Zeki Yildirim

Mutations in SLC34A2 Cause Pulmonary Alveolar Microlithiasis and Are Possibly Associated with Testicular Microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by the deposition of calcium phosphate microliths throughout the lungs. We first identified a PAM locus by homozygosity mapping to 4p15, then identified, by a candidate-gene approach, the gene responsible for the disease as SLC34A2 (the type IIb sodium-phosphate cotransporter gene), which is involved in phosphate homeostasis in several organs. We identified six homozygous exonic mutations in the seven unrelated patients with PAM we studied. Three of the mutations were frameshifts, one was a chain termination, one was an amino acid substitution, and one was a deletion spanning the minimal promoter and the first exon. Absence of functional protein product of the gene is compatible with calcium phosphate deposition in alveolar airspaces. We show that impaired activity of the phosphate transporter is presumably responsible for the microliths and that PAM is a recessive monogenic disease with full penetrance. Testicular microlithiasis (TM) is a disease that is more common than PAM. It is often associated with cancer and infertility. Since the gene we identified is also expressed in testis, we searched for mutations in subjects with TM. In 2 of the 15 subjects with TM we studied, we identified two rare variants, one synonymous and the other noncoding, that are possibly associated with the condition.

Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats.

The effect of oral erdosteine on tissue malondialdehyde (MDA) and nitric oxide (NO) levels, and catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities are investigated in the cisplatin model of acute renal failure in rats. A single dose of cisplatin caused kidney damage manifested by kidney histology as well as increases in plasma creatinine and blood urea nitrogen (BUN) levels. Treatment with free radical scavenger erdosteine attenuated increases in plasma creatinine and BUN, and tissue MDA and NO levels, and provided a histologically-proven protection against cisplatin-induced acute renal failure. Erdosteine also reduced depletion in the tissue CAT, GSH-Px, and SOD activities. These results show that erdosteine may be a promising drug for protection against cisplatin-induced nephrotoxicity. However, further studies with different doses of erdosteine are warranted for clarifying the issue.

Preventive effect of melatonin on bleomycin-induced lung fibrosis in rats

Abstract:  Oxidative stress has an important role in the pathogenesis of idiopathic pulmonary fibrosis. Melatonin has direct and indirect free radical‐detoxifying activity. The present study investigated whether melatonin treatment attenuates bleomycin‐induced lung fibrosis in rats. A group of rats was given one dose of bleomycin while the control animals were given saline. The first dose of melatonin (4 mg/kg/day) was given 2 days before the bleomycin injection. At day 14, fibrotic changes were evaluated using Aschofts criteria and lung hydroxyproline content. Bleomycin produced a 2.7‐fold rise in the fibrosis score that was decreased 65% by melatonin (P < 0.05) and a 1.4‐fold increase in hydroxyproline content which was completely prevented by melatonin. Protein carbonyl and thiobarbituric acid reactive substances levels, which were significantly elevated in the bleomycin treated rats, were significantly attenuated by melatonin. Bleomycin administration significantly reduced the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH‐Px) in lung tissue. The reduction in CAT activity was prevented by melatonin but SOD and GSH‐Px were not influenced. These results revealed that melatonin may prevent the development of bleomycin‐induced lung fibrosis via the repression of protein and lipid peroxidation.

The role of oxidative stress in bronchoconstriction due to occupational sulfur dioxide exposure

BACKGROUND We previously showed that apricot sulfurization workers (ASW) are exposed to high concentrations of SO(2), resulting in an asthma-like syndrome. The aim of this study was to evaluate whether oxidative stress plays a role in the pathogenesis of asthma-like syndrome due to the high concentrations of SO(2) exposure in agricultural environment. METHODS Serum antioxidant enzyme activities and malondialdehyde (MDA) concentrations, which are markers of lipid peroxidation, and pulmonary function tests (PFT) were measured in 40 volunteer ASW and compared to 20 healthy control subjects. RESULTS The superoxide dismutase (SOD, 2.2+/-0.6 vs. 3.2+/-0.7 U/ml), glutathione peroxidase (GSH-Px, 0.6+/-0.3 vs. 1.1+/-0.3 U/ml) and catalase (107.6+/-27.4 vs. 152.6+/-14.3 k/l) activities in ASW were significantly (p<0.0001) lower than controls, whereas the malondialdehyde concentration (4.1+/-0.9 vs. 1.9+/-5.3 nmol/l) was higher in ASW (p<0.0001). ASW had significant decreases in pulmonary function parameters after exposure. CONCLUSION These results show that occupational exposure to high concentrations of SO(2) enhances oxidative stress and lipid peroxidation may be considered as a new mechanism of SO(2)-induced bronchoconstriction.

Environmental exposure to asbestos in eastern Turkey.

In this study, the authors investigated the prevalence of asbestos-related disorders among the inhabitants of Güzelyurt, a town in Malatya, located in eastern Turkey. The authors examined river bed, white soil, and stucco samples taken from various locales in Güzelyurt, and they confirmed the presence of tremolite and chrysotile asbestos fibers. Subjects (N = 920; 449 males and 471 females) were examined by photofluoroscopy. Eighty-five patients (9.2%) had asbestos-related radiological findings; risk increased with age. Calcified pleural plaques were seen more frequently in individuals ≥ 50 yr of age, compared with younger subjects (p < 0.01). Asbestos-related disorders were prevalent in the inhabitants of Güzelyurt, the population of which is exposed environmentally to asbestos—primarily the result of the stuccoing and whitewashing of houses with soil that contains asbestos.

Effects of Ginkgo biloba on plasma oxidant injury induced by bleomycin in rats

Bleomycin is an anti-neoplastic agent and its clinical usage is limited by its toxicity, which is mostly induced by oxygen radicals. The aim of this study was to investigate the effect of Ginkgo biloba on plasma indices of oxidants induced by bleomycin in rats. Male Sprague-Dawley rats were divided into five groups: none medicated or 0.9% NaCl injected or only Ginkgo biloba (orally, 100 mg/kg per day for 14 days) or only a single dose of bleomycin (intratracheal, 2.5 U/kg) or Gingko biloba and bleomycin-treated groups. After 14 days, blood was taken before the rats were sacrificed. The plasma was removed and stored at −85°C until the study day. Plasma superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and xanthine oxidase (XO) enzyme activities with malondialdehyde and nitric oxide (NO) levels were studied. The levels of malondialdehyde and NO with activity of XO were higher in plasma of bleomycin group than the other groups (P B / 0.05). The activities of SOD and GSH-Px were increased in the bleomycin plus Gingko biloba group in comparison with the bleomycin group (P B / 0.05). There was a positive correlation between malondialdehyde and NO levels in the bleomycin group (r-/0.859, P B / 0.05). There were positive correlations between SOD and GSH-Px activities (r-/0.760, P B/0.05) and between XO activity and malondialdehyde level (r-/0.822, P B/0.05) in the bleomycin plus Gingko biloba group. In conclusion, it was thought that bleomycin induced oxidative stress can be prevented by Gingko biloba treatment via high anti-oxidant enzyme activity together with decreased radical production from XO.

The role of nitric oxide and cytokines in asthma-like syndrome induced by sulfur dioxide exposure in agricultural environment

BACKGROUND We previously demonstrated that apricot sulfurization workers are exposed to high concentrations of SO(2), subsequently causing asthma-like syndrome. This study investigated the effects of SO(2) exposure on serum TNF-alpha, IL-1beta, IL-6, IL-8, nitrite and nitrate levels to understand the mechanism of SO(2)-induced bronchoconstriction in asthma-like syndrome. METHODS We measured the serum levels of the cytokines, direct nitrite, total nitrite and nitrate obtained from 40 volunteer workers after an hour of exposure to SO(2) and 23 healthy controls. RESULTS The concentrations of the cytokines, direct nitrite, total nitrite and nitrate were significantly (p<0.0001) higher in the workers than in the controls. The mean serum concentrations of TNF-alpha, IL-1beta, IL-6, IL-8, direct nitrite, total nitrite and nitrate were 430.60+/-397.03 pg/ml, 436.67+/-316.31 pg/ml, 752.11+/-394.95 pg/ml, 262.12+/-287.99 pg/ml, 7.75+/-3.34 micromol/l, 115.72+/-48.78 micromol/l and 107.97+/-46.19 micromol/l in the workers, while they were 9.83+/-3.12 pg/ml, <5 pg/ml, 7.49+/-1.27 pg/ml, 9.38+/-1.99 pg/ml, 2.17+/-0.77 micromol/l, 59.91+/-7.56 micromol/l and 57.74+/-7.20 micromol/l in the controls, respectively. CONCLUSION These results show that TNF-alpha, IL-1beta, IL-6, IL-8 and nitric oxide may play a role in the pathogenesis of bronchoconstriction in asthma-like syndrome due to the SO(2) exposure.

Preventive effect of lacrimal occlusion on topical timolol-induced bronchoconstriction in asthmatics

Aim: To evaluate the potential preventive role of lacrimal occlusion on the topical timolol‐induced bronchoconstriction in asthmatics.

Effects of ranitidine on pulmonary function tests of patients with chronic obstructive pulmonary disease.

Since the incidence of peptic ulcer and gastroesophageal reflux (GER) is more common in patients with chronic obstructive pulmonary disease (COPD) than normal population, H(2) receptor blockers are given more extensively to COPD patients. This study evaluated the effects of Ranitidine on pulmonary function tests (PFT) of the patients having COPD and peptic ulcer or GER, and of healthy volunteers. Fifty milligrams of Ranitidine was given intravenously to 30 COPD patients and 25 healthy volunteers. PFT were done before and 15, 30, 60, 120min after Ranitidine injection. Although mean forced vital capacity (FVC), forced expiratory volume in 1s (FEV(1)) and forced midexpiratory flow rate (FEF(25-75%)) of COPD patients were found to be decreased 60 and 120min after Ranitidine injection, the decrements were statistically insignificant. The decrements in PFT of healthy volunteers were also not statistically significant.H(2) receptor blockers can be used safely for treatment of gastrointestinal disorders in COPD patients who have mild or moderate obstruction. Minimal decreases in FEV(1) and FVC due to treatment by H(2) receptor blockers may clinically worsen COPD patients who have severe obstruction.

Interdialytic weight gain and pulmonary membrane diffusing capacity in patients on hemodialysis

Background: Measurement of pulmonary diffusion capacity for carbon monoxide (DLCO) may be useful for assessing disease affecting the alveolar-capillary bed or the pulmonary vasculature. It was reported that hemodialysis (HD) therapy causes DLCO reduction via decrease of pulmonary capillary blood volume components. The aim of the study was to evaluate the effect of interdialytic weight gain on pulmonary function and especially DLCO. We further determined whether intravascular volume status, assessed by inferior vena cava diameter (IVCD) contributes to DLCO in patients on HD. Methods: Routine pulmonary function testing including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, forced mid-expiratory flow rate (FEF25–75), DLCO IVCD index and other echocardiographic parameters were evaluated in 20 patients (mean age 48.6 ± 18.3 years, mean dialysis duration 17.4 ± 19.2 months) on chronic HD, 1 hour after HD and after an interdialytic period (1 hour before HD therapy). Single-breath DLCO measurements were corrected for hemoglobin concentration (cDLCO). Results: Routine pulmonary function tests (spirometry) showed no significant changes in FEV1, FVC and FEF25–75 whereas a statistically significant fall in FEV/FVC was found. At the end of the interdialytic period a statistically significant increase in weight, IVCD index, left ventriculer diastolic diameter (LVDD), and diastolic blood pressure (DBP) were observed (P < 0.05). Using the single-breath DLCO, we found unchanged cDLCO at the end of the interdialytic period. There was no correlation of cDLCO with increases in weight, DBP, IVCD index, LVDD (P > 0.05). Conclusion: The accumulation of body water between dialyses has no significant influence on DLCO.