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Biomedical subjects

S Rajagopalan

Publications and source records attributed to S Rajagopalan.

At least 73 records · Page 4Linked to original sources
PubMed1995

Regulation of coronary diameter by myogenic mechanisms in arterial microvessels greater than 100 microns in diameter.

We performed the present study to determine the quantitative significance of transient and steady-state myogenic responses in isolated coronary resistance vessels greater than 100 microns in diameter. Small coronary arteries were isolated from freshly excised porcine hearts (n = 14) and were studied under static conditions in a superfused vessel chamber that allowed internal diameter to be assessed continuously using video microscopic techniques. At a mean distending pressure of 50 mmHg, the passive diameter of resistance arteries following sodium nitroprusside averaged 181 +/- 10 (SE) microns. Upon heating, vessels developed spontaneous tone and constricted to 72 +/- 3% of their maximum diameter. After a 30-mmHg step change in coronary pressure from 50 to 80 mmHg, there was an initial dilation from 131 +/- 9 to 149 +/- 11 microns, followed by myogenic constriction that returned diameter to the initial value over a period of several minutes (134 +/- 10 microns, P = NS). Directionally opposite peak transients were observed during reductions in pressure. Steady-state diameter remained relatively constant over a pressure range from 100 to 20 mmHg. Although these data demonstrate that myogenic responses are present in resistance arteries that are greater than 100 microns in diameter, their contribution to steady-state coronary resistance changes as pressure is varied is small. This suggests that additional mechanisms contribute to the phenomenon of coronary autoregulation in this class of resistance vessel.

Animals↗
PubMed1995

Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus.

The production of potentially pathogenic anti-DNA autoantibodies in SLE is driven by special, autoimmune T helper (Th) cells. Herein, we sequenced the T cell receptor (TCR) alpha and beta chain genes expressed by 42 autoimmune Th lines from lupus patients that were mostly CD4+ and represented the strongest inducers of such autoantibodies. These autoimmune TCRs displayed a recurrent motif of highly charged residues in their CDR3 loops that were contributed by N-nucleotide additions and also positioned there by the recombination process. Furthermore, Th lines from four of the five patients showed a marked increase in the usage of the V alpha 8 gene family. Several independent Th lines expressed identical TCR alpha and/or beta chain sequences indicating again antigenic selection. 10 of these Th lines could be tested further for antigenic specificity. 4 of the 10 pathogenic anti-DNA autoantibody-inducing Th lines responded to the non-histone chromosomal protein HMG and two responded to nucleosomal histone proteins; all presented by HLA-DR molecules. Another Th line responded to purified DNA more than nucleosomes. Thus, these autoimmune Th cells of lupus patients respond to charged epitopes in various DNA-binding nucleoproteins that are probably processed and presented by the anti-DNA B cells they selectively help.

Amino Acid Sequence↗
PubMed1995

Accidental acute fatal sodium nitrite poisoning.

An accidental food poisoning outbreak occurred resulting in the death of 14 of the 22 affected persons. Chemical analysis of food materials revealed the presence of sodium nitrite and potassium arsenate. Analysis of urine, gastric contents, liver and kidney, collected at the time of autopsy, confirmed the presence of these chemical substances in high concentrations. Epidemiological data indicated that the food poisoning occurred due to the accidental use of sodium nitrite and potassium arsenate instead of table salt in the preparation of tamarind (Tamarindus indica) soup.

Adolescent↗
PubMed1995

gamma-Glutamyl transpeptidase. What does the organization and expression of a multipromoter gene tell us about its functions?

gamma-Glutamyl transpeptidase is a key enzyme in glutathione (GSH) salvage, metabolism of endogenous mediators such as leukotrienes and prostaglandins, detoxification of xenobiotics including environmentally important compounds and carcinogens, and cellular processes dependent on the oxidation/reduction of glutathione. The enzyme is widely distributed, and these functions often occur in separate tissues and in response to different stimuli. Evidence indicates that gamma-glutamyl transpeptidase plays a direct role in some hepatic and renal responses to injury. In the mouse gamma-glutamyl transpeptidase is a single copy gene expressed from at least seven promoters, and many of the transcribed gamma-glutamyl transpeptidase RNAs are restricted in their expression. Studies that combine analyses of cellular processes with a knowledge of gene structure and expression hold promise for unravelling how these two different levels of function are integrated.

Animals↗
PubMed1995

Transgenic mice carrying a PSArasT24 hybrid gene develop salivary gland and gastrointestinal tract neoplasms.

BACKGROUND: Although prostate cancer is one of the most prevalent tumors in men, knowledge of its biology has been hindered by lack of animal models. We have attempted to develop a prostate cancer model utilizing transgenic mouse technology. EXPERIMENTAL DESIGN: Two lines of transgenic mice were derived from one cell stage embryos injected with a fusion gene consisting of a mutated (codon 12) ras gene driven by the human prostate specific antigen (PSA) promoter in an attempt to target the oncogene specifically to the mouse prostate gland. Nontransgenic FVB/N mice were used as controls. The animals were sacrificed for study between 4 and 55 weeks of age. RESULTS: All organs were normal except the salivary glands and gastrointestinal tracts, both of which developed carcinomas in animals older than 44 weeks. The salivary gland tumors were of ductal origin, exhibited a variable degree of differentiation, and were shown to contain abundant PSAras mRNA by in situ hybridization. The gastrointestinal tract tumors were undifferentiated but appeared to be of stromal origin. Both salivary gland and gastrointestinal tumors occasionally metastasized. No transgene expression could be demonstrated in the prostate gland by either reverse transcription-polymerase chain reaction or in situ hybridization. CONCLUSIONS: Lack of transgene expression by the prostate can be explained on the basis of the apparent species specificity previously observed for PSA. Expression in salivary gland is best attributed to identity between the nucleotide sequences of the PSA promoter and of a mouse glandular kallikrein normally secreted by the salivary gland.

Animals↗
PubMed1995

Development of a customizable universal digital hearing aid.

This paper presents the development of a digital binaural hearing aid using Texas Instruments' floating point TMS320C3X digital signal-processing chip. The device is referred to as the Customized Universal Digital Listening System (CUDLS). CUDLS uses a wide bandwidth (up to 16 kHz) and incorporates speech enhancement (noise reduction) as an integral part of the device. It is capable of sampling up to two input speech channels at a variable sampling rate. We are currently using a sampling rate of 20 kHz for each channel. We have developed our own customized hardware and software to implement CUDLS in real time with zero processing delay. The system has been designed to make it easy for the therapist to modify its features.

Correction of Hearing Impairment↗
PubMed1994

Calnexin retains unassembled major histocompatibility complex class I free heavy chains in the endoplasmic reticulum.

The assembly of major histocompatibility complex (MHC) class I molecules involves the association of heavy (H) chain with beta 2-microglobulin (beta 2m) and peptide. Unassembled class I H chains do not exit the endoplasmic reticulum (ER) and this is exemplified by the beta 2m-deficient human melanoma FO-1 where free class I H chains are unable to complete assembly. In pulse chase experiments involving FO-1 cells, unassembled free class I H chains were shown to be stably associated with calnexin (IP90/p88), a 90-kD integral membrane molecular chaperone of the ER. To establish a role for calnexin in mediating this retention, we transfected FO-1 cells with a cytoplasmic tail deletion mutant of calnexin. Since the cytoplasmic tail contains the ER retention motif, these mutant calnexin molecules leave the ER and progress to the cell surface. In these stable transfectants of FO-1, free class I H chains also exited the ER and trafficked to the cell surface with calnexin, thus establishing a role for calnexin in the quality control of MHC class I assembly through mediating the ER retention of incompletely assembled class I H chains.

Calcium-Binding Proteins↗
PubMed1994

Endogenous Fusarium endophthalmitis in a patient with acute lymphocytic leukemia.

Endogenous fungal endophalmitis is an uncommon complication of systemic mycosis. Only a few cases involving Fusarium have been reported, most with unfavorable visual outcomes. We examined a 31-year-old woman with acute lymphocytic leukemia who developed sudden visual loss in her right eye. A dense, white placoid infiltrate was present in the right macula extending into the vitreous. An iris nodule and hypopyon were present in the left eye. A vitreous aspirate of the right eye was positive for Fusarium species. The patient progressively lost vision despite amphotericin B and 5-fluorocytosine therapy. She died from bronchopneumonia, fungemia, and multisystem failure. Histopathologic study disclosed a panophthalmitis with Fusarium organisms invading all the ocular coats in the right eye. Leukemic infiltrates were present in the left iris, anterior chamber, and trabecular meshwork. The ocular destructiveness of Fusarium may be caused by marked mycotic vascular invasion and occlusion with consequent infarction and necrosis of ocular tissues.

Adult↗
PubMed1994

Retention of unassembled components of integral membrane proteins by calnexin.

Quality control mechanisms prevent the cell surface expression of incompletely assembled multisubunit receptors such as the T cell receptor (TCR). The molecular chaperone function of calnexin (IP90, p88), a 90-kilodalton protein that resides in the endoplasmic reticulum (ER), in the retention of representative chains of the TCR-CD3 complex in the ER was tested. Truncation mutants of calnexin, when transiently expressed in COS cells, were exported from the ER and either accumulated in the Golgi or progressed to the cell surface. CD3 epsilon chains cotransfected with the forms of calnexin that were not retained in the ER exited the ER and colocalized with calnexin. Since engineered calnexin determined the intracellular localization of the proteins associated with it, it is concluded that calnexin interacts with incompletely assembled TCR components and retains them in the ER.

Amino Acid Sequence↗
PubMed1994

Multiple myeloma after cardiac transplantation: an unusual form of posttransplant lymphoproliferative disorder.

Published reports of posttransplant myeloma are extremely uncommon (three cases); to the best of our knowledge there have been no reported cases in cardiac transplant recipients. We are also unaware of any report of Epstein-Barr virus (EBV) genome studies in posttransplant myeloma. We report here the case of a 48-year-old man who developed multiple myeloma 1.5 years after cardiac transplantation. The results of a serum analysis were consistent with past EBV infection. Biopsy of a skull lesion showed a monomorphous population of malignant immature plasma cells that showed monotypic cytoplasmic staining with antibodies to lambda light chains. A monoclonal immunoglobulin heavy chain gene rearrangement was detected by polymerase chain reaction (PCR). Both EBER-1 in situ hybridization and EBNA-1 PCR were negative for the EBV genome. Cyclosporin withdrawal was followed by transient clinical and biological improvement, but the tumor later progressed and eventually stabilized in response to treatment with dexamethasone alone. This case illustrates that posttransplant lymphoproliferative disorders (PTLPDs) encompass not only EBV-positive but also EBV-negative cases and not only lymphomas but also myelomas.

Antigens, Viral↗
PubMed1994

Class II histocompatibility molecules associate with calnexin during assembly in the endoplasmic reticulum.

Class II histocompatibility antigens are composed of polymorphic alpha and beta polypeptides which associate in the endoplasmic reticulum (ER) with a third, non-polymorphic invariant polypeptide (Ii). The alpha beta Ii complexes are subsequently transported through the Golgi to the endosomes, where the Ii chain dissociates before the alpha beta complex is transported to the cell surface. Results from transport-defective class II expression variant studies suggest that class II intracellular transport is regulated in multiple intracellular compartments. Consistent with this, a large number of studies have demonstrated that protein folding and/or oligomerization is facilitated in the ER by a class of proteins collectively known as molecular chaperones. In this report, we show that the ER-resident protein calnexin associates with human and murine class II antigens. Specifically, calnexin associates in the ER with free Ii polypeptides and partially assembled wild-type class II complexes, including A alpha and/or A alpha Ii complexes, as well as with alpha beta dimers isolated from class II transport-defective cells. Calnexin also physically associates with alpha beta Ii complexes, but not with mature alpha beta dimers. These results suggest that calnexin may regulate class II intracellular transport by facilitating the production of transport competent molecules out of the ER. In addition, we report that the nucleotide sequence of the gene encoding murine calnexin shows a high degree of homology to human IP90 and dog calnexin at both the nucleotide and deduced amino acid sequence level. The isolation of cDNA fragments encoding murine calnexin will allow us to further evaluate the functional consequences of calnexin-class II interaction.

Amino Acid Sequence↗
PubMed1993

Six mRNAs with different 5' ends are encoded by a single gamma-glutamyltransferase gene in mouse.

The 5' region of the mouse gamma-glutamyltransferase (gamma GT; EC 2.3.2.2) gene has been cloned and analyzed. This analysis, combined with sequence information obtained from gamma GT cDNA clones, indicates that in mouse a single gamma GT gene codes for six different mRNAs that differ in their 5' sequences. Analysis of steady-state levels of gamma GT RNA reveals different expression patterns for these RNAs in different organs. The six different 5' sequences are widely separated within a 10-kb region and three of them show 75-86% identify with the three known rat gamma GT cDNAs. Although the heterogeneity of the 5' ends of gamma GT RNAs may be explained in part by alternative splicing, it is likely that multiple promoters are involved in their generation.

Animals↗
PubMed1993

Gelsolin immunoreactivity in corneal amyloid, wound healing, and macular and granular dystrophies.

Immunohistologic studies of tissue sections obtained from patients with type 1 or type 2 lattice corneal dystrophy, polymorphic amyloid degeneration, or gelatinous amyloid degeneration were performed by using a monoclonal antibody raised to a chymotryptic fragment inclusive of the carboxy-terminal half of plasma gelsolin, and also with a series of polyclonal antibodies specific for synthetic peptides corresponding to immunogenic epitopes of gelsolin. These epitopes are parts of sequences at the amino- and carboxy-terminal ends of gelsolin, as well as adjacent to and inclusive of the codon 187 mutant 7-11 kD fragment that has been shown to be the subunit protein of amyloid fibrils occurring systemically in patients affected by Finnish type familial amyloidosis. These antibodies were also tested on tissue sections obtained from patients with granular and macular corneal dystrophy, corneal wounds, and normal control corneas. Specificity of staining was established by absorption with gelsolin purified from plasma, or the appropriate synthetic peptide. Gelsolin immunoreactivity was detected in the conjunctival and skin amyloid in familial amyloidosis by using familial amyloid (Finnish type) antibody. In other types of corneal amyloid, including lattice dystrophy type 1, immunoreactivity with gelsolin and synthetic peptides was observed adjacent to the deposits, but rarely within them. In macular dystrophy, variable staining of the deposits could result from the association of subunit proteins with glycosaminoglycans.

Amyloidosis↗
PubMed1993

Interaction with newly synthesized and retained proteins in the endoplasmic reticulum suggests a chaperone function for human integral membrane protein IP90 (calnexin).

A cDNA clone encoding the human endoplasmic reticulum (ER) resident protein IP90 was isolated and sequenced. It predicts a transmembrane protein with a large ER luminal region showing sequence similarity to calreticulin and a short cytoplasmic domain containing a COOH-terminal RKPRRE sequence that may be relevant to its retention in the ER. It is 95% homologous to the canine ER membrane phosphorprotein called pp90 or calnexin (Wada, I., Rindress, D., Cameron, P. H., Ou, W.-J., Doherty, J. J., II, Louvard, D., Bell, A. W., Dignard, D., Thomas, D. Y., and Bergeron, J. J. M. (1991) J. Biol. Chem. 266, 19599-19610). Previously, in lymphocytes, we have characterized IP90 as a protein associated with partially assembled multichain proteins including the T cell receptor, the membrane immunoglobulin, and the heavy chain of the major histocompatibility complex class I molecules (Hochstenbach, F., David, V., Watkins, S., and Brenner, M. B. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 4734-4738). Here, we show that within a short metabolic labeling period, IP90 associates transiently with many different newly synthesized proteins. However, in a T cell line that cannot assemble a complete T cell receptor because it lacks the alpha subunit, the unassembled T cell receptor beta chains, which are retained in the ER, remain associated with IP90 throughout a prolonged chase time period. Together, these data offer further evidence suggesting that IP90 may act in assisting protein assembly and/or in the retention within the ER of unassembled protein subunits.

Amino Acid Sequence↗
PubMed1993

Modulation of retinoblastoma cell characteristics by hexamethylene bis-acetamide and other differentiating agents in culture.

The undifferentiated Y-79 retinoblastoma cell line can be induced by specific agents to express characteristics of mature retinal cells. In the present study, attached Y-79 cell cultures were treated with hexamethylene bis-acetamide (HMBA) and other differentiating agents and examined for "neuronal" and other properties. Immunocytochemical staining was performed with antibodies against neuron- and retina-specific antigens, [synaptophysin, interphotoreceptor retinoid-binding protein (IRBP), neural cell adhesion molecule (N-CAM), and rod- and cone-specific transducin (TR alpha and TC alpha)] and microtubule-associated protein (MAP-1) and tubulin. Enhanced expression of tubulin was observed with cAMP treatment in FBS media. Expression of N-CAM was observed in all groups. Morphological differentiation was pronounced with HMBA and butyrate treatment, with HMBA inducing increased tubulin expression after 2 weeks of treatment. Expression of TR alpha was minimal under all culture conditions, whereas TC alpha was ubiquitously expressed. This supports the concept that Y-79 retinoblastoma is predominantly of cone neuronal origin and that, surprisingly, immunocytochemical differentiation is not correlated with the marked morphological changes induced by the major differentiating agents used.

Acetamides↗
PubMed1993

Retinoblastoma. Interphotoreceptor retinoid binding protein mRNA analysis by polymerase chain reaction.

The authors used the polymerase chain reaction (PCR) to detect the mRNA for interphotoreceptor retinoid-binding protein (IRBP/RBP3), a photoreceptor specific protein, in small samples. They carried out these experiments to assess the feasibility of applying this technique to small tumor samples. Surgically excised tumor samples from four enucleations were analyzed. Messenger RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction was followed by phenol-chloroform purification, reverse-transcription and amplification. The primers used were 5' TGATGACTCTGTCAGTG 3' in exon 3 (sense) and 5' TTGTGCTGGAGCATCTC 3' in exon 4 (antisense). Controls included an IRBP cDNA pIRBP 20-700 and RNA from normal human retina. All samples amplified the same size band if detected. Three tumor samples contained IRBP mRNA as indicated by amplified 234 bp band. These three samples showed a high IRBP protein level by slot blot and RNA for IRBP detected by northern blot. Hematoxylin-eosin staining of one of these samples revealed a well differentiated tumor with numerous Flexner-Wintersteiner rosettes. In the fourth tumor, a poorly differentiated neoplasm, no IRBP mRNA was detected. The authors' results showed a qualitative variation of IRBP mRNA levels, usually related to the histologic differentiation, with IRBP expressed in well differentiated tumors as well as in the normal human retina in contrast to a poorly differentiated tumor with no detectable IRBP. The feasibility of the reverse transcriptase-PCR (RT-PCR) technique to detect IRBP mRNA in small retinoblastoma tumors, was demonstrated.

Base Sequence↗