Biomedical subjects
Publications and source records attributed to T Hupp.
A case of acute rupture of an abdominal aortic aneurysm in a patient with Behçet's disease is reported. The patient was successfully treated by implantation of an endovascular stent graft. The preinterventional diagnostic procedures and the postinterventional follow-up are described and the benefit and risk vs open surgery is discussed.
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Replicative senescence in human fibroblasts is absolutely dependent on the function of the phosphoprotein p53 and correlates with activation of p53-dependent transcription. However, no evidence for posttranslational modification of p53 in senescence has been presented, raising the possibility that changes in transcriptional activity result from upregulation of a coactivator. Using a series of antibodies with phosphorylation-sensitive epitopes, we now show that senescence is associated with major changes at putative regulatory sites in the N and C termini of p53 consistent with increased phosphorylation at serine-15, threonine-18, and serine-376 and decreased phosphorylation at serine-392. Ionizing and UV radiation generated overlapping but distinct profiles of response, with increased serine-15 phosphorylation being the only common change. These results support a direct role for p53 in signaling replicative senescence and are consistent with the generation by telomere erosion of a signal which shares some but not all of the features of DNA double-strand breaks.
The tumour suppressor gene p53 plays a major role in the cellular response to DNA damage, mediating growth arrest and/or apoptosis. Phosphorylation of the protein occurs at numerous sites in vivo and is likely to be a major mechanism for modulation of its activity as a transcriptional transactivator. Not surprisingly, therefore, p53 has been intensively studied by 32P metabolic labelling. Here we show however, using normal human fibroblasts, that typical labelling conditions induce (i) a p53-dependent inhibition of DNA synthesis and (ii) an increase in the cellular content of p53 protein detectable by the phosphorylation-sensitive antibody DO-1 but not by antibody DO-12. These data demonstrate for the first time that 32P labelling is sufficient to induce a biologically-significant, p53-mediated cellular response and strongly suggest that it perturbs the phosphorylation state of p53 which it is being used to measure. This highlights the need to re-evaluate earlier data by non-radioactive approaches using phospho-specific antibodies.
Large multicenter studies have recently provided long-term results substantiating the superiority of surgical as compared to conservative treatment for symptomatic and asymptomatic extracranial internal carotid stenoses of more than 70%. These results led to an increase in the frequency of thrombo-endarteriectomies. However, indications are limited by the peri-operative complication rate. This explains the need for intra-operative quality control. The present study compares the standard method of intra-operative quality control in carotid surgery, i.e., intra-operative angiography (IOA), with direct intra-operative Doppler ultrasonography (IDU). Thirty-four patients who underwent carotid thrombo-endarteriectomy (carotid TEA) for a symptomatic (n = 15) or asymptomatic (n = 19) carotid stenosis of more than 70% were submitted to both intra-operative IOA and IDU. The sensitivity and specificity of the two techniques were compared in the light of the intra-operative findings. IDU seems to be superior to IOA in the detection of vasospasm. IOA has a higher sensitivity in demonstrating minisaccules, which, however, are not therapeutically relevant. The other findings obtained with both methods were considered to be of equal value. There were no false negative results by IDU regarding therapeutically relevant findings. We therefore consider it advisable to apply IDU in every case of carotid TEA. IOA should be performed in patients with vessel changes detected by IDU.
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The tumor suppressor protein p53 is a transcription factor frequently inactivated in human cancers. We have studied the DNA binding potential and the transcriptional activity of p53 variants and p53 protein complexes in in vitro transcription assays. p53 specific transcription was measured via introduction of radioactive UTP into G-free cassette transcripts regulated by promoter sequences containing p53 response elements. Latent and activated p53 fractions were prepared from insect cells infected with p53 encoding baculoviruses by chromatography on heparin columns. p53 fractions distinguishable by their specific DNA binding activities and their recognition by monoclonal antibody PAb421 were obtained. Specific DNA binding and binding to PAb421 are mutually exclusive. The C-terminus of p53 can be phosphorylated by casein kinase II, protein kinase C and cyclin dependent kinases. The antibody PAb421 binds within the PKC phosphorylation site of p53 and is able to activate DNA binding of latent p53 in vitro. Activation of p53 by PAb421 also results in enhanced transactivation in vitro. Dephosphorylation of latent p53 with phosphatase 2A does not change these properties. This suggests that a conformational change in the carboxyl terminal domain of p53 controls the transactivation potential of p53.
UNLABELLED: The exercise renogram is a rarely used diagnostic procedure, but it may visualize an exercise-induced change in renal function related to the pathophysiology of essential hypertension, which could greatly increase interest in this examination. The aim of this study was to demonstrate the interpretative approach and the terminology which is used to describe results of exercise renography, using a population of hypertensives with renovascular disease. METHODS: We reviewed the examinations of 70 hypertensives who had supine renography as well as exercise renography with a 60-80 W work load. Forty-eight patients were examined with 99mTc-MAG3 and 22 with 131I hippurate. The renographic and angiography results were recorded as well as the antihypertensive drugs used and the site of vascular lesions. RESULTS: Thirty-three hypertensives developed a bilateral-abnormal exercise renogram, which appears to be associated with primary hypertension. Eight individuals responded to exercise with a unilateral-abnormal exercise renogram, in a kidney behind a stenosis. Only 19 patients had a normal exercise renogram, and 10 had only one functioning kidney. Pathology recognized but unrelated to the intervention included nonfunctioning and small kidneys and pelvic retention. CONCLUSION: Exercise renography's only indication is for recognition of pathology unique to hypertension, since other function disturbances were recognized in resting renograms.
Fifty-seven patients with 60 transpositions of the femoral artery bifurcation were prospectively analysed. This operation provided limb salvage in 95% and a sufficient revascularisation in 88% after the operation and 81% during follow-up 18 (6-28) months. The transposition of the femoral artery bifurcation is a reasonable operation in patients with a relevant stenosis of the profunda femoris. It does not need alloplastic patches, the saphena vein is conserved and, in our series, subsequent distal bypass was required in less than 10%.
Fifty-six patients with limb-threatening ischaemia had pedal revascularization with either autologous vein (n = 39) or sequential composite graft with a 6-mm polytetrafluoroethylene prosthesis and autologous vein (n = 17); 75 per cent had gangrene and skin necrosis and 25 per cent had ischaemic rest pain alone. Twelve grafts occluded within the first week, and resulted in major amputation in eight patients after unsuccessful revision. Two patients required amputation for persistent ischaemia despite a patent bypass. One patient died from bowel perforation (2 per cent). In 47 (84 per cent) of the 56 patients limb and life were preserved. The primary patency rate after 1, 2 and 4 years was 65, 55 and 55 per cent respectively, the secondary patency rate was 71, 62 and 62 per cent, and cumulative limb salvage rates were 77, 71 and 66 per cent. Life-table survival rates during follow-up (median 25 (range 0-112) months) were 89, 78 and 52 per cent respectively after 1, 2 and 4 years. Thirteen of 21 patients who died during follow-up did not require major amputation. Pedal reconstruction with autologous vein provides limb salvage until death in nearly two-thirds of patients with critical limb ischaemia resulting from crural arterial occlusive disease.
A bilateral, exercise-mediated renal functional abnormality was first described more than a decade ago. The disturbance is specific for hypertension, is seen in different forms of hypertension, and has been studied most extensively in hypertensives with renovascular disease. The bilateral-abnormal exercise renogram identifies the disturbance. Hypertensives with unilateral renovascular disease were studied in the continuing evaluation of the bilateral function disturbance. We examined 31 hypertensives with documented unilateral renovascular disease, all of whom had renography at rest and during 60 to 80 W ergometric exercise. An additional seven normotensives and 17 essential hypertensives served as controls, and had the same sequence of studies. All patients reported upon continued on to an infusion clearance with 131I-hippurate and 111In-diethylenetriamine pentaacetic acid to determine glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) at rest, and during 25 W ergometric exercise. Eighteen of 31 hypertensives with unilateral renovascular disease were found to have a bilateral-abnormal exercise renogram. Clearance examinations in these identified a prominent reduction of the GFR and a lesser decrease in the ERPF during exercise. Hypertensives with normal exercise renograms did not have the exercise mediated abnormal clearance pattern. Similar results were observed in the control population of essential hypertensives, 65% of whom developed the functional disturbance. The seven normotensives controls did not exhibit the exercise mediated function changes. We conclude that an exercise-mediated bilaterally occurring functional disturbance exists in certain hypertensives, who then have a bilateral-abnormal exercise renogram. Associated with this is a distinctly abnormal clearance during exercise which is characterized by a low filtration fraction.
p53 is a transcriptional activator and repressor, but recent evidence suggests that some of its many biological functions may not be dependent on transcription. To determine whether p53 exerts a direct influence on nuclear DNA replication, purified human p53 was added to a transcription-free DNA replication extract from Xenopus eggs. Full-length human p53 that inhibits SV40 DNA replication in vitro had no effect on nuclear DNA synthesis in the Xenopus system. In contrast, a C-terminal truncated form of p53 (p53 delta 30), which is constitutively active for DNA binding and similar to an alternately spliced form found in vivo, showed a concentration-dependent inhibition of DNA replication in both the soluble SV40 system and eukaryotic nuclei. This inhibition occurred primarily at initiation of DNA synthesis. Oxidation of p53 delta 30, which eliminates DNA binding activity, also abrogated the protein's ability to inhibit nuclear DNA synthesis. The p53 binding DNA consensus sequence enhanced rather than competed away inhibitory activity of p53 delta 30. Therefore, p53 that is constitutively active for DNA binding can inhibit nuclear DNA replication in the absence of transcription. This inhibition may require binding of p53 to DNA, in addition to interactions between p53 and proteins of the replication complex.
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Between January 1988 and January 1994, 24 patients with heterologous vascular bypasses were examined with suspected diagnosis of a perigraft reaction (PGR). All patients were subjected to ultrasound and CT. PGR ist defined as a sterile inflammation along the course of a vascular prosthesis. The typical clinical presentation is a fluctuating tumour with a localised painless swelling. In all cases liquid formations could be confirmed by diagnostic imaging procedures; signs of infection could be excluded. The synopsis of the clinical presentation, the time interval after implantation of the prosthetic material and the signs of sonography and CT can reliably exclude infection of the prosthesis and confirm the diagnosis of a PGR.
Besides antihypertensive drug treatment and reconstructive surgery, the percutaneous transluminal angioplasty became an established treatment modality for renal artery stenosis since the late 70's. The treatment aimed at curing the renovascular hypertension, at normalizing and improving of both compensated and decompensated renal insufficiency in order to avoid prolonged hemodialysis after acute renal failure. Endovascular procedures contributed significantly to reach a normotensive state, particularly in cases with renal artery stenosis concomitant with fibromuscular dysplasia and gives similar results as open surgical methods if certain morphological features are considered. However, surgery is generally more effective than endoluminal treatment when all forms of renal artery stenosis are considered together. This holds true in particular for ostial stenosis, complete obstruction of the renal artery, aneurysms and a multitude of rare renovascular diseases. Surgery should be first line treatment to preserve or improve the renal function. According to the pertinent literature, endovascular methods should be considered first for the treatment of renovascular hypertension. Despite the frequent repetition of potential advantages of PTA, a first direct comparison of both modalities demonstrated better primary results after surgical treatment. Even the total cost were similar since PTA requires frequent follow-up with short intervals necessitating secondary interventions.
BACKGROUND: Hypertensives may develop bilateral trapping of para-aminohippurate analogues in the tissue of the kidneys during light exercise, as can be demonstrated using radioactively labelled [131I]-hippurate or [99mTc]-mercaptoacetyl-triglycine. Tracer accumulation in the kidneys during exercise results in a typical renographic pattern, the bilateral-abnormal exercise renogram. The disturbance is common during exercise, being found in almost 60% of all hypertensives, regardless of aetiology. OBJECTIVE: To determine whether bilateral-abnormal exercise renograms are spurious phenomena, or whether the results of exercise renography are reproducible. DESIGN: We reviewed the renographic examinations of 27 hypertensive patients, each of whom had undergone at least one resting and two [131I]-hippurate or [99mTc]-mercaptoacetyl-triglycine gamma-camera exercise renograms. The status of the renal artery at the time of scintigraphy was documented, using available arteriograms. The causes of vascular lesions were noted, as were revascularization procedures and the antihypertensive medication being taken at the time of scintigraphy. RESULTS: The average time between exercise renograms was 15.5 months, and 24 of the 27 hypertensive patients had comparable results in the first and the follow-up exercise renogram, divergent results being noted for the other three patients. Re-evaluation of the scintigrams of the three hypertensive patients with divergent results suggested that intermittent pelvic retention might have caused errors of interpretation in two. We found it notable that neither revascularization nor a change in antihypertensive drug therapy influenced the results of exercise renography. Exercise renograms were reproducible over long periods, and potential extraneous influences on blood flow, such as antihypertensive drugs or revascularization, failed to alter the results. CONCLUSION: The results are considered relevant, because a direct relationship appears probable between hypertension and the disturbance investigated. Reproducible results suggest that the exercise-mediated disturbance is fixed to the kidneys, that it can be reactivated repeatedly and that it may play a role in maintaining hypertension.
UNLABELLED: 22 carotid specimens following eversion-endarterectomy were compared with preoperative assessment of carotid stenosis obtained angiographically and by c-w-Doppler-sonography. The intact, unsplit specimens were perfused with a liquid plastic material (Palavit M). After hardening of the plastic material the specimens were removed. The local degree of carotid stenosis with respect to diameter reduction was assessed by direct measurement of the plastic specimens at the narrowest site compared with the diameter of the carotid eversion specimens at the place of the maximum stenosis. The distal degree of carotid stenosis was assessed by comparison of the diameter of the distal internal carotid artery obtained intraoperatively with the measurements of the plastic specimens (1 mm vascular wall thickness of distal internal carotid artery was taken into account). RESULTS: Both the local and the distal degree of carotid stenosis diameter (mean 84.7% +/- 8.4% and 82.1% +/- 9.1% respectively) were underestimated in the preoperative angiogram (79.8 +/- 9% by ECST-criteria and 69 +/- 10.3% by NASCET-criteria) in most of the cases. The difference of the diameter reduction was statistically significant (p < 0.05 and p < 0.01 respectively, Wilcoxon signed rank test). The c-w-Doppler assessments were 82.6 +/- 8.2% (n.s.). CONCLUSION: Our results suggest that the preoperative assessment of internal carotid stenosis obtained angiographically or by c-w-Doppler-sonography easily underestimate the true degree of carotid stenosis.
The incidence in the literature of dystopic goiter depends on classification of the false endothoracic goiter ("substernal goiter") as dystopic and varies from 2 to 20%. From November 1989 through April 1993 we operated on 530 patients with benign nodular goiters. In 84 patients (15.8%) the operation proved a dystopic goiter. We showed that difficulties in comparing our data with published series were due to misnomers of the dystopic goiter. The dystopic goiter comprises the true endothoracic goiters (alliata vera and isolata vera) as well as the false endothoracic goiters (substernal goiter). The precise classification of the dystopic goiter is crucial to an optimal operative strategy reducing postoperative morbidity.