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Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune small vessel vasculitis characterized by autoreactivity to antigens in type IV collagen chains expressed in glomerular and alveolar basement membrane. The detection of circulating anti-GBM antibodies, which are shown to be directly pathogenic, is central to disease diagnosis. Clinically, anti-GBM disease usually presents with rapidly progressive glomerulonephritis with or without alveolar hemorrhage. Rapid diagnosis and early treatment are required to prevent mortality and to preserve renal function. Relapse in anti-GBM disease is uncommon. Variant and atypical forms of anti-GBM disease are increasingly recognised., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The present study evaluated the effects of s-nitrosoglutathione (GSNO), a nitrosothiol and sustained NO releaser, on experimental model of sporadic Alzheimer`s disease (sAD) in rats. Levels of Aβ40, Aβ42 and BDNF were assessed in brain hippocampal homogenates for correlative purposes. Intracerebroventricular-Streptozotocin (icv-STZ) induced increased escape latencies (acquisition) and reduced time in target quadrant (probe trial) in Morris Water Maze (MWM) test at 3 months post icv-STZ administration. These behavioural changes were associated with increased Aβ depositions and lowered BDNF levels in brain hippocampal homogenates. Pre-treatment with GSNO (50 μg/kg/day), reduced the icv-STZ induced cognitive deficits in acquisition and probe trials in the MWM. The icv-STZ induced elevations in Aβ40 and Aβ42 and reduced levels of BDNF in hippocampal homogenates were also attenuated after GSNO treatment in these rats. The NO-precursor, l-arginine (100 mg/kg) induced similar effects on behavioural and biochemical parameters tested but was marginally less consistent as compared to those seen with GSNO. The results suggest that GSNO ameliorates the cognitive deficits and associated brain biochemical changes in this experimental model of sporadic AD, and NO-BDNF interactions could play crucial role in these effects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The present study was designed to investigate the effects of chronic predictable stress (CPS) and chronic unpredictable stress (CUS) on immunological responses in KLH-sensitized rats and involvement of NOergic signaling pathways mediating such responses. Male Wistar rats (200-250g) were exposed to either CPS or CUS for 14days and IgG antibody levels and delayed type hypersensitivity (DTH) response was determined to assess changes in adaptive immunity. To evaluate the role of nitric oxide during such immunomodulation, biochemical estimation of stable metabolite of nitric oxide (NOx) and 3-nitrotyrosine (3-NT, a marker of peroxynitrite formation) were done in both blood and brain. Chronic stress exposure resulted in suppression of IgG and DTH response and elevated NOx and 3-NT levels, with a difference in magnitude of response in CPS vs CUS. Pretreatment with aminoguanidine (iNOS inhibitor) caused further reduction of adaptive immune responses and attenuated the increased NOx and 3-NT levels in CPS or CUS exposed rats. On the other hand 7-NI (nNOS inhibitor) did not significantly affect these estimated parameters. The results suggest involvement of iNOS and lesser/no role of nNOS during modulation of adaptive immunity to stress. Thus, the result showed that predictability of stressors results in differential degree of modulation of immune responses and complex NO-mediated signaling mechanisms may be involved during responses., (Copyright © 2017. Published by Elsevier B.V.)

The present study evaluated the immunomodulatory effects of chelidonic acid, a secondary plant metabolite, with therapeutic potential in allergic disorders, in experimental animals. In mast cell degranulation studies, ovalbumin immunized and challenged rats, chelidonic acid (1, 3 and 10mg/kg, i.p.) dose relatedly prevented ovalbumin challenge induced mast cell degranulation by differing degrees when compared with vehicle treated group, and these effects were comparable with prednisolone (10mg/kg). A reduction in post-challenge mortality was also observed in all treated groups. Further, there were reductions in the blood eosinophil counts and serum IgE levels after chelidonic acid treatment. Chelidonic acid also inhibited histamine release from rat peritoneal mast cells (RPMC) in vitro, in a dose related manner. In tests for adaptive immunity, in rats immunized with sheep RBC, chelidonic acid differentially suppressed the (a) plaque forming cell (PFC) count in rat splenic cells, (b) anti-SRBC antibody titre and serum IgG levels and (c) increases in foot pad thickness in the DTH assay - all of which were comparable with prednisolone. These experimental results are discussed in light of the possible therapeutic potential of chelidonic acid in allergic disorders., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Stress is known to precipitate neuropsychiatric diseases, and depending upon its nature and intensity it can also influence the functioning of the immune system. Melatonin (N-acetyl-5-methoxy tryptamine) a pineal gland hormone and potent antioxidant is known to protect against many diseases. Effect of melatonin in stress-induced neuro-immunomodulation is not well elucidated. Therefore in the present study, the protective effects of melatonin were evaluated in restraint stress (RS)-induced behavioral and immunological changes in rats. RS for 1 h significantly reduces (i) percentage of open-arm entries and (ii) percentage of time spent on open-arm in elevated plus maze (EPM) test parameters (p < 0.01) and significant increase in MDA levels in brain homogenate when compared to non-RS control groups (p < 0.05). In immunological studies, both humoral and cell-mediated immune responses to antigen were significantly suppressed by RS for 1 h for 5 consecutive days, as evidenced by significant reduction in (i) anti-SRBC antibody titre, (ii) PFC counts, (iii) percentage change in paw volume, and (iv) Th1 (IFN-γ) and Th2 (IL-4) cytokine levels (p < 0.001 in all parameters). These RS-induced immunological changes were associated with significantly increased lipid peroxidation (MDA) levels in serum and significantly decreased activity of (i) SOD, (ii) CAT, and (iii) GSH levels in RS (X5)-exposed group (p < 0.02). Pretreatment with melatonin (10, 50, and 100 mg/kg) significantly reversed these RS-induced changes in EPM test parameters and humoral and cell-mediated immunological parameters, as well as oxidative stress markers in a dose-dependent manner by differential degrees (p < 0.001). Results are strongly suggestive of the involvement of free radicals during stress-induced neurobehavioral and immunological changes. These changes were significantly restored by melatonin pretreatment. We can conclude that melatonin may have a protective role during such stress-induced neuro-immunomodulation.

The changes in urine flow and renal sympathetic nerve activity (RSNA) due to pulmonary lymphatic obstruction (PLO) were examined in anesthetized, artificially ventilated New Zealand white rabbits. PLO was produced by pressurizing an isolated pouch created in the right external jugular vein at the points of entry of the right lymphatic ducts. During this maneuver, urine flow increased from 8.5 ± 0.3 mL/10 min to 12 ± 0.5 mL/10 min (P < 0.0001) and RSNA increased from 24.0 ± 4 to 40.0 ± 5 μV·s (P < 0.0001). Bilateral lesioning of the paraventricular nucleus (PVN) of the hypothalamus or cervical vagotomy abolished these responses. PLO increased c-fos gene expression in the PVN. The increase in urine flow due to PLO was attenuated by muscimol and abolished by kynurenic acid microinjections into the PVN. The results show that (i) neurons in the PVN are an important relay site in the reflex arc, which is activated by PLO; and (ii) this activation is regulated by glutamatergic and partly by GABAergic input to the PVN.

Stress and stress related disorders are a major cause of morbidity and mortality and understanding stress mechanisms is of great importance for devising appropriate therapeutic measures in such situations. The brain and its complex neurotransmitter systems regulate physiological and behavioral responses to a variety of stressors. Several other factors like age, gender and emotionality of the organism, as well as type, intensity and duration of the stressor may decide the nature and extent of stress effects. Nitric oxide (NO) is widely distributed in the brain and its role in Central nervous system (CNS) pathophysiology has been suggested. Recent studies have shown that free radicals and in particular NO may play a crucial role in the regulation of stress effects. All the various factors, mentioned above, that might influence stress responsiveness have been discussed with reference to regulatory role of NO during stress and it appears that NO may act as a therapeutic target for development of novel strategies against stress related disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Bronchial asthma is a chronic inflammatory disorder of the airways and pharmacotherapy is dependent on anti-inflammatory and bronchodilator agents. However, adverse effects of these agents on chronic administration and sometimes non-responsiveness to these drugs have prompted the search for viable alternatives from medicinal plant sources. UNIM-352 is a polyherbal preparation traditionally used in the Unani system of Indian medicine for the treatment of bronchial asthma. The present study defines the possible cellular and molecular mechanisms of action of UNIM-352 in experimental models of bronchial asthma and validates the observed therapeutically beneficial effects. Wistar rats were immunized and challenged with ovalbumin, and blood and bronchoalveolar lavage (BAL) fluid were assayed for cytological and biochemical markers. UNIM-352 (200 and 400 mg/kg) markedly reduced the eosinophil and neutrophil counts in both blood and BAL compared to control. The polyherbal agent also attenuated the levels of TNF-α, IL-4, GM-CSF and NF-κB whereas histone deacetylase (HDAC) levels were elevated, in both blood and BAL fluid. All effects of UNIM-352 were comparable with the standard drug, prednisolone. The results demonstrated possible cellular and molecular mechanisms of UNIM-352 and thus explain its beneficial effects in bronchial asthma.

The present study evaluated the effects of morphine on acute and chronic restraint stress (RS) induced anxiety modulation and the possible involvement of nitric oxide (NO) and heat shock proteins (Hsp70) during such effects. Acute RS (×1) induced anxiogenesis in the elevated plus maze (EPM) test which was associated with lowered brain NO metabolites (NOx) and elevated Hsp70 levels. Pretreatment with morphine (1 and 5 mg/kg) and L-arginine (500 mg/kg) attenuated the RS effects on EPM activity and brain NOx, whereas, Hsp70 levels were further augmented. Co-administration of both agents showed synergistic effects. By contrast, repeated RS (×15) did not induce any significant changes in EPM activity or brain NOx, but brain Hsp70 levels stayed elevated. Administration of morphine or L-arginine prior to chronic RS did not influence such chronic stress induced changes in behavioral and biochemical markers, but appreciably attenuated chronic RS induced elevation in Hsp70 levels. These results suggest that acute and chronic RS induced anxiety modulations were differentially influenced by morphine and L-arginine and that complex interactions involving brain NO and unregulated Hsp70 could regulate such effects., (Copyright © 2014. Published by Elsevier Inc.)

Gender related differences in stress induced neurobehavioral disorders have been reported although the mechanisms involved are not yet clear. The present study investigated the role of nitric oxide, an important biomodulator in the sex related differences in stress induced anxiety like behavior in rats. Restraint stress (RS for 1 h) was used as the experimental stressor and the effects of NO modulators were assessed in the elevated plus maze (EPM) test in both male and female rats. No metabolites (NOx) and asymmetric dimethyl arginine (ADMA) were measured in brain homogenates of these rats for corroborative purposes. RS induced anxiogenesis in both male and female rats and such changes were greater in males as compared to females. The behavioral alterations were associated with enhanced levels of ADMA and reductions in levels of NOx in brain homogenates - the effects being greater in intensity in males as compared to females. Pretreatment with NO precursor L-arginine (500 mg/kg) reversed the RS induced behavioral and biochemical changes, while NO synthase inhibitor L-NAME (50 mg/kg) had opposite effects. Additionally, Formestane (50 mg/kg), an estrogen synthesis blocker, aggravated stress induced anxiogenesis with a corresponding increase in ADMA and decrease in NOx levels in the females. To our knowledge, this is the first report indicating the involvement of ADMA, an endogenous nitric oxide synthase inhibitor in stress induced neurobehavioral changes. Furthermore, it is also evident that nitric oxide and its interactions with estrogens play a crucial modulatory role in the differential anxiogenic response to stress among males and females., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Nitric oxide is a simple, ubiquitous, diatomic molecule with complex neuromodulatory functions. Anxiety and seizures are closely similar neurobehavioral disorders and are regulated by limbic system. The present study evaluated the regulatory roles of NO in these pathophysiological states in experimental models. In test for anxiety, aminophylline induced anxiogenic responses were assessed by the elevated plus maze (EPM) test, and a low dose of the drug (50 mg/kg) reduced both open arm entries and open arm time in rats. Pretreatment with the NO mimetic, L-arginine (500 and 1000 mg/kg) and melatonin (50 mg/kg) attenuated aminophylline induced anxiogenesis whereas the NO synthase inhibitors, L-NAME and 7-NI (30 mg/kg) aggravated the anxiogeneic response. Such aminophylline induced neurobehavioral suppression in the EPM activity was accompanied by increases in MDA levels and reductions in GSH and NOx activity in brain homogenates - changes which were reversed by L-arginine and melatonin pretreatments. In tests for seizures, aminophylline induced seizures and mortality at higher dose levels of the drug (300 mg/kg). Interestingly, such seizures and mortality in rats were antagonized by L-NAME and 7-NI pretreatments. On the other hand, L-arginine tended to potentiate seizures after sub-convulsive dose (100 mg/kg) of this methylxanthine. Aminophylline induced seizures were accompanied by greater elevations in brain MDA levels, whereas, GSH levels were consistently lowered. Unlike that seen during anxiety, NOx levels were increased in brain homogenates of these rats. The changes in oxidative stress markers were neutralized by NO synthase inhibitors. Synergistic anticonvulsant effect on aminophylline seizures was seen when L-NAME was combined with melatonin. These pharmacological and biochemical data indicate that aminophylline induced anxiety and seizures are differentially modulated by NO., (Copyright © 2014. Published by Elsevier Inc.)

The present study evaluated the effects of morphine treatments on elevated plus maze test parameters, oxidative stress markers and Hsp70 expression in normal and stressed rats. Acute and chronic stress caused neurobehavioral suppression, altered prooxidant-antioxidant balance and increased Hsp70 expression in brain homogenates in a differential manner. Morphine (1 and 5mg/kg) attenuated RS induced anxiogenesis, changes in MDA and GSH but further enhanced Hsp70 expression. Similar anxiolytic and Hsp70 enhancing effects were seen after morphine in normal rats (no RS). Exposure to chronic RS did not elicit any appreciable neurobehavioral response in EPM but enhanced MDA, lowered GSH and exaggerated the Hsp70 expression. Pretreatment with morphine did not affect the neurobehavioral response to chronic RS, but reverted the GSH and Hsp70 expression. The results suggest that morphine differentially influences acute and chronic stress induced changes in anxiety behavior and complex interactions between oxidative stress markers and Hsp70 expression which may contribute to these effects., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Size-specific dose estimate (SSDE), which corrects CT dose index (CTDI) for body diameter and is a better measure of organ dose than is CTDI, has not yet been validated in vivo., Objective: The purpose was to determine the correlation between SSDE and measured breast entrance skin dose (ESD) for pediatric chest CT angiography across a variety of techniques, scanner models, and patient sizes., Methods: During 42 examinations done on 4 different scanners over 7 years, we measured mid-sternal ESD as an approximation of breast dose with skin dosimeters. We recorded age, weight, effective tube current, kilovoltage potential, console CTDI, and dose-length product, from which we calculated effective dose. We measured effective chest diameter to convert CTDI to SSDE, and we correlated SSDE with measured ESD, using linear regression. We evaluated image quality to answer the clinical question., Results: Patient mean (±SD) age was 8.4 ± 6.1 years (median, 7.9 years; range, 0.02-19.5 years); mean weight was 35 ± 27 kg (median, 26 kg; range, 3.5-115 kg); effective chest diameter was 20 ± 7 cm (median, 19 cm; range, 10-35 cm). Mean effective dose was 2.9 ± 2.8 mSv (median, 2.2 mSv; range, 0.1-14.4 mSv). We observed a linear correlation (R(2) = 0.98, P < .005) between SSDE (mean, 11 ± 11mGy; median, 7 mGy; range, 0.5-40 mGy) and breast ESD (mean, 12 ± 11 mGy; median, 7 mGy; range, 0.3-44 mGy). Our doses, which compared favorably with those previously reported, decreased significantly (P < .05) during the course of our study, because of the introduction of automatic exposure control, low kilovoltage, and high pitch techniques. All studies were of diagnostic quality., Conclusion: SSDE is a valid dose measure in children undergoing chest CT angiography over a wide range of scanner platforms, techniques, and patient sizes, and it may be used to model breast dose and to document the results of dose reduction strategies., (Copyright © 2014 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

The present study evaluated the effects of the opioid agonist, morphine on stress induced anxiogenesis and the possible involvement of nitric oxide (NO) in such effects in rats. Acute restraint stress consistently induced an anxiety-like response in the elevated plus maze test, i.e. reduced number of open arm entries and time spent in the open arms as compared to controls. Pretreatment with morphine (1 and 5mg/kg), attenuated the restraint stress induced anxiogenic response in a dose related manner. Restraint stress induced neurobehavioral suppression was associated with reductions in brain NO oxidation products (NOx) levels, which were also reversed with morphine. Interaction studies showed that sub-effective doses of morphine and l-arginine (a NO precursor) had synergistic effects on stress induced elevated plus maze activity and brain NOx, whereas, l-NAME (a NO synthase inhibitor) neutralized these effects of morphine. Repeated restraint stress (×5) induced adaptative changes as evidenced by normalization of behavioral suppression and elevations in brain NOx, as compared to acute stress. Pretreatment with morphine in combination with repeated stress (×5) showed potentiating effects in the induction of behavioral adaptation in the elevated plus maze and elevations in brain NOx, as compared to repeated stress alone. Further, l-NAME, when administered prior to morphine, blocked this effect of morphine on stress adaptation. These results suggest differential morphine-NO interactions during acute and repeated restraint stress., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Environmental pollutants have a significant impact on the ecosystem and disrupt balance between environment, human and non-human components that result in deleterious effects to all forms of life. Identifying environmental factors for potential imbalance are extremely crucial for devising strategies for combating such toxic dysregulation. Automobile exhaust (in air), heavy metals (in food and water) and pesticides (in air, food, soil and water) are the most common environmental pollutants and their short and long-term exposures can cause hazardous effects in humans leading to systemic disorders involving lungs, kidney and immune systems. Mechanisms involved in genesis of such toxic effects have revealed complex, interactive pathways. Strategies for the protection of homeostasis and health, viz., general preventive measures, nutritional supplements and herbal agents have been described, to counter these pollutants induced damaging effects on various body systems.

The present study evaluated the possible protective role of Livina (a polyherbal preparation) against anti-tubercular therapy (ATT)-induced liver dysfunction in patients of pulmonary tuberculosis. Patients were given intensive phase treatment with 4-drugs (rifampicin, INH, pyrazinamide and ethambutol) used for anti-tubercular therapy for 2 months, followed by a 4-month continuous phase treatment with 2 drugs (rifampicin and INH) under clinical advice and supervision. Both qualitative and quantitative measures of liver function were assessed, at different time intervals, before and after ATT. Analysis of data showed that the incidence of qualitative manifestations of liver dysfunction were greater in the placebo treated group as compared to the test drug group. None of the patients of either group showed clinical jaundice. Most signific changes ant were observed in the SGOT and SGPT levels in the placebo group, wherein the levels of both enzymes were higher at 4 and 8 weeks post-ATT, as compared to the respective baseline (0 week) values. When Livina (2 capsules twice daily) was given with ATT drugs, incidence of qualitative manifestation of liver dysfunction was insignificant and SGOT and SGPT levels were also significantly lower than the placebo+AITT drugs treated group. These results indicate that the test drug (Livina) was efficacious, against ATT-induced hepatic dysfunction in patients of pulmonary tuberculosis.

Effect of restraint stress (RS) and its modulation by antioxidants were evaluated on elevated plus maze (EPM) and open field (OF) tests in rats. Restraint stress (RS for 1 hr) reduced the number of open arm entries, as also the time spent on open arms indicating enhanced anxiogenic response in the EPM test as compared to normal non RS group of rats. Pretreatment with ascorbic acid (100 and 200 mg/kg) and alpha-tocopherol (30 and 60 mg/kg) attenuated these RS-induced effects. In the OF test, RS-reduced (a) ambulations; and (b) rearings, whereas an increase was seen in (a) latency of entry and (b) number of fecal boluses. The RS-induced changes in OF parameters were reversed after pretreatment with the antioxidants, (ascorbic acid and alpha tocopherol). Biochemical data showed that RS enhanced MDA levels in both serum and brain, and these were attenuated after pretreatment with the antioxidants. The pharmacological and biochemical results indicate that free radicals might be involved in such stress-induced neurobehavioural effects.

The present study evaluated the regulatory role of nitric oxide (NO) in stress susceptibility and adaptation in rats. Acute restraint stress (RS x1) reduced the number of entries and time spent in the open arms in the elevated plus maze (EPM) test and raised plasma corticosterone levels. RS (x1)-induced neurobehavioral suppression and raised corticosterone levels were attenuated by pretreatment with the NO precursor, L-arginine (500 and 1000 mg/kg)and unaffected or further aggravated by NO synthase inhibitor, L-NAME or 7-nitroindazole (10 and 50 mg/kg). Biochemical assay of plasma and brain homogenates showed that these RS - induced behavioral and neuroendocrinal changes were associated with lowered levels of plasma and brain total nitrates/nitrites (NOx). L-Arginine attenuated the RS-induced suppression of NOx levels in plasma and brain, whereas, the NO synthase inhibitors tended to produce reverse effects. In the experiments involving repeated stress i.e. RS (x5), exposure resulted in attenuation/reversal of (a) neurobehavioral suppression in the EPM test and (b) lowered brain NOx, that was seen after RS (x1). The RS (x5)-induced changes in EPM parameters and brain Nox were further potentiated after L-arginine pretreatment, whereas, the NO synthase inhibitors were less effective. Rats were screened as high and low emotional in the open-field test, and high emotional rats showed greater(a) behavioral suppression in the EPM, (b) corticosterone responses (c) brain NOx suppression, and (d) cold-restraint stress (CRS) induced gastric mucosal lesions as compared to their low emotional counterparts. L-Arginine pretreatment was more effective in modulating the above RS induced stress responses/markers in the high emotional group of rats. Our data suggest that NO plays a differential role during exposure to acute and repeated stress situations, and that the relationship between stress and emotionality status may be under the regulatory influence of NO.

In the present study, the possible role of free radicals in aminophylline-induced seizures was evaluated in albino rats. Aminophylline (theophylline in ethylene diamine; 50 - 300 mg/kg) induced convulsions in rats in a dose-dependent manner, and both incidence of seizure and mortality were maximum at 300 mg/kg. Conventional anti-epileptics, diphenylhydantoin and dizocilpine, as well as adenosine agonists were ineffective in antagonizing these seizures. On the other hand, phosphodiesterase inhibitors, pentoxyphylline and rolipram, showed insignificant seizurogenic effects. Pretreatment with antioxidants (ascorbic acid, alpha-tocopherol, and melatonin) showed differential attenuating effects on aminophylline seizures and lethality. Further, prior administration of 1-buthionine sulfoxamine (BSO, glutathione depletor) and triethyltetramine (TETA, superoxide dismutase inhibitor), precipitated seizures and enhanced lethality in response to subthreshold doses of aminophylline. The present results suggested of the possible involvement of oxidative stress during aminophylline-induced seizures.