Massive Fibrosis Research Articles

Compositional and structural analysis of engineered stones and inorganic particles in silicotic nodules of exposed workers

BackgroundEngineered stone silicosis is an emerging disease in many countries worldwide produced by the inhalation of respirable dust of engineered stone. This silicosis has a high incidence among young workers, with a short latency period and greater aggressiveness than silicosis caused by natural materials. Although the silica content is very high and this is the key factor, it has been postulated that other constituents in engineered stones can influence the aggressiveness of the disease. Different samples of engineered stone countertops (fabricated by workers during the years prior to their diagnoses), as well as seven lung samples from exposed patients, were analyzed by multiple techniques.ResultsThe different countertops were composed of SiO2 in percentages between 87.9 and 99.6%, with variable relationships of quartz and cristobalite depending on the sample. The most abundant metals were Al, Na, Fe, Ca and Ti. The most frequent volatile organic compounds were styrene, toluene and m-xylene, and among the polycyclic aromatic hydrocarbons, phenanthrene and naphthalene were detected in all samples. Patients were all males, between 26 and 46 years-old (average age: 36) at the moment of the diagnosis. They were exposed to the engineered stone an average time of 14 years. At diagnosis, only one patient had progressive massive fibrosis. After a follow-up period of 8 ± 3 years, four patients presented progressive massive fibrosis. Samples obtained from lung biopsies most frequently showed well or ill-defined nodules, composed of histiocytic cells and fibroblasts without central hyalinization. All tissue samples showed high proportion of Si and Al at the center of the nodules, becoming sparser at the periphery. Al to Si content ratios turned out to be higher than 1 in two of the studied cases. Correlation between Si and Al was very high (r = 0.93).ConclusionSome of the volatile organic compounds, polycyclic aromatic hydrocarbons and metals detected in the studied countertop samples have been described as causative of lung inflammation and respiratory disease. Among inorganic constituents, aluminum has been a relevant component within the silicotic nodule, reaching atomic concentrations even higher than silicon in some cases. Such concentrations, both for silicon and aluminum showed a decreasing tendency from the center of the nodule towards its frontier.

Analysis of the pulmonary function characteristics and associated factors in silicosis patients with progressive massive fibrosis

Objective: To investigate the characteristics of and associated risk factors for pulmonary dysfunction in silicosis patients with progressive massive fibrosis (PMF) . Methods: In-patients with PMF treated in the Department of Occupational Medicine and Toxicology in Beijing Chao-Yang Hospital, Capital Medical University from June 2014 to October 2020 were enrolled in this study. Based on their pulmonary ventilation function, the patients were divided into normal ventilation group, obstructive ventilation dysfunction group, restrictive ventilation dysfunction group, and mixed ventilation dysfunction group. The location and area of the large opacity and the grade of emphysema were evaluated by high-resolution CT (HRCT) of the chest. Based on the location, the large opacity was classified into central type, peripheral type, and mixed type. Results: A total of 115 silicosis patients with PMF were enrolled, with 85 (73.91%) having different types of pulmonary dysfunction, including 36 cases (31.30%) in the obstructive ventilation dysfunction group, 9 cases (7.83%) in the restrictive ventilation dysfunction group and 40 cases (34.78%) in the mixed ventilation dysfunction group. As for the location of the large opacity, 41 cases (35.65%) were central type, 52 cases (45.22%) were peripheral type, and 22 cases (19.13%) were mixed type. Logistic regression analysis showed that the central large opacity and grade 3-4 emphysema were risk factors for obstructive ventilation dysfunction (OR=52.179, 5.500, P<0.05) , class C large opacity was the risk factor for restrictive ventilation dysfunction (OR=33.146, P<0.05) , class B, class C large opacity and central large opacity were the risk factors for mixed ventilation dysfunction (OR=6.414, 11.561, 19.600, P<0.05) . Conclusion: In silicosis patients with PMF, the incidence rate of pulmonary ventilation dysfunction is higher, mainly obstructive and mixed ventilation dysfunction. The area and location of large opacity are associated with the incidence and types of pulmonary ventilation dysfunction.

Focused Cardiac Ultrasound Examination as a Tool for Diagnosis of Infective Endocarditis and Myocarditis in Dogs and Cats.

Simple SummaryInfective endocarditis and myocarditis are rarely diagnosed conditions with high mortality rates in dogs and cats. As their clinical signs are highly nonspecific, and advanced cardiological diagnostics are not always available in small animal clinics, both diseases seem to be underdiagnosed. Infective endocarditis affects mainly the mitral and aortic valves. In myocarditis, thickening of the left ventricle walls is usually observed; however, in some cases dilatation of the left ventricle lumen with thinning of the walls can be visible. In human medicine, basic cardiac ultrasound examination enables a quick initial diagnosis of these two conditions. Using this technique, we tentatively diagnosed 7 cases of myocarditis and/or infective endocarditis in dogs and cats, and these diagnoses were later confirmed by other methods. Because the initial diagnoses were made by a general practitioner after relatively short training, not by a cardiology specialist, we conclude that common use of this technique in small animal practices equipped with ultrasound device could increase the rate of diagnosis of these conditions, leading to earlier treatment initiation.Symptoms of infective endocarditis (IE) and myocarditis are usually nonspecific and include fever, apathy, and loss of appetite. This condition can lead to severe heart failure with ascites or/and fluid in the thoracic cavity or/and in the pericardial sac. We describe infective endocarditis and myocarditis in 3 dogs and 4 cats. In all animals, the initial diagnosis was performed on the basis of a focused cardiac ultrasound examination performed by a general practitioner after a training in this technique. The initial findings were confirmed by a board-certified specialist in veterinary cardiology. Post mortem positive microbiological results from valves were obtained in 4 of 7 patients. Methicillin-resistant Staphylococcus aureus was confirmed in 2 cases and Staphylococcus epidermidis was confirmed in 2 cases, one of which included Enterococcus sp. coinfection. Histopathological examination confirmed initial diagnosis in 5 of 7 animals. In the remaining 2 patients, the time elapsed from the onset of clinical symptoms to death was about 1 month and no active inflammation but massive fibrosis was found microscopically. This is, to our best knowledge, the first report of IE and myocarditis diagnosed in small animals using focused cardiac ultrasound examination. Therefore, we conclude that common usage of this technique by trained general veterinarians may increase the rate of diagnosed patients with these conditions.

Burden of Silicosis among stone crushing workers in India.

In North India, the mining industry is disorganized and profit-driven. It predisposes its workers towards the development of silicosis. Haryana, a major North Indian state, has developed a compensation-rehabilitation policy for mining workers. This study is the review of the policy's functioning and limitation from the first 4 years of implementation. The labour department does surveillance of workers in the mining industry. All suspected cases of silicosis are evaluated by a multidisciplinary team. Based on the final diagnosis, the compensation is decided. Nearly 5000 workers were screened, and 729 appeared before the medical board. Of these 729, 465 were having silicosis, and their data are presented here (data of 7 patients were missing). All workers were males. The mean age was 44.54 ± 9.6 years, and the mean exposure (work experience) was 17.25 ± 6.7 years. Most of the workers were between the age of 40 and 50 years and had exposure for 10-20 years. Chest radiography examination showed that progressive massive fibrosis (large size type C opacities) was the most common type of presentation (23%). Smaller opacities (p, q, r and s, t, u) were combined for further analysis, given their similar prognostic significance. It was found that age and experience both had a linear and significant correlation with the severity of lung involvement. Nearly a quarter of subjects were suffering from the worst type of lung involvement at screening itself. The policy has laid a foundation for the welfare of workers, but there is still a long way to go.

Фізична терапія та легенева реабілітація у пацієнтів із COVID-19

The global pandemic of the novel coronavirus disease COVID-19 is continueing for the second year, despite tremendous progress in the development and implementation of vaccinations to prevent this disease. The incidence is increasing all over the world, affecting people of different age groups. The inability to predict the severe course of the disease, the development of complications or the so-called "long-COVID" remain one of the most important problems. In patients with COVID-19, damage to the respiratory and cardiovascular systems prevails, manifests itself in the progression of shortness of breath, decrease in blood oxygen saturation and respiratory failure and requires the use of intensive methods of respiratory support, mainly in patients with concomitant diseases such as diabetes mellitus, obesity, coronary heart disease, cancer, chronic obstructive pulmonary disease. COVID-19 reconvalescents, who had significant lung and airway damage, suffer from respiratory complications for a long time due to massive fibrosis of the lung tissue, the development of restrictive respiratory disorders, which significantly impairs the quality of life of such patients. The purpose of the study was to discuss the feasibility and effectiveness of pulmonary rehabilitation and its recommended strategies in patients with COVID-19, based on data from modern literature. The evidence-based rehabilitation process is governed by a functional assessment using the International Classification of Functioning, Disability and Health. The rehabilitation process is based on the strategy of the rehabilitation cycle and consists of sequential stages: assessment, appointment, intervention, quality estimation. Rehabilitation is provided by the multidisciplinary team and begins with a specialized rehabilitation examination, determining the presence or risk of a functional limitation, quantifying them and creating an individual rehabilitation plan. Continuous monitoring of patients' respiratory and hemodynamic parameters before, during and after a physical therapy session is essential to ensure patient safety and assess cardiorespiratory stress in order to optimize an individualized plan and rehabilitation program. Conclusion. Taking into account the phased use of physical therapy and pulmonary rehabilitation, depending on the severity of COVID-19, existing complications and comorbid pathology, a maximally individual syndromic-pathogenetic approach is proposed that realizes the maximum effectiveness of each rehabilitation technique, depending on the patients’ pathological changes, the level of fitness and exercise tolerance

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy.

Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, cardiomyocyte-based functional arrhythmogenic mechanisms are likely prevalent at earlier stages of the disease. In this review, we will describe studies conducted in human surgical samples from HCM patients, transgenic animal models and human cultured cell lines derived from induced pluripotent stem cells. Current pieces of evidence concur to attribute the increased risk of ventricular arrhythmias in early HCM to different cellular mechanisms. The increase of late sodium current and L-type calcium current is an early observation in HCM, which follows post-translation channel modifications and increases the occurrence of early and delayed afterdepolarizations. Increased myofilament Ca2+ sensitivity, commonly observed in HCM, may promote afterdepolarizations and reentry arrhythmias with direct mechanisms. Decrease of K+-currents due to transcriptional regulation occurs in the advanced disease and contributes to reducing the repolarization-reserve and increasing the early afterdepolarizations (EADs). The presented evidence supports the idea that patients with early-stage HCM should be considered and managed as subjects with an acquired channelopathy rather than with a structural cardiac disease.

Silicosis and the countertop industry

Silicosis and the countertop industry

HISTOPATHOLOGICAL FINDINGS OF ACUTE EOSINOPHILIC PNEUMONIA

TOPIC: Lung Pathology TYPE: Original Investigations PURPOSE: It has been reported that AEP histopathologically exhibits diffuse alveolar damage (DAD) with eosinophilia. However, acute respiratory distress syndrome (ARDS), acute interstitial pneumonia (AIP), and acute exacerbation of idiopathic pulmonary fibrosis, also exhibiting DAD histopathologically, are all life-threatening diseases. AFP is rapidly improved by steroids alone without remaining of fibrosis or sometimes even without treatment, whereas these diseases with the same histopathology show greatly different clinical courses, which remains a question to solve. METHODS: Here we investigated the histopathology of AEP in2surgical lung biopsy and 14 TBLB cases. Additionally, we determined the presence or absence of DAD by histopathology in these AEP cases. RESULTS: Characteristic histopathological findings of AEP consist of alveolar edema with infiltration of eosinophils and lymphocytes and edema of perivascular area and interlobular septa. The alveolar spaces showed fibrinous exudates. There were no hyaline membranes or massive intraluminal fibrosis. These histopathological findings of interstitial edema and fluid exudates are consist with radiological findings of lung edema and can explain the rapid and complete improvement. CONCLUSIONS: Because AEP dose not exhibit lung fibrosis histopathologically, it should not to be included in DAD which is associated with lung fibrosis. CLINICAL IMPLICATIONS: We reveal the true histopathology of AEP. DISCLOSURES: No relevant relationships by Hiroshi Mochimaru, source=Web Response

SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling.

Simple SummaryDiffuse-type gastric carcinoma (DGC) is characterized by rapid infiltrative growth associated with massive stroma and frequent peritoneal dissemination, which leads to poor patient outcomes. In this study, we found that the oncogenic tyrosine phosphatase SHP2 is tyrosine-phosphorylated downstream of the amplified receptor tyrosine kinases (RTKs) Met and fibroblast growth factor receptor 2 (FGFR2) in DGC cell lines. SHP2 knockdown or pharmacological inhibition selectively suppressed the growth of DGC addicted to amplified Met and FGFR2. Moreover, targeting SHP2 abrogated malignant phenotypes, including peritoneal dissemination, of Met-addicted DGC and could overcome acquired resistance to Met inhibitors. Our findings suggest that SHP2 is a potential target for the treatment of DGC addicted to amplified RTK signaling.Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.

A Sodium Oxalate-Rich Diet Induces Chronic Kidney Disease and Cardiac Dysfunction in Rats.

Chronic kidney disease (CKD) is a worldwide public health issue affecting 14% of the general population. However, research focusing on CKD mechanisms/treatment is limited because of a lack of animal models recapitulating the disease physiopathology, including its complications. We analyzed the effects of a three-week diet rich in sodium oxalate (OXA diet) on rats and showed that, compared to controls, rats developed a stable CKD with a 60% reduction in glomerular filtration rate, elevated blood urea levels and proteinuria. Histological analyses revealed massive cortical disorganization, tubular atrophy and fibrosis. Males and females were sensitive to the OXA diet, but decreasing the diet period to one week led to GFR significance but not stable diminution. Rats treated with the OXA diet also displayed classical CKD complications such as elevated blood pressure and reduced hematocrit. Functional cardiac analyses revealed that the OXA diet triggered significant cardiac dysfunction. Altogether, our results showed the feasibility of using a convenient and non-invasive strategy to induce CKD and its classical systemic complications in rats. This model, which avoids kidney mass loss or acute toxicity, has strong potential for research into CKD mechanisms and novel therapies, which could protect and postpone the use of dialysis or transplantation.

Spin-echo and diffusion-weighted MRI in differentiation between progressive massive fibrosis and lung cancer.

We aimed to investigate the value of magnetic resonance imaging (MRI)-based parameters in differentiating between progressive massive fibrosis (PMF) and lung cancer. This retrospective study included 60 male patients (mean age, 67.0±9.0 years) with a history of more than 10 years working in underground coal mines who underwent 1.5 T MRI of thorax due to a lung nodule/mass suspicious for lung cancer on computed tomography. Thirty patients had PMF, and the remaining ones had lung cancer diagnosed histopathologically. The sequences were as follows: coronal single-shot turbo spin echo (SSH-TSE), axial T1- and T2-weighted spin-echo (SE), balanced turbo field echo, T1-weighted high-resolution isotropic volume excitation, free-breathing and respiratory triggered diffusion-weighted imaging (DWI). The patients' demographics, lesion sizes, and MRI-derived parameters were compared between the patients with PMF and lung cancer. Apparent diffusion coefficient (ADC) values of DWI and respiratory triggered DWI, signal intensities on T1-weighted SE, T2-weighted SE, and SSH-TSE imaging were found to be significantly different between the groups (p < 0.001, for all comparisons). Median ADC values of free-breathing DWI in patients with PMF and cancer were 1.25 (0.93-2.60) and 0.76 (0.53-1.00) (× 10-3 mm2/s), respectively. Most PMF lesions were predominantly iso- or hypointense on T1-weighted SE, T2-weighted SE, and SSH-TSE, while most malignant ones predominantly showed high signal intensity on these sequences. MRI study including SE imaging, specially T1-weighted SE imaging and ADC values of DWI can help to distinguish PMF from lung cancer.

Curative endoscopic resection for a recurrent rectal neoplasm with massive submucosal fibrosis after a transanal endoscopic microsurgery-associated leak.

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Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

An amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.

A Case Report of Silicosis: Culprit of Progressive Massive Fibrosis

Silicosis is a fibronodular lung disease secondary to the inhalation of crystalline silica dust. It had continued to cause significant morbidity and mortality worldwide. Here is a case of a 63-year-old woman, a lifelong non-smoker who complained of intermittent wheezing since retired 8 years ago. She had worked in the clay and piping industry for more than a decade. She wore only a simple 3-ply face mask at work without other protective devices. She had multiple hospital admissions for acute exacerbation of chronic lung disease for the past several years. Respiratory examinations revealed bilateral fine crepitations and occasional rhonchi on auscultation. Chest radiograph revealed ground glass changes. Pulmonary function testing showed an irreversible severe obstruction picture with an FEV1 of 45%. High resolution computed tomography thorax demonstrated hyperinflated lungs with emphysematous changes and multiple nodules over subpleural region, conglomerate mass with calcifications over bilateral lungs. Her imaging findings combined with a significant occupational history were suggestive of progressive massive fibrosis (PMF) due to silicosis. She is currently being treated with several inhalers and does not require home oxygen therapy. She is suffering from accelerated silicosis which may potentially progress to radiological deterioration, altered respiratory function and premature death. Therefore, it is essential to avoid any potential hazards that may predispose to silicosis.

SQSTM1/p62 Inhibits whereas Nrf2 Promotes Tumorigenesis by Inducing Cell Population Remodeling and Metabolic Reprograming in Mouse Livers with mTORC1 Activation and Defective Autophagy

Tsc1 (Tuberous Sclerosis 1) and Tsc2 are tumor suppressor genes and negative regulators of mTORC1, and the mutation of Tsc1 or Tsc2 is associated with various cancers including hepatocellular carcinoma (HCC). mTORC1 activation promotes anabolic protein synthesis and inhibits catabolic autophagy process. Either hepatic persistent activation of mTORC1 due to the loss of Tsc1 or impaired hepatic autophagy due to the loss of Atg5 leads to spontaneous liver tumorigenesis in mice. However, how autophagy impacts mTORC1-mediated liver metabolic changes and tumorigenesis is less clear. Here we show that deletion of Atg5 in liver-specific Tsc1 knockout (L-Tsc1 KO) mice inhibited liver tumorigenesis but increased mortality of L-Tsc1 KO mice. Histological and unbiased RNA-seq as well as metabolomic analysis revealed that lack of hepatic autophagy dramatically induced the remodeling of liver cell population and hepatic metabolic reprogramming in L-Tsc1 KO mice. RNA-seq analysis revealed increased cholangiocyte, hepatic stellate cell and macrophage but decreased hepatocyte gene signatures in liver-specific Tsc1 and Atg5 double knockout (DKO) mice. Histologically, Atg5 and Tsc1 DKO mice had increased hepatomegaly, ductular reactions, increased number of macrophage/Kupffer cells and infiltrated neutrophils as well as massive fibrosis, and the DKO mice died at the age of approximately 8-months-old with no detectable liver tumors. Metabolomic analysis revealed marked increased hepatic glutathione and glutathione metabolites but decreased hepatic levels of glucose and lipid with accumulation of TCA cycle intermediate metabolites and fatty acid oxidation intermediates in Atg5 and Tsc1 DKO mice. Deletion of hepatic p62 partially but deletion of Nrf2 almost completely rescued the liver cell type remodeling and metabolic reprogramming and the mortality of Atg5 and Tsc1 DKO mice. Deletion of p62 promoted whereas deletion of Nrf2 suppressed the liver tumorigenesis of Atg5 and Tsc1 DKO mice. These results reveal a critical role of Nrf2 in regulating liver cell type remodeling and metabolic reprogramming in mice lack of hepatic autophagy with mTORC1 activation. Our data may provide a mechanistic basis for a precision medicine to target Nrf2 pathway for treating as subset of HCC, especially in HCV- or alcohol-associated liver cancers that may have defective autophagy and mTOR activation.

Mechanism of hepatocyte mitochondrial NDUFA13 deficiency-induced liver fibrogenesis: the role of abnormal hepatic stellate cell activation

To investigate the role of hepatocyte mitochondrial NDUFA13 loss in the liver fibrogenesis in mice and explore the possible mechanisms. We used liver-specific NDUFA13 heterozygous knockout mouse models (NDUFA13fl/-; Alb-Cre) established previously by intercrossing NDUFA13fl/fl and Alb-Cre mice, with their littermate control NDUFA13fl/fl mice as the control (n=8). The mice were euthanized at the age of 4 weeks and 2 years, and the liver tissues were collected for HE and Masson staining to observe the pathological changes and fibrosis phenotypes. Western blotting was performed to detect the expression of NDUFA13 protein in the liver tissues, and the infiltration of F4/80+ macrophages and the expressions of TGF-β1, TNF-α and IL-1β were analyzed by immunofluorescence assay. The expression levels of α-SMA, matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteases 1 (TIMP-1), collagen-Ⅰ and collagen-Ⅲ were assayed by immunohistochemistry. HE and Masson staining showed obvious inflammatory infiltration but no significant fibrosis in the liver tissues of 4-week-old NDUFA13fl/- mice, but severe liver damage with massive fibrosis was observed in 2-year-old NDUFA13fl/- mice. NDUFA13 expression in 2-year-old NDUFA13fl/- mice markedly decreased compared with that in the control NDUFA13fl/fl mice as shown by Western blotting (P < 0.05). Immunohistochemistry showed obvious infiltration of F4/80+ macrophages in the liver tissue with a large amount of TGF-β1 production (P < 0.05) and TNF-α and IL-1β secretions in NDUFA13fl/- mice (P < 0.05). NDUFA13 knockout obviously promoted α-SMA expression (P < 0.05) and collagen-Ⅰ and collagen-Ⅲ deposition (P < 0.05) while significantly decreased MMP-9 and increased TIMP-1 expression in the liver (P < 0.05). Hepatocytes-specific NDUFA13 deficiency can trigger spontaneous and chronic liver fibrosis phenotypes in mice probably in association with abnormal activation of hepatic stellate cells induced by macrophages and inflammatory factors.

Cinacalcet as a surrogate therapy for diabetic cardiomyopathy in rats through AMPK-mediated promotion of mitochondrial and autophagic function

Decreased activity of AMP-activated protein kinase (AMPK) is implicated in the pathogenesis of diabetic cardiomyopathy (DCM). Recent evidence suggests a crosstalk between cinacalcet and AMPK activation. This study investigated the effects of cinacalcet on cardiac remodeling and dysfunction in type 2 diabetic rats (T2DM). High fat diet for 4 weeks combined with single intraperitoneal injection of streptozotocin (30 mg/kg) was used to induce type 2 diabetes in rats. Diabetic rats were either orally treated with vehicle, 5 or 10 mg/kg cinacalcet for 4 weeks. Control rats were fed standard chow diet and intraperitoneally injected with citrate buffer. T2DM rats showed lower body weight (BW), hyperglycemia and dyslipidemia, along with increased heart weight (HW) and HW/BW ratio. Masson's trichrome stained cardiac sections revealed massive fibrosis in T2DM rats. There were increased TGF-β1 and hydroxyproline levels, coupled with up-regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in hearts of T2DM rats. These alterations were associated with redox imbalance and impaired cardiac functions. Decreased phosphorylation of AMPK at threonine172 residue was found in T2DM hearts. Cinacalcet for 4 weeks significantly activated AMPK and alleviated cardiac remodeling and dysfunction in a dose-dependent manner, without affecting blood glucose, serum calcium and phosphorus levels. Cinacalcet increased the mitochondrial DNA content, and expressions of PGC-1α, UCP-3, beclin-1 and LC3-II/LC3-I ratio. Cinacalcet decreased the pro-apoptotic Bax, while increased the anti-apoptotic Bcl-2 in cardiac tissue of T2DM rats. These findings might highlight cinacalcet as an alternative therapy to combat the development and progression of DCM.

Association between Financial Conflicts of Interest and International Labor Office Classifications for Black Lung Disease.

Rationale: The U.S. Department of Labor administers the Federal Black Lung Program (FBLP), an administrative system charged with managing claims by coal miners for workers' compensation for totally disabling coal mine dust lung disease. Specific case reports have raised concern that financial conflicts of interest (COIs) may systematically bias physicians when they are classifying chest X-rays (CXRs) for the absence, presence, and severity of pneumoconiosis. Objectives: To evaluate the direction and magnitude of association between financial COIs of physicians participating in the FBLP and international standards for the classification of radiographs of pneumoconiosis. Methods: An epidemiologic assessment of black lung claims filed to the FBLP from 2000 to 2013 was conducted to determine physician classifications of radiographs. FBLP court decisions from 2002 to 2019 (n = 7,656) were used to evaluate financial COIs of each physician. The main outcome measures used were classifications of radiographs for the absence of pneumoconiosis (small opacity classifications of 0/0 or 0/1), simple pneumoconiosis (small opacity classifications of 1/0 through 3/+), and progressive massive fibrosis (PMF) (large opacities with classifications of A, B, or C). Results: Of 63,780 radiograph classifications made by 264 physicians, 31.4% were read positive for simple pneumoconiosis and 3.6% were read as having PMF. There were 52 physicians who classified CXRs as having no evidence of pneumoconiosis in 99%+ of their readings and 18 physicians who classified CXRs as positive for simple pneumoconiosis in 99%+ of their readings. The adjusted odds of a negative classification of pneumoconiosis was 1.46 (95% confidence interval [CI], 1.44-1.47) per 10% increase in the proportion of court records demonstrating that a physician was hired by the employer. Per 10% increase in court records indicating a physician was hired by the miner/claimant, the adjusted odds ratio for classifying simple pneumoconiosis was 1.51 (95% CI, 1.49-1.52), and the adjusted odds ratio for finding PMF was 1.28 (95% CI, 1.26-1.30). Conclusions: There was a strong association between source of payment and radiograph classification, suggesting the importance of eliminating financial COIs in what should be an objective determination of eligibility for Black Lung Workers' compensation benefits.

Silicosis, progressive massive fibrosis and silico-tuberculosis among workers with occupational exposure to silica dusts in sandstone mines of Rajasthan state: An urgent need for initiating national silicosis control programme in India.

Context:Silicosis is a progressive, irreversible and incurable respiratory morbidity and often becomes a cause for pre-mature mortality among occupationally silica dust-exposed workers in India and similar countries. It has a dual problem of associated silico-tuberculosis as a co-morbidity. The present study was done to assess the respiratory morbidity caused by silicosis in sandstone mine of Rajasthan, India.Methods:The chest X-rays of 529 subjects having history of employment in stone mines with respiratory morbidity were subjected for this study and evaluated in accordance with ILO Classification 2000. The X-rays were classified into various categories of silicosis and progressive massive fibrosis (PMF) in relation to years of work in stone mines.Results:Out of 529 chest radiographs evaluated, 275 (52%) showed radiological evidence of silicosis. Of them, 40 (7.5%) subjects showed large opacities suggestive of progressive massive fibrosis. Both silicosis and progressive massive fibrosis were associated with increasing duration of work in stone mines. Sixty-one (12.4%) subjects with silicosis also had associated pulmonary tuberculosis, termed as silico-tuberculosis.Conclusion:The present study showed a high prevalence of silicosis, progressive massive fibrosis and silico-tuberculosis among stone mine workers. It appears that that unless silicosis is controlled, elimination of tuberculosis is far from reality in the country. Hence, states and central authorities must work together towards control of both silicosis as well as silico-tuberculosis. Similarly, there is an urgent need of initiation of national silicosis control programme, similar to existing national tuberculosis control programme, considering the huge burden of silicosis in India

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy.

Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the “hallmarks of cancer.” Their expression is dysregulated in cancer, and they are “misused” to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same “profibrotic” ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.