Abstract This study explored the role of gasotransmitters in lead-induced nephrotoxicity. Long-term exposure of rats to lead resulted in its accumulation in kidney. The accumulated metal impaired kidney function and structure. Lead intoxication resulted in oxidative stress, inflammation and apoptosis in kidney. In addition, it resulted in nitric oxide (NO) overproduction and decrease in hydrogen sulfide (H2S) level and heme oxygenase (HO-1) concentration in kidney. Inhibition of NO overproduction by L-N(G)-nitroarginine methyl ester (L-NAME) and increasing of H2S level by sodium hydrosulfide (NaHS) and CO level by carbon monoxide-releasing molecule-A1 (CORM-A1) inhibited lead-induced impairment of kidney function and structure. These agents inhibited lead-intoxication induced oxidative stress, inflammation, apoptosis, nitrosative stress and reduction of H2S level and HO-1 concentration. Also, concomitant treatment with these agents inhibited lead intoxication-induced increase in protein expressions of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and caspase-3 as well as decrease in protein expressions of HO-1 and cystathionine- γ-lyase (CSE) in kidney. The NO donor, L-arginine and the H2S and CO biosynthesis inhibitors, trifluoro-DL-alanine and zinc deutroporphyrin, respectively produced opposite effects and aggravated the toxic effects of lead. These results demonstrate, for the first time, that gasotransmitters play an important role in lead-induced nephrotoxicity.

Abstract This study explored the role of gasotransmitters in lead-induced nephrotoxicity. Long-term exposure of rats to lead resulted in its accumulation in kidney. The accumulated metal impaired kidney function and structure. Lead intoxication resulted in oxidative stress, inflammation and apoptosis in kidney. In addition, it resulted in nitric oxide (NO) overproduction and decrease in hydrogen sulfide (H2S) level and heme oxygenase (HO-1) concentration in kidney. Inhibition of NO overproduction by L-N(G)-nitroarginine methyl ester (L-NAME) and increasing of H2S level by sodium hydrosulfide (NaHS) and CO level by carbon monoxide-releasing molecule-A1 (CORM-A1) inhibited lead-induced impairment of kidney function and structure. These agents inhibited lead-intoxication induced oxidative stress, inflammation, apoptosis, nitrosative stress and reduction of H2S level and HO-1 concentration. Also, concomitant treatment with these agents inhibited lead intoxication-induced increase in protein expressions of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and caspase-3 as well as decrease in protein expressions of HO-1 and cystathionine- γ-lyase (CSE) in kidney. The NO donor, L-arginine and the H2S and CO biosynthesis inhibitors, trifluoro-DL-alanine and zinc deutroporphyrin, respectively produced opposite effects and aggravated the toxic effects of lead. These results demonstrate, for the first time, that gasotransmitters play an important role in lead-induced nephrotoxicity.

Abstract This study explored the role of gasotransmitters in lead-induced nephrotoxicity. Long-term exposure of rats to lead resulted in its accumulation in kidney. The accumulated metal impaired kidney function and structure. Lead intoxication resulted in oxidative stress, inflammation and apoptosis in kidney. In addition, it resulted in nitric oxide (NO) overproduction and decrease in hydrogen sulfide (H2S) level and heme oxygenase (HO-1) concentration in kidney. Inhibition of NO overproduction by L-N(G)-nitroarginine methyl ester (L-NAME) and increasing of H2S level by sodium hydrosulfide (NaHS) and CO level by carbon monoxide-releasing molecule-A1 (CORM-A1) inhibited lead-induced impairment of kidney function and structure. These agents inhibited lead-intoxication induced oxidative stress, inflammation, apoptosis, nitrosative stress and reduction of H2S level and HO-1 concentration. Also, concomitant treatment with these agents inhibited lead intoxication-induced increase in protein expressions of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and caspase-3 as well as decrease in protein expressions of HO-1 and cystathionine- γ-lyase (CSE) in kidney. The NO donor, L-arginine and the H2S and CO biosynthesis inhibitors, trifluoro-DL-alanine and zinc deutroporphyrin, respectively produced opposite effects and aggravated the toxic effects of lead. These results demonstrate, for the first time, that gasotransmitters play an important role in lead-induced nephrotoxicity.

Objectives: To evaluate the prognostic role of post-therapy 99mTc-DMSA-V brain SPECT/CT scans in patients with glioma. Methods: Patients with glioma underwent post-treatment SPECT/CT scanning using 99mTc-DMSA-V in this prospective study. Scan results were reported as positive or negative for tumor residual/recurrence. Three -year overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. Results: A total of 37 patients were eligible for analysis with mean survival of 37.5 months (range = 28.6 – 46.5). At the end of follow-up, 13 patients died (3-year OS = 42%). Ten out of 17 patients with positive DMSA-V scan findings died compared to 3 out of 20 patients with negative scans. Three-year OS were 13% for the positive group with mean survival of 22.2 months compared to 74% and mean survival of 50.3 months for the negative group (P = 0.003). Additionally, patients with negative scans survived significantly longer than positive group after their date of scanning (mean survival 20.7 months vs. 11.0 months; P = 0.001). DMSA-V scan results were still significant predictor of OS after adjusting for age, gender and pathology in Cox proportional hazard model (P = 0.03; Hazards ratio [HR] = 4.8 [95% CI = 1.2 – 19.7]). However, DMSA-V scan results were strongly associated with Karnofsky performance scale (KPS) (P = 0.002). A scoring system which includes both DMSA-V scan results and KPS (cut-off 80) identified 3 different groups with significant difference in OS; score 0 = negative scan & KPS 蠅 80 (reference group), score 1 = positive scan or KPS 80 and score 2 = positive scan with KPS 80 (P = 0.006). Patients with score 2 have HR of 11.4 compared to 3.8 for score 1. Conclusion: Post-therapy SPECT/CT scanning with 99mTc-DMSA-V in patients with glioma is a potential prognostic factor for OS and may be helpful in risk stratification of glioma patients after their treatment. Supporting graph: Supporting Tables

Objectives: To evaluate the prognostic role of post-therapy 99mTc-DMSA-V brain SPECT/CT scans in patients with glioma. Methods: Patients with glioma underwent post-treatment SPECT/CT scanning using 99mTc-DMSA-V in this prospective study. Scan results were reported as positive or negative for tumor residual/recurrence. Three -year overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. Results: A total of 37 patients were eligible for analysis with mean survival of 37.5 months (range = 28.6 – 46.5). At the end of follow-up, 13 patients died (3-year OS = 42%). Ten out of 17 patients with positive DMSA-V scan findings died compared to 3 out of 20 patients with negative scans. Three-year OS were 13% for the positive group with mean survival of 22.2 months compared to 74% and mean survival of 50.3 months for the negative group (P = 0.003). Additionally, patients with negative scans survived significantly longer than positive group after their date of scanning (mean survival 20.7 months vs. 11.0 months; P = 0.001). DMSA-V scan results were still significant predictor of OS after adjusting for age, gender and pathology in Cox proportional hazard model (P = 0.03; Hazards ratio [HR] = 4.8 [95% CI = 1.2 – 19.7]). However, DMSA-V scan results were strongly associated with Karnofsky performance scale (KPS) (P = 0.002). A scoring system which includes both DMSA-V scan results and KPS (cut-off 80) identified 3 different groups with significant difference in OS; score 0 = negative scan & KPS 蠅 80 (reference group), score 1 = positive scan or KPS 80 and score 2 = positive scan with KPS 80 (P = 0.006). Patients with score 2 have HR of 11.4 compared to 3.8 for score 1. Conclusion: Post-therapy SPECT/CT scanning with 99mTc-DMSA-V in patients with glioma is a potential prognostic factor for OS and may be helpful in risk stratification of glioma patients after their treatment. Supporting graph: Supporting Tables

Objectives: To evaluate the prognostic role of post-therapy 99mTc-DMSA-V brain SPECT/CT scans in patients with glioma. Methods: Patients with glioma underwent post-treatment SPECT/CT scanning using 99mTc-DMSA-V in this prospective study. Scan results were reported as positive or negative for tumor residual/recurrence. Three -year overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. Results: A total of 37 patients were eligible for analysis with mean survival of 37.5 months (range = 28.6 – 46.5). At the end of follow-up, 13 patients died (3-year OS = 42%). Ten out of 17 patients with positive DMSA-V scan findings died compared to 3 out of 20 patients with negative scans. Three-year OS were 13% for the positive group with mean survival of 22.2 months compared to 74% and mean survival of 50.3 months for the negative group (P = 0.003). Additionally, patients with negative scans survived significantly longer than positive group after their date of scanning (mean survival 20.7 months vs. 11.0 months; P = 0.001). DMSA-V scan results were still significant predictor of OS after adjusting for age, gender and pathology in Cox proportional hazard model (P = 0.03; Hazards ratio [HR] = 4.8 [95% CI = 1.2 – 19.7]). However, DMSA-V scan results were strongly associated with Karnofsky performance scale (KPS) (P = 0.002). A scoring system which includes both DMSA-V scan results and KPS (cut-off 80) identified 3 different groups with significant difference in OS; score 0 = negative scan & KPS 蠅 80 (reference group), score 1 = positive scan or KPS 80 and score 2 = positive scan with KPS 80 (P = 0.006). Patients with score 2 have HR of 11.4 compared to 3.8 for score 1. Conclusion: Post-therapy SPECT/CT scanning with 99mTc-DMSA-V in patients with glioma is a potential prognostic factor for OS and may be helpful in risk stratification of glioma patients after their treatment. Supporting graph: Supporting Tables

Objectives: To evaluate the prognostic role of post-therapy 99mTc-DMSA-V brain SPECT/CT scans in patients with glioma. Methods: Patients with glioma underwent post-treatment SPECT/CT scanning using 99mTc-DMSA-V in this prospective study. Scan results were reported as positive or negative for tumor residual/recurrence. Three -year overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. Results: A total of 37 patients were eligible for analysis with mean survival of 37.5 months (range = 28.6 – 46.5). At the end of follow-up, 13 patients died (3-year OS = 42%). Ten out of 17 patients with positive DMSA-V scan findings died compared to 3 out of 20 patients with negative scans. Three-year OS were 13% for the positive group with mean survival of 22.2 months compared to 74% and mean survival of 50.3 months for the negative group (P = 0.003). Additionally, patients with negative scans survived significantly longer than positive group after their date of scanning (mean survival 20.7 months vs. 11.0 months; P = 0.001). DMSA-V scan results were still significant predictor of OS after adjusting for age, gender and pathology in Cox proportional hazard model (P = 0.03; Hazards ratio [HR] = 4.8 [95% CI = 1.2 – 19.7]). However, DMSA-V scan results were strongly associated with Karnofsky performance scale (KPS) (P = 0.002). A scoring system which includes both DMSA-V scan results and KPS (cut-off 80) identified 3 different groups with significant difference in OS; score 0 = negative scan & KPS 蠅 80 (reference group), score 1 = positive scan or KPS 80 and score 2 = positive scan with KPS 80 (P = 0.006). Patients with score 2 have HR of 11.4 compared to 3.8 for score 1. Conclusion: Post-therapy SPECT/CT scanning with 99mTc-DMSA-V in patients with glioma is a potential prognostic factor for OS and may be helpful in risk stratification of glioma patients after their treatment. Supporting graph: Supporting Tables

Objectives: To evaluate the diagnostic accuracy of 99mTc- DMSA (V) brain SPECT/CT in post-treatment evaluation of patients with glioma. Methods: Thirty-seven patients with documented glioma of different pathological grades were prospectively studied. After surgical resection the patients received external beam radiotherapy with concomitant and adjuvant chemotherapy. SPECT/CT scans were acquired at 2-3 h. after i.v. injection of 555-740 MBq of Tc-99m DMSA (V). Regions of interest (ROIs) were drawn over the lesion (L) and contralateral normal brain tissue (N) to obtain the mean count and calculate L/N uptake ratio. The results of DMSA (V) SPECT/CT were compared against the clinical/neuroimaging follow up and pathology whenever available. Results: Total of 37 patients were recruited. Follow-up revealed recurrence in 19 patients while 18 were disease free, DMSA (V) successfully diagnosed disease in 17/19 giving sensitivity of 89% (CI:80-99%). DMSA (V) ruled out recurrence in all negative cases (specificity = 100%). Mean and SD of L/N uptake ratio for positive and negative lesions were (6 ± 6.2) and (1.3 ± 0.9); respectively (P=0.003). A cut-off ratio of L/N ratio of 2.3 obtained from ROC analysis showed diagnostic accuracy of 0.9 (CI: 0.78- 1.00; P 0.001). Conclusion: 99mTc- DMSA (V) brain SPECT/CT is an accurate tool for correct identification of residual/recurrent disease after treatment in patients with glioma. Supporting Figure

Objectives: To evaluate the diagnostic accuracy of 99mTc- DMSA (V) brain SPECT/CT in post-treatment evaluation of patients with glioma. Methods: Thirty-seven patients with documented glioma of different pathological grades were prospectively studied. After surgical resection the patients received external beam radiotherapy with concomitant and adjuvant chemotherapy. SPECT/CT scans were acquired at 2-3 h. after i.v. injection of 555-740 MBq of Tc-99m DMSA (V). Regions of interest (ROIs) were drawn over the lesion (L) and contralateral normal brain tissue (N) to obtain the mean count and calculate L/N uptake ratio. The results of DMSA (V) SPECT/CT were compared against the clinical/neuroimaging follow up and pathology whenever available. Results: Total of 37 patients were recruited. Follow-up revealed recurrence in 19 patients while 18 were disease free, DMSA (V) successfully diagnosed disease in 17/19 giving sensitivity of 89% (CI:80-99%). DMSA (V) ruled out recurrence in all negative cases (specificity = 100%). Mean and SD of L/N uptake ratio for positive and negative lesions were (6 ± 6.2) and (1.3 ± 0.9); respectively (P=0.003). A cut-off ratio of L/N ratio of 2.3 obtained from ROC analysis showed diagnostic accuracy of 0.9 (CI: 0.78- 1.00; P 0.001). Conclusion: 99mTc- DMSA (V) brain SPECT/CT is an accurate tool for correct identification of residual/recurrent disease after treatment in patients with glioma. Supporting Figure

Objectives: To evaluate the diagnostic accuracy of 99mTc- DMSA (V) brain SPECT/CT in post-treatment evaluation of patients with glioma. Methods: Thirty-seven patients with documented glioma of different pathological grades were prospectively studied. After surgical resection the patients received external beam radiotherapy with concomitant and adjuvant chemotherapy. SPECT/CT scans were acquired at 2-3 h. after i.v. injection of 555-740 MBq of Tc-99m DMSA (V). Regions of interest (ROIs) were drawn over the lesion (L) and contralateral normal brain tissue (N) to obtain the mean count and calculate L/N uptake ratio. The results of DMSA (V) SPECT/CT were compared against the clinical/neuroimaging follow up and pathology whenever available. Results: Total of 37 patients were recruited. Follow-up revealed recurrence in 19 patients while 18 were disease free, DMSA (V) successfully diagnosed disease in 17/19 giving sensitivity of 89% (CI:80-99%). DMSA (V) ruled out recurrence in all negative cases (specificity = 100%). Mean and SD of L/N uptake ratio for positive and negative lesions were (6 ± 6.2) and (1.3 ± 0.9); respectively (P=0.003). A cut-off ratio of L/N ratio of 2.3 obtained from ROC analysis showed diagnostic accuracy of 0.9 (CI: 0.78- 1.00; P 0.001). Conclusion: 99mTc- DMSA (V) brain SPECT/CT is an accurate tool for correct identification of residual/recurrent disease after treatment in patients with glioma. Supporting Figure