A transgenic mouse model for the study of apoptosis during limb development.
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Animals↗
Biomedical subjects
L Nagy
Publications and source records attributed to L Nagy.
Retinoid-induced apoptosis in normal and neoplastic tissues.
Vitamin A and its derivatives (collectively referred to as retinoids) are required for many fundamental life processes, including vision, reproduction, metabolism, cellular differentiation, hematopoesis, bone development, and pattern formation during embryogenesis. There is also considerable evidence to suggest that natural and synthetic retinoids have therapeutical effects due to their antiproliferative and apoptosis-inducing effects in human diseases such as cancer. Therefore it is not surprising that a significant amount of research was dedicated to probe the molecular and cellular mechanisms of retinoid action during the past decade. One of the cellular mechanisms retinoids have been implicated in is the initiation and modulation of apoptosis in normal development and disease. This review provides a brief overview of the molecular basis of retinoid signaling, and focuses on the retinoid-regulation of apoptotic cell death and gene expression during normal development and in pathological conditions in vivo and in various tumor cell lines in vitro.
Apoptosis↗
Effect of benazepril on endothelial function in previously untreated hypertensive patients. The Working Group of Cardiology of the Academic Committee of Veszprém, Hungary.
The aim of this study was to determine whether angiotensin-converting enzyme inhibitor administration improves the endothelial function of patients with previously untreated essential hypertension. Using high-resolution ultrasonography, we measured the arteria brachialis diameter at rest, during reactive hyperemia (endothelium-dependent flow-mediated dilatation [FMD]), and after sublingual nitroglycerin (endothelium-independent dilatator). Twenty-one previously untreated hypertensive patients participated in the study (13 men, 8 women; mean age, 39.1 +/- 15 years). In the 21 patients, the basal FMD was 5.02% +/- 4.1%. Two hours after the first 10-mg benazepril dose, the FMD was 6.67% +/- 3.9%, and after 1 month of daily 10-mg benazepril administration, the FMD was 5.59% +/- 2.9%. These changes were not significant compared with the baseline value. Nine patients had relatively normal FMD (>5%), whereas the other 12 patients had abnormal FMD (<5%) at baseline. In the latter group, the first 10 mg benazepril produced significant improvement in FMD, from 2.4% +/- 2.5% to 5.08% +/- 2.4% (P < 0.05), but 10 mg benazepril daily for 1 month resulted in no further improvement (4.78% +/- 2.7%) compared with the acute effect. No difference was found between groups with regard to age, gender, blood pressure, blood lipids, and basal arteria brachialis diameter. The previously untreated patients with essential hypertension have endothelial dysfunction, but individual differences were found. The angiotensin-converting enzyme inhibitor treatment improves endothelial function only in those patients who had endothelial dysfunction before the treatment.
Adult↗
Arrhythmic effects of intermittent dobutamine therapy in chronic heart disease failure. The Working Group of Cardiology of the Academic Committee of Veszprém, Hungary.
It is known that intermittent dobutamine therapy improves the symptoms and physical condition of patients with chronic heart failure, but its arrhythmogenic effect is insufficiently described. The aim of this study was to assess ventricular arrhythmias and the condition of patients before, during, and after intermittent dobutamine therapy. The 23 patients participating in the study were in New York Heart Association functional classes III and IV despite therapy with digitalis, diuretics, and angiotensin-converting enzyme inhibitors. Starting dosage of dobutamine was 2 microg/kg/min, which was raised gradually up to 12 microg/kg/min, or until the appearance of complaints or symptoms. In group I (7 patients), for 24 hours before dobutamine infusion, Holter monitoring had been performed. In the subsequent 24 hours, during the infusion, patients were monitored in the critical care unit, but the second Holter test was performed only after the infusion, i.e., in the third 24 hours. In group II (16 patients), the Holter monitoring was started 4 hours before dobutamine infusion and was continued for an additional 20 hours, during the drug administration. In the 24 hours after dobutamine treatment, another Holter monitoring was performed. There was no increase in frequency of ventricular arrhythmias after the dobutamine infusion compared with the preinfusion period, but during dobutamine administration, ventricular arrhythmias occurred more frequently than in the preinfusion and postinfusion periods. No ventricular fibrillation was observed in the 23 patients. In conclusion, ventricular arrhythmias are frequent in congestive heart failure, and dobutamine infusion increases their incidence. The arrhythmogenic effect of dobutamine subsides on the day after the dobutamine infusion. Because of the arrhythmogenic effect of dobutamine, admission to the critical care unit is suggested during the infusion, but monitoring is not necessary after the end of the infusion.
Adrenergic beta-Agonists↗
TNF-alpha modulates expression of the tissue transglutaminase gene in liver cells.
One of several postulated roles for tissue transglutaminase (tTG) is the stabilization and assembly of extracellular matrix via peptide cross-linking. We previously determined that tTG activity increased in an animal model of hepatic fibrogenesis and in human liver disease. To further study the role of tTG in liver disease, we initiated investigations into the effect of a proinflammatory mediator, tumor necrosis factor (TNF)-alpha, on tTG activity in cultured liver cells. Treatment of human Hep G2 cells with 1 ng/ml TNF-alpha increased [14C]putrescine cross-linking to cellular proteins. An increase in tTG mRNA content was observed 1 h after addition of TNF-alpha, and levels of tTG mRNA remained elevated after 24 h. Hep G2 cells, transiently transfected with a luciferase reporter containing 1.67 kb of the human tTG promoter, showed an increase in reporter activity after addition of TNF-alpha. Gel shift experiments using nuclear extracts from TNF-alpha-treated cells and oligonucleotides containing the tTG nuclear factor (NF)-kappa B motif revealed increased binding, concordant with mRNA data. Transient transfections with a truncated reporter construct lacking the tTG NF-kappa B sequence showed an attenuated response to TNF-alpha treatment. Similar responses were seen in stably transfected HeLa cells. Primary hepatocytes isolated from a transgenic mouse line containing the mouse tTG promoter driving the beta-galactosidase reporter, show similar time-dependent increases in promoter activity when treated with TNF-alpha. Furthermore, Hep G2 cells are incapable of upmodulating tTG promoter reporter activity in the presence of TNF-alpha when those cells overexpress a transdominant, negative mutant NF-kappa B subunit. Because TNF-alpha expression is upregulated in hepatic inflammation, the data suggest TNF-alpha-mediated increases in tTG expression may play an important role in the process of hepatic fibrogenesis.
Animals↗
Tyrosine phosphatase inhibitors, vanadate and pervanadate, stimulate glucose transport and GLUT translocation in muscle cells by a mechanism independent of phosphatidylinositol 3-kinase and protein kinase C.
Vanadate and pervanadate (pV) are protein tyrosine phosphatase (PTP) inhibitors that mimic insulin to stimulate glucose transport. To determine whether phosphatidylinositol (PI) 3-kinase is required for vanadate and pV, as it is for insulin, cultured L6 myotubes were treated with vanadate and pV. The two compounds stimulated glucose transport to levels similar to those stimulated by insulin; however, while PI 3-kinase activity and the increase in the lipid products PI 3,4-bisphosphate and PI 3,4,5-trisphosphate were inhibited by wortmannin after stimulation by all three agents--insulin, vanadate, and pV--wortmannin blocked glucose transport stimulated by insulin but not vanadate or pV. Vanadate and pV stimulated the translocation of GLUTs from an intracellular compartment to the plasma membrane; this stimulation was not blocked by wortmannin, but insulin-induced GLUT translocation was inhibited. Similar results were obtained in cultured H9c2 cardiac muscle cells in which wortmannin did not inhibit glucose transport or the vanadate-induced translocation of GLUT4 in c-myc-GLUT4 transfected cells. The ser/thr kinase PKB (Akt/PKB/RAC-PK) is activated by insulin, lies downstream of PI 3-kinase, and has been implicated in signaling of glucose transport. Insulin and pV stimulated PKB activity, and both were inhibited by wortmannin. In contrast, vanadate, at concentrations that maximally stimulated glucose transport, did not significantly increase PKB activity. To determine the potential role of protein kinase C (PKC), L6 cells were incubated chronically with phorbol myristate acetate (PMA) or acutely with the PKC inhibitors calphostin C and bisindolylmaleimide. There was no inhibition of glucose transport stimulation by insulin, vanadate, or pV, and a combination of wortmannin and PKC inhibitors also failed to block the effect of vanadate and pV. In contrast, disassembly of the actin network with cytochalasin D blocked the stimulation of glucose transport by all three agents. In conclusion, vanadate and pV are able to stimulate glucose transport and GLUT translocation by a mechanism independent of PI 3-kinase and PKC. Similar to that by insulin, glucose transport stimulation by vanadate and pV requires the presence of an intact actin network.
Androstadienes↗
Preventive therapy of asthma steroid and other antiasthmatic drugs.
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Adrenal Cortex Hormones↗
[Is panarthrodesis the gold standard in wrist joint surgery?].
In order to determine the value of panarthrodesis, 109 cases have been reviewed. Relevant complications occurred in 36%, whereof 20 were serious entailing reoperations. The procedure was most rewarding in patients with inflammatory arthritis which were mostly painfree and regained full strength, whereas in cases following trauma and avascular necrosis of the lunate, only 56% were painfree, and only 6% achieved contralateral strength. In comparison with 52 cases which had undergone procedures preserving wrist motion, the results were not different with regard to pain relief and strength, whereas in the patients treated accordingly, a functional amount of wrist motion could be preserved.
Adolescent↗
[Instability of the distal radio-ulnar joint].
Instability of the distal radioulnar joint is caused either by bone deformity, fracture or by ligament deficiency. The logical treatment will consist either in osteotomy, osteosynthesis, or in reconstruction of the ligamentous support. The refixation of the TFCC or the ulnar styloid has been demonstrated to be effective in correcting instability biomechanically and clinically. Near-anatomical TFCC reconstruction should always be striven for, rather than resorting to non-anatomical reconstructive procedures. Nevertheless, great efforts will be necessary in the future in order to better understand biomechanics, epidemiology, diagnosis, and treatment of distal radioulnar joint instability.
Fracture Fixation, Internal↗
[Incidence and mortality of aortic dissection].
A population-based study was carried out over a 24-year period between January 1, 1973 and December 31, 1996 to determine the incidence and mortality of the aortic dissection in an administratively defined population of 106,000 inhabitants. The study comprises the consecutive cases of both inpatients and outpatients. Altogether, 74 cases of aortic dissection were found corresponding to 2.89%/year incidence. From the 74 patients 60 were admitted to hospital and 14 outpatients dead before the admission. In the first half of the observational interval (1973-84) 32 cases and in it's second half (1985-96) 42 cases were occurred with incidence of 2.50%/year and 3.28%/year, respectively. The higher incidence of the cases in the second half interval was explained by the significant increase of the autopsy rate of the dead outpatients. The male/female ratio was 1:1.6. The age ranged from 36 years to 97 years with a mean of 66.4 years and the women have had higher mean by the 7.0 years (p < 0.05). The mortality was explosively abrupt at the onset of the disease. Fourteen outpatients (18.9% of the total) died suddenly before admission and in the inpatients after the admission 28.4% died within the first hour, 44.6% within 12 hours, 62.2% within 24 hours and 75.5% within the first two days. Six patients were surgically treated and their perioperative mortality was 2/6, one month survived 4/6 and three years survived 3/6. The other 71 patients died. On the bases of the above-mentioned facts this work may be considered as an representative study. Hereby, the incidence of the aortic dissection in Hungary at least 3.0/100,000/year or rather 300 cases/year should be assessed.
Adult↗
[AT1 angiotensin receptor inhibition as a new therapeutic possibility].
The octapeptide hormone, angiotensin II, binds to two major subtypes of cell surface receptors: the AT1 and the AT2 angiotensin receptors. The important physiological and pathophysiological effects of angiotensin II on cardiovascular regulation and salt-water balance are mediated by the AT1 receptor subtype. As a consequence of the outstanding clinical success of angiotensin-converting enzyme inhibitors, the appearance of AT1 receptor inhibitors in the therapy of hypertension and other cardiovascular diseases was preceded with great expectations. The available experimental and clinical data indicate that the first AT1 receptor inhibitor, losartan, has the same therapeutic potential as angiotensin-converting enzyme inhibitors, but it does not evoke the angiotensin-independent side-effects of ACE inhibitors, such as dry cough or angioedema. The physiological importance and the biochemical, molecular biological and pharmacological properties of AT1 and AT2 receptors are reviewed in this paper, and a summary of the available clinical data is presented.
Angiotensin I↗
Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300.
We report here the identification of a novel cofactor, ACTR, that directly binds nuclear receptors and stimulates their transcriptional activities in a hormone-dependent fashion. ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex. In addition, and unexpectedly, we show that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family. Thus, hormonal activation by nuclear receptors involves the mutual recruitment of at least three classes of histone acetyltransferases that may act cooperatively as an enzymatic unit to reverse the effects of histone deacetylase shown to be part of the nuclear receptor corepressor complex.
Acetyltransferases↗
Lack of induction of tissue transglutaminase but activation of the preexisting enzyme in c-Myc-induced apoptosis of CHO cells.
The intracellular activity and expression of tissue transglutaminase, which crosslinks proteins through epsilon(gamma-glutamyl)lysine isodipeptide bond, was investigated in CHO cells and those stably transfected with either inducible c-Myc (which leads to apoptosis) or with c-myc and the apoptosis inhibitor Bcl-2. Protein-bound cross-link content was significantly higher when apoptosis was induced by c-Myc while the concomitant presence of Bcl-2 markedly reduced both apoptosis and enzymatic protein cross-linking. The expression of tissue transglutaminase did not change following the initiation of apoptosis by c-Myc or when it was blocked by Bcl-2. Studying transiently co-transfected elements of the mouse tissue transglutaminase promoter linked to a reporter enzyme revealed their overall repression in cells expressing c-Myc. This repression was partially suspended in cells also carrying Bcl-2. Our data suggest that tissue transglutaminase is not induced when c-Myc initiates apoptosis but the pre-existing endogenous enzyme is activated.
Animals↗
Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase.
The transcriptional corepressors SMRT and N-CoR function as silencing mediators for retinoid and thyroid hormone receptors. Here we show that SMRT and N-CoR directly interact with mSin3A, a corepressor for the Mad-Max heterodimer and a homolog of the yeast global-transcriptional repressor Sin3p. In addition, we demonstrate that the recently characterized histone deacetylase 1 (HDAC1) interacts with Sin3A and SMRT to form a multisubunit repressor complex. Consistent with this model, we find that HDAC inhibitors synergize with retinoic acid to stimulate hormone-responsive genes and differentiation of myeloid leukemia (HL-60) cells. This work establishes a convergence of repression pathways for bHLH-Zip proteins and nuclear receptors and suggests this type of regulation may be more widely conserved than previously suspected.
Antineoplastic Agents↗
Psychiatric disorders in women with bulimia nervosa and their first-degree relatives: effects of comorbid substance dependence.
OBJECTIVE: Women with bulimia nervosa (BN) and comorbid substance dependence often display impulsive behaviors. We assessed Axis I and II psychiatric diagnoses in their first-degree relatives in order to understand the etiological factors that may contribute to this subtype of BN. METHOD: We used contemporary family-epidemiological methodology to compare the lifetime prevalence of psychiatric disorders among 47 women with BN and 44 non-eating-disordered community control women, and their first-degree relatives (177 and 190, respectively). BN probands were stratified by the presence (n = 20) or absence (n = 27) of a lifetime history of alcohol and/or drug dependence. RESULTS: Social phobia, conduct disorder, and clusters B and C personality disorders were significantly more prevalent among BN probands with substance dependence than among BN probands without substance dependence or control women probands. Substance use disorders, social phobia, panic disorder, and cluster B personality disorders were significantly more prevalent among the relatives of BN probands with substance dependence than the relatives of the other two groups. DISCUSSION: Women with BN and substance dependence have problems with social anxiety, antisocial behavior, and a variety of personality disturbances, and come from families where there are problems with substance use disorders, anxiety, impulsivity, and affective instability. These data raise the possibility that a familial vulnerability for impulsivity and affective instability may contribute to the development of substance dependence in a subgroup of women with BN.
Adult↗
Normal kinematics of carpal bones: a three-dimensional analysis of carpal bone motion relative to the radius.
Normal carpal kinematics were studied in 22 cadaver specimens using a biplanar radiography method. The kinematics of the trapezium, capitate, hamate, scaphoid, lunate, and triquetrum were determined during wrist motion in sagittal and coronal planes. The results were expressed using the concept of the screw displacement axis and converted to describe the magnitude of rotation about and translation along three axes (X-axis: pronation-supination axis, Y-axis: flexion-extension axis, and Z-axis: radial-ulnar deviation axis) commonly used for the wrist. The orientation of these axes is expressed relative to the radius. Within the proximal carpal row, considerable differences of carpal behavior around the Y-axis were observed during sagittal plane motion of the wrist. The scaphoid exhibited the greatest magnitude of rotation, and the lunate the least. The magnitude of rotation of the carpal bones around the X-axis during sagittal plane motion of the wrist was small. The proximal carpal bones exhibited some ulnar deviation in 60 degrees of wrist flexion. During coronal plane motion of the wrist, the magnitude of radial-ulnar deviation of the distal carpal bones was mutually similar and generally of a greater magnitude than that of the proximal carpal bones. The proximal carpal bones experienced some flexion during radial deviation of the wrist and extension during ulnar deviation of the wrist. Translation was generally minimal in all carpal bones throughout wrist motion. This study reports results from the largest cadaver wrist kinematics study completed to date. The accuracy of the current method was improved when compared to previous studies. A sufficient number of specimens to allow statistical comparison was used and minimal interspecimen variability was noted. This study enabled a precise description of quantitative analyses of normal carpal kinematics relative to the radius.
Adult↗
Long-term results of radioscapholunate fusion following fractures of the distal radius.
Fifteen patients with radioscapholunate (RSL) fusion for traumatic lesions of the radiocarpal junction, whose short-term results have been previously reported, were reassessed after an average follow-up time of 8 years. Five patients had undergone wrist fusion because of non-union or early progressive arthritis. Of the ten wrists with retained mobility, eight continued to function satisfactorily. Two wrists were painful for reasons other than secondary midcarpal arthritis. Patient satisfaction was comparable in both groups with the wrist score better for wrists with residual motion. The survival of RSL partial wrist fusion corresponded inversely with the number of preceding operations and the range of motion before partial fusion. Secondary midcarpal arthritis, if present, arose early and was well tolerated. Failures were strongly linked to technical mistakes and complications.
Adult↗
Surgical treatment of cardiac myxomas: a 20-year follow-up.
Clinical experience in the diagnosis and management of 50 cases of cardiac myxoma seen over a 20-year period from 1974 to 1994 has been reviewed. There were 17 men and 33 women of mean age 55.2 (range 16-81) years. Echocardiography confirmed the diagnosis in all patients. The location of myxomas was as follows: left atrial alone in 42 patients, right atrial alone in three, right ventricular alone in one, left atrial+right atrial in two, left atrial+right atrial+right ventricular in one, and left atrial+left ventricular in one. Nineteen patients were operated on within 48 hours of the diagnosis. All tumours were successfully removed with the aid of cardiopulmonary bypass. The hospital mortality rate was 10%. Excision of the tumour resulted in marked symptomatic improvement. There was one late death. The current survivors are symptom-free at a mean follow-up of 76.4 (range 1-241) months. Echocardiographic studies were performed in all survivors and no recurrences have been observed. It is concluded that excision of cardiac myxomas is curative and long-term survival is excellent. Radical tumour excision may prevent recurrences.
Adolescent↗