan in the 3 patients. In addition, the eosinophil percentage in peripheral blood was all >5%. Pulmonary infiltrates, brown phlegm plugs, and growth of Aspergillus fumigatus were also noted in some cases. After the diagnosis of ABPA, the patients were all given oral prednisone therapy, with notable improvement in dyspnea and FEV1. CONCLUSIONS: ABPA in COPD is uncommon, but early identification and initiation of systemic corticosteroid therapy can lead to improvement in symptoms and prognosis. For COPD patients with recurrent attacks of wheezing or are unresponsive to combination therapy of inhaled long-acting bronchodilators and corticosteroids, concurrent ABPA should be suspected and investigated accordingly.

New-onset COVID-19-related diabetes: an early indicator of multi-organ injury and mortally of SARS-CoV-2 infection.

Objective: The pandemic of 2019 coronavirus (SARS-CoV-2) disease (COVID-19) has imposed a severe public health burden worldwide. Most patients with COVID-19 were mild. Severe patients progressed rapidly to critical condition including acute respiratory distress syndrome (ARDS), multi-organ failure and even death. This study aims to find early multi-organ injury indicators and blood glucose for predicting mortality of COVID-19. Methods: Fasting blood glucose (FBG) ≥7.0 mmol/L for two times during hospitalization and without a history of diabetes were defined as new-onset COVID-19-related diabetes (CRD). Indicators of injuries for multiple organs, including the lung, heart, kidney and liver, and glucose homeostasis were specifically analyzed for predicting death. Results: A total of 120 patients with a severity equal to or greater than Moderate were hospitalized. After excluding patients with history of diabetes, chronic heart, kidney, and liver disease, 69 patients were included in the final analysis. Of the 69 patients, 23 were Moderate, 20 were Severe, and 26 were Critical (including 16 deceased patients). Univariable analysis indicated that CRD, lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), creatine kinase (CK) and creatinine (Cr) were associated with death. Multivariable analysis indicated that CRD was an independent predictor for death (HR = 3.75, 95% CI 1.26-11.15). Abnormal glucose homeostasis or CRD occurred earlier than other indicators for predicting poor outcomes. Indicators of multiple organ injury were in parallel with the expression patterns of ACE2 (the SARS-CoV-2 receptor) in different organs including pancreatic islet. Conclusions: New-onset COVID-19-related diabetes is an early indicator of multi-organ injury and predictor for poor outcomes and death in COVID-19 patients. As it is easy to perform for clinical practices and self-monitoring, glucose testing will be helpful for predicting poor outcomes to facilitate appropriate intensive care.

[Sarcoidosis with upper airway involvement as the presenting symptoms: case report and literature review].

OBJECTIVE: To investigate the clinical characteristics of sarcoidosis with upper airway (including nose/paranasal sinus, pharynx, larynx and middle ear) involvement as the presenting symptoms, and therefore to minimize the misdiagnosis of sarcoidosis with special manifestations. METHODS: Four cases of sarcoidosis with upper airway involvement as the presenting symptoms diagnosed at our hospital were described. The clinical data were analyzed and related literatures were reviewed. RESULTS: Three female patients aged 52, 53, 34 years and one 15-year-old male patient, with the main complaints as "mycteric mass", "chronic otitis media", "hoarseness" and "chronic tonsillitis" respectively, were referred to our hospital for further evaluation. The diagnosis of sarcoidosis was finally confirmed by biopsy of bronchial mucous membrane, enlarged peripheral lymph nodes, and otorhinolaryngological lesions. Physical examination and imaging findings showed involvements of the lungs and/or the lymph nodes in 3 patients. Seven Chinese articles about upper airway sarcoidosis (all involving the nose) were found after literature search with "sarcoidosis" as the key word at the CNKI database (1915 - 2011). English literature search with the same key word at "Pubmed" showed that the rate of upper airway involvement in sarcoidosis varied from 2.3% - 6.0%, mostly concurrent with thoracic and lymph node diseases, whereas cases of sarcoidosis presenting with otorhinolaryngological symptoms were occasionally reported. CONCLUSIONS: Although upper airway sarcoidosis was rare, it may be the cause of chronic otorhinolaryngological disease which responded poorly to routine treatments. Careful collection of medical history, physical examination and necessary accessory examinations, especially better understanding of the exceptional manifestations of sarcoidosis, can help to minimize misdiagnosis and therefore to improve the prognosis of the patients.

[A comparative clinical analysis of thoracic sarcoidosis and multi-organ sarcoidosis].

OBJECTIVE: To investigate the clinical characteristics of thoracic sarcoidosis compared with multi-organ sarcoidosis. METHODS: The clinical data of 24 patients with thoracic sarcoidosis and 29 patients with multi-organ sarcoidosis histologically diagnosed at Beijing Tongren Hospital from 1995 to 2010 were retrospectively analyzed. The demographic data, clinical manifestations, diagnostic procedures, involved organs, serum angiotensin converting enzyme (ACE) levels, lung functions, and cellular characteristics of bronchoalveolar lavage fluid (BALF) were compared. RESULTS: No difference was found in the age of onset between the 2 groups [(49 ± 12), (48 ± 11) years old; t = 0.114, P > 0.05]. Multi-organ sarcoidosis was more frequent in females compared with thoracic sarcoidosis (13/24, 24/29; χ² = 5.094, P < 0.05), and 72.41% of the patients with multi-organ disease were females above 40 years old. The patients with thoracic sarcoidosis mostly presented first to respiratory physicians or chest surgeons, often with the symptoms of lung involvement. The manifestations of multi-organ sarcoidosis varied considerably and the patients might present to any clinical departments. Sarcoidosis with rare involvement of organs as the presenting symptoms was easy to be misdiagnosed. A higher incidence of systemic constitutional symptoms (25.0%, 58.6%; χ² = 6.043, P < 0.05) and a longer duration for definite diagnosis [1.75 (0.625 - 3.000), 6 (0 - 40) months; Z = -3.377, P < 0.01] were found in patients with multi-organ sarcoidosis compared with thoracic sarcoidosis. There was no difference in the serum ACE level between the 2 groups [(72 ± 33), (75 ± 59) U/L; t = -0.193, P > 0.05]. Although forced expiratory volume in one second (FEV(1))/forced vital capacity (FVC), FEV1 %predicted (pred), FVC%pred and total lung capacity (TLC)%pred showed no difference (t = 0.134 - 0.683, P > 0.05), the diffusing capacity of the lung of carbon monoxide (D(LCO))%pred decreased more remarkably in multi-organ sarcoidosis [(84 ± 8), (69 ± 21); t = 2.674, P < 0.05]. The total cell count, alveolar lymphocyte percentage and CD4/CD8 ratio of BALF demonstrated no significant difference between the 2 groups (t = -0.628 - -0.367, P > 0.05), but the neutrophil percentage was significantly higher in multi-organ sarcoidosis compared with thoracic sarcoidosis [(10.9 ± 4.9)%, (5.1 ± 2.1)%; t = -4.187, P < 0.01]. CONCLUSIONS: Compared with thoracic sarcoidosis, multi-organ sarcoidosis seemed to be more common in females and more serious. Increased percentage of neutrophils in BALF may be a suggestive index for multiple organ involvements.

Gender Differences in Patients With COVID-19: Focus on Severity and Mortality.

Objective: The recent outbreak of Novel Coronavirus Disease (COVID-19) is reminiscent of the SARS outbreak in 2003. We aim to compare the severity and mortality between male and female patients with COVID-19 or SARS. Study Design and Setting: We extracted the data from: (1) a case series of 43 hospitalized patients we treated, (2) a public data set of the first 37 cases of patients who died of COVID-19 and 1,019 patients who survived in China, and (3) data of 524 patients with SARS, including 139 deaths, from Beijing in early 2003. Results: Older age and a high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. Age was comparable between men and women in all data sets. In the case series, however, men's cases tended to be more serious than women's (P = 0.035). In the public data set, the number of men who died from COVID-19 is 2.4 times that of women (70.3 vs. 29.7%, P = 0.016). In SARS patients, the gender role in mortality was also observed. The percentage of males were higher in the deceased group than in the survived group (P = 0.015). Conclusion: While men and women have the same prevalence, men with COVID-19 are more at risk for worse outcomes and death, independent of age.

[Idiopathic diffuse pulmonary ossification: a case report and review of the literature].

OBJECTIVE: To describe the clinical features and diagnosis of idiopathic diffuse pulmonary ossification (DPO). METHODS: A case of DPO confirmed by video-assisted thoracoscopic (VATS) lung biopsy was reported, and the literature was reviewed. RESULTS: A 32 year-old male was admitted to this hospital because of increased lung markings on chest X-ray for 7 years, and diffuse micro-nodular and reticular lesions on chest CT for 2 years. There were no significant symptoms, such as cough, sputum production and shortness of breath. Routine examinations and transbronchial lung biopsy failed to give a definite diagnosis, and therefore VATS lung biopsy was performed. The pathological study confirmed the presence of bone tissue in the lung, and the diagnosis of idiopathic DPD was made after careful exclusion of underlying diseases. Eleven cases of DPO diagnosed by lung biopsy in living patients were collected by review of the literature. The patients were all males, with a mean age of (48 +/- 17) years. No clinical symptoms were present in 4 cases, while spontaneous pneumothorax was the initial presentation in 3 cases. Other complaints included cough and shortness of breath. No case was reported in the Chinese literature. CONCLUSION: DPO is a rare disease, often without significant symptoms despite radiologically diffuse pulmonary lesions, which are easily misdiagnosed as other interstitial lung diseases.

Geotechnical behavior of the MSW in Tianziling landfill.

The valley shaped Tianziling landfill of Hangzhou in China built in 1991 to dispose of municipal solid waste (MSW) was designed for a service life of 13 years. The problem of waste landfill slope stability and expansion must be considered from the geotechnical engineering point of view, for which purpose, it is necessary to understand the geotechnical properties of the MSW in the landfill, some of whose physical properties were measured by common geotechnical tests, such as those on unit weight, water content, organic matter content, specific gravity, coefficient of permeability, compressibility, etc. The mechanical properties were studied by direct shear test, triaxial compression test, and static and dynamic penetration tests. Some strength parameters for engineering analysis were obtained.