Empagliflozin and sacubitril/valsartan reverse methotrexate cardiotoxicity by repressing oxidative stress and hypoxia in heart embryonic H9c2 cardiomyocytes - the role of morphology of mitochondria observed on electron microscopy.

OBJECTIVE: Oxidative stress and hypoxia play an important role in the pathogenesis of various cardiovascular diseases. We aimed to evaluate the effectiveness of sacubitril/valsartan (S/V) and Empagliflozin (EMPA) on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 rat embryonic cardiomyocyte cells. MATERIALS AND METHODS: BH9c2 cardiomyocyte cells were treated with methotrexate (MTX) (10-0.156 µM), empagliflozin (EMPA; 10-0.153 µM) and sacubitril/valsartan (S/V; 100-1.062 µM) for 24, 48 and 72 h. The half maximum inhibitory concentration (IC50) and half maximum excitation concentration (EC50) values of MTX, EMPA and S/V were determined. The cells under investigation were exposed to 2.2 µM MTX before treatment with 2 µM EMPA and 25 µM S/V. The cell viability, lipid peroxidation, oxidation of proteins and antioxidant parameters were measured while morphological changes were also observed by transmission electron microscopy (TEM). RESULTS: The results showed that treatment with 2 µM EMPA, 25 µM S/V or their combination produced a protective effect against the reduction in cell viability caused by 2.2 µM MTX.  While HIF-1α levels plunged to their lowest with S/V treatment, oxidant parameters dipped, and antioxidant parameters soared to their highest level with S/V and EMPA combination treatment. A negative correlation was found between HIF-1α and total antioxidant capacity in the S/V treatment group. CONCLUSIONS: A significant decrease in HIF-1α and oxidant molecules together with an enhancement in antioxidant molecules and normalization of the mitochondria morphology as observed on electron microscopy in S/V and EMPA-treated cells were detected. Although S/V and EMPA have both protective effects against cardiac ischemia and oxidative damage, this effect may be increased more with S/V treatment alone compared to combined treatment.

The relationship between carotid intima-media thickness and serum secreted frizzled-related protein-4 and dipeptidyl peptidase-4 in diabetic patients with cardiovascular diseases.

We investigated the association between carotid intima-media thickness (CIMT) with clusterin (CLU), amylin, secreted frizzled-related protein-4 (SFRP-4), glucagon-like peptide-1 (GLP-1) levels, and dipeptidyl peptidase-4 (DPP-4) in type 2 diabetes mellitus (T2DM) individuals with or without coronary artery disease (CAD). This study consisted of four groups: control group (mean ages: 50.3±10.7 years; 20 females and 15 males), diabetic group (DM; mean ages: 53.9±11.1; 14 females and 23 males), CAD group (mean ages: 60.1±43.5; 17 females and 17 males) and CAD+DM group (mean ages: 62.6±11.8 years; 18 females and 18 males). CIMT levels in both CAD and CAD+DM groups are higher than those in controls. CIMT levels in CAD+DM group are also significantly higher than those in DM group. Left external carotid artery (ECA) was found different from controls only in DM group. The levels of SFRP-4 in control group were significantly lower than those in DM, CAD and CAD+DM groups. Serum GLP-1total levels were found to be significantly low in CAD+DM group when compared to control group. DPP-4 and SFRP-4 levels may be a predictive marker for atherosclerosis in diabetes while particularly in diabetes, they correlate well with HOMA-IR. CIMT has the potential to be a clinically useful predictor of vascular risk in diabetic patients with CAD (Tab. 3, Fig. 2, Ref. 39). Keywords: type 2 diabetes mellitus, carotid intima-media thickness, glucagon-like peptide-1, dipeptidyl peptidase-4, clusterin, amylin, secreted frizzled-related protein-4.

Effects of treatment regimens on survival in patients with malignant pleural mesothelioma.

BACKGROUND AND OBJECTIVE: In this study, we aimed to investigate the factors affecting the survival of patients with malignant pleural mesothelioma (MPM) according to their treatment regimens, including best supportive care (BSC), chemotherapy, surgical group and multimodality (MM) therapy. PATIENTS: A retrospective analysis was performed on clinical data and treatment outcomes of 400 patients registered in our hospital with MPM between January 1989 and April 2010. RESULTS: Mean age (p < 0.001), presence of asbestos exposure (p = 0.0014), presence of smoking history (p < 0.001), Karnofsky performance status (p < 0.001), histological subtype (p = 0.034) and stage (p < 0.001) variables were found to be significantly different among the four treatment regimens. Mean survival time of all patients was 12.32 months. Mean survival time 10.5 months for the BSC group, 15.7 for the surgical group, 16.02 for the chemotherapy group, and 26.55 for the MM group. There were significant differences in mean survival time among the four treatment regimens. In addition, a significant difference was found in survival time between the two chemotherapy groups (p = 0.032). Mean survival time for cisplatin + gemcitabine was found to be 14.49 months and for cisplatin + pemetrexed, 18.34 months. CONCLUSIONS: The MM group had better survival rates than the other groups. The new chemotherapy combination, cisplatin + pemetrexed, can be helpful in improving survival time.      

The incidence of mesothelioma has not decreased for the last twenty years in Southeast region of Anatolia.

BACKGROUND: Malignant pleural Mesothelioma (MPM) is a very rarely encountered tumor in the normal population. OBJECTIVES: To investigate the variations in incidence of MPM in Southeast region of Turkey. METHODS: We retrospectively investigated the data of 161 MPM patients who were diagnosed from January 2000 to December 2009. The residential areas were determined according to asbestos exposure which plays a role in MPM etiology; previously reported as having asbestos (Region 1) and asbestos has not been determined previously (Region 2). RESULTS: One hundred nine (109) of the patients (67.7%) included from the Region 1 and 52 of them (32.3%) included from the Region 2. MPM incidence of the last decade was 3.9/100,000 person/year for the whole region. In Region 1, 2000-2004 incidences was 12.6/100,000 person/year and 2005-2009 incidences was 14.9/100,000 person/year. In Region 2, 2000-2004 incidences was 0.4/100,000 person/year and 2005-2009 incidences was 1.0/100,000 person/year. According to the recently conducted incidence studies in our region, MPM incidence increased in region 1 and decreased in region 2. The number of patients applying to our hospital has increased in the last three years. CONCLUSION: This increase, in Region 1 may be associated with continuous use of asbestos.

Pulmonary alveolar microlithiasis: a rare familial inheritance with report of six cases in a family. Contribution of six new cases to the number of case reports in Turkey.

Pulmonary alveolar microlithiasis (PAM) is a lung disease characterized by deposits of calcium within the alveoli. Our aim was to emphasize the familial character and the clinical features of the disease, and to draw attention to the increasing number of Turkish patients reported in the world. We detected 6 cases of PAM. Three cases had been diagnosed 4 years earlier, and 3 new cases were detected during the screening of the family members. All patients were male and the mean age was 11.5 ranging between 5 and 29 years. Five of the patients were cousins and the other one was their uncle. Radiographic studies showed a sand-like appearance in all patients. One case showed small subpleural bullae and bronchiectatic changes in both lower lobes in recent high-resolution CT scans, while his CT performed 4 years ago showed only sand-like appearance. The cases were diagnosed with the demonstration of microliths by bronchoalveolar lavage in 5 patients and transbronchial biopsy in 1. Recently reported cases from Turkey have constituted a considerable percentage among all cases in the world. In conclusion, (1) our patients constitute one of the largest series of cases reported in one family in the world. The disease seems to have familial and racial characteristics. The Turkish race has to be further investigated for genetic transmission. (2) Contrary to female predominance in previous reports, all 6 cases were male and 5 of them were below 12 years of age. (3) The disorder may show rapid progression in some cases probably due to the severity of the genetic disturbance.

Incidence of malignant pleural mesothelioma due to environmental asbestos fiber exposure in the southeast of Turkey.

BACKGROUND: Inhabitants of the southeast of Turkey (ST) have been exposed since childhood to inhalation of asbestos, from a material containing tremolite, used for whitewashing. This has resulted in an increased incidence of malignant pleural mesothelioma (MPM). OBJECTIVES: To review the epidemiological features of MPM cases in ST; to calculate and compare the incidence with the previously reported ones. SUBJECTS AND METHODS: The study included 176 MPM cases from different places in ST. The incidence of MPM was calculated for those places according to the distribution of the cases. RESULTS: In the previously identified regions of asbestos (region 1) where the population had been informed of the danger with the soil some decades ago, the MPM incidence was decreased, as compared to the previous reports. The annual incidence of MPM in these places was found to be 42.9 per million in this study while it had been reported to be 105.5 per million in the previous studies. In contrast, the incidence that was reported previously to be 2.75 per million in the regions where asbestos exposure had not been identified before (region 2) was found to be 8.6 per million in this study. In region 2 the incidence of MPM increased even in the second half of the last decade (5.9 versus 11.9 per million). CONCLUSIONS: Use of asbestos-containing soil continues in different places in ST. Even if the use of this soil is abandoned today, MPM will be an important health problem in this region till the third or fourth decades of this century. Informing the villagers of the danger and preventing the use of this soil may result in a considerable decrease in the incidence of MPM.

Malignant pleural mesothelioma caused by environmental exposure to asbestos in the Southeast of Turkey: CT findings in 117 patients.

BACKGROUND AND OBJECTIVES: Malignant pleural mesothelioma (MPM) is reported to be common in the southeast of Turkey, as a result of environmental asbestos exposure. The aim of this study was to evaluate the computed tomography (CT) features of MPM in patients with a history of asbestos exposure. METHODS: The CT scans of 117 patients who had a diagnosis of MPM were retrospectively evaluated. Additionally, CT findings of histologic subtypes were compared. RESULTS: The most common CT findings included pleural effusion (n = 104, 89%), pleural thickening (n = 96, 82%), mediastinal pleural involvement (n = 77, 66%) and interlobar fissural involvement (n = 62, 53%). Histologic subtype analysis was performed in 89 patients; of these, epithelial, sarcomatous and mixed types were identified in 46, 23 and 20 patients, respectively. An analysis of CT findings demonstrated that the involvement of mediastinal pleural (91%), interlobar fissure (87%) and lung parenchyma (48%) was significantly more frequent in sarcomatous type, as compared to epithelial (61% and p < 0.01; 35 and 4%, p < 0.0001, respectively) and mixed types (65% and p < 0.05; 10% and p < 0.0001; 10% and p < 0.01, respectively). Furthermore, there was a significant correlation between pericardial involvement and chest wall involvement (r = 0.42, p < 0.05) in sarcomatous type. Similarly, lymphadenopathy and parenchymal involvement (r = 0.23, p < 0.02), pericardial and chest wall involvement (r = 0.25, p < 0.01), chest wall and interlobar fissural involvement (r = 0.25, p < 0.01) were significantly correlated, when CT findings of all histologic subtypes were combined. CONCLUSIONS: These results suggest that although CT findings of MPM vary, they may provide valuable clues to the diagnosis, at least in patients with a history of asbestos exposure. In addition, the presence of extensive lesions may suggest MPM of sarcomatous subtype.

Comparison of the effectiveness of some pleural sclerosing agents used for control of effusions in malignant pleural mesothelioma: a review of 117 cases.

BACKGROUND AND OBJECTIVES: Management of malignant pleural mesothelioma (MPM) has been an important clinical issue regardless of the treatment modality employed. We aimed to investigate the efficacy of oxytetracycline (OT), Corynebacterium parvum (CP), and nitrogen mustard (NM) in the management of pleural effusion associated with MPM. METHODS: One hundred and seventeen patients who had stage-2 MPM or over according to the Butchart staging system and unilateral or bilateral pleural effusion took part in the study. The patients received either OT (35 mg/kg), CP (7 mg), or NM (0.4 mg/kg) through a chest tube for pleurodesis. The association between several clinical parameters and patient survival was also investigated. RESULTS: OT was applied to 59, CP to 29 and NM to 29 cases. A statistical analysis of the results obtained by these agents have demonstrated that OT (30 days, 81%; 90 days, 76.2%) and CP (30 days, 86.2%; 90 days, 79.3%) led to a significantly higher rate of successful pleurodesis as compared to NM (30 days, 48.2%; 90 days, 41.3%; p <0.05). Although the procedure was generally well tolerated by the patients, the NM-treated group experienced significantly more nausea-vomiting (46.1%) and hypotension (35.8%) compared to patients who received OT (nausea-vomiting and hypotension 4.3%; p < 0.001) and CP (nausea-vomiting and hypotension 5.1%; p < 0.001). Furthermore, we found that thrombocytosis, chest pain and weight loss were significantly associated with poor prognosis, whereas epithelial type had a positive effect on survival. CONCLUSION: These results suggest that OT and CP may be used as effective sclerosing agents for pleurodesis in the control of pleural effusions associated with MPM, without major side effects.

High-resolution computed tomography in cases with environmental exposure to asbestos in Turkey.

BACKGROUND AND OBJECTIVES: Although all parts of the lung can be affected as a consequence of asbestos exposure, most CT protocols tend to scan only the middle and lower parts of the thorax. The aim of this study was to investigate parenchymal and pleural lesions of persons exposed to environmental asbestos, using a high-resolution computed tomography (HRCT) protocol scanning the whole thorax. METHODS: We analyzed the chest radiographs and HRCT scans of 26 patients who presented bilaterally with multiple pleural plaques related to environmental asbestos exposure. RESULTS: Twenty-four cases (92%) had an abnormal HRCT suggestive of asbestosis. Apart from common HRCT changes related to asbestosis, we detected apical pleural thickening (APT) in 9 cases as well as a coarse honeycomb pattern adjacent to APT in 7 of these cases. Cavitary lesions due to pulmonary tuberculosis were observed on HRCT scans from 4 patients in total. Neither apical pulmonary fibrosis nor cavitary lesions were visible on chest radiographs. CONCLUSIONS: We suggest that the HRCT protocol for examining asbestos-exposed individuals with pleural plaques on chest X-rays should include the whole thorax, since the asbestos-related pathologies may involve all parts of the lung.