Crystallisation of tryparedoxin I from Crithidia fasciculata.
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Animals↗
Biomedical subjects
B Hofmann
Publications and source records attributed to B Hofmann.
Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13.
Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.
Carcinoma, Adenoid Cystic↗
Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin.
In vivo imaging of endothelial markers in intact tumour neovasculature would have applications in assessing the efficacy of anti-angiogenic agents in clinical trials. Although a variety of different endothelial markers have been described, few have been evaluated as imaging markers. The transforming growth factor-beta (TGF-beta) binding receptor endoglin is a proliferation-associated endothelial marker. We hypothesised that endoglin would be an ideal target for imaging since it is strongly upregulated in proliferating endothelial cells of the tumour neovasculature. We used a radiolabelled monoclonal anti-endoglin antibody and compared its neovascular binding, accumulation and in vivo behaviour to an isotype-matched control IgG(2a). Our data show that the probe binds specifically and rapidly within minutes in vivo and that correlative autoradiography and immunohistology support the in vivo imaging findings. Imaging of abundantly expressed endothelial targets circumvents delivery barriers normally associated with other tumour targeting strategies, and can potentially be used to quantitate molecular angiogenic markers.
Antigens, CD↗
Identification of the familial cylindromatosis tumour-suppressor gene.
Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).
Amino Acid Sequence↗
[The development of artificial kidney--from sausage casing to capillary fibers].
In 1994, Willem Kolff published his results on haemodialysis on humans. His achievements were based on 19th century medicine. Richard Bright had contributed to the knowledge of kidney diseases and Graham and Fick had described diffusion through semipermeable membranes. Some initial tests of haemodialysis had been performed by Abel and Haas in the beginning of the 20th century. But it was Kolff's publication that initiated three innovative decades of development of artificial kidneys: the development from sausage casing to the hollow fiber kidneys.
Animals↗
Mechanism of gadophrin-2 accumulation in tumor necrosis.
The molecular mechanism by which gadophrin-2 targets necrotic tumor tissue was investigated. Biodistribution studies and magnetic resonance imaging (MRI) and histologic/autoradiographic correlation were performed in xenograft mouse models bearing human tumors (HT 29, WiDr, LX 1). Binding of gadophrin-2 to DNA, lipids, or proteins was determined by fluorescence spectrophotometry. Protein binding was determined by dialysis and gel electrophoresis. Accumulation of gadophrin-2 was low (<0.7% injected dose/g tissue at 24 hours after injection) in viable tumor but higher in necrotic tumor regions and was readily detectable by MRI. Within a given tumor, the agent preferentially localized in the periphery of necrotic areas. Within these regions gadophrin-2 was bound to interstitial albumin and not other proteins, lipids, or DNA. Tumoral accumulation of gadophrin-2 most likely occurs through its binding to plasma albumin and subsequent slow extravasation into the tumor interstitium.
Animals↗
[Psycho-neurogenic factors as a cause of life-threatening arrhythmias].
Tachyarrhytmias often occur during increased emotional arousal or mental excitation. The implantable cardioverter defibrillator (ICD) allows the exact documentation of arrhythmic episodes and their time of onset. Therefore, the type of arrhythmia can be differentiated as well as the circumstances surrounding the event. These features allow the assessment of possible psychic arrhythmogenic factors in the natural environment. We analyzed the ICD-protocols of three male patients (in ages between 60 and 68), whose devices had successfully terminated a ventricular tachycardia and compared the onset of the episodes with the patients' detailed descriptions of the corresponding life situations. The analysis of the circumstances at the time of arrhythmia-onset revealed a relationship between the occurrence of life-threatening arrhythmias in natural environment and emotional stress. The stressors could be defined as situations of increased vulnerability leading to sympathetic excitation. The induction of tachyarrhythmia was promoted in case 1 by acute psychic distress (public speaking), by the increasing panic-attack-like vicious circle of the cognitive anticipation of an unfavorable outcome (case 2), and an adverse anger reaction superimposed on persistent feelings of help- and hopelessness (case 3). These findings are in line with several experimental and epidemiological studies providing evidence for a relationship between psychic arousal and the induction of tachyarrhythmias. The knowledge of emotional and mental factors that function as a trigger for arrhythmias may lead to new therapeutic approaches in the prevention of sudden cardiac death.
Aged↗
Effect of topical tazarotene in the treatment of congenital ichthyoses.
The clinical efficacy and tolerability of the topical receptor-selective retinoid tazarotene in the treatment of congenital ichthyoses was investigated. Twelve consecutive patients with different forms of congenital ichthyosis were enrolled in an open, non-randomized, intraindividually controlled, half-side pilot study. Diagnoses were X-linked recessive ichthyosis, non-erythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant ichthyosis vulgaris and ichthyosis bullosa of Siemens (IBS). Tazarotene 0.05% gel was applied unilaterally daily on a defined body area measuring 10% of the body surface area. The contralateral side was treated with an ointment containing 10% urea. After 14 days, application frequency was reduced to three times a week, and stopped after another 2 weeks. The follow-up period was 3 months. Reduction in scaling and roughness was used to assess the clinical response in the tazarotene-treated area compared with the control area. Clinical and laboratory assessments were performed every 14 days during the trial. Unilateral improvement in favour of the tazarotene-treated side was observed in nine of 12 patients (75%). Four patients (33%) achieved an excellent response and four (33%) achieved a good response. No therapeutic effect was seen in patients with IBS. The remission persisted during the reduction phase and after discontinuation for up to 2 months. Local irritation in three patients was the only side-effect detectable. Short-term topical application of tazarotene 0.05% gel is a very effective and well-tolerated treatment modality in different forms of congenital ichthyoses and may be an alternative to systemic retinoid therapy.
Administration, Cutaneous↗
[Multifocal malignant transformation of extreme fibromatosis with pulmonary involvement].
We report on the case of a 40-year old patient with extreme neurofibromatosis with severe kyphoskoliosis and deformation of the thorax. The patient died from malignant transformation which occurred multifocally with extensive pulmonary metastases. The well-known thoracic manifestations of neurofibromatosis are reviewed.
Adult↗
Gadolinium neutron capture therapy (GdNCT) of melanoma cells and solid tumors with the magnetic resonance imaging contrast agent Gadobutrol.
RATIONALE AND OBJECTIVES: The therapeutic gain of neutron capture therapy with a neutral macrocyclic gadolinium (Gd) complex (Gadobutrol) was evaluated through in vitro and in vivo studies in a beam of low-energy neutrons. METHODS: Neutron irradiation for both the in vitro and in vivo studies was performed in a beam of low-energy neutrons produced by the research reactor of the Hahn-Meitner-Institut, Berlin. Malignant melanoma cells of human origin were irradiated in the presence or absence of Gadobutrol. In vivo irradiation was performed on tumor-bearing nude mice. The tumor site was irradiated subsequent to intratumoral injection of Gadobutrol and compared with irradiation in the absence of the Gd complex. RESULTS: In vitro studies showed a Gd-dependent delay of cell proliferation as a consequence of neutron irradiation. In animals, intratumoral administration of the Gd complex at a dose of 1.2 mmol Gd/kg before neutron irradiation results in a significant delay in tumor growth with respect to the control groups. CONCLUSIONS: In vitro and in vivo studies showed a therapeutic benefit with the neutral Gd complex and suggest Gd-containing magnetic resonance contrast media are potential candidates for neutron capture therapy. The Gd dose used in the irradiation experiments was four times the presently accepted high dose in clinical magnetic resonance imaging.
Animals↗
Crystallization and preliminary X-ray analysis of tryparedoxin I from Crithidia fasciculata.
The thioredoxin-related protein tryparedoxin I from Crithidia fasciculata has been crystallized using PEG 4000 as a precipitant. The enzyme forms long needle-shaped crystals which diffract to at least 1.7 A. A native data set has been collected at the DESY synchrotron from a flash-frozen crystal at 90 K to 1.7 A resolution. The data set shows that the crystals belong to the orthorhombic space group P212121 and have unit-cell parameters a = 37.94, b = 51. 39, c = 71.46 A. Tryparedoxin I is involved in a trypanothione-dependent peroxide metabolic pathway specific for trypanosomatids and may therefore be a suitable candidate for the design of drugs for the specific treatment of a variety of important tropical diseases caused by these parasites.
Animals↗
[Medical equipment--old, of poor quality and hazardous?].
In the public debate on Norwegian health care it is claimed that hospitals use old and hazardous medical equipment. A survey carried out on 2,031 pieces of equipment at Lillehammer hospital showed an average age of 7.35 years and a mean life span of 14.91 years. The survey showed that the failure rate was highest for newer equipment. It also showed that the operator error rate was higher for newer devices, older equipment being less complex and therefore easier to use. The results did not support the claim that hospitals use old and hazardous medical equipment.
Equipment Failure↗
Structural investigation of the cofactor-free chloroperoxidases.
The structures of cofactor-free haloperoxidases from Streptomyces aureofaciens, Streptomyces lividans, and Pseudomonas fluorescens have been determined at resolutions between 1.9 A and 1.5 A. The structures of two enzymes complexed with benzoate or propionate identify the binding site for the organic acids which are required for the haloperoxidase activity. Based on these complexes and on the structure of an inactive variant, a reaction mechanism is proposed for the halogenation reaction with peroxoacid and hypohalous acid as reaction intermediates. Comparison of the structures suggests that a specific halide binding site is absent in the enzymes but that hydrophobic organic compounds may fit into the active site pocket for halogenation at preferential sites.
Amino Acid Sequence↗
Topical application of tazarotene in the treatment of nonerythrodermic lamellar ichthyosis.
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Administration, Topical↗
Detection of staphylococcal genes directly from cerebrospinal and peritoneal fluid samples using a multiplex polymerase chain reaction.
A multiplex polymerase chain reaction (PCR) that can simultaneously detect eubacterial isolates and the methicillin-susceptibility of staphylococcal isolates from cerebrospinal and peritoneal fluid samples was compared to conventional microbiological methods. Using conventional methods, bacteria were isolated from 8% (29/350) of the cerebrospinal fluid samples and from 5% (3/60) of the peritoneal fluid samples. All isolates except two Staphylococcus epidermidis isolates were also detected using the multiplex PCR. Coagulase-negative staphylococci and Staphylococcus aureus were correctly identified using both methods. The multiplex PCR can rapidly and simultaneously detect eubacteria, and the methicillin susceptibility of staphylococci from samples containing > or = 10(2) cfu/ml of bacteria.
Ascitic Fluid↗
Acquired syphilis II in early childhood: reappearance of syphilis brephotrophica.
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Child Care↗
Drinking water fluoridation: bone mineral density and hip fracture incidence.
The role of drinking water fluoride content for prevention of osteoporosis remains controversial. Therefore, we analyzed the influence of drinking water fluoridation on the incidence of osteoporotic hip fractures and bone mineral density (BMD) in two different communities in eastern Germany: in Chemnitz, drinking water was fluoridated (1 mg/L) over a period of 30 years; in Halle, the water was not fluoridated. BMD was measured in healthy hospital employees aged 20-60 years (Halle: 214 women, 98 men; Chemnitz: 201 women, 43 men, respectively) using dual-energy X-ray absorptiometry. Hip fractures in patients > or = 35 years admitted to the local hospitals in the years 1987-1989 were collected from the clinic registers. There was no difference in age, anthropometric, hormonal, or lifestyle variables between the two groups. Mean fluoride exposure in Chemnitz was 25.2 +/- 7.3 years. No correlation was found between fluoride exposure and age-adjusted BMD. We found no significant difference in spinal or femoral BMD between subjects living in Halle and Chemnitz [lumbar spine: 0.997 +/- 0.129 (g/cm2) vs. 1.045 + 0.171 (g/cm2), p = 0.08, for men; 1.055 +/- 0.112 (g/cm2) vs. 1.046 +/- 0.117 (g/cm2), p = 0.47, for women]. The fracture incidence showed an exponential increase with aging in men and women with an incidence about 3.5 times higher for women. In Chemnitz, we calculated an age-adjusted annual incidence of 142.2 per 100,000 for women and 72.5 per 100,000 for men, respectively. In Halle, the incidences were 178.5 per 100,000 for women and 89.2 per 100,000 for men. There was a lower hip fracture incidence after the age of 85 in women in Chemnitz (1391 per 100,000 in Chemnitz vs. 1957 per 100,000) in Halle, p = 0.006). Using the age-adjusted incidences, significantly fewer hip fractures occurred in Chemnitz in both men and women. In conclusion, our study suggests that optimal drinking water fluoridation (1 mg/L), which is advocated for prevention of dental caries, does not influence peak bone density but may reduce the incidence of osteoporotic hip fractures in the very old.
Adult↗
Alpha1-antitrypsin alleles and phenotypes in patients with inflammatory bowel disease.
BACKGROUND: Several studies suggest an imbalance of protease activation and inhibition in inflammatory bowel disease. Alpha1-Antitrypsin (AAT), one protease inhibitor of paramount importance, exists in numerous subtypes, some of them representing deficient phenotypes. The present study evaluated the prevalence of AAT-alleles and phenotypes in patients with inflammatory bowel disease. METHODS: The study population comprised 74 patients with Crohn's disease and 61 patients with ulcerative colitis. Isoelectric focusing was used for AAT subtyping. The prevalence of AAT alleles and phenotypes was compared with the frequency in 752 healthy unrelated controls. RESULTS: The rare phenotype M2F was detected in one patient with ulcerative colitis. No further significant differences in the distribution of AAT alleles or phenotypes between patients with inflammatory bowel disease and the healthy controls were observed. CONCLUSION: The low prevalence of deficient AAT subtypes does not point towards a contribution of AAT deficiency in the pathophysiology of IBD.
Adolescent↗