Combination chemotherapy for extensive small cell lung cancer -- experience from India.
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Adult↗
Biomedical subjects
S C Sharma
Publications and source records attributed to S C Sharma.
Effects of increased intraocular pressure on rat retinal ganglion cells.
The effects of elevated intraocular pressure (IOP) on the morphology of rat retinal ganglion cells (RGCs) was analyzed in this study. After cauterizing two limbal derived episcleral veins, IOP in experimental eyes was elevated 1.5--1.8 times that of control. RGCs of experimental and control eyes were analyzed after: bilateral tectal injections of Fluoro-Gold, and application of fluorescent dye crystals, 4-Di-10-ASP to the proximal stump of the cut optic nerve, at different time intervals after IOP elevation. The RGCs in control and experimental eyes were evaluated at 4, 6, 8, and 10 weeks by counting, as well as by determining the soma diameter. The dendritic field of three types (I, II, III) of RGCs between control and experimental eyes were also studied at 4,6,10 weeks after IOP elevation. At every time point, the number of cells in experimental eyes were significantly less than those of the control eyes. The average retinal ganglion cell death was 3--4% per week in the eyes with elevated IOP. The soma and dendritic field diameter of the RGCs in the experimental eyes were significantly larger in all cell types. However, types I and III cells expanded their dendritic fields more rapidly than type II cells. Furthermore, dendritic fields of surviving RGCs in experimental eyes occupied about the same extent of the retina as the controls. The increase in soma diameter and expansion of dendritic fields in the remaining RGCs in eyes with elevated IOP suggests the existence of plasticity in adult retina.
Animals↗
Indolent behaviour of low-grade B cell lymphoma of mucosa-associated lymphoid tissue arising in the kidney.
We report a case of low-grade MALT lymphoma (mucosa-associated lymphoid tissue) arising in the kidney. It had very indolent behaviour with multiple extranodal relapses (parotid gland, orbit, skin, breast, prostate) over a period of 13 years; presently, the patient is asymptomatic.
Humans↗
Regulation of AP1 (Jun/Fos) factor expression and activation in ovarian granulosa cells. Relation of JunD and Fra2 to terminal differentiation.
AP1 transcription factors control rapid responses of mammalian cells to stimuli that impact proliferation, differentiation, and transformation. To determine which AP1 factors are present in and regulated by hormones in ovarian cells during specific stages of proliferation and differentiation, we used both in vitro and in vivo models, Western blotting, immunohistochemistry, DNA binding assays, and transfections of AP1 promoter-reporter constructs. The expression patterns of Jun and Fos family members in response to hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH), and cAMP) were distinct. JunB, c-Jun, c-Fos, and Fra2 were rapidly but transiently induced by FSH in immature granulosa cells. JunD and Fra2 were induced by LH and maintained as granulosa cells terminally differentiated into luteal cells. Forskolin and phorbol myristate acetate acted synergistically to enhance transcription of an AP1(-73COL)-luciferase construct. JunD appears to be one mediator of this effect, since JunD was a major component of the AP1-DNA binding complex in granulosa cells, and menin, a selective inhibitor of JunD, blocked transcription of -73COL-luciferase. Thus, FSH and LH via cAMP induce specific AP1 factors, the AP1 expression patterns are distinct, and that of JunD and Fra2 correlates with the transition of proliferating granulosa cells to terminally differentiated, non-dividing luteal cells.
Animals↗
Prevention of renal ischemia-reperfusion-induced injury in rats by picroliv.
Picroliv is a potent antioxidant extracted from the roots and rhizome of Picrorhiza kurrooa. It has been shown to impart significant hepatoprotective activities, partly by modulation of free radical-induced lipid peroxidation. Lipid peroxidation and reactive oxygen species are associated with tissue injury in post-ischemic acute renal failure. The efficacy of picroliv was assessed in an in vivo model of renal ischemia-reperfusion injury (IRI) in rats at a dose of 12 mg/kg orally for 7 days. The animals were killed at various times after reperfusion. Increased lipid peroxidation and apoptotic cell number reflected the oxidative damage following renal IRI. Picroliv-pretreated rats exhibited lower lipid peroxidation, improved antioxidant status, and reduced apoptosis, indicating better viability of renal cells. Immunohistochemical studies revealed that picroliv pretreatment attenuated the expression of intercellular adhesion molecule-1 in the glomerular region. These results suggested that picroliv pretreatment protects rat kidneys from IRI, perhaps by modulation of free radical damage and adhesion molecules.
Animals↗
Picroliv preconditioning protects the rat liver against ischemia-reperfusion injury.
Cell death following ischemia-reperfusion injury is a major concern in clinical issues such as organ transplantation and trauma. The need to identify agents with a potential for preventing such damage has assumed great importance. We have evaluated the efficacy of picroliv, a potent antioxidant derived from the plant Picrorhiza kurrooa, in protecting against hepatic ischemia-reperfusion injury in vivo. Picroliv was fed to male Sprague Dawley rats in a dose of 12 mg/kg once daily by oral gavage for 7 days prior to hepatic ischemia. Ischemia was induced by occluding the hepatic pedicel with a microaneurysm clip for 30 min and reperfusion was allowed thereafter for varying period (15-120 min) by releasing the microaneurysm clip. Picroliv pretreatment resulted in better hepatocyte glycogen preservation and reduced apoptosis. Reduction in apoptosis was associated with decreased mRNA expression of caspase-3 and Fas. Oxidant induced cellular damage as measured by tissue malondialdehyde (MDA) levels was significantly less following picroliv pretreatment. Both a reduction in neutrophil infiltration and an increased level of intracellular antioxidant enzyme superoxide dismutase possibly contributed to the reduction in tissue lipid peroxidation. Tissue inflammatory cytokines level of interleukin-1alpha (IL-1alpha) and interleukin-1beta (IL-1beta) was also lower in picroliv group. Furthermore, picroliv pretreatment resulted in enhanced proliferating cell nuclear antigen (PCNA) immunoreactivity. These studies strongly suggest picroliv to be a promising agent for ameliorating injury following ischemia-reperfusion.
Animals↗
Functional human heme oxygenase has a neuroprotective effect on adult rat ganglion cells after pressure-induced ischemia.
Adult retina subjected to transient ischemia and reperfusion leads to controlled retinal ganglion cell (RGC) death over a period. Modification of intracellular mechanisms through a specific adenoviral vector containing the hemoxygenase gene (HO-1) provides avenues for RGC survival following HO-1 gene transfer and ischemia. RGC death rate was reduced by an average of 15% at 1, 2 and 3 weeks. A significant number of RGC transfected with functional HO-1 survived ischemic insults. Pharmacological stimulation of HO-1 may constitute a novel therapeutic approach to rescuing RGC experiencing ischemic/reperfusion injury.
Adenoviridae↗
The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma.
UNLABELLED: PURPOSE. Brain-derived neurotrophic factor (BDNF) had a limited effect on the survival of retinal ganglion cells (RGCs) in rats' eyes with elevated intraocular pressure (IOP). The combined treatment of BDNF and a nonspecific free radical scavenger N-tert-butyl-(2-sulfophenyal)-nitrone (S-PBN) was investigated on the RGCs in hypertensive eyes of rats. METHODS: Adult Wistar rats were separated into five groups: BDNF (0.5 microg) + S-PBN; BDNF (1. 0 microg) + S-PBN; BDNF (1.0 microg); S-PBN; and phosphate-buffered saline. Right eyes served as normal controls (n = 10). RGCs were labeled with 5% Fluoro Gold; injected into the superior colliculus. Three days after intratectal injection, the episcleral veins of the left eyes were cauterized. Intravitreal injection of BDNF was performed on days 5, 13, 21, and 29 after IOP elevation. S-PBN was injected intraperitoneally (100 mg/kg body wt) every 12 hours starting 30 minutes after cauterization. RESULTS: The survival of RGCs using BDNF treatment alone in moderately hypertensive eyes and systemic administration of S-PBN alone did not significantly rescue the RGCs. However, the combination of BDNF and S-PBN increased the survival of RGCs to 90.1%. CONCLUSIONS: Trophic factors and antioxidants have synergistic effects on rescuing RGCs from death in eyes with elevated IOP. Further studies of different combined treatment therapies may provide avenues to save RGCs from death in eyes with elevated IOP.
Animals↗
Caspase inhibitors block the retinal ganglion cell death following optic nerve transection.
Retinal ganglion cells die by apoptosis following axotomy. The molecular mechanisms of the retinal ganglion cell death are not well understood. In the present study using RT-PCR and in situ hybridization techniques we demonstrated that levels of mRNA for Bcl-2 and Bcl-x decreased after axotomy. Bax levels remained high until 4 days after axotomy, decreased by day 7 and remained low up to day 10. CPP32 levels increased at day 7 and remained high after optic nerve cut. We studied whether inhibitors of CPP32/caspase would save the axotomy induced ganglion cell death. DEVD-CHO (Ac-Asp-Glu-Val-aspartic acid aldehyde) and DEVD-FMK (Z-Asp-Glu-Val-Asp-FMK), caspase inhibitors, when administered intraocularly at the time of optic nerve cut, at days 3 and 7 protect about 30-35% the ganglion cells from death. We further demonstrated that the number of reactive microglia decrease in the retina when the inhibitors were given as compared with retina where no inhibitors were given. The present data offers new avenues for studying the complex interactions between the retinal ganglion cell death and the activation of resident microglia/macrophages.
Animals↗
Ascending spinal projections to the optic tectum, facial and vagal lobes in the goldfish, Carassius auratus.
Using biotinylated dextran-amines as tracer, we observed prominent ascending spinal projections to three unreported areas in the gold fish brain viz. the optic tectum (OT), facial (FL) and vagal (VL) lobes. From the lateral spinal lemniscus (LSL), some fiber tracts separated off and extended mediodorsally, fanned out and innervated the FL. The VL was clearly laminated and showed three layers-the inner primary motor neuron and fiber layer (PMNF), outer secondary neuron layer (SN) and middle primary and secondary fiber layer (PSF). The PMNF received maximal innervation. Besides several fibers extending directly into the SN from the LSL, a few fibers extended dorsolaterally from the PMNF and innervated the SN. Several ascending fibers extended into the torus semicircularis, thalamic and pretectal areas and innervated the OT. The possible functional significance of the spinal innervation of these brain areas has been discussed.
Afferent Pathways↗
Natural history of late radiation proctosigmoiditis treated with topical sucralfate suspension.
Rectal bleeding due to radiation proctosigmoiditis is often difficult to manage. We had earlier shown the efficacy of short-term therapy with topical sucralfate in controlling bleeding in the radiation proctosigmoiditis. We now report our long-term results with this form of therapy. The study comprised 26 patients with radiation proctosigmoiditis. Sigmoidoscopically, 9 (34.6%) patients had severe changes, 15 (57.69%) had moderate, and 2 (7.69%) had mild changes. Severity of bleeding was graded as severe (> 15 episodes per week), moderate (8-14 episodes per week), mild (2-7 episodes per week), negligible (< or = 1 episode per week), or nil (no bleeding). Ten patients had moderate rectal bleeding, while 16 had severe bleeding. All patients were treated with 20 ml of 10% rectal sucralfate suspension enemas twice a day until bleeding per rectum ceased or failure of therapy was acknowledged. Response to therapy was considered good whenever the severity of bleeding showed improvement by a change of two grades. Rectally administered sucralfate achieved good response in 20 (76.9%) patients at 4 weeks, 22 (84.6%) patients at 8 weeks, and 24 (92.3%) patients at 16 weeks. This change was significant by Wilcoxon matched-pairs signed-ranks test. Two patients required surgery due to poor response. Over a median follow-up of 45.5 months (range 5-73 months) after cessation of bleeding, 17 (70.8%) patients had no further bleeding while 7 (22.2%) had recurrence of bleeding. All recurrences responded to short-term reinstitution of therapy. No treatment-related complications were observed. Ten patients had other associated late toxicity due to pelvic irradiation in the form of asymptomatic rectal stricture (N = 3), rectovaginal fistula (N = 1), intestinal stricture (N = 1), vaginal stenosis (N = 1), and hematuria (N = 6). Three patients had progression of the primary disease in the form of pelvic recurrence (N = 2) and hepatic metastases (N = 1). We conclude that topical sucralfate induces a lasting remission in a majority of patients with moderate to severe rectal bleeding due to radiation proctosigmoiditis.
Administration, Topical↗
Expression and function of estrogen receptor subtypes in granulosa cells: regulation by estradiol and forskolin.
The expression and function of estrogen receptor ERalpha/beta subtypes and ERbeta variants in granulosa cells have been determined using several integrated approaches:, Western blotting, indirect immunofluorescence, RT-PCR, and transient transfection assays. Each of these approaches has provided specific details concerning the dynamics of ER expression, ER functional activity, and estradiol (E) regulation of target genes in granulosa cells. Specifically, the studies presented herein document that messenger RNAs (mRNAs) encoding ERbeta and its splice variants, as well as mRNA encoding ERalpha, are expressed in granulosa cells of immature rats before and during culture in serum-free medium. The results also provide the first documentation that functional (DNA binding and transcriptionally active) ER is present in cultured granulosa cells and that its ability to bind consensus estrogen response element (ERE) oligonucleotide and to transactivate an ERE promoter-reporter construct is associated with the level (type?) of receptor protein as well as the stage of granulosa cell differentiation. Using a labeled ERE consensus oligonucleotide and antibodies specific for ERbeta and ERalpha, we show that ERbeta but not ERalpha was detected (supershifted in electrophoretic mobility shift assays) in extracts of granulosa cells cultured overnight (0 h) in defined medium alone. When the cells were cultured with FSH and testosterone (T) to stimulate their differentiation, ERbeta binding activity, as well as immunoreactive ERbeta as determined by Western blot analyses, decreased progressively from 24 to 48 h and was undetectable by 72 h. ERbeta mRNA was low, and ERbeta binding activity was not observed in luteinized granulosa cells. ERalpha DNA binding activity was not observed in any of the granulosa cell cultures, although low levels of immunoreactive ERalpha were detected by Western blot analyses. Immunofluorescent analyses documented that ERbeta, as well as ERalpha, were localized to granulosa cell nuclei and that the intensity of nuclear staining was related to agonist stimulation and differentiation: forskolin increased, whereas E decreased immunostaining for ERbeta and ERalpha at 48 h. When an ERE-E1b-luciferase vector was transfected into granulosa cells of unprimed rats, basal luciferase activity was low but increased by forskolin (3-4x) and by E (2x), responses to both agonists being blocked by the ER antagonist, ICI. When the same vector was transfected into differentiated granulosa cells (cultured for 48 h with FSH/T), forskolin alone increased activity. Collectively, these results show that ERbeta protein is preferentially expressed in immature granulosa cells, is functionally active (binds DNA), can transactivate (either as a homodimer or heterodimer with ERalpha) ERE-containing promoter constructs, and might be associated with increased expression of the endogenous gene encoding c-Jun.
Animals↗
Aural cholesteatoma: role of tumor necrosis factor-alpha in bone destruction.
HYPOTHESIS: The bone destruction in cholesteatoma is multifactorial. This study was undertaken to define the role of tumor necrosis factor-alpha (TNF-alpha) in bone destruction associated with cholesteatoma. BACKGROUND: Tumor necrosis factor-alpha is an important inflammatory cytokine secreted by activated macrophages. It stimulates keratinocytes as an autocrine growth regulator. Few authors have localized TNF-alpha in aural cholesteatoma. An attempt was made in this study to show a correlation between TNF-alpha and cholesteatoma associated bone destruction by localizing TNF-alpha in cholesteatoma and measuring its serum level. METHODS: Serum TNF-alpha levels were measured in 20 patients with cholesteatoma of temporal bone and histochemical staining was used to localize TNF-alpha in pathologic tissue excised at surgery. RESULTS: Serum TNF-alpha levels in patients with cholesteatoma were significantly higher than in controls. In addition, TNF-alpha levels in patients with bone destruction were higher than in those without bone destruction. However, there was no correlation between age of the patient and serum TNF-alpha levels. The TNF-alpha was localized in various layers of cholesteatoma epithelium using indirect immunoperoxidase staining. CONCLUSION: TNF-alpha is one of the cytokines produced by cholesteatoma that may be an important mediator of bone destruction associated with cholesteatoma. TNF-alpha has been localized in various layers of cholesteatoma and exerts a locally destructive effect on bone. Serum TNF-alpha levels are related to the extent of bone destruction.
Adolescent↗
Laminar restriction of retinal macrophagic response to optic nerve axotomy in the rat.
Following optic nerve transection, most of the retinal ganglion cells die. Their debris is promptly cleared by phagocytic cells. It is currently not known to what extent peripherally derived macrophages contribute to this activity. Using antibodies OX42 and ED-1, phagocytic cells were labeled in the retinas of optic nerve lesioned adult rats. To distinguish whether the cells were reactive microglial or macrophagic in origin, blood-borne monocytes were labeled with fluorescent microspheres while in the systemic circulation. Macrophages invaded the retina, but only in the nerve fiber layer, sparing the ganglion cell and other layers. These macrophages engulfed only the axonal debris from dying ganglion cells, not their degenerating cell bodies. These results indicate that although peripherally derived monocytic cells are recruited into the retrogradely degenerating retina, their role in clearing debris is limited to the optic fiber layer.
Animals↗
Atrial fibrillation in a general hospital: how well are we doing?
Atrial fibrillation (AF) is an important risk factor for ischaemic stroke, and anticoagulation is now indicated in many patients, particularly those with congestive cardiac failure, hypertension, a history of transient ischaemic attacks or embolic stroke. In a retrospective study (and audit), we examined 280 cases of AF (acute, paroxysmal non-sustained and chronic sustained) admitted to a general hospital in the UK. The commonest underlying medical condition was ischaemic heart disease (57%), while the commonest presenting feature was congestive cardiac failure (60%). Pharmacological cardioversion was preferred against electrical cardioversion for reverting to sinus rhythm. Fifty-six patients (20%) received warfarin, 55 patients (20%) were on aspirin, and the remaining 169 (60%) received neither warfarin nor aspirin. More awareness is needed among physicians managing AF particularly in relation to anticoagulation.
Acute Disease↗
Rescue of retinal ganglion cells from axotomy-induced apoptosis through TRK oncogene transfer.
Following axonal injury, central neurons die through programmed cell death. Modification of intracellular mechanisms through specific gene transfer might provide a mechanism for survival. Here we present rescue of rat retinal ganglion cells (RGCs) through gene transfer of TRK oncogenes. Administration of plasmid DNA at the optic axon terminals in the superior colliculus results in retrograde transport to their soma and significant expression of the exogenous DNA. Using this approach for transfection, a TRK oncogene containing plasmid was introduced in RGCs. Three days after plasmid injection, optic nerves were transected. TRK oncogene transfection induced extended survival of the axotomized neurons, lasting over 10 days. Gene delivery to specific cell types is an initial step in the development of therapeutic strategies for regeneration of the damaged nervous system.
Animals↗
MK801-a neuroprotectant in rat hypertensive eyes.
Excitatory synaptic transmission in the mammalian CNS and retina is mainly mediated through l-glutamate. The effect of MK-801, a non-competitive antagonist of the NMDA subtype of glutamate receptor was studied on rat retinal ganglion cells in hypertensive eyes. MK-801 was administered intraperitoneally to the first group, 1 day before the increase, and in the second group, 2 days after the intraocular pressure (IOP) elevation. Phosphate-buffered saline was administered to the control group. Animals were sacrificed 2 and 4 weeks post-IOP increase. The retinal ganglion cells were counted and compared between control (right) and experimental (left) eyes. The data presented here suggests that MK-801 has neuroprotective properties.
Animals↗