Association of heavy metals and trace elements in carcinoma urinary bladder: A case-controlled study.

Introduction: Abnormal levels of heavy metals (HM) and trace elements (TE) affect body metabolism and can induce carcinogenesis. This study aims to evaluate the role of HM and TE in carcinoma urinary bladder (CAUB). Methods: Patients with biopsy-proven CAUB (n = 100) were taken as the study group, while age-and sex-matched healthy volunteers were taken as control (n = 100). Blood and urine samples were compared for Arsenic (As), Copper (Cu), Manganese (Mn), Selenium (Se), Cadmium (Cd), Lead (Pb), and Mercury (Hg) levels. Serum glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and lipid peroxidation (LPO) levels were assessed to know the redox status between the two groups. Results: A significantly higher blood level of As, Mn, and Pb was observed in CAUB cases as compared to controls. Blood Se level was significantly lower in CAUB patients. On comparing urinary levels, CAUB patients had a higher As, Mn, and Pb levels compared to controls. Further, 68% and 59% of patients had their blood and urinary HM and TE levels above the permitted level, respectively. CAUB cases also had a lower GSH-Px (113.5 ± 44.7 vs. 163.9 ± 120.5, P = 0.0002), lower SOD levels (11.35 ± 5.6 vs. 13.75 ± 3.9, P = 0.008), and a higher LPO levels (15.5 ± 14.7 vs. 11.18 ± 11.2, P = 0.02) in the serum. Conclusions: A significantly higher concentration of As, Mn, and Pb was noted in the blood and urine of CAUB patients compared to controls. CAUB cases also had lower serum GSH-Px and SOD levels with a concomitant increased serum LPO assay suggesting underlying oxidative stress.

Can Superoxide Anions Predict the Malignant Potential of Carotid body Tumor? - A Pilot Study.

Currently, there is no consensus on estimating the malignant potential of Carotid Body Tumor (CBT) and the only way to predict a metastatic CBT is through DOTANOC Positron Emission Tomography (PET) scan. There is a well-established correlation between CBT and superoxide anions inside tumor cells. The purpose of this pilot study was to measure superoxide anions inside CBT cells and find if these can be used as marker to predict malignant potential of CBT. The results were also co-related with findings of DOTANOC PET scan retrospectively. The CBT tissue from 10 patients was stained using a fluorogenic dye and superoxide anions were measured by analysis of fluorescent image. The patients were divided into two groups - First group with four patients having potentially malignant CBT based upon clinico-surgical characteristics and second group with the rest of the six patients. It was seen that the superoxide anions were highest in the first group which included patients with metastatic carotid body tumor, patients with multiple paragangliomas and patient with positive family history (p = 0.011). The same patients also had metastasis and multiple tumors detected on DOTANOC PET scan. It was concluded that measuring superoxide anions in excised tumor tissue can be used to estimate malignant potential of CBT and can identify patients who truly require DOTANOC PET scan; without affecting the treatment, as it is an expensive investigation involving ionizing radiation and may not be available in all centres. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-03623-6.

Estimation of Serum Levels of Heavy Metals in Patients with Chronic Invasive Fungal Rhinosinusitis Before the COVID-19 Era: A Pilot Study.

Objective: Various metals play role in the survival and pathogenesis of the invasive fungal disease. The objectives of this study were to compare the levels of heavy metals in patients with chronic invasive fungal rhinosinusitis (CIFR) and healthy controls, and to analyze their role in disease outcome. Methods: Twenty-three patients (15 with invasive mucormycosis and 8 with invasive aspergillosis, Group 1), and 14 healthy controls (Group 2) were recruited. Blood samples were collected from each group into ion-free tubes and analyzed for serum levels of Nickel (Ni), Copper (Cu), Zinc (Zn), Gallium (Ga), Arsenic (As), Selenium (Se), Rubidium (Rb), Strontium (Sr), Cadmium (Cd), and Lead (Pb). The final outcome of the patients during their hospital stay was categorized clinico-radiologically as improved or worsened, or death. Results: The levels of all metals were higher in Group 1 except for As and Pb. However, the differences in Cu (p=0.0026), Ga (p=0.002), Cd (p=0.0027), and Pb (p=0.0075) levels were significant. Higher levels of Zn (p=0.009), Se (p=0.020), and Rb (p=0.016) were seen in the invasive aspergillosis subgroup. Although Zn (p=0.035), As (p=0.022), and Sr (p=0.002) levels were higher in patients with improved outcome, subgroup analysis showed no differences. Conclusion: The levels of some heavy metals in CIFR significantly differ from those of the general population and also vary with the type of the disease and its outcome. These levels may not have a direct effect on the outcome of the patient, but they do play a role in the pathogenesis of the invading fungus.

Arsenic intoxication with renal failure managed with hemodialysis alone: A case report.

Arsenic has widespread use in agriculture, in alternative medicine and in treatment of certain malignancies, therefore it is vital to timely recognize and treat arsenic toxicity in a suspected patient. Hemodialysis conventionally is thought to play only a supportive role in managing arsenic toxicity but it can be life-saving when chelation is not possible or available. A middle-aged female with a history of non-dialysis-dependent chronic kidney disease (CKD) was brought to the emergency with altered sensorium. On presentation, she was hemodynamically stable with pallor and exfoliating lesions on palms, hyperkeratotic lesions on soles and hyperpigmented macules on the trunk. Investigations revealed pancytopenia and deranged kidney function tests. In view of skin lesions, the toxicological analysis was sent which revealed high levels of Arsenic (594 and 2,553 mcg/L in blood and urine respectively). Thus, a diagnosis of metabolic encephalopathy with the underlying cause being uremic or/and arsenic intoxication was made. Considering renal failure, she was managed with thrice-weekly hemodialysis. Chelation was not possible due to unavailability of agents during lockdown in Coronavirus disease (COVID-19) pandemic. Following dialysis, there was a significant improvement in sensorium, skin lesions, and pancytopenia depicting the utility of hemodialysis in such cases. Thus, hemodialysis is an effective and perhaps underutilized modality in the treatment of arsenic intoxication with impaired renal function.

Association of heavy metals and trace elements in renal cell carcinoma: A case-controlled study.

PURPOSE: Trace elements and/or heavy metals are important for various biological activities. However, excess amount of these elements is associated with a variety of diseases, including cancer. We aimed to analyse the alterations of trace elements levels in renal cell carcinoma (RCC) patients. MATERIALS AND METHODS: In this observational study, patients with biopsy proven RCC were taken as study group while age- and sex-matched healthy volunteers were taken as control. Blood and urine samples were compared for Arsenic (As), Copper (Cu), Manganese (Mn), Selenium (Se), Cadmium (Cd), Lead (Pb) and Mercury (Hg) levels measured by inductively coupled plasma mass-spectroscopy. Serum glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) antioxidant enzymes and lipid peroxidation (LPO) levels were assessed to know the redox status between 2 groups. RESULTS: A total of 76 RCC cases and 64 controls were recruited in the study. A significantly higher concentration of As, Cu, Mn, Cd, Pb and Hg were observed in the blood of RCC patients as compared to controls. However, blood Se level was significantly lower in RCC patients. In 33 (43.4%) patients, one or more heavy metals were higher in the blood above their permitted level as compared to 10 (15.6%) subjects in control group. RCC patients had a higher urinary Mn and Se levels compared to controls. A significantly lower GSH-Px (182.08 ± 132.91 vs. 236.95 ± 132.94, P = 0.04) and a higher LPO levels (26.02 ± 20.79 vs. 14.06 ± 8.44, P = 0.003) were noted in RCC patients than controls. SOD levels were comparable between two groups. CONCLUSIONS: A significantly altered heavy metals concentration is noted in the blood and urine in RCC patients as compared to healthy controls. An associated lower levels of GSH-Px antioxidant enzyme and increased LPO in RCC patients signifies an imbalance in the redox status.

Trace Elements Levels in Serum of Patients with Recurrent Respiratory Papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a chronic airway disease characterized by unpredictable recurrences and relapses. Our study aimed to identify the role of trace elements, a proven risk factor for various malignancies, in the development of papilloma and to correlate their serum levels with various disease parameters. 32 RRP patients with 20 age-matched controls were recruited in the study. Analysis of serum trace elements was performed by atomic absorption spectrophotometry in whole blood samples from cases and controls. The serum levels of trace elements were correlated with age of onset, history of previous surgeries, tracheostomy status, Derkay's score, and presence of dysplasia. Among the 32 cases there were 18 males and 14 females with a mean age of 20.85 years (range: 3-60 years). The mean serum levels of Thallium, Zinc, and Gallium were higher among cases compared to their controls whereas the levels of Arsenic, Copper, Cobalt, Selenium, Cadmium, and Lead were higher in control subjects compared to RRP patients. There was a statistically significant correlation of serum level of Cobalt with more than 3 surgeries per year (p = 0.02), Gallium and Thallium with Derkay's score of more than 20 (p = 0.04 and 0.05) and Lead, Arsenic and Gallium with presence tissue dysplasia (p = 0.05, 0.04 and 0.04). Our study had shown a variable association of trace elements in RRP patients. The usefulness of these values need to be completely elucidated and our study calls for future investigations to identify the casual association of various trace elements in the pathogenesis of RRP.

Quantitative plasma proteomics identifies metallothioneins as a marker of acute-on-chronic liver failure associated acute kidney injury.

Background: Acute kidney injury (AKI) considerably increases the risk of short-term mortality in acute-on-chronic liver failure (ACLF) but predicting AKI is not possible with existing tools. Our study aimed at de novo discovery of AKI biomarkers in ACLF. Methods: This observational study had two phases- (A) Discovery phase in which quantitative proteomics was carried-out with day-of-admission plasma from ACLF patients who initially had no-AKI but either progressed to AKI (n=10) or did not (n=9) within 7 days of admission and, (B) Validation phase in which selected biomarkers from the discovery phase were validated by ELISA in a larger set of ACLF plasma samples (n=93) followed by sub-group analyses. Results: Plasma proteomics revealed 56 differentially expressed proteins in ACLF patients who progressed to AKI vs those who did not. The metallothionein protein-family was upregulated in patients who progressed to AKI and was validated by ELISA as significantly elevated in both- (i) ACLF-AKI vs no-AKI (p-value ≤ 0.0001) and (ii) progression to AKI vs no-progression to AKI (p-value ≤ 0.001). AUROC for AKI vs no-AKI was 0.786 (p-value ≤0.001) and for progression to AKI vs no-progression to AKI was 0.7888 (p-value ≤0.001). Kaplan-Meier analysis revealed that ACLF patients with plasma MT concentration >5.83 ng/mL had a high probability of developing AKI by day 7 (p-value ≤0.0001). High expression of metallothionein genes was found in post-mortem liver biopsies of ACLF patients. Conclusion: Day-of-admission measurements of plasma metallothionein can act as predictive biomarkers of AKI in ACLF.

Apoptotic and Degenerative Changes in the Enteric Nervous System Following Exposure to Fluoride During Pre- and Post-natal Periods.

Children born in fluorosis endemic areas usually suffer from gastrointestinal complications and are unable to attain normal growth as per their age group. The enteric nervous system (ENS) controls gut movement and functions. It is highly vulnerable to any ingested toxins. Based on observations, it was hypothesized that fluoride exposure during pregnancy and lactation might induce ENS developmental defects. The aim of this study is to investigate the effects of fluoride exposure during pregnancy and lactation on ENS of the first-generation rat pups. After confirmation of pregnancy, female rats were divided into 3 groups and kept on normal water (group 1), 50 ppm of fluoride (group 2), and 100 ppm of fluoride (group 3). The fluoride exposure started at the start of pregnancy and continued until lactation. On the 21st post-natal day, the pups were euthanized and the gut tissue and blood were harvested and subjected to fluoride measurement, oxidative stress estimation, histopathological and ultrastructural analysis, TUNEL, and immunofluorescence. The quantitative expressional analysis of embryonic lethal abnormal vision-like 4 (ELAVL4) (a pan-neuronal marker) and glial fibrillary acidic protein (GFAP) (a glial cell marker) genes was performed by RT-qPCR. An increase in oxidative stress, subcellular and cellular injuries, and apoptosis in enteric neuronal, glial, and epithelial cells was observed in the distal colon of the first-generation pups. Ganglionic degeneration, reduced expression of HuC/D and GFAP, altered colon muscle layer thickness, and tissue edema were observed in the fluoride-treated groups compared with the control. Fluoride exposure during prenatal and lactation period leads to subcellular and cellular injuries due to increased oxidative stress and apoptosis in the ENS. The reduction in the number of neurons and glia due to increased apoptosis may cause alterations in ENS development.

Fluoride induced tissue hypercalcemia, IL-17 mediated inflammation and apoptosis lead to cardiomyopathy: Ultrastructural and biochemical findings.

An increased prevalence of cardiac complications has been observed in residents of fluorosis endemic areas chronically exposed to fluoride. Fluoride induces soft tissue injury due to oxidative stress, lipid peroxidation (LPO) and mitochondriopathy. It was hypothesized that chronic fluoride exposure induces apoptosis in cardiomyocytes due to inflammation, lysis of extra cellular matrix and altered calcium metabolism. This study was planned to evaluate the effects of chronic fluoride exposure and the mechanism of action in the cardiac muscle. Fifteen week old male Wistar rats were administered a human equivalent dose of fluoride (50 and 100 ppm ad-libitum, HED = 5 & 10 ppm in human) for 75-days. After 75-days of fluoride exposure, the animals were euthanized and fluoride, oxidative stress (SOD, GPX, Catalase activities) and LPO were measured. Histopathological and ultrastructural pathological examinations were conducted on the cardiac tissues using light, atomic force and electron microscopies. The cardiac tissues were also assessed for apoptosis (TUNEL/Caspase assays), and tissue calcium levels (Alizarin-assay and SEM-EDX). Tissue inflammation and expression of IL-17, MMP-9, Caspase-3 and Bcl-2 were evaluated. In the fluoride exposed groups, a significant (≤0.05) increase in levels of oxidative stress, LPO and apoptosis were observed. The IL-17, MMP-9 and Caspase-3 were significantly (≤0.05) higher in the cardiac muscle after chronic fluoride exposure. The fluoride seems to have induced inflammation in the cardiac tissues, as well as an increase in tissue calcium (≤0.05). There was significant damage to cardiac muscle fibres including, thinning, distortion and neo-vasculogenesis following chronic fluoride exposure. Mitochondriopathy, lysis of ground substance, oedema, and hyper-vacuolation was seen in fluoride treated groups. Remarkable levels of distortion and bending in Z band were observed under the AFM. Many of these observed changes mimic those occurring in cardiomegaly, cardiac hypertrophy and cardiomyopathies.

Multiple Myeloma-Like Spinal MRI Findings in Skeletal Fluorosis: An Unusual Presentation of Fluoride Toxicity in Human.

Endemic fluorosis is a worldwide environmental problem due to excessive fluoride, commonly due to increased drinking water fluoride levels but sometimes due to other sources such as food with high fluoride content. In India, 21 of the 35 states are known to have health problems associated with fluoride toxicity. The present report is a case of a 50-year-old female who was seen with progressive spinal complications and a MRI of the spine suggestive of multiple myeloma. The MRI of the lumbosacral spine showed a diffuse and heterogeneous marrow signal of the lower dorsal and lumbosacral vertebrae. The MRI was also suggestive of coarse trabeculation and appeared predominantly hypointense on the T1W image and had mixed signal intensity on the T2W image. These findings were suggestive of neoplastic bone marrow infiltration and the presence of a proliferative disorder, with multiple myeloma being the most likely. During the patient workup, it was found that other family members were also having similar complications and, after investigation of these family members, it was found that they are suffering from systemic fluorosis. The patient was then evaluated for skeletal fluorosis, and this condition was found to be present. Multiple myeloma was ruled out by the finding of a negative serum protein electrophoresis. The spinal complications appeared to be mainly due to the compression of the spinal cord and nerve roots by protruding osteophytes, thickening of the posterior longitudinal ligament, and thickening of the ligamentum flavum resulting in a compressive myeloradiculopathy and compressive myelopathy. The finding of multiple myeloma-like findings on the spinal MRI in association with skeletal fluorosis was considered to be a very rare event. This case report underlines the need to consider the presence of spinal skeletal fluorosis when evaluating spinal complications with unusual pseudo-multiple myeloma-like changes on the spinal MRI.