Biomedical subjects
Publications and source records attributed to M Varga.
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The antiostheophorotic agent ipriflavone [7-(1-methyl-ethoxy)-3-phenyl-4H-1-benzopyran-4-one, C18H16O3] is an important member of the isoflavone family. The structure of the molecule is dominated by the dihedral angle (50 degrees) between the planes of the phenyl and benzo-pyran moieties. A structural comparison with other related published structures is represented.
We have earlier shown that stimulation of human CD4+ T cells with SEA presented on Chinese hamster ovary (CHO)-DR transfectants coexpressing either B7 or LFA-3 resulted in distinct cytokine profiles. We now demonstrate that B7, but not LFA-3, strongly costimulated IL-2 transcription and mRNA expression in CD4+ T cells. Maximal increase in IL-2 transcription was recorded with CHO-DR/B7/LFA-3, suggesting a cooperative effect of B7 and LFA-3 at the transcriptional level. Gel-shift analysis demonstrated that stimulation of CD4+ T cells with CHO-DR and staphylococcal enterotoxin A was sufficient to induce significant amounts of NF-kappa B binding proteins, whereas induction of AP-1 binding proteins required costimulation. LFA-3 induced moderate levels of AP-1, but did not influence the levels of NF-kappa B, while B7 costimulation strongly induced both AP-1 and substantially enhanced NF-kappa B binding proteins. The CHO-DR/B7/LFA-3 triple transfectant induced a further increase in AP-1 and NF-kappa B binding proteins compared with the double transfectants. The level of Oct-1 binding proteins remained similar in all samples. Super-shift analysis revealed that the NF-kappa B complex of costimulated CD4+ T cells contained large amounts of p50, substantial amounts of p65, and marginal levels of c-Rel proteins. The AP-1 binding proteins contained c-Jun, Jun-D, and Fra-1, but marginal amounts of Jun-B and c-Fos. Our results indicate distinct effects of B7 and LFA-3 costimulation on the activity of AP-1 and NF-kappa B. These may partly account for the differential effects of B7 and LFA-3 costimulation on IL-2 expression.
Two signals are required for induction of cell proliferation and cytokine production in resting T cells. Occupancy of the T cell receptor by antigen/MHC complexes delivers the first signal to the T cell, while the second signal is provided by interaction with costimulatory ligands on APC. CD2, LFA-1, and CD28 are the major costimulatory and adhesive molecules on T cells and bind to the LFA-3, ICAM-1 and B7 ligands, respectively, on APC. LFA-3 plays a central role for naive and memory T helper cells during the early phase of an immune response. The LFA-3/CD2 pathway initiates strong antigen-independent cell adhesion, substantial expansion of naive T helper cells, and induction of large amounts of IFN-gamma in memory cells. The release of IFN-gamma may upregulate expression of ICAM-1 and B7 on APC and allows multiple adhesion pathways to amplify the immune response. The LFA-1/ICAM-1 pathway stimulates adhesion and cell proliferation more efficiently in memory T helper cells than in naive cells. Further, the results suggest that naive T helper cells express functionally inactive LFA-1 molecules on the cell surface, which may have a physiological role in keeping these cells in a resting state. B7 costimulation superinduces IL-2 production in both naive and memory T helper cells and generates long-lasting cell proliferation. This permits transition from an autocrine to a paracrine immune response. Coexpression of B7/LFA-3 provides an optimal APC function and enables a vigorous T cell response to minute amounts of antigen. AP-1 and NF-kappa B transcription factors are involved in the induction of several cytokine gene promoters and play a central role in the regulation of IL-2 gene transcription. LFA-3 costimulation only moderately enhances AP-1 DNA-binding activity and does not influence the NF-kappa B activity induced by TCR engagement, whereas B7 costimulation induces large amounts of NF-kappa B and AP-1 activity in T helper cells. The costimulatory ligands represent a family of adhesion molecules with considerable redundancy. Interfamily redundancy of LFA-3, B7, and ICAM ligands offers an opportunity to regulate distinct T cell response profiles in various microenvironments at separate time points of an immune response.
v-Ha-Ras, an oncogenic Ras mutant, causes malignant transformation of mammalian cells by recruiting c-Raf-1, a cytosolic Ser/Thr kinase, to the plasma membranes/cytoskeleton. The kinase activity of c-Raf-1 resides in the C-terminal half, which activates mitogen-activated protein (MAP) kinase kinase, while it is the N-terminal half of c-Raf-1 (Raf257, residues 1-257) that binds the Ras-GTP complex and can compete Ras GTPase-activating proteins such as NF1 for binding to Ras. However, it still remains to be clarified whether overexpression of Raf257 or its minimal Ras-binding fragment alone is sufficient to suppress Ras-induced malignancy. In this paper we demonstrate for the first time that the 81-amino acid fragment (Raf81, residues 51-131), the minimal Ras-binding fragment of Raf, indeed can suppress v-Ha-Ras-induced malignant phenotype. A further deletion of the first 6 amino acids causes 65% reduction in the Ras binding of Raf81. The resultant 75 amino acid fragment (Raf75, residues 57-131) consists of a single alpha-helix, five anti-paralleled beta-sheets and five loops. We have found that a further deletion of either the first beta-sheet/loop or the last two beta-sheets/loops completely abolishes Ras binding. In addition we have found that the removal of the C-terminal 35 amino acids from a Ras-binding 91-amino acid fragment of NF1 (NF91, residues 1441-1531) does not abolish its ability to suppress the Ras-induced malignancy.
Previously, we have cloned a candidate for the 595-amino acid neurofibromatosis type 2 tumor suppressor called NF2 or Merlin, with striking sequence similarity in its N-terminal half to an F-actin-binding protein family called TERM, which includes talin, ezrin, radixin, and moesin (Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Kley, N., Menon, A. G., Pulaski, K., Haase, V. H., Ambrose, C. M., Munro, D., Bove, C., Haines, J. L., Martuza, R. L., MacDonald, M. E., Seizinger, B. R., Short, M. P., Buckler, A. J., and Gusella, J. F. (1993) Cell 72, 791-800). In an attempt to determine whether NF2 serves as a tumor suppressor and if so whether its N-terminal half is involved in its anti-oncogenicity, both full-length NF2 and its N-terminal half (NF2-N, residues 9-359) have been expressed in v-Ha-Ras-transformed NIH/3T3 cells. Like neurofibromatosis type 1 (NF1) fragments (Nur-E-Kamal, M. S. A., Varga, M., and Maruta, H. (1993) J. Biol. Chem. 268, 22331-22337), full-length NF2 can reverse the Ras-induced malignant phenotype, i.e. anchorage-independent growth in a soft agar, and restore contact inhibition of cell growth, indicating that NF2 is indeed a tumor suppressor. Furthermore, NF2-N also suppresses the Ras-induced malignant phenotype, although it appears to be less effective than the full-length NF2. These observations indicate that the anti-Ras function of NF2 resides in part in its N-terminal half. Thus, NF2 appears to be a new member of the tumor suppressor family of actin-cytoskeleton-associated proteins, which includes vinculin, alpha-actinin, tropomyosin-1, gelsolin, and tensin.
An improved method for the isolation and purification of infectious pancreatic necrosis virus (IPNV) is described. Virions released into the clarified growth medium are adsorbed to an anion exchange resin of diethylaminoethyl cellulose at pH 8.1. IPNV together with the likewise released and accumulated excess pool of the precursor to the major capsid protein, ICP62, are eluted at a salt concentration between 100 and 125 mM NaCl. The bovine serum albumin content of the growth medium supplement also elutes close to this position. Upon one step of combined sucrose- and CsCl-gradient centrifugation the recovered viruses display lower levels of aggregation, higher specific nucleic acid contents and an approximately 350% higher specific infectivity as compared with pools of viruses processed in parallel and isolated according to the established method relying on precipitation with poly(ethylene glycol).
During hospitalization for severe acute necrotizing pancreatitis, a connection between the onset of retinopathy of pancreatitis and multiple-organ failure was studied. Ophthalmoscopy was repeated every second day and continuous staging for multiple-organ failure was performed in 38 patients. Typical retinopathy of pancreatitis developed in 7 of 10 patients with multiple-organ failure and only in 4 of the 28 patients without multiple-organ failure. Retinopathy of pancreatitis was observed in 7 of the 18 cases leading to lethal outcome and only in 4 of the 20 surviving patients. No correlation was observed between the development of retinopathy of pancreatitis and hemodialysis, pre-existing diabetes mellitus, abnormal platelet count, result of hemoculture, c reactive protein value, fraction of inspired oxygen and adult respiratory distress syndrome. In the 21 control patients in grave general state but without acute pancreatitis, retinopathy of pancreatitis was never observed. In our prospective study the onset of retinopathy of pancreatitis had clinical prognostic value and indicated multiple-organ failure and poor prognosis in severe acute necrotizing pancreatitis.
A study was conducted with medical students to observe their drinking habits and alcohol misuse. The students completed questionnaires composed of AUDIT and SMAST questions. A significant proportion (33%) of students drank more than the recommended safe limit and screened positive at the AUDIT cut-off score of 11. The high scores of DSM-III criterion questions indicate that problem drinking on college campuses continues to be a significant public health concern. Our opinion is that prevention of alcohol misuse should be started at medical universities. The medical school curriculum must integrate education about alcohol. First the attitude of medical professionals should be changed so that we can achieve results in alcohol misuse prevention in society as a whole.
The authors report on the virological findings of 59 transplant recipients. The following procedures were used for the detection of human cytomegalovirus (HCMV) infection: detection of antiviral antibodies by ELISA, the detection of virus-coded antigens in the patients' leucocytes (HCMV antigenemia test), "accelerated" virus isolation using immunofluorescence (IF). Serial examinations revealed the HCMV infection in 12 patients following organ transplantation. The antigenemia test proved to be positive in all cases. Two third of the cases suffered from viremia. The virus specific serology possess diagnostic value only in every second acute illness. Since the antigenemia test used to be successful in the earliest phase of acute illnesses, the chance of effective chemotherapy can be increased significantly. The virus serological examinations are of essential importance during the pretransplantation screening of donors and recipients. The "accelerated" procedure of virus isolation experiments indicates the presence of infective HCMV within 1 to 4 days. Transplant recipients obtain new life perspectives, nevertheless, the modern diagnostic procedures may only support the prevention of life-threatening virus infections under the conditions of immunosuppression. The excellent mutual cooperation of the clinicians and diagnostic virologists seems to be at least as important condition of successful transplantation medicine as the high technology in surgery and clinical diagnostics.
The human neurofibromatosis type 1 gene encodes a Ras GAP (GTPase-activating protein) of 2818 amino acids called NF1. This GAP contains a domain of 338 amino acids (residues 1194-1531) called NF1-GRD, which shares 26% sequence identity with the C-terminal domain (GAP1C, residues 709-1044) of another Ras GAP called GAP1. Both NF1-GRD and GAP1C activate normal Ras GTPases but not oncogenic mutants such as v-Ha-Ras. Any attempt to reverse the v-Ha-Ras-induced malignant transformation by the GAP1C has, so far, been unsuccessful. However, we have found that when the NF1-GRD is overexpressed in v-Ha-Ras-transformed NIH/3T3 cells, it greatly reduces their ability to form colonies in a soft agar, the property tightly associated with their malignancy. This is, so far, the first demonstration that a Ras-binding protein can act as a potent antagonist of the oncogenic Ras mutants in mammalian cells. In an attempt to further screen the smallest anti-oncogenic fragment derived from the NF1-GRD, we have prepared a series of its deletion mutants and examined their interaction with Ras first by monitoring their GAP activity (ability to activate the normal Ras GTPase). The deletion analysis has revealed that the N-terminal 247 amino acids (residues 1194-1440) of NF1-GRD are not required for its GAP activity, suggesting that its remaining domain of 91 amino acids (NF91, residues 1441-1531) is sufficient to bind the v-Ha-Ras, although its GAP activity is 20 times lower than the NF1-GRD. The NF91 is indeed able to reverse the v-Ha-Ras-induced malignant transformation as the NF1-GRD. The NF91 is, so far, the smallest among the tumor suppressor proteins that show the anti-v-Ha-Ras action in vivo. Thus, the NF91 appears to be a good starting material from which a smaller and more potent v-Ha-Ras antagonist could be devised to be used as a potential cure for the human cancers caused by the Ras mutants.
Transesophageal echocardiography was performed in 34 patients before coronary angiography for suspected coronary artery disease to determine the usefulness in the detection of proximal left coronary stenosis. The control group consisted of 18 patients in whom coronaroangiography seemed to be negative. The diameter of the visualized coronary arteries, the systolic and diastolic peak flow velocities were measured. The left main coronary artery was visualized in 32 patients, the left anterior descending artery in 31 and the proximal part of the circumflexus artery in 23 patients of the coronary artery disease group, and in the same rate in the control group. The visualization of the right coronary artery was available only in 20-25% because of technical difficulties. The diastolic peak flow velocity over 60 cm/s in the left anterior descending artery reflected proximal stenosis with high sensitivity. In four patients transesophageal echocardiography was performed before angioplasty and after successful intervention. The high diastolic peak flow velocity significantly decreased in every patient. According to the observations the method can be used to perform morphologic and functional measurements on the left proximal coronary arteries.
Authors performed dobutamin stress test since 1987 and combined their examinations with 2D-echocardiography in case of suspected coronary artery disease since October 1991. In this study they report on their experiences obtained in the course of the first 32 examinations. The results of the dobutamine stress echocardiography were analysed on the basis of coronarography which was performed in every patient. According to their observations dobutamine stress echocardiography has very good sensitivity and specificity and it is practically a harmless method, but as it requires instruments, assistants, time and work. Authors recommend the method first of all as a complementary to the physical loading method as well as alternative loading examination.
The authors studied the relationship between the blood alcohol concentration and the categories of alcohol intoxication established by means of examining the clinical signs of intoxication in a drinking test, and by analyzing the reports on driving while intoxicated (DWI). In the drinking test the relative increase of viso-motor reaction time was an accurate indicator of the blood alcohol levels. In almost half of the cases there was no correlation between the clinical signs and the blood alcohol concentration. When alcohol and medicine was used in combination a more severe intoxication was frequently assumed. Therefore, if the reported intoxication based on clinical signs indicates a more severe intoxication than that correlating with the blood alcohol concentration, the toxicologic analysis of the blood samples are unconditionally necessary.
Six external recti muscles chosen from a material of 20 muscles were studied with the transmission electron microscope. The specimens were obtained during enucleation procedure. All of the patients suffered from diabetes mellitus. Specimens of non-diabetic patients of the same age group were used as controls. The age-related changes were less distinct than those found in the diabetic material. In diabetes muscular atrophy dominated and serious signs of vasculopathy were present.
Quality assurance is an essential requirement of clinical and forensic laboratories, especially in the determination of ethanol. Opinions differ as to whether normal gas chromatographic methods should be used with modified procedures, or whether different chromatographic strategies should be adopted, the choice being based entirely on practical considerations. We have evaluated the influence on the blood ethanol determination of the frequently used glass and steel columns, as well as the use of isopropanol and tert-butanol as internal standards. All the different combinations of column type and standard provided accurate and reliable results with no significant deviation. Standardization of the analytical procedure is therefore unnecessary, but international ethanol standards should be analysed sequentially to test the method and the staff performing the analyses in the different laboratories.
Authors give an account of their experiences about the visualization of the proximal coronary arteries on the basis of the transesophageal echocardiographic examination of 45 patients. According to their observations the left main coronary artery, the bifurcation, the left anterior descending artery and the circumflex coronary artery were well visualized in 40 patients. With the help of pulsed Doppler-echocardiography the Doppler flow velocity spectrum of the coronary flow can be detected, which could be analysed in 25 patients. At the same time the visualization of the right coronary artery is less sensitive, valuable images could be detected only in 12 patients. The technique of the TEE visualization of the proximal coronary arteries is described. TEE seems to be a promising approach to the morphologic evaluation of the proximal coronary arteries and for functional pathophysiologic examinations of coronary blood-flow.
A 23-year-old man committed suicide by detonating an explosive substance clutched to his abdomen. The face was singed, the hands were lacerated and the chest and the upper part of abdomen were badly mutilated. The death was due to the destruction of several vital organs. The injuries had a directional nature. Only the consideration of all the facts of the case in relation to the situation, nature, distribution and extent of wounds and the preceding medical and social history allowed a reconstruction of the circumstances.