Biomedical subjects
Publications and source records attributed to M Varma.
We have described a patient with unilateral adrenal hyperplasia, a rare cause of primary aldosteronism, and reviewed the literature on this subject. The treatment of this disorder appears to be surgical. Whether its pathogenesis is related to the more common varieties of primary aldosteronism is open to speculation.
The pattern of cerebrovascular disease in North-West India has been studied in a necropsy series of 362 cases over a 14 year period. One hundred and thirty eight cases of intracranial haemorrhage were found, 89 of cerebral embolism, 101 of cerebral arterial thrombosis and 34 of cerebral venous thrombosis. Nearly 37% of the affected patients were below 40 years of age. Cerebral embolism and cerebrovenous thrombosis were important causes of stroke in the young. Rheumatic heart disease and infective endocarditis formed the major causes of cerebral embolism. Cerebral venous thrombosis associated with pregnancy and puerperium was relatively more common in our series than has been reported in the West.
Mutagenesis of a diploid human fibroblast strain, KD, with the chemical carcinogen 4 nitroquinolin-1-oxide led to the isolation of stably immortalized neoplastic substrains. Four of these transformed strains, HuT-11, -12, -13, and -14, have been characterized in great detail with regard to morphology and changes in gene expression from the parental KD strain. The HuT-11, -12 and -13 substrains are immortalized and non-tumorigenic, in contrast to HuT-14 which is both immortalized and tumorigenic. The HuT-14 substrain expresses a defective beta-actin as a consequence of a point mutation in 1 of the 2 functional beta-actin alleles. All 4 HuT strains have induced expression of the phosphoprotein plastin and 2 EGF-related polypeptides, and down-regulated expression of the transformation-sensitive tropomyosin isoforms. KD and HuT cells expressing high levels of exogenous mutant beta-actin after gene transfection show morphological alterations. HuT-12 transfectants with excessive mutant beta-actin expression exhibit an elevated tumorigenic potential and tropomyosin-isoform switching characteristic of the tumorigenic HuT-14 strain.
The phosphoprotein plastin was originally identified as an abundant transformation-induced polypeptide of chemically transformed neoplastic human fibroblasts. This abundant protein is normally expressed only in leukocytes, suggesting that it may play a role in hemopoietic cell differentiation. Protein microsequencing of plastin purified from leukemic T lymphocytes by high-resolution two-dimensional gel electrophoresis produced eight internal oligopeptide sequences. An oligodeoxynucleotide probe corresponding to one of the oligopeptides was used to clone cDNAs from transformed human fibroblasts that encoded the seven other oligopeptides predicted for human plastin. Sequencing and characterization of two cloned cDNAs revealed the existence of two distinct, but closely related, isoforms of plastin--l-plastin, which is expressed in leukocytes and transformed fibroblasts, and t-plastin, which is expressed in normal cells of solid tissues and transformed fibroblasts. The leukocyte isoform l-plastin is expressed in a diverse variety of human tumor cell lines, suggesting that it may be involved in the neoplastic process of some solid human tumors.
We have identified a novel actin-related 60-kDa polypeptide in mammalian cells. The relatedness of this polypeptide to actin is indicated by its affinity for DNase I, two monoclonal anti-actin antibodies, and two independent peptide-specific anti-actin antibodies which bind to actin at around amino acid 244. It is not incorporated into cytoskeletal stress fibers, although it is a stable protein. Its expression (60-kDa polypeptide, pI of 5.4 to 5.5) is inhibited by the K+ ionophore, nonactin, which is known to collapse the energy-dependent translocation of cytoplasmically synthesized proteins into mitochondria.
Two different mutant human beta-actin genes have been introduced into normal diploid human (KD) fibroblasts and their immortalized derivative cell line, HuT-12, to assess the impact of an abnormal cytoskeletal protein on cellular phenotypes such as morphology, growth characteristics, and properties relating to the neoplastic phenotype. A mutant beta-actin containing a single mutation (Gly-244----Asp-244) was stable and was incorporated into cytoskeletal stress fibers. Transfected KD cells which expressed the stable mutant beta-actin in excess of normal beta-actin were morphologically altered. In contrast, a second mutant beta-actin gene containing two additional mutations (Gly-36----Glu-36 and Glu-83----Asp-83, as well as Gly-244----Asp-244) did not alter cell morphology when expressed at high levels in transfected cells, but the protein was labile and did not accumulate in stress fibers. In both KD and HuT-12 cells, endogenous beta- and gamma-actin decreased in response to high-level expression of the stable mutant beta-actin, in a manner consistent with autoregulatory feedback of actin concentrations. Since the percent decreases in the endogenous beta- and gamma-actins were equal, the ratio of net beta-actin (mutant plus normal) to gamma-actin was significantly increased in the transfected cells. Antisera capable of distinguishing the mutant from the normal epitope revealed that the mutant beta-actin accumulated in stress fibers but did not participate in the formation of the actin filament-rich perinuclear network. These observations suggest that different intracellular locations differentially incorporate actin into cytoskeletal microfilaments. The dramatic impact on cell morphology and on beta-actin/gamma-actin ratios in the transfected diploid KD cells may be related to the acquisition of some of the characteristics of cells that underwent the neoplastic transformation event that originally led to the appearance of the beta-actin mutations.
Mutant human beta-actin genes were introduced into normal human (KD) fibroblasts and the derivative cell line HuT-12, which is immortalized but nontumorigenic, to test their ability to promote conversion to the tumorigenic state. Transfected substrains of HuT-12 fibroblasts that expressed abundant levels of mutant beta-actin (Gly-244----Asp-244) produced subcutaneous tumors in athymic mice after long latent periods (1.5 to 3 months). However, transfected substrains of KD fibroblasts retained their normal finite life span in culture and consequently were incapable of producing tumors. Substrains of HuT-12 cells transfected with the wild-type beta-actin gene and some transfected strains that expressed low or undetectable levels of mutant beta-actin did not produce tumors. Cell lines derived from transfectant cell tumors always exhibited elevated synthesis of the mutant beta-actin, ranging from 145 to 476% of the level expressed by the transfected cells that were inoculated to form the tumor. In general, primary transfectant cells that expressed the highest levels of mutant beta-actin were more tumorigenic than strains that expressed lower levels. The tumor-derived strains were stable in tumorigenicity and produced tumors with shortened latent periods of only 2 to 4 weeks. These findings imply that the primary transfectant strains develop subpopulations of cells that are selected to form tumors because of their elevated rate of exogenous mutant beta-actin synthesis. Actin synthesis and accumulation of gamma-actin mRNA from the endogenous beta- and gamma-actin genes were diminished in tumor-derived strains, apparently to compensate for elevated mutant beta-actin synthesis and maintain the normal cellular concentration of actin. Synthesis of the transformation-sensitive tropomyosin isoforms was decreased along with mutant beta-actin expression. Such modulations in tropomyosin synthesis are characteristically seen in transformation of avian, rodent, and human fibroblasts. Our results suggest that this mutant beta-actin contributes to the neoplastic phenotype of immortalized human fibroblasts by imposing a cytoarchitectural defect and inducing abnormal expression of cytoskeletal tropomyosins.
Chronic administration of Danazol (25 mg/kg body wt) caused lesions in the testes of Rattus rattus Rufescens. Depletion of spermatocytes, spermatids and spermatozoa was conspicuous. Impairment of Leydig cell function was correlated with reduced cell size and depressed accessory sex organ weights. Epididymal cell height was greatly reduced. The lumen was devoid of spermatozoa. Danazol administration inhibited the synthesis of RNA, protein, sialic acid in the testes and accessory sex organs. Total cholesterol of the testes was increased, whereas the acid phosphatase enzyme activity was reduced. Testosterone propionate did not enhance the growth of accessory sex organs in castrated rats receiving Danazol. In conclusion, Danazol inhibits the system of steroidogenesis and spermatogenesis in Rattus rattus, when treated chronically for a period of 40 days. These effects are reversible after 60 days of cessation of drug administration.
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1. The identification of cholesterol as a constituent in the genesis of coronary artery disease in man and experimental animals are well documented. 2. The hypolipidemic effects of Commiphora mukul (guggulu) and Alium sativum (Garlic powder) were screened in dog and Presbytis monkeys. 3. Progressive decrease in the mean values of cholesterol, triglycerides and phospholipids were conspicuous for forty eight hours following the administration of guggulu/garlic powder. 4. 25 mg/kg body weight garlic powder was more effective in lowering the serum cholesterol and triglycerides as compared with that of guggulu. 5. A comparative hypolipidemic action of the two compounds is discussed.
Three siblings with congenital lipodystrophy were studied extensively for endocrine abnormalities. A severe disturbance in carbohydrate metabolism was observed. Plasma concentrations of glucagon and insulin were markedly elevated both in the basal state and in response to provocative stimuli. In addition, marked resistance to exogenous insulin and a diabetic oral glucose tolerance test were demonstrated. Lipid metabolism, GH, and ACTH secretion were normal...
Tobacco smoking reduces appetite and body weight (BW). Cessation of smoking leads to hyperphagia and weight gain. Daily food intake (FI) is a function of meal number (MN) and meal size (MZ), i.e., FI=MNxMZ. Under normal conditions, the female Fischer rat has a periodic reciprocal fluctuation between MZ and MN corresponding to phase of estrous cycle. Wide fluctuations between MZ and MN compensate each other to keep FI constant. Nicotine (5 mg/kg BW/day) was infused via osmotic minipump for 7 days. Controls received saline. FI, MZ, and MN were measured by an Automated Computerized Rat Eater Meter. Nicotine significantly decreased BW and FI via a decrease in MZ without compensatory increase of MN. Nicotine cessation led to hyperphagia, normalizing BW loss via an increase in MZ, which exceeded a compensatory decrease in MN. Nicotine significantly prolonged the estrous cycle by an extension of proestrous phase. Nicotine significantly lengthened the intermeal interval (IMI), delaying the start of the next meal and simultaneously decreasing subsequent MZ. Stopping nicotine led to normalization of IMI and MZ. Data show that nicotine alters the usual reciprocal regulation between MZ and MN and leads to a prolongation of the estrous cycle.
Gender differences of feeding pattern in normal male and female rats are well recognized. Differences in gender-related feeding patterns have also been established following a variety of experimental manipulations, such as hypothalamic lesions, nicotine infusion, and total parenteral nutrition administration. Anorexia is a common feature during tumor growth. The present study examined whether the feeding indices constituting the feeding patterns differed with the development of cancer anorexia in male and female rats. Sixteen male and 15 female Fischer-344 rats had their food intake (FI) and feeding indices, meal number (MN) and meal size (MZ), continuously measured by a computerized rat eater meter. Viable methylcholanthrene (MCA) sarcoma cells (10(6)) were inoculated subcutaneously in 10 male (M-TB) and 8 female (F-TB) Fischer rats, while the rest were controls and received an equal volume of vehicle. Tumor-bearing (TB) rats became anorectic by Day 18, when the weight of the tumor was approximately 8% of the total body weight (BW). A notable decrease in BW was observed in both M-TB and F-TB. A decrease in FI resulted from different feeding indices between male and female rats. In male rats, lower FI was due to a decrease in both MN and MZ. In female rats, lower FI was solely due to a decrease in MN. The data show that gender differences in feeding patterns, which are an external manifestation of biochemical changes in the brain, occur following development of cancer-related anorexia suggesting that besides other factors, cancer anorexia is also influenced by sex-related hormones.
The product of meal number x meal size, over time, is food intake. Because estrogens modulate feeding activity via their action on the hypothalamus, and because there is a diurnal rhythm in the expression of cytoplasmic estrogen receptors and in estrogen binding activity, the present study examined the effects of ovariectomy and later hormone therapy on acute changes in body weight, and on the meal number-to-meal size relationship as reflected by food intake in the dark/light feeding patterns, in adult female rats in the intact state and after ovariectomy. Twelve female Fischer rats were randomized into ovariectomy and sham operation groups. A rat eater meter measured the feeding indexes for 15 days before and 25 days after ovariectomy, and later for 35 days with hormone therapy. We report: (a) mean body weight gain was linear before and up to ovariectomy, while exponential after ovariectomy; (b) increase in daily food consumption is mainly via an increase in food intake during the light phase; (c) light phase meal number remains unchanged, meal size significantly increases, with the resultant increase in overall food intake; (d) during the dark phase, meal size also significantly increases, but is accompanied by a proportional decrease in meal number, resulting in unchanged dark-phase food intake; and (e) estrogen restoration with either estradiol valerate or estradiol-progesterone combination, reversed the above changes. Data show that in the female Fischer 344 rat: (a) changes in daily rhythm in food intake are brought about by differential effects of the hormones on both meal size and meal number in both the total daily levels as well as in the dark-to-light distribution; (b) estadiol appears to have a tonic inhibitory effect on the light phase meal size and a phasic effect on the dark phase meal size and number, but no significant effect on the light-phase meal number; and (c) in the Fischer rats, progesterone augments estradiol's effect on these indicies.
We describe an integrative approach to the modeling of biophysical radiation effects. The model takes aim at practical applications of the knowledge provided by molecular studies of radiation-matter interactions in DNA. The central proposition is the idea that the distribution of molecular lesions (i.e., a molecular lesion spectrum, MLS) generated in DNA by exposure to a particular radiation is a characteristic of that causal radiation (i.e., is a radiation signature, RS). We have found that adaptive neural networks (ANN's) provide an efficient way to validate that proposition and that ANN's are also likely to be invaluable in any attempt to correlate cancers with radiation types (i.e., with RS's), to use RS's for evaluating individual carcinogenic susceptibilities, and to develop a low-dose personalized monitoring capability. Although efforts to identify products of radiation that are specific to radiation type and to link those with biological responses are almost a century old, the RS concept has provided the first quantitative confirmation of such causal relations. That is, RS's and radiation markers have been identified for various types of radiation, electromagnetic (EM) and particulate, and these signatures and markers may constitute a new way for fast radiation exposure estimates, risk assessment, and cumulative low-dose evaluation. In this work, while we will present a short review of the concepts and methods related to both RS's and markers, almost the entire effort will relate to the modeling and interpretation of RS's using ANN processing.
BACKGROUND AND AIMS: Chest radiographs (CXRs) are performed routinely after permanent pacemaker implantation to identify pacemaker lead position and exclude pneumothorax. We assessed the clinical value and need for this procedure. DESIGN: Retrospective analysis of pacemaker data and CXRs following permanent pacemaker insertion between December 2002 and February 2004. MATERIALS AND METHODS: Post-procedural CXRs were available in 125/126 consecutive patients after either first endocardial pacemaker implantation or insertion of at least one new lead. Subclavian vein puncture was used for venous access in all cases. CXRs were examined to establish the incidence of pneumothorax and assess pacing lead positions. The clinical records were examined in all patients who had subsequent CXRs or a further pacemaker procedure to identify the indication for these and to establish whether CXR had influenced patient management. RESULTS: In total, 192 post-procedural CXRs were performed, either postero-anterior (PA) and/or lateral views. Ventricular and/or atrial pacing lead contour and electrode position was considered radiographically appropriate in 86% CXRs. Fourteen per cent of post-procedural radiographs were considered to have radiologically sub-optimal pacemaker lead positioning. None of the patients with these "abnormal" radiographs experienced subsequent pacemaker complications or had further radiographs recorded at a later date. Later repeat CXRs were performed in 16 patients (13%) but only 3 patients (2%) had pacing abnormalities as the primary indication. All three had satisfactory pacing lead position on initial post-implantation and later radiographs, but required further procedures for lead re-positioning. Iatrogenic pneumothorax occurred in one patient (incidence 0.8%) in our series. CXR confirmed the clinical diagnosis and allowed an assessment of size to guide treatment. CONCLUSION: Routine CXR after permanent pacemaker insertion is not necessary in uncomplicated cases with adequate pacing characteristics.