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Biomedical subjects

G Probst

Publications and source records attributed to G Probst.

At least 19 recordsLinked to original sources
PubMed2004

[The cartilage conserving concept of surgical tracheostomy].

BACKGROUND: Most techniques of tracheostomy include a resection or at least incision of the cartilage himself. This may result in local tracheomalacia and chondritis. METHODS/PATIENTS: We performed 48 tracheotomies (173 cases were totally performed in our in 2002 excluding laryngectomie patients) in with horizontal incision between 2 (nd) and 3 (rd) ring sparing all cartilage. The detailed technique is described and the (endoscopic controlled) follow-up data showed no complications. We called this techniques the visor-tracheostomy. RESULTS: It is shown, that a modified concept of conservating cartilage while doing tracheostomy is easy to perform without any increasing in time and costs. The most important thing is to choose the right incision range. CONCLUSIONS: It seems to us, that healing of these tracheotomies is better and secondary complications as stenosis of trachea should be less instead of the cases where Björk-flaps or simply local resection were performed.

Adult↗
PubMed2000

AMP deaminase inhibitors. 3. SAR of 3-(carboxyarylalkyl)coformycin aglycon analogues.

N3-Substituted coformycin aglycon analogues with improved AMP deaminase (AMPDA) inhibitory potency are described. Replacement of the 5-carboxypentyl substituent in the lead AMPDA inhibitor 3-(5-carboxypentyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1, 3]diazepin-8-ol (2) described in the previous article with various carboxyarylalkyl groups resulted in compounds with 10-100-fold improved AMPDA inhibitory potencies. The optimal N3 substituent had m-carboxyphenyl with a two-carbon alkyl tether. For example, 3-[2-(3-carboxy-5-ethylphenyl)ethyl]-3,6,7,8-tetrahydroimidazo[4, 5-d][1,3]diazepin-8-ol (43g) inhibited human AMPDA with a K(i) = 0. 06 microM. The compounds within the series also exhibited >1000-fold specificity for AMPDA relative to adenosine deaminase.

AMP Deaminase↗
PubMed2000

IgE-binding epitopes of enolases, a class of highly conserved fungal allergens.

BACKGROUND: Cladosporium herbarum and Alternaria alternata are two of the most prominent fungal species inducing type I allergy. Previously, we have demonstrated that enolase (Cla h 6) is the second most important allergen of C herbarum in terms of frequency of sensitization. OBJECTIVE: IgE-reactive B-cell epitopes of C herbarum enolase were analyzed, and cross-reactivity between fungal enolases was investigated. METHODS: Cla h 6 glutathione-S-transferase fusion peptides were constructed by means of PCR cloning. A alternata enolase (Alt a 5) was isolated by screening a complementary (c)DNA expression library with a C herbarum enolase DNA probe. RESULTS: Mapping of Cla h 6 IgE-binding epitopes identified a peptide with a length of 69 amino acids (peptide 9), which bound IgE from 8 of 8 patients. Analysis of the conformation of peptide 9 revealed that it does not form a compact structure but rather spans the whole length of the protein, with side chains exposed to solvent at 3 locations. Peptide 9 in the context of Escherichia coli glutathione-S-transferase not only binds IgE but also competitively inhibits IgE binding to Alt a 5. This result indicates that the epitope or epitopes on peptide 9 constitute a major cross-reacting epitope or epitopes on the enolases from C herbarum and A alternata in the case of the one patient tested. CONCLUSIONS: We demonstrated that the glycolytic enzyme enolase is an allergen not only in C herbarum but also in A alternata. Additionally, enolase was shown to exhibit high cross-reactivity to other fungal enolases. On the basis of the results presented here, we propose the use of recombinant Cla h 6 or maybe even peptide 9 of Cla h 6 for diagnosis and possibly therapy of mold allergy.

Allergens↗
PubMed1999

Astrocytes and neurons express the tight junction-specific protein occludin in vitro.

The expression of occludin, an integral plasma membrane protein specifically located at tight junctions, was studied in various epithelial and nonepithelial tissues by means of RT-PCR, Western blotting, and immunofluorescent staining. Besides detection in epithelial and endothelial tissue, expression of occludin was found in primary and secondary cultures of neurons and astrocytes. Differentiation of astrocytes in vitro led to a marked decrease in occludin expression. Extractability of occludin from plasma membranes differed considerably between epithelial and nonepithelial cells. Following treatment with Triton X-100, occludin was completely extracted from astrocytic membranes but not from membranes derived from MDCK cells, suggesting a difference in the cytoplasmic and/or plasma membrane anchoring of occludin between these cell types.

Animals↗
PubMed1999

ICH-harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has convened an expert working group which consisted of the authors of this paper and their respective committees, consulting groups and task forces. Two ICH guidances regarding genotoxicity testing have been issued: S2A, 'Guidance on Specific Aspects of Regulatory Genotoxicity Tests' and S2B, 'Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.' Together, these guidance documents now form the regulatory backbone for genotoxicity testing and assessment of pharmaceuticals in the European Union, Japan, and the USA. These guidances do not constitute a revolutionary new approach to genotoxicity testing and assessment, instead they are an evolution from preexisting regional guidelines, guidances and technical approaches. Both guidances describe a number of specific criteria as well as a general test philosophy in genotoxicity testing. Although these guidances were previously released within the participating regions in their respective regulatory communiqués, to ensure their wider distribution and better understanding, the texts of the guidances are reproduced here in their entirety (see Appendix A) and the background for the recommendations are described. The establishment of a standard battery for genotoxicity testing of pharmaceuticals was one of the most important issues of the harmonisation effort. This battery currently consists of: (i) a test for gene mutation in bacteria, (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tk assay, (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. A major change in testing philosophy is the acceptance of the interchangeability of testing for chromosomal aberrations in mammalian cells and the mouse lymphoma tk assay. This agreement was reached on the basis of the extensive review of databases and newly generated experimental data which are in part described in this publication. The authors are fully aware of the fact that some of the recommendations given in these ICH guidances are transient in nature and that the dynamic qualities and ongoing evolution of genetic toxicology makes necessary a continuous maintenance process that would serve to update the guidance as necessary.

Animals↗
PubMed1999

Fast control of DNA replication in response to hypoxia and to inhibited protein synthesis in CCRF-CEM and HeLa cells.

In order to elucidate whether data about the fast regulation of DNA replication in dependence on oxygen supply and on a functioning protein synthesis, previously elaborated with Ehrlich ascites cells, are valid for human cells too, we repeated key experiments with CCRF-CEM and HeLa cells. The most important techniques employed were DNA fibre autoradiography and alkaline sedimentation analyses of growing (pulse-labeled) daughter strand DNA. It was found that CCRF-CEM and HeLa cells responded to transient hypoxia and to transient inhibition of protein synthesis in an almost identical fashion. Scheduled replicon initiations were reversibly suppressed and the progress rates of replication forks, which were already active before the respective inhibitory conditions were established, were reversibly slowed down. The inclusion of the fork progress rate in the response differs from Ehrlich ascites cells, which respond only by suppressing initiation. Further circumstances of the fast oxygen dependent response, concerning the behaviour of ribonucleotide reductase and of the dNTP pools, revealed no significant differences among the three cell lines. The striking identity of the response of each of the cell lines to hypoxia and to inhibited protein synthesis prompts the suspicion that converging fast regulatory pathways act on the cellular replication machinery. The phenomena as such seem to be rather widespread among mammalian cells.

Autoradiography↗
PubMed1998

Design, synthesis, and structure-activity relationships of the first highly potent, selective, and bioavailable adenosine 5'-monophosphate deaminase inhibitors.

Structure-activity studies have been performed to optimize the potency of this novel series of AMPDA inhibitors. Conformational rigidification of the N-3 sidechain resulted in substantial effect on the potency. Addition of the hydrophobic groups provided further benefit. The most potent compound identified, 4g (Ki = 3 nM), bears little structural resemblance to AMP and exhibits a remarkable improvement (10(3) and 10(5)) in binding affinity relative to the original lead and AMP, respectively. The application of prodrug strategy achieved a large improvement (benzyl ester 5d) in oral bioavailability, resulting in compounds that should be useful in evaluating the role of AMPDA in normo- and pathophysiological states.

AMP Deaminase↗
PubMed1994

[Diagnosis, therapy and prognosis of atypical mycobacterial infections--results of a retrospective study].

The most important mycobacteria causing disease in humans are Mycobacterium tuberculosis and Mycobacterium leprae. These germs contrast the so-called atypical mycobacteria. The importance of the atypical mycobacteria was recognized in the fifties. Even if the quantity of atypical mycobacterial disease has increased during the last decades in Germany, it is still a rare disease today, but it is seen in patients with acquired immunodeficiency syndrome more often nowadays. In the period from 1st January 1986 til 31st December 1992 31 HIV-negative patients with a diagnosis of atypical mycobacterial disease have been seen in the department for lung diseases in the Thoraxklinik Heidelberg-Rohrbach. During the same period an atypical mycobacterial disease was diagnosed in 12 out of 413 HIV-positive patients (2.9%) of the AIDS-ambulance of the skin hospital of the University of Heidelberg. Most of the HIV-negative patients showed additional diseases which reduce the immunological resistance. In HIV-positive patients an atypical mycobacteriosis heralds a severe immunodeficiency. Because it is a rare disease and an exact diagnosis is difficult to establish there is a lack of controlled clinical trials and therefore detailed therapeutical guidelines do not exist. A therapeutical approach is also complicated by a lack of effective drugs. With disseminated disease in AIDS-patients, which is mostly caused by Mycobacterium avium-intracellulare, the therapy should be stopped, if there are any severe side-effects. The present results of therapy are still disappointing. In the future the management of atypical mycobacterial disease will be more important, because there is an increasing number of patients with acquired immunodeficiency.

AIDS-Related Opportunistic Infections↗
PubMed1993

Staurosporine suppresses replicon initiation in mammalian cells.

Replication in cellular replicons of mouse Ehrlich ascites, human CCRF-CEM and hamster BHK-21 cells was analyzed, after exposition of the cells to staurosporine, by measuring the overall DNA synthesis rate, by alkaline sedimentation analysis of length distributions of growing daughter strand DNA and by DNA fibre autoradiography. The results consistently indicated that micromolar concentrations of staurosporine caused, in all three cell lines, a fast suppression of replicon initiation which was reversible if the drug treatment did not exceed about 2 h. The inhibition of initiation was accompanied by a slight reduction of rates of propagation of replication forks. The data are interpreted in terms of the existence of a so far unknown factor which seems to be involved relatively directly in the initiation process of cellular replicons and has to be activated, like the large T antigen of SV 40 for the replication initiation in the viral genome, by a specific phosphorylation event. Unlike several other protein phosphorylations of cellular regulation, the kinase concerned here seems to be inhibited only by relatively high staurosporine concentrations.

Alkaloids↗
PubMed1992

[Monotherapy with the ACE-inhibitor ramipril or the calcium antagonist nitrendipine in essential hypertension].

Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists have, by reason of their potentially favourable pharmacological profile, become increasingly established in the treatment of hypertension in recent years. In a double-blind randomized study with an initial placebo phase, carried out by practising physicians and thus aimed at the "usual" practice patients with essential hypertension, we assessed (1) the antihypertensive effect and tolerability of an ACE inhibitor (ramipril, 5 mg/d) or a calcium antagonist (nitrendipine, 20 mg/d) given in a single daily dose, and (2) a possible age-dependent blood pressure (BP) effect of these therapies. In the 4 weeks' placebo phase, the two treatment groups were comparable as regards average age (49.6 and 49.4 years), age-range (27-67 and 25-64 years) and BP. Fifty-two patients completed the following 6 weeks' phase with active drug therapy. On ramipril (n = 26), the BP measured 24-25 hours after the last drug administration was reduced in the supine position from an average of 155/102 to 142/91 mmHg (mean reduction -10.1%) and in the upright position from 156/106 to 141/96 mmHg (-9.3%). Nitrendipine (n = 26) reduced the average BP from 155/102 to 147/94 mmHg (-6.8%) and from 155/106 to 146/99 mmHg (-6.6%) respectively. BP-lowering effects of both treatments were largely independent of age. Including the patients who discontinued the study prematurely because of side effects (1 on ramipril, 4 on nitrendipine), the "intention to treat analysis" shows BP normalization rates (diastolic < or = 90 mm Hg) of 55% (ramipril) and 30% (nitrendipine) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

New aspects in the staging of lung cancer. Prospective validation of the International Union Against Cancer TNM classification.

BACKGROUND AND METHODS: To validate the new TNM definitions for lung cancer (International Union Against Cancer [UICC] TNM classification, 4th edition, 1987), the data of 3823 patients were analyzed prospectively in terms of concordance between clinical (TNM) and pathologically confirmed classification (pTNM), the value of the various diagnostic techniques in estimating the pathologically confirmed classification, and the prognostic relevance of the new TNM definitions. RESULTS: With regard to the primary tumor (T), clinical and pathologic classifications were identical in 63%; with regard to lymph node involvement (N), the agreement was 47%; for distant metastasis agreement occurred in 91% of cases and for the stages it occurred in 56%. As to the primary tumor (T), the accuracy of radiography (59%) was nearly identical to that of computed tomography (CT) (58%). Both techniques were less precise in determining the extent of lymph node involvement (CT, correct assessments in 50%; radiography, correct assessments in 43%). The statistically significant differences in the prognosis for the T, N, and M categories and for the stages and the categories of the new R classification could be confirmed. Allowance should be made for the different prognosis between T1N0M0 and T2N0M0 by the new Substages IA and Ib of Stage I. CONCLUSIONS: By the new TNM definitions for bronchus carcinoma, international conformity became feasible and practical, and the improvement of its prognostic relevance provided a more reliable basis for establishing guidelines for individual oncologic concepts.

Bronchial Neoplasms↗
PubMed1992

Cycloheximide inhibits cellular, but not SV40, DNA replication.

We have prepared extracts from cycloheximide-treated cells for the study of simian-virus-40 (SV40)-DNA replication in vitro. When supplemented with the viral initiator protein (large T antigen), these extracts fully supported SV40-DNA replication. We also determined that SV40-DNA replication in vivo is much more resistant to cycloheximide than cellular DNA replication. SV40 encodes its own initiator protein, T antigen, which also functions as a DNA helicase, but depends on cellular functions for all additional replication reactions. Therefore, it appears to be quite likely that cycloheximide affects cellular DNA replication by blocking the synthesis of (a) cellular function(s) that is(are) performed by T antigen in SV40-DNA replication. Indeed, DNA fiber autoradiography and alkaline sucrose gradient centrifugation of pulse-labeled cellular DNA showed that cycloheximide treatment almost completely suppressed replicon initiation and reduced the rate of replication fork movement to about one third of the control.

Antigens, Polyomavirus Transforming↗
PubMed1992

Does ND-YAG laser extend the indications for resection of pulmonary metastases?

Surgery forms part of a combined oncological concept in the management of pulmonary metastases. The following questions are relevant for its role: Does survival depend on the type of primary tumor? Are there any prognostic factors? What are the limits on radical resection? We analyzed retrospectively 657 patients who had undergone 759 resections of pulmonary metastases between 1973 and 1990. After conducting in vitro and in vivo experiments with the non-contact neodymium aluminum garnet (Nd-YAG) laser with a generating and delivery power of 10-120 W at the site of operation for 0.1-9.9 s, we have treated 65 patients by laser resection and/or vaporization since January 1990. Our preferred surgical approach was median or transverse thoracotomy. The 5-year survival of all resected patients was 30%, ranging from 21% (soft tissue sarcoma) to 60% (testicular carcinoma). Statistically significant differences in prognosis were seen related to the type of primary tumor, the disease-free interval, the caval or portal type of metastatic spread, the number of metastases and the potential degree of radical resection. The potential degree of conventional radical resections (wedge, anatomical sub-/segmental) was negatively influenced by the number of metastases (n > 9: 79% "radical" surgery = 38% 5-year survival). Laser treatment allowed parenchyma-preserving resection in cases of metastases of more than 0.5 cm in diameter, and vaporization in smaller ones. Resection with the intention of achieving complete remission was possible in up to 72 unilateral metastases. The complication rate was comparable to conventional resections.

Female↗
PubMed1991

Validation of the TNM classification (4th edn) for lung cancer: first results of a prospective study of 1086 patients with surgical treatment.

For the purpose of testing the validity of the new TNM classification (fourth edition) for lung cancer, data from 1086 patients with surgical treatment were analysed prospectively. Several items were examined: (1) the agreement between clinical (TNM) and pathologically confirmed classification (pTNM); (2) the value of the various diagnostic tests in estimating the pathologically confirmed classification; (3) the influence of the TNM definitions on separating distinct prognostic groups. With regard to the primary tumour (T), clinical and pathological classification were identical in 64% of the cases. With regard to lymph node involvement (N), the agreement was 48%, for distant metastasis 90% and for the staging 55%. As for the primary tumour (T), the accuracy of radiography (59%) was nearly identical with that of computed tomography (58%). Both these diagnostic techniques were less precise in determining the extent of lymph node involvement (computed tomography 50% correct assessments, radiography 43%). The statistically significant differences in the prognoses for the various pT, pN and pM categories as well as for the pathological stages and the categories of the new R classification could be confirmed. The new 1987 TNM definitions for lung cancer make possible international conformity; the classification is also practically useful and the prognostic relevance improved. The new classifications thus provide a more reliable basis for establishing guidelines for individual oncological therapy strategies and for the exchange of information between different centres on the progress made in diagnosis and therapy of lung cancer.

Carcinoma, Bronchogenic↗
PubMed1990

Site, size, and tumour involvement of resected extrapulmonary lymph nodes in lung cancer.

A prospective study was performed analyzing resected extrapulmonary lymph nodes of 544 operated lung carcinoma patients. Volume of lymph nodes was determined by weight. Lymph nodes were cut in serial sections 300 microns thick, and the volume of tumour metastasis in each resected lymph node was computed measuring the tumourous area in the lymph node sections. The following results were obtained: Percentage of resected lymph nodes varied with lymph node site and site of the primary lung cancer. Hilar lymph nodes were resected in 50% of the patients, lymph nodes of the main and stem bronchi in 57% and 63%, respectively. Tumour metastases were found in 10%-15% of the resected lymph nodes. The size of the lymph nodes varied to a large amount and was found to be independent of the lymph node site if no metastases could be detected. Lymph nodes measuring less than 0.1 ccm were tumour infiltrated in 9% (77/706 lymph nodes), large lymph nodes (greater than 10 ccm) in 62% of the cases (20/32). Tumourous involved lymph nodes of the main bronchus were found more frequently in cases of central localized lung cancer compared to carcinoma arising from the peripheral lung, where the opposite was seen in subaortal located lymph nodes. The percentage of lymph node involvement and size of tumour infiltrated lymph nodes was found to be independent of tumour cell type. Size of resected lymph nodes is not a reliable parameter for estimating existence of tumour infiltrations.

Adenocarcinoma↗