Objectives : To evaluate the difference in the renal protective effects of allopurinol and n-acetyl cysteine along with saline hydration in patients of contrast induced nephropathy (CIN) post cardiac interventions.
Background: CIN remains a common complication of cardiac procedures. Radio contrast agents can cause a reduction in renal function that may be related to oxidative stress underlining various patho- physiologies. Conflicting evidence suggests that administration of allopurinol, a xanthine oxidase inhibitor can prevent CIN.
Materials and Methods: This is a study of 500 patients undergoing angiography and coronary revascularisation in patients showing significant coronary block. The angiography positive patients (275) were prospectively randomised to different treatment protocol to study for their reno-protective effect. The patients received either of the three drugs saline hydration (SH, 1ml/kg/hr), n-acetylcysteine (SH+NAC, 600 mg bd) or Allopurinol (SH+ALLP, 300 mg/day) 12 hours before and after administration of radio contrast agent. Levels of serum creatinine and blood urea of the 275 patients recorded at 24 hour interval were noted post angioplasty over a course of 5 days in patients receiving either omnipaque (125) or visipaque (150) contrast media. All the 500 patients were also assessed for development of any kind of adverse drug effects/reactions with the two contrast media.
Results: CIN occurred in 56 of 500 the patients (10.6%) who underwent angiography and 49 of 275 patients (17.8%) who underwent angioplasty. In the omnipaque group CIN occurred in 16/40, 8/40, nil/45 in patients receiving SH, NAC plus SH and SH plus ALLP respectively. In the visipaque group CIN occurred in 15/50, 10/50, nil/50 in the three treatments groups respectively. Allopurinol maintained a consistent fall in the serum creatinine & blood urea levels from the baseline values from the end of the 1st day (p < .01 & .001) in both the category. Visipaque proved to be better dye than omnipaque with less adverse drug effects/ reactions.
Conclusion: Prophylactic oral administration of allopurinol (300 mg/day) along with hydration is better than n-acetylcysteine and saline hydration alone for protection against CIN in patients undergoing coronary procedures.
Allopurinol; Contrast nephropathy; Omnipaque; Percutaneous coronary interventions; Visipaque
Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8+CD57+ cytotoxic T cells but not CD4+CD57+ cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8+CD57+ T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH.
bromodichloromethane; lipid peroxidation; fibrosis; apoptosis; CD3; P53; caspase-3; TUNEL; IL-2; OB/OB mice
Introduction: The incidence of soft tissue tumours, especially the frequency of benign tumours relative to malignant ones, is nearly impossible to determine accurately. Benign soft tissue tumours outnumber malignant tumours by a wide margin.
Objectives: The main purpose of this study was to look into the clinicopathological profile of benign soft tissue tumour in terms of hospital incidence of age, sex, site distribution and comparison of histological types of benign soft tissue tumours with other similar studies.
Materials and Methods: The operated specimens or biopsy material of benign soft tissue tumours received from January, 2010 to July, 2010 in the Department of Histopathology of our hospital, were studied in detail. Age and sex incidence, site of lesion, clinical features, gross and microscopic appearance were carefully studied.
Results: In our study, most common benign soft tissue tumour was lipoma (50.8%) followed by hemangioma (17.5%) which in turn was followed by neurofibroma, angiofibroma & schwannoma. Most common age group for benign soft tissue tumour were 31-40y (27.5%) followed by 21-30y (22.5%). Overall a male predominance was seen with 60.83% in males. The most common site of occurrence of benign soft tissue tumour overall was found to be trunk (25%), followed by upper extremities (21.7%), lower extremities (17.5%) and nose and nasopharynx (10.8%) in that order.
Conclusion: With our study, we were able to reassess the clinical profile of soft tissue tumours and their different types with respect to age, sex, site distribution.
Benign soft tissue tumours; Clinicopatholical profile; Hemangioma; Lipoma
Sperm cells exhibit extremely high sensitivity in response to slight changes in temperature, osmotic pressure and/or presence of various chemical stimuli. In most cases throughout the evolution, these physico-chemical stimuli trigger Ca2+-signaling and subsequently alter structure, cellular function, motility and survival of the sperm cells. Few reports have recently demonstrated the presence of Transient Receptor Potential (TRP) channels in the sperm cells from higher eukaryotes, mainly from higher mammals. In this work, we have explored if the sperm cells from lower vertebrates can also have thermo-sensitive TRP channels. In this paper, we demonstrate the endogenous presence of one specific thermo-sensitive ion channel, namely Transient Receptor Potential Vanilloid family member sub type 1 (TRPV1) in the sperm cells collected from fresh water teleost fish, Labeo rohita. By using western blot analysis, fluorescence assisted cell sorting (FACS) and confocal microscopy; we confirm the presence of this non-selective cation channel. Activation of TRPV1 by an endogenous activator NADA significantly increases the quality as well as the duration of fish sperm movement. The sperm cell specific expression of TRPV1 matches well with our in silico sequence analysis. The results demonstrate that TRPV1 gene is conserved in various fishes, ranging from 1–3 in copy number, and it originated by fish-specific duplication events within the last 320 million years (MY). To the best of our knowledge, this is the first report demonstrating the presence of any thermo-sensitive TRP channels in the sperm cells of early vertebrates as well as of aquatic animals, which undergo external fertilization in fresh water. This observation may have implications in the aquaculture, breeding of several fresh water and marine fish species and cryopreservation of fish sperms.
Labeo rohita; Ca2+ channels; Ca2+-signaling; Capsaicin; NADA; TRPV1; Vertebrate evolution; sperm cells; sperm motility; teleost fish
Heme, in the presence of hydrogen peroxide, can act as a peroxidase. Intravascular hemolysis results in a massive release of heme into the plasma in several pathophysiological conditions such as hemolytic anemia, malaria, and sickle cell disease. Heme is known to induce heme oxygenase-1(HO-1) expression, and the extent of induction depends on the ratio of albumin to heme in plasma. HO-1 degrades heme and ultimately generates the antioxidant bilirubin. Heme also causes oxidative stress in cells, but whether it causes protein-radical formation has not yet been studied. In the literature, two purposes for the degradation of heme by HO-1 are discussed. One is the production of the antioxidant bilirubin and the other is the prevention of heme-dependent adverse effects. Here we have investigated heme-induced protein-radical formation, which might have pathophysiological consequences, and have used immunospin trapping to establish the formation of heme-induced protein radicals in two systems: human serum albumin (HSA)/H2O2 and human plasma/H2O2.We found that excess heme catalyzed the formation of HSA radicals in the presence of hydrogen peroxide. When heme and hydrogen peroxide were added to human plasma, heme was found to oxidize proteins, primarily and predominantly HSA; however, when HSA-depleted plasma was used, heme triggered the oxidation of several other proteins, including transferrin. Thus, HSA in plasma protected other proteins from heme/H2O2-induced oxidation. The antioxidants ascorbate and uric acid significantly attenuated protein-radical formation induced by heme/ H2O2; however, bilirubin did not confer significant protection. Based on these findings, we conclude that heme is degraded by HO-1 because it is a catalyst of protein-radical formation and not merely to produce the relatively inefficient antioxidant bilirubin.
Heme; Nitrone adducts; Peroxidase; Protein radical; Protein oxidation; Oxidative stress
Editor’s Highlight: Seth and colleagues examined a two-hit model for nonalcoholic steatohepatitis, showing that bromodichloromethane interacts with a high fat diet to induce liver inflammation and metabolic alterations in a CYP2E1-dependent manner. Moreover, bromodichloromethane dramatically affected the satiety-inducing leptin pathway, which appears to be mechanistically involved in the metabolic pathogenesis. In addition to characterizing the phenomenon, this study highlights the potential that genetic polymorphisms and diet may play in determining susceptibility to the metabolic outcomes of common environmental contaminants. The overall metabolic disturbances are likely to be more complex and systemic than described in the present article and future research in this area will be exceedingly valuable to understanding the impact of environmental contaminants on public health. — Matthew Campen
Obesity is associated with strong risks of development of chronic inflammatory liver disease and metabolic syndrome following a second hit. This study tests the hypothesis that free radical metabolism of low chronic exposure to bromodichloromethane (BDCM), a disinfection byproduct of drinking water, causes nonalcoholic steatohepatitis (NASH), mediated by cytochrome P450 isoform CYP2E1 and adipokine leptin. Using diet-induced obese mice (DIO), mice deficient in CYP2E1, and mice with spontaneous knockout of the leptin gene, we show that BDCM caused increased lipid peroxidation and increased tyrosine nitration in DIO mice, events dependent on reductive metabolism by CYP2E1. DIO mice, exposed to BDCM, exhibited increased hepatic leptin levels and higher levels of proinflammatory gene expression and Kupffer cell activation. Obese mice exposed to BDCM also showed profound hepatic necrosis, Mallory body formation, collagen deposition, and higher alpha smooth muscle actin expression, events that are hallmarks of NASH. The absence of CYP2E1 gene in mice that were fed with a high-fat diet did not show NASH symptoms and were also protected from hepatic metabolic alterations in Glut-1, Glut-4, phosphofructokinase and phosphoenolpyruvate carboxykinase gene expressions (involved in carbohydrate metabolism), and UCP-1, PGC-1α, SREBP-1c, and PPAR-γ genes (involved in hepatic fat metabolism). Mice lacking the leptin gene were significantly protected from both NASH and metabolic alterations following BDCM exposure, suggesting that higher levels of leptin induction by BDCM in the liver contribute to the development of NASH and metabolic alterations in obesity. These results provide novel insights into BDCM-induced NASH and hepatic metabolic reprogramming and show the regulation of obesity-linked susceptibility to NASH by environmental factors, CYP2E1, and leptin.
bromodichloromethane; hepatocyte; lipid peroxidation; fibrosis; Glut-1; glycolysis; gluconeogenesis; PPAR-γ; SREBP-1c; tumor necrosis factor; ob/ob mice.
This is a unique case of cervical rib since the patient presented as a firm neck swelling of short duration which was clinically palpable as a superficial neck mass and referred for FNAC for the same. Since FNAC did not yield any positive result, the patient was then referred for CT which showed bilateral cervical ribs with pseudoarticulation with the 1st thoracic rib on the right side which is quite rare. The clinical importance of our case is to keep in mind a differential diagnosis of cervical rib in firm to hard clinically palpable posterior triangle neck masses. It is also important to diagnose cervical ribs in patients undergoing CT of the neck since they are under reported as determined in previous studies.
Cervical rib; supraclavicular swelling; CT
Today’s developed world faces a major public health challenge in a rise in the obese population and an increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation, protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-α levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver.
Adipocytokines; Kupffer cell; oxidative stress; lipid peroxidation; tyrosine nitration; necrosis; tumor necrosis factor; OB/OB mice
A rare case of primary extranodal lymphoma of nasal cavity is here with reported in a 11 years old female child. Patient presented with space occupying extensive lesion in nasal cavity with destraction of nasal septum and obliteration of paranasal sinuses. After histological examination and routine stain showed a round cell tumor with provisional diagnosis of large cell non-Hodgkin’s lymphoma was made. Immunohistochemical stain were used to further differentiate from other possibilities mimics as carcinoma and round cell tumors. Immunohistochemical stain confirm the diagnosis of extranodal T-cell lymphoma. We report this case for its rarity in paediatric patients.
T-cell lymphoma; Extranodal; Nasal cavity
In Diabetes, the chronic hyperglycemia and associated complications affecting peripheral nerves are one of the most commonly occurring microvascular complications with an overall prevalence of 50–60%. Among the vascular complications of diabetes, diabetic neuropathy is the most painful and disabling, fatal complication affecting the quality of life in patients. Several theories of etiologies surfaced down the lane, amongst which the oxidative stress mediated damage in neurons and surrounding glial cell has gained attention as one of the vital mechanisms in the pathogenesis of neuropathy. Mitochondria induced ROS and other oxidants are responsible for altering the balance between oxidants and innate antioxidant defence of the body. Oxidative-nitrosative stress not only activates the major pathways namely, polyol pathway flux, advanced glycation end products formation, activation of protein kinase C, and overactivity of the hexosamine pathway, but also initiates and amplifies neuroinflammation. The cross talk between oxidative stress and inflammation is due to the activation of NF-κB and AP-1 and inhibition of Nrf2, peroxynitrite mediate endothelial dysfunction, altered NO levels, and macrophage migration. These all culminate in the production of proinflammatory cytokines which are responsible for nerve tissue damage and debilitating neuropathies. This review focuses on the relationship between oxidative stress and neuroinflammation in the development and progression of diabetic neuropathy.
Background and Aims
Progression from steatosis to steatohepatitic lesions is hypothesized to require a second hit. These lesions have been associated with increased oxidative stress, often ascribed to high levels of leptin and other proinflammatory mediators. Here we have examined the role of leptin in inducing oxidative stress and Kupffer cell activation in CCl4-mediated steatohepatitic lesions of obese mice.
Male C57BL/6 mice fed with a high fat diet (60%kcal) at 16 weeks were administered CCl4 to induce steatohepatitic lesions. Approaches included use of immuno-spin trapping for measuring free radical stress, gene-deficient mice for leptin, p47 phox, iNOS and adoptive transfer of leptin primed macrophages in vivo.
Diet-induced obese (DIO) mice, treated with CCl4 increased serum leptin levels. Oxidative stress was significantly elevated in DIO mice liver but not in OB/OB mice, or in DIO mice treated with leptin antibody. In OB/OB mice, leptin supplementation restored markers of free radical generation. Markers of free radical formation were significantly decreased by the peroxynitrite decomposition catalyst FeTPPS, the iNOS inhibitor 1400W, the NADPH oxidase inhibitor apocynin, or in iNOS or p47 phox-deficient mice. These results correlated with the decreased expression of TNF-alpha and MCP-1. Kupffer cell depletion eliminated oxidative stress and inflammation, whereas in macrophage-depleted mice, the adoptive transfer of leptin-primed macrophages significantly restored inflammation.
These results, for the first time, suggest that leptin action in macrophages of steatotic liver through induction of iNOS and NADPH oxidase caused peroxynitrite-mediated oxidative stress thus activating Kupffer cells.
Adipocytokines; Kupffer cell; oxidative stress; tyrosine nitration; NADPH oxidase; OB/OB mice
In human beings, Parkinson’s disease (PD) is associated
with the oligomerization and amyloid formation of α-synuclein
(α-Syn). The polyphenolic Asian food ingredient curcumin has
proven to be effective against a wide range of human diseases including
cancers and neurological disorders. While curcumin has been shown
to significantly reduce cell toxicity of α-Syn aggregates, its
mechanism of action remains unexplored. Here, using a series of biophysical
techniques, we demonstrate that curcumin reduces toxicity by binding
to preformed oligomers and fibrils and altering their hydrophobic
surface exposure. Further, our fluorescence and two-dimensional nuclear
magnetic resonance (2D-NMR) data indicate that curcumin does not bind
to monomeric α-Syn but binds specifically to oligomeric intermediates.
The degree of curcumin binding correlates with the extent of α-Syn
oligomerization, suggesting that the ordered structure of protein
is required for effective curcumin binding. The acceleration of aggregation
by curcumin may decrease the population of toxic oligomeric intermediates
of α-Syn. Collectively; our results suggest that curcumin and
related polyphenolic compounds can be pursued as candidate drug targets
for treatment of PD and other neurological diseases.
Curcumin; α-synuclein; amyloid; oligomers; toxicity; Parkinson’s disease
We report whole-genome sequences of two clinical isolates of Mycobacterium tuberculosis isolated from patients in Odisha, India. The sequence analysis revealed that these isolates are of an ancestral type and might represent some of the “pristine” isolates in India that have not admixed with other lineages.
Originally identified as an innate cytotoxin, nitric oxide (•NO) formation in tumors can influence chemotherapy and exacerbate cancer progression. Here, we examined the hypothesis that •NO generation contributes to cancer cell drug resistance towards the widely used anticancer drug Etoposide (VP-16). The UV-V is spectrum of VP-16 was not changed by exposure of VP-16 to •NO in aqueous buffer. In contrast, reddish-orange compound(s) characteristic of o-quinone- and nitroso-VP-16, were readily generated in a hydrophobic medium (chloroform) in an oxygen-dependent manner. Similar products were also formed when the VP-16 radical, generated from VP-16 and horseradish peroxidase/H2O2, was exposed directly to •NO in chloroform in the presence of oxygen. Separation and spectral analysis of VP-16 reaction extracts by electron spin resonance and UV-Vis indicated generation of the phenoxy radical and the o-quinone of VP-16, as well as putative nitroxide, iminoxyl and other nitrogen oxide intermediates. Nitric oxide products of VP-16 displayed significantly diminished topoisomerase II-dependent cleavage of DNA and cytotoxicity to human HL-60 leukemia cells. LPS-mediated induction of nitric oxide synthase in murine macrophages resulted in VP-16 resistance compared to Raw cells. Furthermore, •NO products derived from iNOS rapidly reacted with VP-16 leading to decreased DNA damage and cytotoxicity. Together, these observations suggest that formation of •NO in tumors (associated macrophages) can contribute to VP-16 resistance via detoxification of VP-16.
Etoposide; Nitric Oxide; Electron Spin Resonance; Cytotoxicity; Topoisomerase II
Brooke-Spiegler syndrome is a rare entity. It is an autosomal dominant syndrome in which multiple trichoepitheliomas, cylindromas, or other adnexal tumors are seen. Very few cases of Brooke-Spiegler syndrome are reported in the literature. We came across a 40 -year-old female in which multiple trichoepitheliomas and cylindromas were seen on scalp. In view of clinical history and histopathological examination it was diagnosed as Brooke-Spiegler syndrome. We report this case because of its rarity.
Titania; Genotoxicity; Nanotoxicity
Titania; Micronucleus; Nanotoxicity; Flow cytometry
Peripheral neuropathy is a severe dose limiting toxicity associated with cancer chemotherapy. Ever since it was identified, the clear pathological mechanisms underlying chemotherapy induced peripheral neuropathy (CIPN) remain sparse and considerable involvement of oxidative stress and neuroinflammation has been realized recently. Despite the empirical use of antioxidants in the therapy of CIPN, the oxidative stress mediated neuronal damage in peripheral neuropathy is still debatable. The current review focuses on nerve damage due to oxidative stress and mitochondrial dysfunction as key pathogenic mechanisms involved in CIPN. Oxidative stress as a central mediator of apoptosis, neuroinflammation, metabolic disturbances and bioenergetic failure in neurons has been highlighted in this review along with a summary of research on dietary antioxidants and other nutraceuticals which have undergone prospective controlled clinical trials in patients undergoing chemotherapy.
Targeting chemotherpay induced peripheral neuropathy with natural antioxidants.
•Oxidative stress contributes to the pathophysiology of chemotherapy induced peripheral neuropathies (CIPN).•Mitotoxicity and mitochondrial dysfunction contribute to amplified oxidative stress.•Pharmacological interventions targeted at maintenance of mitochondrial health and function may be beneficial against CIPN.
Chemotherapy; Mitochondria; Mitotoxicity; Nutraceuticals; Oxidative stress; Peripheral neuropathy