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Biomedical subjects

R Kiefer

Publications and source records attributed to R Kiefer.

At least 19 recordsLinked to original sources
PubMed2006

Filling a cervical spine cage with local autograft: change of bone density and assessment of bony fusion.

To date, it remains debatable whether cervical spine fusion cages should be filled with any kind of bone or bone substitute. Using a bone substitute would produce additional costs, using an autologous bone graft from the iliac crest would make the use of the cage at least questionable. As an alternative, cortical and subcortical bone from the anterior osteophytes of the segment in which the disc has been removed could be used to fill the cage: higher costs and complications at the iliac crest could both be avoided and the cage could be filled. However, the fate of these bone chips made from the anterior osteophytes is unclear as well as whether fusion will occur using this technique. The objective of the current study was to investigate possible changes in the bone density of this local autograft in the cage within the first 12 months after surgery by means of computed tomography. A second objective was to assess segmental bony fusion using this technique. 21 patients, suffering from degenerative disc disease of the cervical spine, were included into this prospective study. They all underwent anterior decompression, cage insertion and plate stabilisation. The cage (Rabea, Signus Medizintechnik, Alzenau, Germany), was filled with bone chips made from the anterior osteophytes of the segment that underwent discectomy. On the third day after surgery as well as three, six and 12 months after surgery, an axial computed tomography scan through the cage was taken and density within the apertures of the cage was measured in a standardised manner. Flexion-extension lateral radiographs were taken to investigate segmental fusion. Statistical significance was assumed to be at a 95 % level of significance. 23 cages were implanted. The mean value of the bone density obtained by computed tomography was 505 (+/- 119) HU on day three, 635 (+/- 156) HU after three months, 769 (+/- 162) HU after six months, and 814 (+/- 198) after 12 months. There was a significant difference when the values after 12 months were compared to those obtained after three days (p < 0.001) and after three months (p = 0.004). Bony fusion was seen in 21 out of 23 segments (91.3 %) after 12 months. It may be concluded that this technique could be an alternative to the current treatment options.

Bone Density↗
PubMed2005

[Intelligence, attention, and memory in patients with myasthenia gravis].

BACKGROUND: In patients with myasthenia gravis (MG), poor performance on cognitive tests has been found. Performance on memory tasks has been reported to correlate with disease activity, but memory in MG patients was also recently found to be unimpaired. PATIENTS AND METHODS: Cognitive functioning was examined in 23 patients with MG and 23 healthy controls. The patients were assessed for IQ, memory, attention, and motor performance. Immunoglobulin G antiacetylcholine receptor autoantibody titers were determined. Event-related potentials were generated for patients and controls. RESULTS: Mean IQs of patients were at average. Memory and attention were not more impaired in patients than controls. Event-related potentials were not delayed in either group. Patients with elevated autoantibody concentrations similarly showed unimpaired neurocognitive and motor functioning. CONCLUSION: In this study, no evidence of neuropsychological impairment was found in MG, arguing against the involvement of higher cortical functions. Sleep abnormalities rather than central mechanisms may explain the memory impairments reported by some studies.

Adolescent↗
PubMed2004

Synaptic congenital myasthenic syndrome in three patients due to a novel missense mutation (T441A) of the COLQ gene.

Congenital myasthenic syndromes (CMS) with deficiency of endplate acetylcholinesterase (AChE) are caused by mutations in the synapse specific collagenic tail subunit gene (COLQ) of AChE. We identified a novel missense mutation (T441A) homozygously in three CMS patients from two unrelated German families. The mutation is located in the C-terminal region of the ColQ protein, which initiates assembly of the triple helix, and is essential for insertion of the tail subunit into the basal lamina. Density gradient analysis of AChE extracted from muscle of one of the patients revealed the absence of asymmetric AChE. All patients were characterized by an onset of disease in childhood, exercise-induced proximal weakness, absence of ptosis and ophthalmoparesis, a decremental EMG response, and deterioration in response to anticholinesterase drugs. However, age at onset, disease progression, disease severity, and functional impairment varied considerably among the three patients. As adults, two siblings from one family experience only mild impairment, while the third patient requires a wheelchair for most of the day and assisted ventilation at night.

Acetylcholinesterase↗
PubMed2003

["Problem-based learning--inflammation and transplantation": an integrated, subject-centred course in the clinical section of the medical curriculum at the medical school of the University of Muenster].

Conventional medical curricula present information pertinent to chronic inflammatory diseases, infectious diseases and transplantation, via systematic lectures and courses in medical specialties without any integrated approach. The authors report on a 3-week model course that attempts to provide students with an overview of clinical presentation, diagnostics, and therapy of representative disease entities with particular emphasis on the interdisciplinary approach to these problems in hospital practice. In addition to problem-based learning in small groups, the model course comprises interdisciplinary concept lectures, practical demonstrations of specific diagnostic procedures, and bedside teaching. In the meantime, the course "Problem-Based Learning--Inflammation and Transplantation" has been held twice successfully as a mandatory course in the clinical part of the curriculum at the Muenster Medical School.

Autoimmune Diseases↗
PubMed2001

Rapid response of identified resident endoneurial macrophages to nerve injury.

Macrophages play a central role in the pathogenesis of peripheral neuropathy but the role of resident endoneurial macrophages is undefined because no discriminating markers exist to distinguish them from infiltrating hematogenous macrophages. We identified and characterized resident endoneurial macrophages during Wallerian degeneration in radiation bone marrow chimeric rats created by transplanting wild-type Lewis rat bone marrow into irradiated TK-tsa transgenic Lewis rats. In such animals, resident cells carry the transgene, whereas hematogenous cells do not. As early as 2 days after sciatic nerve crush and before the influx of hematogenous macrophages, resident transgene-positive endoneurial macrophages underwent morphological and immunophenotypic signs of activation. At the same time, resident macrophages phagocytosing myelin were found, and proliferation was detected by bromodeoxyuridine incorporation. Continuous bromodeoxyuridine feeding revealed that resident endoneurial macrophages sequentially retracted their processes, proliferated, and expressed the ED1 antigen, rendering them morphologically indistinguishable from hematogenous macrophages. Resident endoneurial macrophages thus play an early and active role in the cellular events after nerve lesion before hematogenous macrophages enter the nerve. They may thus be critically involved in the pathogenesis of peripheral neuropathy particularly at early stages of the disease and may act as sensors of pathology much like their central nervous system counterparts, the microglial cells.

Animals↗
PubMed2001

The role of macrophages in immune-mediated damage to the peripheral nervous system.

Macrophage-mediated segmental demyelination is the pathological hallmark of autoimmune demyelinating polyneuropathies, including the demyelinating form of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. Macrophages serve a multitude of functions throughout the entire pathogenetic process of autoimmune neuropathy. Resident endoneurial macrophages are likely to act as local antigen-presenting cells by their capability to express major histocompatibility complex antigens and costimulatory B7-molecules, and may thus be critical in triggering the autoimmune process. Hematogenous infiltrating macrophages then find their way into the peripheral nerve together with T-cells by the concerted action of adhesion molecules, matrix metalloproteases and chemotactic signals. Within the nerve, macrophages regulate inflammation by secreting several pro-inflammatory cytokines including IL-1, IL-6, IL-12 and TNF-alpha. Autoantibodies are likely to guide macrophages towards their myelin or primarily axonal targets, which then attack in a complement-dependent and receptor-mediated manner. In addition, non-specific tissue damage occurs through the secretion of toxic mediators and cytokines. Later, macrophages contribute to the termination of inflammation by promoting T-cell apoptosis and expressing anti-inflammatory cytokines including TGF-beta1 and IL-10. During recovery, they are tightly involved in allowing Schwann cell proliferation, remyelination and axonal regeneration to proceed. Macrophages, thus, play dual roles in autoimmune neuropathy, being detrimental in attacking nervous tissue but also salutary, when aiding in the termination of the inflammatory process and the promotion of recovery.

Animals↗
PubMed2001

Progress in Guillain-Barré syndrome.

This editorial review summarizes and critically analyses reports published in the preceding 18 months on the pathogenesis of Guillain-Barré syndrome, with particular emphasis on the role of ganglioside antibodies, antecedent infections, and the concept of molecular mimicry. It concludes with an appraisal of currently available and proposed therapies.

Autoantibodies↗
PubMed2000

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease.

Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA(+)CD8(+) T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8(+) phenotype. Moreover, it is primarily the proportion of circulating CD45RA(+)CD8(+) T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma. (Blood. 2000;96:3872-3879)

Adolescent↗
PubMed2000

Co-localization of multiple antigens and specific DNA. A novel method using methyl methacrylate-embedded semithin serial sections and catalyzed reporter deposition.

Co-localization of proteins and nucleic acid sequences by in situ hybridization and immunohistochemistry is frequently difficult as the process necessary to detect the target structure of one technique may negatively affect the target of the other. Morphological impairment may also limit the application of the two techniques on sensitive tissue. To overcome these problems we developed a method to perform in situ hybridization and immunohistochemistry on semithin sections of methyl methacrylate-embedded tissue. Microwave-stimulated antigen retrieval, signal amplification by catalyzed reporter deposition, and fluorescent dyes were used for both techniques, yielding high sensitivity and excellent morphological preservation compared to conventional paraffin sections. Co-localization of in situ hybridization and immunohistochemistry signals with high morphological resolution was achieved on single sections as well as on adjacent multiple serial sections, using computerized image processing. The latter allowed for the co-localization of multiple antigens and a specific DNA sequence at the same tissue level. The method was successfully applied to radiation bone marrow chimeric rats created by transplanting wild-type Lewis rat bone marrow into TK-tsa transgenic Lewis rats, in an attempt to trace and characterize TK-tsa transgenic cells. It also proved useful in the co-localization of multiple antigens in peripheral nerve biopsies.

Animals↗
PubMed2000

Small thymomas and myasthenia gravis: a poorly understood association.

Myasthenia gravis (MG) is associated with about 20% of all patients with thymomas, but the occurrence in patients with small thymomas is rare. The pathogenetic relevance of these small thymomas for MG is poorly understood until now. We report on the clinical course of a 39-year-old female patient suffering from MG and undergoing thymectomy for a small thymoma and discuss the pathogenetic importance of small thymomas for MG.

Adult↗
PubMed2000

Enhanced B7 costimulatory molecule expression in inflammatory human sural nerve biopsies.

OBJECTIVES: To define the role of the costimulatory molecules B7-1 and B7-2 in inflammatory disorders of the peripheral nervous system. B7 molecules are essential for effective antigen presentation and may determine the differentiation of T cells into a Th-1 or Th-2 phenotype, thus modulating immune response and disease course. METHODS: Forty nine sural nerve biopsies from patients with neuroborreliosis, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), CIDP variants and hereditary neuropathies, and those with no detectable abnormality were investigated. The expression of B7-1 and B7-2 mRNA and protein was investigated by polymerase chain reaction (PCR) and immunocytochemistry. RESULTS: B7-1 mRNA was strongly upregulated in both cases of neuroborreliosis, in two cases of GBS and one case of variant CIDP. Moderate to low levels were detected in the remaining GBS and CIDP biopsies and were rarely found in a non-inflammatory control group consisting of hereditary neuropathy and normal nerves. At the immunocytochemical level, strong expression of B7-1 protein was found in both neuroborreliosis cases, and moderate or low expression in six of eight GBS cases and seven of 17 CIDP cases investigated, whereas only one of five non-inflammatory control nerves showed staining, which was very weak. In neuroborreliosis, B7-1 protein was found very pronounced in epineurial infiltrates, whereas in GBS and CIDP, labelling was predominantly endoneurial and localised to putative macrophages. B7-2 mRNA and protein were expressed only at low levels in neuroborreliosis and selected autoimmune neuropathy cases, and were essentially absent from non-inflammatory controls. CONCLUSIONS: B7 molecules are expressed in the peripheral nervous system and regulated during disease, and their presence in macrophages underlines the putative function of endoneurial macrophages as local antigen presenting cells in the immunopathology of peripheral nerve. B7-1 rather than B7-2 is preferentially upregulated, possibly promoting the induction of a Th-1-type T cell response within the nerve.

B7-1 Antigen↗
PubMed1999

Autosomal dominant burning feet syndrome.

Familial burning feet syndrome inherited as an autosomal dominant trait has been described in only one family. Due to an associated sensory neuropathy the autosomal dominant burning feet syndrome was suggested to represent a variant form of hereditary sensory and autonomic neuropathy type I (HSAN I). Clinical, histopathological, and molecular genetic studies were performed in a large German kindred with autosomal dominant burning feet syndrome. The autosomal dominant burning feet syndrome was associated with a neuropathy predominantly affecting small unmyelinated nerve fibres. Linkage to the HSAN I locus on chromosome 9q22 and to the Charcot-Marie-Tooth disease type 2B (CMT 2B) locus on chromosome 3q13-q22 was excluded. The autosomal dominant burning feet syndrome is neither allelic to HSAN I nor to CMT 2B and thus represents a distinct genetic entity.

Female↗
PubMed1998

Prevalence of diabetes mellitus and associated cardiovascular risk factors in an adult urban population in Paraguay.

A cross-sectional study was conducted on a 20-74-year-old population in an urban white-Hispanic population in Paraguay to determine the prevalence of diabetes mellitus (DM), impaired glucose tolerance (IGT), and associated cardiovascular disease (CVD) risk factors. In total 1606 subjects completed the study (response rate 80.3%; 1094 women, 512 men). The overall prevalences were: DM 6.5%, IGT 11.3%, hypertension 17.1%, and obesity 31.6% with more obesity in women (35.7% vs 22.8%, p < 0.05). Age-standardized prevalences were: DM 6.5%, IGT 13.5% in females and DM 5.5%, IGT 7.2% in males. DM and IGT subjects had two or more CV risk factors significantly more often than the normal population. In conclusion, DM, IGT, hypertension, and obesity are common in this South American Hispanic urban population, particularly in women. Public health measures, such as lifestyle education, are required to decrease these noncommunicable diseases.

Adult↗
PubMed1998

Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats.

The potentially neurotrophic cytokine transforming growth factor-beta1 (TGF-beta1) is locally expressed following human stroke and experimental ischemic lesions, but the cellular source(s) and profile of induction have so far not been established in experimental focal cerebral ischemia. This study presents the time course and a cellular localization of TGF-beta1 mRNA, visualized by in situ hybridization combined with immunohistochemical staining for microglia, macrophages, or astrocytes, on brain sections from adult spontaneously hypertensive rats subjected to transient proximal occlusion of their middle cerebral artery. Six hours after ischemia, an early and transient neuronal and microglial expression of TGF-beta1 mRNA was observed in the extraischemic cingulate and frontal cortices. Both early and protracted expression of TGF-beta1 mRNA in the caudate-putamen and neocortical infarcts and in the caudate-putamen penumbra colocalized with OX42/ED1-immunoreactive microglia and macrophages, whereas TGF-beta1 mRNA in the neocortical penumbra colocalized with OX42/ED1-immunoreactive cells of a microglial morphology. No astrocytes were double-labeled. The number of TGF-beta1 mRNA-expressing microglia and macrophages increased strongly during the first week. Thereafter, TGF-beta1 mRNA became increasingly restricted to the neocortical penumbra (3 weeks), and after 3 months it was confined to activated microglia in the anterior commissure. Our data establish activated microglia and macrophages as the major source of TGF-beta1 mRNA following experimental focal cerebral ischemia. Consequently, TGF-beta1-mediated functions may be exerted by microglia both in the early degenerative phase, and later in combination with blood-borne macrophages, in the remodeling and healing phase after focal cerebral ischemia.

Animals↗
PubMed1998

Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis.

Matrix metalloproteinases (MMPs) comprise a group of proteolytic enzymes that are implicated in the pathogenesis of inflammatory diseases of the nervous system such as multiple sclerosis. However, the exact function and expression pattern of MMPs in the inflamed nervous system are not known. In the present study we investigated the expression of 92-kDa gelatinase (MMP-9) in spinal cord from animals with adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), using a semiquantitative competitive reverse transcriptase-polymerase chain reaction assay. Increased levels of MMP-9 mRNA were found with peak values at times of maximum disease severity. Increased mRNA expression was associated with enhanced proteolytic activity of this enzyme, as demonstrated by gelatin zymography. Immunohistochemistry revealed immunoreactivity along the meninges, around blood vessels and within the parenchyma, in diseased but not in normal spinal cord. Furthermore, the expression pattern of five other MMPs was investigated. Matrilysin (MMP-7) was also found to be upregulated with maximum mRNA levels at the peak of the disease. In contrast, mRNAs for collagenase-3, 72-kDa gelatinase, and stromelysin-1 and -3 were not changed. Our findings indicate that 92-kDa gelatinase and matrilysin are selectively upregulated during AT-EAE and thus may contribute to the pathogenesis of inflammatory diseases of the CNS.

Animals↗
PubMed1998

Macrophage differentiation antigens in acute and chronic autoimmune polyneuropathies.

The pathological differential diagnosis between potentially treatable autoimmune neuropathies and degenerative neuropathies is often difficult if major T-cell infiltrates are absent in sural nerve biopsies. Since it is suggested that macrophages play a central pathogenetic role in inflammatory neuropathies, we investigated the expression of macrophage differentiation antigens associated with acute (MRP14 and 27E10 antigens) and more chronic inflammation (MRP8 and 25F9 antigens) in 76 sural nerve biopsies from patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, other inflammatory neuropathies, hereditary neuropathies and normal sural nerves. Macrophage differentiation antigens were immunocytochemically detected in a majority of inflammatory biopsies but rarely in non-inflammatory disease controls and normal-looking nerves. Quantification of labelled endoneurial cells revealed significantly elevated cell counts compared with controls. In individual biopsies, elevated levels of one differentiation antigen were not necessarily associated with high expression of the other antigens, pointing to functional heterogeneity of endoneurial macrophages. Endoneurial cell counts for at least one of the differentiation markers that were greater than in any of the non-inflammatory control nerves were found in two-thirds of all inflammatory biopsies, whereas T-cell counts and in particular total macrophage counts were less sensitive in picking up biopsies from patients with inflammatory neuropathies. Antibodies to macrophage differentiation antigens are additional simple and helpful diagnostic tools in differentiating autoimmune from non-inflammatory neuropathies in sural nerve biopsies.

Acute Disease↗