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S Hofmann

Publications and source records attributed to S Hofmann.

At least 73 records · Page 4Linked to original sources
PubMed1999

Mitochondrial disorders. A diagnostic challenge in clinical chemistry.

Mitochondria play a pivotal role in cellular metabolism and in energy production in particular. Defects in structure or function of mitochondria, mainly involving the oxidative phosphorylation (OXPHOS), mitochondrial biogenesis and other metabolic pathways, have been shown to be associated with a wide spectrum of clinical phenotypes. The ubiquitous nature of mitochondria and their unique genetic features contribute to the clinical, biochemical and genetic heterogeneity of mitochondrial diseases. We will focus on the recent advances in the field of mitochondrial disorders and their consequences for an advanced clinical and genetic diagnostics. In addition, an overview on recently identified genetic defects and their pathogenic molecular mechanisms will be given.

Chemistry, Clinical↗
PubMed1999

MR arthrography of the adult acetabular capsular-labral complex: correlation with surgery and anatomy.

OBJECTIVE: Our purpose was to describe the appearance of the acetabular capsular-labral complex on MR arthrography and to correlate this appearance with surgical findings in adult patients and with gross anatomic findings in cadavers. SUBJECTS AND METHODS: MR arthrography of the hip joint was performed in 40 patients and six cadavers. All patients underwent subsequent arthrotomy of the hip. MR arthrography consisted of a T1-weighted three-dimensional gradient-echo sequence in both the coronal oblique and sagittal oblique planes after intraarticular injection of a 2 mmol/l solution of gadopentetate dimeglumine. The normal and pathologic appearance of the capsular-labral complex was assessed, and the labra were evaluated on the basis of morphology, signal intensity, presence of a tear, and attachment to the acetabulum. MR arthrography findings were correlated with the surgical results in all patients and with the anatomic sections of the cadaveric hip joint specimens. RESULTS: MR arthrography images of the T-weighted three-dimensional gradient-echo sequences allowed visualization of the anatomic structures. The normal labrum was triangular, without any sublabral sulcus, and of homogeneous low signal intensity. A recess between the labrum and the joint capsule could be identified in instances in which no thickened labrum was present. Labral lesions included labral degeneration, a tear, or a detached labrum either with or without thickening of the labrum. The sensitivity for detection and correct staging of labral lesions with MR arthrography in the patient study was 91%; the specificity, 71%; and the accuracy, 88%. CONCLUSION: MR arthrography with T1-weighted three-dimensional gradient-echo sequences allows excellent assessment of the normal and pathologic acetabular capsular-labral complex.

Acetabulum↗
PubMed1999

General short-term indomethacin prophylaxis to prevent heterotopic ossification in total hip arthroplasty.

This prospective study evaluated heterotopic ossification prophylaxis with indomethacin for 14 days in 201 consecutive patients undergoing total hip arthroplasty. Ranitidine was administered concurrently to alleviate gastrointestinal side effects. None of the patients with mild gastrointestinal side effects (12%) had to suspend the prophylaxis, and no major postoperative bleeding or gastrointestinal ulcers were observed. After 12 months of follow-up, 67% of patients had no evidence of heterotopic ossification, 32% percent had grades I and 1% had grade III without clinical significance, and 0% had grade IV ossification according to Brooker's classification. These results indicate that short-term indomethacin prophylaxis is an effective, inexpensive, and easily administrated alternative to single-dose radiotherapy for nearly all patients undergoing THA.

Adult↗
PubMed1998

Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)) gene.

We report seven unrelated families with mitochondrial tRNA(Ser(UCN)) gene mutations at three different loci. A novel G7497A mutation is found in two families, both of which present with progressive myopathy, ragged-red fibers, lactic acidosis, and deficiency of respiratory chain complexes I and IV. This mutation presumably affects the tertiary tRNA(Ser(UCN)) dihydrouridine interaction. Mutations 7472 insC and T7512C, found in three and two families, respectively, are associated with myoclonus epilepsy, deafness, ataxia, cognitive impairment, and complex IV deficiency. No ragged-red fibers or ultrastructural abnormalities are seen. It is interesting that 6 of our 7 index patients are apparently homoplasmic, indicating a minor pathogenetic power of the tRNA(Ser(UCN)) mutations.

Adolescent↗
PubMed1998

[Labrum lesions in residual dysplasia of the hip joint. Biomechanical considerations on pathogenesis and treatment].

The capsular-labrum-complex consists of the triangular fibrocartilaginous labrum, which is fixed at the bony acetabular ring and supported by the ligamentum transversum actetabuli in the caudal part. In a normally developed and correctly orientated acetabulum, the femoral head is symmetrically covered by the contact area of the lunate surface. The vertical component of the resultant hip joint force concentrically meets the horizontal weight bearing surface: Evenly distributed compressive forces are transmitted; the capsular-labrum-complex does not have to compensate excessive shear or tension. In contrast, in a "dysplastic" acetabulum the femoral head is poorly covered by the pathologically orientated lunate surface: The lunate surface is sloping in an anterolateral direction, leading to tension and shear on the superolateral capsular-labrum-complex, which becomes a secondary stabilizer ("guide rail") against the decentering femoral head. The vertical component of the resultant hip force eccentrically meets the oblique weight bearing surface, causing extra stress in the labrum: The capsular-labrum-complex is trying to compensate this biomechanical stress with hypertrophy (Type IB). Progressive mechanical decompensation of the capsular-labral-complex might lead to tears (Type IIB) or complete avulsions (Type IIIB) of the labrum. In conclusion labral lesions result from pathobiomechanics caused by residual hip dysplasia (RHD). Logically, the basic therapeutic principle can only be corrective osteotomy.

Acetabulum↗
PubMed1998

[Clinical and diagnostic imaging of labrum lesions in the hip joint].

Labral lesions are common findings in residual hip dysplasia, indicating biomechanical decompensation of the hip joint. MR-Arthrography has shown an excellent accuracy of over 90% to detect these lesions. Nevertheless, so far clinical sings, radiological diagnosis and therapeutical consequences are not well known. In a prospective study, patients suspicious for labral lesions were evaluated using a standard clinical protocol, including history, clinical signs, radiography and MR-Arthrography. Clinical signs were tested by six criteria and two provocation tests. In 11% patients clinical suspicious was wrong. Best agreement with MR-Arthrography was found for "knife sharp" groin pain (100%), impingement test (100%) and painful giving way (83%). 35% of patients showed minor (grade 2) and 52% severe (grade 3 and 4) dysplasia. Independent from grade of dysplasia, no or only slight arthrosis (grade 0 and 1) was found in 64% of patients. In 16% a single acetabular cyst could be detected on radiographs, which all could be identified as intraosseous ganglia on MR-Arthrography. Labral lesions type A (post traumatic) were found in 23% of the patients with only no or minor dysplasis (grade 1 and 2), whereas labral lesions type B (dysplastic) were found in 67% of the patients with severe dysplasia (grade 3 and 4). Clinical signs for labral lesions are typical but can also be observed in other pathologies of the hip joint. Based on the findings of this study, we recommend radiographic evaluation for dysplasia and MR-Arthrography in patients with clinical suspicion for labral lesions of the hip joint.

Acetabulum↗
PubMed1998

[MRI arthrography in labrum lesions of the hip joint. Method and diagnostic value].

Magnetic Resonance imaging with its excellent soft tissue contrast represents the method of choice for examination of intraarticular and periarticular structures of joints. However, conventional MR-imaging without intraarticular contrast application is not suitable for the diagnosis of labral lesions. MR-arthrography (MRA) of the hip clearly demonstrates labral pathology by distension of the joint space and entrance of the contrast medium into the lesion. Multiplanar 3-D-gradient echo sequences enable visualisation of the most important cranio-ventral portion of the labrum. With the MRA labral lesions can be subdivided into different, clinically relevant stages. Furthermore accompanying lesions (intra- and extraosseous ganglia, stress-bone marrow-edema) can be demonstrated. In our study including operatively verified cases, MRA showed excellent sensitivity (90%) and accuracy (91%) in detecting labral lesions. So far no complication occurred with more than 100 MRA's. Therefore this technique represents the method of choice for the radiological evaluation of labral lesions of the hip joint. In this review the technical details and results of our MRA method will be presented.

Acetabulum↗
PubMed1998

Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease.

Complete sequence analysis of all mitochondrial complex I genes was performed in 22 cases of neuropathologically confirmed idiopathic Parkinson disease (PD). DNA from the substantia nigra was used as a template for polymerase chain reaction-based genomic sequencing. Seven novel mutations causing the exchange of amino acids were detected in subunit genes ND1 (3992 C/ T, 4024 A/G), ND4 (11253 T/C, 12084 C/T), ND5 (13711 G/A, 13768 T/C), and ND6 (14582 T/C). In addition, five known missense mutations affecting the ND1 (3335 T/C, 3338 T/C), ND2 (5460 G/A), ND3 (10398 A/G), and ND5 (13966 A/G) genes as well as three secondary LHON mutations (4216 T/C, 4917 A/ G, 13708 G/A) were found in the PD group. Among the novel mutations, the 11253 T/C transition which changes a conserved isoleucine residue into threonine is most likely to be of functional relevance. Furthermore, 43 synonymous polymorphisms were detected in PD brains, including 20 novel sequence variants. Haplogroup analysis revealed that most unique missense mutations were found in PD cases belonging to the D(c) haplogroup. Our data are in line with the view that PD is not a single disease entity but comprises a genetically heterogeneous group of disorders. The results of our study further suggest that 90% or more of all idiopathic PD cases are not due to sequence variation of mitochondrial complex I, but that mitochondrial mutations may play a pathogenic role in a subset of PD patients.

Aged↗
PubMed1998

Molecular markers of the endothelium, the coagulation and the fibrinolytic systems in healthy newborns.

Endothelium derived substances may play a role in the physiological adaptation processes at the time of birth. The aim of this study was to investigate plasma concentrations of activation markers of the endothelium (endothelin-1, thrombomodulin, von Willebrand factor), of the coagulation and the fibrinolytic systems (thrombin-antithrombin III complex, D-dimer, plasmin-alpha2-antiplasmin complex) during the first days of life. Venous blood from peripheral veins was collected from 79 healthy newborns and for comparison from 38 healthy infants and schoolchildren, as well as from 17 healthy adults. Except for endothelin and von Willebrand factor, the concentrations of activation markers were significantly higher in the newborn group. During the first 12 days of life thrombomodulin, thrombin-antithrombin III complex, and plasmin-alpha2-antiplasmin complexes showed a continuous decline whereas the concentrations of endothelin, von Willebrand factor and D-dimer did not change. The highest D-dimer concentrations were found at low umbilical arterial pH and after birth by vaginal operation suggesting an influence of birth stress. Thrombomodulin was correlated with endothelin (r=+0.471) and with von Willebrand factor (r=-0.415). In conclusion, endothelial, coagulation, and fibrinolytic systems are activated in newborns which might occur during birth by the mechanical stress, the adaptation of circulation, and the short-term hypoxic state. An additional intrauterine activation should also be considered.

Adult↗
PubMed1998

Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein.

Wolfram syndrome is an autosomal recessive disorder characterized by juvenile diabetes mellitus, diabetes insipidus, optic atrophy and a number of neurological symptoms including deafness, ataxia and peripheral neuropathy. Mitochondrial DNA deletions have been described in a few patients and a locus has been mapped to 4p16 by linkage analysis. Susceptibility to psychiatric illness is reported to be high in affected individuals and increased in heterozygous carriers in Wolfram syndrome families. We screened four candidate genes in a refined critical linkage interval covered by an unfinished genomic sequence of 600 kb. One of these genes, subsequently named wolframin, codes for a predicted transmembrane protein which was expressed in various tissues, including brain and pancreas, and carried loss-of-function mutations in both alleles in Wolfram syndrome patients.

Adolescent↗
PubMed1998

A systematic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy.

COX deficiency is believed to be the most common defect in neonates and infants with mitochondrial diseases. To explore the causes of this group of disorders, we examined 25 mitochondrial genes (three COX subunit genes and 22 tRNA genes) and 10 nuclear COX subunit genes for disease associated mutations using PCR-SSCP and direct sequencing of polymorphic SSCP fragments. DNA from one patient with severe COX deficiency and with consanguineous parents was entirely sequenced. The patient population consisted of 21 unrelated index patients with mitochondrial disorders and predominant (n=7) or isolated (n=14) COX deficiency. We detected two distinct tRNA(Ser)(UCN) mutations, which have been recently described in single kindreds, in a subgroup of four patients with COX deficiency, deafness, myoclonic epilepsy, ataxia, and mental retardation. Besides a number of nucleotide variants, a single novel missense mutation, which may contribute to the disease phenotype, was found in the mitochondrial encoded COX 1 gene (G6480A). Mutations in nuclear encoded COX subunit genes were not detected in this study.

Adolescent↗
PubMed1998

[The Donauspital-Stolzalpe concept (Danube Hospital, Vienna, Austria). Corrective osteotomy with selective labrum surgery following preoperative MRI arthrography].

Concomitant pathologies (labral lesions, intra-/extra-osseous ganglia and stress bone marrow edema) in adult residual hip dysplasia (RHD) might influence the outcome of conservative hip surgery. The aim of our prospective clinical study was to assess the value of preoperative MR arthrography in diagnosing concomitant lesions and in making surgical decisions in RHD. The first 37 consecutive patients with a minimum follow-up of 18 months have been analysed. All 37 patients presented RHD with the clinical symptomatology of labral lesions and underwent routine preoperative MRA. According to clinical, radiological and MR arthrographical criteria, these 37 patients were subdivided into four therapeutic subgroups: (1) reorientation of the acetabulum using the Tönnis triple pelvic osteotomy (TPO); (2) intertrochanteric varisation osteotomy (IVO); (3) palliative decompression with only symptomatic partial resection of the torn labrum (PALL); (4) primary total hip replacement (TEP). Based on the preliminary clinical and radiological outcomes of these four subgroups, the following conclusions can be drawn: labral lesions are considered to be a sign of chronic joint instability. Therefore, acetabular malorientation should be corrected by redirectional osteotomy of the acetabulum (TPO-subgroup) even in low grades of RHD if labral lesions are present. "Palliative" labral resections without corrective osteotomy (PALL subgroup) in secondary osteoarthritis due to RHD are definitively obsolete, because they rapidly progress to severe osteoarthritis due to surgically accelerated joint instability. In RHD with highly osteoarthritic hip joints and concomitant lesions, one should not hesitate to perform primary THR even in young patients.

Acetabulum↗
PubMed1998

[Labrum lesions and residual dysplasia of the hip joint. Definition and prospectives].

Labral lesions are a sign of biomechanical decompensation of the hip joint and often represent the first clinical symptom of residual hip dysplasia (RHD) in the adult. Provocation tests (impingement, apprehension) are typical but not specific. Labral lesions and concomitant findings (intra- and extraosseous ganglia, stress bone marrow oedema) can be detected by magnetic resonance arthrography (MRA) with an accuracy of 91%. Primary therapeutic goal is the normalization of the underlying pathomorphology and instability by a redirectional acetabular osteotomy. There are several concepts concerning simultaneous arthrotomy at the time of osteotomy: no arthrotomy at all, selective arthrotomy, routine arthrotomy in every case. There are more clinical studies necessary before one of these concepts can be widely accepted and recommended. Based on preliminary results, palliative arthrotomy with partial labral resection but without corrective osteotomy in osteoarthritis secondary to residual hip dysplasia gives poor results; we therefore urgently dissuade from palliative labral surgery via arthrotomy. Whether labral surgery via arthroscopy might be a useful concept in symptomatic residual hip dysplasia, is still an open question. In this review article, the "state of the art" presented at the "Vienna Labral Symposium 1997" is reflected and summarized. At the end of this article, a "common statement" of the experts is published in English and German language.

Acetabulum↗
PubMed1997

Relation of hemodynamic variables to augmentation of left anterior descending coronary flow by intraaortic balloon pulsation in coronary artery disease.

Recent studies suggest prophylactic intraaortic balloon-pulsation (IABP) in patients undergoing coronary reperfusion therapy. However, variable effects of IABP on coronary blood flow are reported. It is suggested that augmentation of coronary flow is more effective in patients with a compromised hemodynamic status, which might have potential relevance in selecting IABP treatment in patients undergoing reperfusion therapy.

Aged↗
PubMed1997

Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes.

Because Wolfram (or DIDMOAD) syndrome is supposed to be a mitochondrial (mt)-mediated disease, we investigated a group of eight DIDMOAD patients with respect to point mutations of the mtDNA thus far described as being associated with defined mitochondrial disorders such as MELAS, MERRF, and LHON. Furthermore, to screen DIDMOAD patients for other mtDNA defects we used Southern blot analysis to detect mtDNA length mutations and rearrangements as well as PCR-SSCP and direct sequencing to screen all ND genes (complex I of the respiratory chain), the 22 tRNAs, and a part of the cyt b gene for unknown mutations. As a disease control group, 17 LHON patients (harboring one of the primary LHON mutations) were included in this study because of the overlapping clinical symptoms (optic atrophy) in both syndromes. We compared mtDNA variants identified in DIDMOAD patients with those found in LHON patients as well as in a control group consisting of 67 healthy German blood donors. In total, the control group was characterized by 29 polymorphic sites in ND and tRNA genes that define certain major Caucasian haplotypes. We found that a cluster of nucleotide exchanges at nucleotide positions (nps) 4216 and 11,251 roughly discriminates controls (12/67 controls, 18%) from the disease groups (6/8 DIDMOAD patients, 75%; 10/17 LHON patients, 59%). All 4216-positive LHON patients (10 patients) were concentrated in a haplogroup defined by additional exchanges at nps 10,398, 12,612, and 13,708 (haplogroup A), while the bulk of 4216-positive DIDMOAD patients (5 patients) were found in a distinct haplogroup consisting of nucleotide exchanges at nps 4917, 10,463, 13,368, 14,233, and 15,928. The frequencies of both haplogroups were significantly lower in the control group versus the respective disease groups. A more detailed analysis was performed by sequencing the two hypervariable regions of the non-coding D-loop region from patients and controls and corroborated the ranging in the two major haplogroups. Thus, the different clinical features of the mitochondrial disease groups investigated here corresponded to different clusters of mtDNA variants, which might act as predisposing haplotypes, increasing the risk for disease.

Adult↗