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Biomedical subjects

W Friedl

Publications and source records attributed to W Friedl.

At least 19 recordsLinked to original sources
PubMed1999

Peutz-Jeghers syndrome: four novel inactivating germline mutations in the STK11 gene. Mutations in brief no. 227. Online.

The diagnosis of Peutz-Jeghers syndrome is based on the occurrence of hamartomatous gastrointestinal polyps and perioral pigment spots. In view of the development of hamartomatous polyps in several syndromes and the variability of pigment spots in Peutz-Jeghers patients, identification of affected individuals is difficult. Recently, germline mutations in the STK11 gene have been reported as a molecular cause of Peutz-Jeghers syndrome. We present four novel inactivating mutations identified by direct sequencing of all 9 exons of the STK11 gene in 4 patients suggestive of Peutz-Jeghers syndrome: three frameshift mutations (125-137del; 474-480del; 516-517insT) and one nonsense mutation (Q220X). Our data obtained in these patients and in those reported previously emphasize the diagnostic value of histological discrimination between different types of hamartomatous polyps and of molecular analysis, particularly in cases with no family history of the disease.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

[In Process Citation]

To optimise the microsurgical training in our clinic we organized a permanent possibility to practice microsurgical techniques of vascular anastomosis. This includes step-wise education by means of plastic materials, human placenta and the rat model. The most important role in this concept is played by the placenta. It supplies a realistic simulation of different in vivo situations concerning microvascular anastomosis. As to availability, handling and costs the placenta is superior to animal models and has replaced them almost completely in our educational concept.

Journal Article↗
PubMed1999

Prospective randomized comparison of gliding nail and gamma nail in the therapy of trochanteric fractures.

In a prospective randomized study, we compared the new intramedullary implant of the gliding nail to the gamma nail in the fixation of 80 unstable trochanteric fractures in elderly patients. The preconditions of both groups were comparable. We found no differences concerning the operation time, blood loss, period of stationary treatment or social situation. Also, the anatomic reconstruction and the long-term function according to the Merle d'Aubigne score were comparable. Regarding postoperative complications, the gliding nail showed a minor tendency of cutting out; this we attribute to the special design of the dynamic blade and regard it as the most favourable advantage of this new implant.

Aged↗
PubMed1999

Relationship between natriuretic peptides and hemodynamics in patients with heart failure at rest and after ergometric exercise.

Sixteen patients with heart failure who underwent right heart catherization were studied with regard to plasma natriuretic peptide levels and hemodynamic parameters at rest and immediately after symptom-limited ergometry. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured and correlated with left ventricular ejection fraction (LVEF), mean pulmonary arterial pressure (MPAP), pulmonary arterial wedge pressure (PAWP) and cardiac index (CI). Compared to normal controls, ANP and BNP were elevated at rest. During exercise ANP and BNP increased. BNP was highly significantly correlated with LVEF (P = 0.005) at rest, whereas ANP did not (P = 0.082). BNP significantly correlated with MPAP and PAWP after exercise and showed a significant inverse correlation with CI. Our data provide evidence that BNP might be a better indicator for LVEF at rest than ANP. In addition, BNP correlates very well with MPAP and PAWP, after exercise. This close correlation is likely to reflect a correlation of BNP with left ventricular enddistolic pressure in heart failure when patients are exposed to physical exercise.

Atrial Natriuretic Factor↗
PubMed1999

Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer.

BACKGROUND: Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed. AIMS: To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations. METHODS: Systematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI+ tumours. RESULTS: A similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations. CONCLUSIONS: MSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.

Adult↗
PubMed1998

[Germline mutation analysis in hMLH 1 and hMSH 2 genes in hereditary nonpolyposis colorectal cancer and colorectal cancer patients with familial history].

OBJECTIVE: Analysis for germline mutation in mismatch repair genes, hMLH1 and hMSH2, in hereditary nonpolyposis colorectal cancer (HNPCC) patients and presymptomatic diagnosis in HNPCC families. METHODS: Genomic DNA extracted from peripheral blood were subjected to mutation analysis in 35 exons of the hMLH1 and hMSH2 genes by heteroduplex and single strand conformation polymorphism(SSCP) followed by DNA sequencing of aberrant bands in 14 HNPCC and 10 colorectal cancer patients with familial history. RESULTS: Germline mutations were identified in 4/14 HNPCC patients and in 1/10 colorectal cancer patients with familial history, 2 of them in the hMLH1 and 3 in hMSH2 genes. The five mutations are all unique and are predicted to result in nonfunctional proteins by either frameshift (three), nonsense (one) or missense mutation (one) in evolutionarily conserved region. CONCLUSION: HNPPC is closely related to the mutations of mismatch repair genes. Germline mutation analysis for presymptomatic diagnosis in HNPCC could not be limited in the patients meeting clinical diagnosis criteria (Amsterdam 1991).

Adaptor Proteins, Signal Transducing↗
PubMed1998

[Val384Asp in hMLH1 gene in Chinese, Japanese and German and its etiological role in colorectal cancer].

OBJECTIVE: To investigate Va1384Asp of hMLH1 gene in Chinese, Japanese and German after the missense mutation were identified in Chinese colorectal cancer patients and to inquire into the etiological role of this mutation in colorectal cancer. METHODS: Genomic DNA extracted from normal colon tissue or peripheral blood were subjected to analysis in exon 12 of the hMLH1 gene by single strand conformation polymorphism (SSCP) followed by DNA sequencing of aberrant bands in 26 Chinese and 109 German colorectal cancer patients and in 80 healthy Chinese, 80 Japanese and 100 German individuals . RESULTS: Va1384Asp in hMLH1 gene was found in 4 out of 26 Chinese colorectal patients; 3 of them were out of the 9 patients with colorectal cancer at young age (<50 years). Although 3 and 4 carriers of Va1384Asp in hMLH1 gene were identified in 80 healthy Chinese and 80 healthy Japanese individuals respectively, none were identified in German neither in 109 colorectal cancer patients, nor in 100 healthy German individuals. The frequency of Va1384Asp in hMLH1 gene in the Chinese with colorectal cancer at young age was higher than that in Chinese healthy individuals (P=0.013). CONCLUSION: Va1384Asp can be taken as a polymorphism in hMLH1 gene in Chinese and Japanese populations and may have a potential effect on age at onset of colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene is associated with atrial natriuretic peptide activity after exercise.

An insertion/deletion polymorphism in the gene coding for the angiotensin-converting enzyme (ACE) is strongly associated with ACE activity. This polymorphism may be a marker for an increased risk for cardiovascular events. Our study examined a possible relationship between the D/I polymorphism and myocardial release of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Ninety-six individuals with normal or impaired left ventricular function were included in the study. ANP and BNP plasma levels were measured at rest and after exposure to physical stress. At rest no association of ACE genotypes with ANP and BNP was found. After exercise homozygotes with the genotype DD had significantly higher ANP plasma levels than homozygotes with the genotype II. In contrast to ANP, BNP levels were not significantly different between genotype groups after exercise. Differences in site of production and mode of release between ANP and BNP might explain this difference. We hypothesize that our result might represent a variability gene effect of the ACE gene locus on endocrine processes in the heart during exposure to physical stress.

Adult↗
PubMed1998

[Gliding nail osteosynthesis. A new universally applicable implant for management of per- and subtrochanteric femoral fractures].

Age, high physiological load and the great number and different fracture types of the proximal femur are the main challenges for implants used in the management of these fractures. For use in these types of fracture with immediate restoration of full weight-bearing capacity and for reduction of the intra- and postoperative complication rate, the gliding nail was developed. The development is based on a large number of experimental and clinical examinations of per- and subtrochanteric fractures. The advantages of an intramedullary implant and the gliding screw systems are combined with increased moment of resistance of the double-T femor-neck blade profile. We performed a prospective clinical evaluation of the first 186 patients with per- and subtrochanteric fractures who were treated between 15 September 1994 and 29 February 1996 in the Aschaffenburg Trauma Department with a follow-up examination at least 3 months after the operation. The intraoperative complication rate was 1.1%. The postoperative complication rate was 4.9%. Change of the blade because of fracture impaction and tractus iliotibialis problems was the most frequent problem with 2.2%. The most severe complication (1.1%) were caused by subchondral placement of the blade in the cranial one-third of the femur head. In these cases reosteosynthesis was indicated. Ninety-three percent of the survivors were able to return home. The rate of bed-ridden patients (7.7% and 11.7%) was not very different before or after the operation. However, many patients do not reach the condition they had before the fracture and they are one step worse in mobility and social independence.

Activities of Daily Living↗
PubMed1998

Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria.

Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy. About half of MTS patients are affected by colorectal cancer. In a subgroup of MTS patients the disease has an underlying DNA mismatch-repair (MMR) defect and thus is allelic to hereditary nonpolyposis colorectal cancer (HNPCC). The purpose of this study was to examine to what extent germ-line mutations in DNA MMR genes are the underlying cause of the MTS phenotype. We ascertained 16 MTS patients with sebaceous skin tumors and colorectal cancer, and we examined their skin and visceral tumors for microsatellite instability. All the patients exhibited high genomic instability in at least one tumor. The search for germ-line mutations in the hMSH2 and hMLH1 genes in 13 of the MTS patients revealed truncating mutations in 9 (69%): eight mutations in the hMSH2 gene and one in the hMLH1 gene. This is the first systematic search for germ-line mutations in patients ascertained on the basis of sebaceous skin tumors. Our results indicate that (1) MTS patients exhibit significantly more mutations in the hMSH2 gene than in the hMLH1 gene; and (2) the subpopulation of MTS patients who are also affected by colorectal cancer, irrespective of family history and age at onset of tumors, may have a likelihood for an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clinical criteria for HNPCC.

Adult↗
PubMed1998

Mosaicism for Charcot-Marie-Tooth disease type 1A: onset in childhood suggests somatic reversion in early developmental stages.

A 1.5 Mb duplication on chromosome 17p11.2 is typical for the great majority of patients suffering from Charcot-Marie-Tooth type 1A (CMT1A) disease. A female child of 4 years with clinical signs and symptoms of a demyelinating neuropathy was examined for the presence of this duplication. Analysis of MspI polymorphisms in DNA extracted from peripheral blood failed due to homozygosity for probes pVAW409R3a and pEW401HE. Also, no EcoRI/SacI 3.2 kb junction fragment or dosage difference with probe pLR7.8, characteristic of the CMT1A duplication, was found. However, fluorescence in situ hybridization (FISH) analysis with the PMP22 specific probe c132G8 revealed in peripheral blood lymphocytes 60% of interphase nuclei with CMT1A duplication indicating the probability of mosaicism. In interphase nuclei extracted from nerve tissue the duplication was detectable in 88%, in muscle tissue in 72% of the analyzed nuclei. This suggests the presence of a somatic CMT1A duplication mosaicism that can only be reliably detected by FISH. The early onset and severity of the phenotype indicates that the hypothesized somatic reversion is probably fixed to early developmental stages.

Age of Onset↗
PubMed1998

A beta-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of beta-catenin germline mutations in FAP patients.

As a signaling protein in the Wnt pathway beta-catenin plays a crucial role in the regulation of cellular proliferation. Recently, oncogenic beta-catenin mutations were described in human colorectal cancer and melanoma cell lines. Since activating mutations in the beta-catenin gene have similar effects on the biochemical level as inactivating mutations in the tumor suppressor gene APC, it is speculated that beta-catenin mutations may substitute APC gene inactivation in carcinogenesis. To address this question we analyzed twenty-three sporadic colorectal tumors of different progression states for mutations in the beta-catenin gene. Eighteen of these tumors showed the wildtype APC gene sequence. In only one of the tumors with wildtype APC a beta-catenin gene mutation was found. This tumor was of the RER (replication error) phenotype which may explain the finding that the mutation occurred in a sequential repeat motif of the beta-catenin gene. The second aim of this study was to investigate whether differences in the phenotypic variability in FAP (familial adenomatous polyposis coli) might be due to inherited alterations in the beta-catenin gene. For this we analyzed DNA from fourteen FAP patients from eight different families for germline mutations in the beta-catenin gene. We did not find any beta-catenin gene alteration in these samples. Our results indicate that somatic beta-catenin activating mutations contribute only to a minor part of human colorectal tumors and that germline beta-catenin mutations do not play a role in the variability of symptoms in FAP.

Adenomatous Polyposis Coli↗
PubMed1998

[Importance of blade geometry for stability of fixation with short intramedullary nailing systems for the proximal end of the femur (gliding nail)].

Three biomechanical examinations of the double-T blade of the gliding nail were performed. Under alternating load, also after 100,000 cycles and 2000 N load, no instability occurred after gliding nail osteosynthesis. The best relationship between the introduction forces of the blade (1.771-1.329 N) and the extraction forces (1.474-477 N) was seen after glass pearl treatment of the blade surface. Displacement of the plate in a sow bone femor head after 1000 cycles at 1500 N was 1.0-4.00 mm for a double-T blade, but 4.0-8.0 mm for a 10 mm screw like the gamma-nail screw.

Aged↗
PubMed1997

Microsatellite instability analysis: a multicenter study for reliability and quality control.

The molecular biology section of the Hereditary Non-Polyposis Colorectal Cancer study group-Germany, instituted a multicenter study to test the reliability and quality of microsatellite instability (MSI) analysis. Eight laboratories compared MSI analyses performed on 10 matched pairs of normal and tumor DNA from patients with colorectal carcinomas. A variety of techniques were applied to the detection of microsatellite changes: (a) silver and ethidium bromide staining of polyacrylamide gels; (b) radioactive labeling; and (c) automated fluorescence detection. The identification of highly unstable tumors and tumors without MSI was achieved in high concordance. However, the interpretation of the band patterns resulted in divergent classifications at several microsatellite marker loci for a large fraction of this tumor/normal panel. The data on more than 30 primers per case suggest that the enlargement of the microsatellite panel to more than 10 loci does not influence the results. In this study, cases with MSI in less than 10% of loci were classified as microsatellite stable, whereas MSI was diagnosed in cases with more than 40% of all markers unstable. We propose that a panel of five microsatellite loci consisting of repeats with different lengths should be analyzed in an initial analysis. When less than two marker loci display shifts in the microsatellite bands from tumor DNA, the panel should be enlarged to include an additional set of five marker loci. The number of marker loci analyzed as well as the number of unstable marker loci found should always be identified. These criteria should result in reports of MSI that are more comparable between studies.

Chromosome Deletion↗
PubMed1997

[Biomechanics of combined Kirschner wire osteosynthesis in the human model of unstable dorsal, distal radius fractures (Colles type)].

In an experimental study, the biomechanical qualities of the combined Kirschner wire osteosynthesis (KWO) in the unstable Colles' fracture were analyzed. This type of pin fixation is our preferred osteosynthesis in the treatment of unstable Colles' fracture because it allows immediate functional therapy. It represents a modification of Kapandji's dynamic KWO, compensating for the insufficient volar stability by means of the conventional static KWO. Clinical experience according to the anatomical and functional results, was very encouraging suggesting that a clinical concept based on the biomechanical principles of combined KWO and its single components should be constituted. Simulation of the unstable Colles' fracture was realized by dorsal wedge osteotomy of the distal end of the radius using cadaveric material. This fracture model was subsequently pinned using the different KWO types and tested by a standardized vector energy testing device regarding its stability in the four main loading directions. The combined KWO unifies the advantage of volar stability of the conventional KWO with the high dorsal stability of dynamic KWO. The main functional principle of dynamic KWO with regard to its axial stability consists in the repositioning of the dorsal bone fragmentation zone and hence the reconstitution of cortical load transmission. Besides its good stabilization, dynamic KWO also leads to optimal alignment of the distal metaphyseal fragment. Furthermore, the experiments yielded important information about technical aspects of the surgical procedure, which helps us to avoid anatomical and functional deficiencies. Based on these experimental findings, the surgical technique of combined KWO was standardized.

Biomechanical Phenomena↗
PubMed1997

[The prospects for Kirschner-wire osteosynthesis in the dorsally unstable distal radius fracture (Colles' type)].

The following experimental study was conducted to develop biocompatible methods of osteosynthesis in fractures of the distal radius and to evaluate their stability. A model of dorsal wedge osteotomy in the distal radial metaphysis was used to develop the surgical technique and to test the stability of the alternative methods of osteosynthesis. The concept for this model was based on commercially available materials which were either biodegradable or osteoconductive. Four different forms of biocompatible osteosynthesis were compared to combined Kirschner wire osteosynthesis (KWO), our preferred method of treatment of unstable Colles fracture. Biocompatible osteosynthesis was achieved with an invasivity and stability comparable to that of KWO. In conclusion, injection osteosynthesis exceeded the other biocompatible methods of osteosynthesis in all respects. Regarding the recent developments in injectable materials for osteosynthesis it offers the best perspective for clinical application.

Biocompatible Materials↗