Adrenocortical reserves in patients with Graves' disease.
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Adrenal Cortex↗
Biomedical subjects
R Goswami
Publications and source records attributed to R Goswami.
Does ceramide play a role in neural cell apoptosis?
Ceramide is a lipid second messenger, that is generated in response to stimulation of the cell death pathways by a number of ligands binding to surface receptors, growth factor withdrawal, treatment with chemotherapeutic agents, or high doses of ionizing radiation or oxidizing agents. Depending on the target cell, ceramide induces diverse biological responses including apoptosis, cell-cycle arrest, differentiation, and also proliferation. In this review we consider the evidence for its role in apoptosis in cells of the nervous system.
Animals↗
Multiple polyphosphoinositide pathways regulate apoptotic signalling in a dorsal root ganglion derived cell line.
The polyphosphoinositides play important roles in transmembrane signalling but are also involved in anchoring cell surface proteins, organellar transport, cytoskeleton organization, and cell survival. The polyphosphoinositides synthesized by phosphatidylinositol-3 kinase (PI-3K), (Ptd(3,4)InsP2, and PtdIns(3,4,5)P3), appear to play a critical role in cell survival by membrane recruitment and activation of Akt kinase. Inhibitors of PI3K, wortmannin, and LY294002, induced a time-dependent activation of caspase-3 (CPP32), with a peak at 6 hr, leading to subsequent cell death by apoptosis in a dorsal root ganglion cell line (F-11). Lowering cyclic AMP (cAMP) levels enhanced both caspase-3 activation and cell death induced by PI3K inhibitors, whereas a nonhydrolyzable cAMP analog (Bt2cAMP), lowered CPP32 and was protective. We stably transfected the F-11 cells with the constitutively active p110 catalytic subunit of PI-3 kinase and observed resistance to both caspase-3 (CPP32) activation and subsequent apoptosis induced by either wortmannin or LY294002. Treatment of F-11 cells with bradykinin (BK) stimulated the hydrolysis of a different polyphosphoinositide, PtdIns(4,5)P2, and enhanced both wortmannin-induced caspase-3 (CPP32) activation and subsequent apoptosis. PtdIns(4,5)P2 is also a precursor of the anti-apoptotic PtdIns(3,4,5) P3 and lowering cAMP levels with opioid agonists for 30 min enhanced both the hydrolysis of PtdIns(4,5) P2 and cellular apoptosis. The enhancement was opioid dose-dependent and opioid antagonist (naloxone)-reversible and was also seen following 24-hr exposure to opioids such as U69,593 and Dala2, Dleu5 enkephalin (DADLE). However, unlike the bradykinin stimulation of PtdIns(4,5)P2 hydrolysis following activation of phospholipase C, the opioid-enhanced hydrolysis was independent of external Ca2+ and was blocked by pertussis toxin, suggesting a different mechanism involving GI, GO, or betagamma-subunits. In summary, both the receptor-mediated lowering of cAMP levels and the hydrolysis of 4,5-polyphosphoinositides have no direct effect on caspase-3 activity or apoptosis but do exacerbate the activation of caspase-3-like activity and subsequent cell death by apoptosis induced by inhibitors of 3-polyphosphoinositide synthesis. We suggest that multiple polyphosphoinositide pathways are involved in the regulation of apoptosis.
Androstadienes↗
Insulin antibody response to bovine insulin therapy: functional significance among insulin requiring young diabetics in India.
The majority of young diabetics in India prefer to use low-cost bovine insulin for economic reasons. Therefore, the question of insulin antibody response to bovine insulin and its functional significance is still relevant in the Indian context. We assessed insulin antibody response in 52 young diabetics (type 1, n=25, malnutrition modulated form of diabetes, n=19 and fibrocalculous pancreatopathy (FCP) n=8) on bovine insulin therapy (mean duration 3.0+/-2.1 years) using an internationally standardised in-house radioligand assay. The functional significance of insulin antibody was assessed by calculating their affinity constant, maximum binding capacity and total insulin binding power by Scatchard analysis (type 1, n=14, malnutrition modulated form of diabetes, n=11). All the patients treated with bovine insulin showed high titers of insulin antibodies with S.D. score ranging from 5.1 to 42.0. No significant difference was observed in the mean S.D. score of insulin antibodies in the three diabetic groups. The mean daily insulin dose, maximum insulin binding capacity and total insulin binding power were significantly higher in type 1 when compared to the malnutrition modulated form of diabetes (36+/-8 vs. 26+/-11 IU/day, P<0.05; 9. 7+/-7.8 vs. 4.0+/-3.9 nmol/l, P=0.03 and 59+/-29 vs. 29+/-43, P=0.01, respectively). Insulin antibodies S.D. score and its affinity did not show significant relationship with daily insulin dose and glycemic control (HbAl) at admission. Only 24+/-7% variations in daily insulin requirement were accounted for by total insulin binding power. There was a significant inverse relationship between insulin antibody S.D. score and duration of insulin therapy (r=-0. 4172, P<0.0004). To conclude, insulin antibody response following bovine insulin therapy is not different among type 1, malnutrition modulated form of diabetes and FCP diabetes. The insulin antibody response to bovine insulin therapy does not contribute significantly to increase in daily insulin requirement in bovine insulin treated insulin requiring young diabetics.
Adolescent↗
Species-specific prevalence of vaginal candidiasis among patients with diabetes mellitus and its relation to their glycaemic status.
OBJECTIVES: Non- C. albicans Candida species are increasingly being recognized as the cause of vulvo-vaginal candidiasis. These species are often less susceptible to antifungal agents. Patients with diabetes mellitus are at risk for vulvo-vaginal candidasis. We assessed the species-specific prevalence rate and risk of candidiasis in patients with diabetes mellitus and healthy controls. METHODS: Genital tract examination, direct microscopy and fungal cultures of discharge collected by high vaginal swab were undertaken among 78 consecutive patients with diabetes mellitus (mean (+/-sd) age 32+/-12 years and body mass index (BMI) 22.3+/-5.5kg/m(2)) and 88 age- and BMI-matched healthy females. Glycaemic control in the diabetic cohort was assessed by measuring total glycosylated haemoglobin. RESULTS: Candida species were isolated in 36 of 78 (46%) subjects with diabetes mellitus and in 21 of 88 (23%) healthy subjects (Chi-squared 9.11, P=0.0025). The predominant Candida species isolated in diabetics with vulvo-vaginal candidiasis were Candida glabrata (39%), C. albicans (26%) and C. tropicalis (17%). In contrast, in the control group, C. albicans, C. glabrata and C. hemulonii comprised 30% each, with none having C. tropicalis infection (for C. tropicalis: diabetic vs. control; 17% vs. nil, P=0. 05). Among the diabetic group, subjects with vulvo-vaginal candidiasis had significantly higher mean HbA1 when compared to those who had no such infection (12.8+/-2.6% vs. 9.7+/-1.7% respectively, P=0.001). The overall accuracy of direct microscopy and clinical examination for predicting vulvo-vaginal candidiasis was only 77% and 51%, respectively, in the diabetic group, and 83% and 65% in the control group. CONCLUSIONS: Patients with diabetes mellitus had a high prevalence rate (46%) of vulvo-vaginal candidiasis with relative risk of 2.45. The non- C. albicans species such as C. glabrata and C. tropicalis were the predominant species isolated among them. There seems to be a significant link between hyperglycaemia and vulvo-vaginal candidiasis.
Adult↗
Prevalence and significance of low 25-hydroxyvitamin D concentrations in healthy subjects in Delhi.
BACKGROUND: Despite abundant sunlight, rickets and osteomalacia are prevalent in South Asian countries. The cause of this paradox is not clear. OBJECTIVE: The objective was to assess 25-hydroxyvitamin D [25(OH)D] status and its functional significance in apparently healthy subjects residing in Delhi, a city in the northern part of India. DESIGN: Serum 25(OH)D, total calcium, inorganic phosphate, alkaline phosphatase, intact parathyroid hormone, and 1, 25-dihydroxyvitamin D [1,25(OH)(2)D] were measured in groups of healthy subjects who differed with respect to variables relevant to vitamin D and bone mineral metabolic status, such as direct sunlight exposure, season of measurement, skin pigmentation, dietary calcium and phytate contents, and altered physiologic states such as pregnancy and neonatal age. RESULTS: All groups except one with maximum direct sunlight exposure had subnormal concentrations of 25(OH)D. The 25(OH)D-deficient groups tended to have an imbalance in bone mineral metabolic homeostasis when exposed to winter weather and low dietary calcium and high dietary phytate, with significantly low calcium and elevated intact parathyroid hormone concentrations, chemical osteomalacia, or both. Increased values of 1,25(OH)(2)D during pregnancy did not help correct the imbalance in bone mineral metabolic homeostasis. CONCLUSION: Healthy subjects with low 25(OH)D concentrations are at risk of bone mineral metabolic imbalance when exposed to factors that strain bone mineral homeostasis.
Adult↗
Overexpression of Akt (protein kinase B) confers protection against apoptosis and prevents formation of ceramide in response to pro-apoptotic stimuli.
An immortalized dorsal root ganglion cell line F-11 exhibits many properties of spinal cord neurons and undergoes apoptosis in response to growth factor withdrawal and the exogenous addition of inhibitors of phosphatidylinositol-3-kinase (PI3K). To elucidate the mechanism of apoptosis we generated F-11 clones which overexpressed either the p110 subunit of PI3K, a constitutively active form of protein kinase B/Akt (Myristoylated Akt), or a dominant-negative form (c-Akt). The first two constructs were protective against apoptosis induced by PI3K inhibitors such as wortmannin and LY294002. Caspase-3 (CPP32) levels peaked at 4 hr to 6 hr in response to pro-apoptotic drugs, and this increase was attenuated by 50% in F-11 with constitutively active Akt. The Akt protection was confirmed by DNA fragmentation studies. Both neo-transfected and the c-Akt dominant-negative transfected F-11 cells showed increased ceramide formation (twofold) in response to staurosporine, wortmannin, or LY294002; whereas cells with a constitutively active Akt (Myr-Akt) showed no increase in ceramide when treated with staurosporine, wortmannin, or LY294002. Ceramide was a more potent activator of CPP32 and an inducer of apoptosis when added as the native form (hydroxy- or nonhydroxy-), rather than the more water-soluble C(2)-ceramide. Overexpression of PI3K (p110) and Akt protected cells against ceramide-induced apoptosis, suggesting that Ceramide action is upstream of Akt in these cells and suggesting that Akt might be a target for inhibition by ceramide. Both staurosporine and C(2)-ceramide activated the Jun kinase (JNK) cascade and C(2)-ceramide increased caspase-3 (CPP32) activity in cells expressing wild-type c-Jun, but not dominant-negative (TAM-67) c-Jun. We suggest that this pathway is also involved in apoptosis, consistent with the idea that ceramide has multiple kinase and kinase-modulating targets in the apoptotic pathway of neurons. J. Neurosci. Sci. 57:884-893, 1999.
Animals↗
Residual pituitary enlargement in primary hypothyroidism despite 1 1/2 years of L-thyroxine therapy.
Pituitary hyperplasia consequent to untreated primary hypothyroidism undergoes impressive regression following thyroxine therapy. We describe a young man with primary hypothyroidism and pituitary hyperplasia, who showed significant but incomplete regression of pituitary enlargement despite 18 months of L-thyroxine therapy (1 year in replacement dose (150 micrograms/day) and an additional 6 months in suppressive dose (300 micrograms/day)).
Adult↗
Insulin autoantibodies before and after carbimazole therapy in Asian Indian patients with Graves' disease.
Carbimazole therapy can induce insulin autoantibodies (IAA) in Japanese Graves' disease patients, a phenomenon possibly linked to their immunogenetic profile. This phenomenon is not observed in Caucasians. We assessed IAA levels in 114 North Indian Graves' disease patients before and after carbimazole therapy (mean duration 6.2 +/- 3.9 months). The functional significance of IAA was assessed in 46 of them by first phase (sum of +1 and +3 min) insulin response to intravenous glucose (IVGTT) and an oral glucose tolerance test (OGTT) undertaken before commencement of the carbimazole therapy. IAA were measured using a radiobinding assay and expressed as the assay precision unit, S.D. scores (S.D.S), over healthy controls. Before treatment 22 of 114 (19.3%) patients were IAA positive (mean +/- S.D., 5.9 +/- 3.2 S.D.S). After carbimazole therapy a further 11 (9.6%) showed positive for IAA (mean +/- S.D., 3.5 +/- 1 S.D.S). Of the 22 patients who were IAA positive before treatment, 12 became negative after carbimazole therapy. The fasting insulin and first phase insulin responses were similar in IAA positive and IAA negative Graves' disease patients (mean +/- S.D., 61.7 +/- 35.9 versus 88.3 +/- 46.6 pmol/l, P = 0.123 and 1127 +/- 696 versus 1033 +/- 430 pmol/l, P = 0.716, respectively). The OGTT results were comparable in the IAA positive and the IAA negative groups. Thus, North Indian Graves' disease patients, who resemble Caucasians in their HLA haplotypes, behave like Japanese in their tendency to become IAA positive with carbimazole therapy. A subset of the patients who were IAA positive before treatment also demonstrated negative IAA (12/22) after carbimazole therapy.
Adult↗
Cyclic AMP protects against staurosporine and wortmannin-induced apoptosis and opioid-enhanced apoptosis in both embryonic and immortalized (F-11kappa7) neurons.
The mechanism by which opiates affect fetal development is unknown, but one potential target is the programmed cell death (apoptosis) pathway of neurons. Apoptosis was induced in both primary neuronal cultures from embryonic day 7 cerebral hemispheres of chick brain (E7CH) and the F-11kappa7 cell line (an immortalized mouse neuroblastoma x dorsal root ganglion hybrid stably transfected to overexpress kappa-opioid receptors) by either staurosporine or the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002. Cells pretreated with either the mu-specific opioid agonist morphiceptin (E7CH) or the kappa-specific opioid agonist U69,593 (F-11kappa7) for 24 h showed increased apoptosis in response to staurosporine or wortmannin when compared with non-pretreated cells. The effects of morphiceptin and U69,593 were time- and dose-dependent and antagonist-reversible, suggesting that they were receptor-mediated. Neither morphiceptin nor U69,593 by themselves had any measurable effect on cell viability or DNA fragmentation, and coaddition of opiates at the same time as staurosporine, wortmannin, or LY294002 did not enhance apoptosis. Time course studies indicated a maximal opioid effect at a time (16-24 h) when inhibition of adenylate cyclase had been maximal for many hours. Addition of dibutyryl cyclic AMP either before or at the time of opioid addition protected against apoptosis and reduced fragmentation to levels seen for staurosporine plus dibutyryl cyclic AMP alone. The specificity for cyclic AMP was confirmed by showing protection with the specific agonist Sp-adenosine 3',5'-cyclic monophosphothioate and increased killing with the antagonist Rp-adenosine 3',5'-cyclic monophosphothioate. We conclude that the opioid enhancement of apoptosis is based on the inhibition of adenylate cyclase and that the effect is time-dependent.
Androstadienes↗
Prevalence and significance of steatorrhea in patients with active Graves' disease.
OBJECTIVE: The aim of this study was to determine the prevalence of steatorrhea in patients with Graves' disease and to assess its significance and correlation with changes in body mass index (BMI), coefficient of fat absorption (COFA), and pancreatic exocrine function in these patients. METHODS: Daily dietary fat intake, 24 h fecal fat, COFA, fecal chymotrypsin activity (as an index of pancreatic exocrine function), and total T3, T4, and TSH levels were assessed in 28 patients with active Graves' disease. In 24 patients, reassessment was done after attaining a euthyroid state with carbimazole therapy. RESULTS: In the thyrotoxic state, 13 of 28 patients had steatorrhea, whereas 15 had normal (<6 g/day) fat excretion (11.4 +/- 6.7 g vs 2.9 +/- 0.8 g, p = 0.0007). Daily fat intake, basal BMI, and serum T3 and T4 levels were similar in the steatorrheic and nonsteatorrheic groups. The mean COFA of the steatorrheic group was significantly lower than that of nonsteatorrheic group (91.6% +/- 4.8% vs 97.7% +/- 0.9%, respectively; p = 0.0006). In the steatorrheic group, fat excretion and COFA normalized after attainment of euthyroidism (changes in fat excretion and COFA = 7.3% +/- 6.3 g/day and 7.7% +/- 5.4%, respectively). Fecal chymotrypsin levels were similar in the steatorrheic and nonsteatorrheic thyrotoxics and in 16 healthy control subjects. The levels did not show any significant changes following attainment of euthyroid status. CONCLUSION: Steatorrhea associated with a decrease in COFA can occur in a reversible manner in 46% of patients with Graves' disease. However, steatorrhea in these patients is not linked with weight loss or with pancreatic exocrine dysfunction.
Absorption↗
Observations on hepatic structure and function in fibro-calculous pancreatic diabetes (FCPD) vis-a-vis other diabetic subtypes.
Investigations of liver function and histology were undertaken in thirty four patients with Fibrocalculous Pancreatic Diabetes (FCPD). The data obtained were compared with those of similarly aged members of a diabetic control group comprising twelve patients with Protein Deficient Diabetes Mellitus (PDDM), twelve with Type 1 diabetes or Insulin Dependent Diabetes Mellitus (IDDM) and four young patients with Type 2 Diabetes of Non-Insulin Dependent Diabetes Mellitus (NIDDM). None of them had apparent past or present liver disease. Elevations of serum ALT (SGPT) and alkaline phosphatase levels were fairly common and was often associated with mild fatty changes and occasionally with focal necrosis and inflammatory changes. Cirrhosis and inflammatory changes per se were infrequent and fatty changes per se did not occur. In contrast patients belonging to the other diabetic subsets were very occasionally afflicted with hepatic abnormalities or not afflicted at all. We propose that loss of hepatotrophic actions mediated by insulin and glucagon could initiate and/or enhance hepatic abnormalities in FCPD where deficiencies of insulin and glucagon coexist.
Adolescent↗
The formation of ceramide from sphingomyelin is associated with cellular apoptosis.
The apoptotic response of the immature B-cell to the cross-linking of surface IgM receptors provides a good model for cell death and we show in WEHI-231 B-cells that the time course of apoptosis corresponds to the increased formation of ceramide, as measured either by mass (using the diacylglycerol kinase method) or radiolabelling with [3H]palmitate. Inhibitors of sphingosine biosynthesis have no effect on cell death induced by anti-IgM in WEHI-231 but inhibitors of ceramidase accelerate apoptosis, suggesting that activation of sphingomyelinase is the key event in apoptosis. We have demonstrated this by in vitro assay of neutral sphingomyelinase. Apoptosis is also important in normal brain development and neuronal survival is dependent upon phosphatidylinositol 3-kinase (PI3-kinase) activation by growth factors (insulin, nerve growth factor etc.). Withdrawal of these growth factors or inhibition of PI3-kinase with wortmannin or LY294002 activated the pro-apoptotic CPP32 (Yama/Apopain/caspase 3, EC 3.4.22), activated neutral sphingomyelinase and increased ceramide formation in an immortalized dorsal root ganglion cell line F-11. Protection against apoptosis can be achieved by overexpression of the bc12 family of proteins or addition of drugs which elevate cAMP levels. cAMP protects against apoptosis induced by either wortmannin or staurosporine. The specificity for cAMP was confirmed by showing protection with the specific agonist (Sp)cAMPS and increased killing with the antagonist (Rp)cAMPS. However, cAMP did not protect against ceramide killing, suggesting that there are at least two major pathways of apoptosis in neuronal cells.
Animals↗
Prevalence of enuresis and other bladder symptoms in patients with active Graves' disease.
OBJECTIVE: To determine the prevalence of bladder symptoms in patients with Graves' disease and assess their abnormalities on urodynamic studies. PATIENTS AND METHODS: The study comprised 30 consecutive patients (13 female, 17 male, mean age 31 years, SD 10) with active Graves' disease. Before and after attaining euthyroidism with carbimazole, their bladder symptoms were assessed using a questionnaire adapted from the American Urologic Association voiding symptom score, the serum levels of total triiodo-L-thyronine (T3), serum thyroxine (T4) and thyroid-stimulating hormone (TSH) were measured by radioimmunoassay, and uroflowmetry, cystometry and perineal muscle electromyography were performed. RESULTS: Twelve of the 30 patients (40%) had the onset of bladder symptoms 1-6 months after the onset of symptoms of Graves' disease; four of the 12 patients had enuresis. Urodynamic studies were possible in five patients and showed reduced flow rates in all, a significant post-void residual volume in four, and enlarged bladder capacity and increased perineal muscle electromyographic activity during the voiding phase in three. Voiding disturbances and urodynamic abnormalities resolved after attaining euthyroidism. CONCLUSION: Significant bladder symptoms can occur in about 40% of patients with active Graves' disease but resolve on euthyroidism; in some patients, urodynamic studies show significant abnormalities which are also reversible.
Adolescent↗
Chronic exposure to kappa-opioids enhances the susceptibility of immortalized neurons (F-11kappa 7) to apoptosis-inducing drugs by a mechanism that may involve ceramide.
Chronic exposure of embryonic brain to opioids leads to microcephaly and developmental abnormalities. An immortalized mouse neuroblastoma x dorsal root ganglion hybrid cell line stably transfected to overexpress kappa-opioid receptors (F-11kappa7) showed complete loss of kappa-receptor binding to [3H]U69,593 after exposure to the kappa-agonist U69,593 for 24 h. U69,593 had no measurable effect on cell viability as determined by either cell viability or DNA fragmentation assays. However, when cell death (apoptosis) was induced by either staurosporine or the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002, cells pretreated with U69,593 for 24 h showed increased apoptosis compared with untreated cells. Thus, staurosporine (50 nM), wortmannin (4 microM), and LY294002 (30 microM) treatment for 24 h induced a 50% loss of cell viability and DNA fragmentation in 24 h. U69,593 pretreatment produced the same killing at lower concentrations, namely, 20 nM staurosporine, 2 microM wortmannin, and 14 microM LY294002, respectively. The effects of U69,593 were time-, dose-, and naloxone-reversible, suggesting that they are receptor-mediated. However, coaddition of U69,593 at the same time as staurosporine, wortmannin, or LY294002 did not enhance apoptosis. All three drugs that induced apoptosis were found to increase the level of ceramide, and pretreatment with U69,593 further increased the rate of formation of ceramide, a lipid that induces apoptosis in cells. We propose that chronic exposure to kappa-receptor agonists promotes increased vulnerability of neurons to apoptosis.
Analgesics↗
Circulatory collapse in a 30-year-old amenorrheic woman.
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Adult↗
Diabetes mellitus, fever, proptosis, and rapid loss of vision.
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Amphotericin B↗
Remission with carbimazole therapy & assessment of T4 suppression test as an index of relapse in patients with Graves' disease in India.
This study determined the relapse rate following the use of antithyroid drugs (ATD) in patients with Graves' disease and assessed T4 suppression test as a follow up index for predicting relapse after carbimazole treatment in 21 patients who had taken 9-12 months of ATD treatment continuously with good compliance. T4 suppression test was done before stopping ATD treatment. During one year of follow up after stopping ATD therapy, 12 (57%) patients relapsed and 9 (43%) remained in remission. Six of the 12 relapses occurred in the first 3 months of stopping ATD therapy. The response following the use of carbimazole therapy was comparable to that reported from iodine sufficient western countries and may be because of the salt iodination programme in our country. T4 suppression test was normal in 14 (66%) and abnormal in 7 (34%) patients. All the patients with abnormal T4 suppression test relapsed after stopping ATD. The overall accuracy of the T4 suppression test (76%) also favourably compared with reported values of other useful but less readily available markers such as thyrotropin releasing hormone (TRH) stimulation test and thyroid receptor antibodies. Thus, in our experience antithyroid drugs were able to induce long term remission in 43 per cent patients with Graves' disease and abnormal T4 suppression test can be used as a reliable parameter for predicting relapse.
Adult↗