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Biomedical subjects

H Wilms

Publications and source records attributed to H Wilms.

At least 19 recordsLinked to original sources
PubMed2003

Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration.

Autopsy studies and animal experiments suggest that microglial inflammation contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). Monocyte-chemoattractant protein (MCP-1) might play an important role in microglial recruitment. We studied MCP-1 levels in sera and cerebrospinal fluid of 29 ALS patients and compared the results with 11 control patients with tension headache. The MCP-1 level was determined using enzyme-linked immunosorbent assays (ELISA). A significant increase in cerebrospinal fluid MCP-1 level but not serum level was seen in the patients with ALS compared to the control subjects. These results suggest that cerebrospinal fluid MCP-1 activity may be a sensitive marker for neuroinflammation in ALS useful for monitoring treatment trials in ALS.

Age of Onset↗
PubMed2003

Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro.

Increased binding of a ligand for the peripheral benzodiazepine binding receptor is currently used in PET studies as an in vivo measurement of inflammation in diseases like multiple sclerosis and Alzheimer's disease. Although peripheral-type benzodiazepin receptors (PBRs) are abundant in many cell types and expressed in the CNS physiologically only at low levels, previous reports suggest that after experimental lesions in animal models and in human neurodegenerative/-inflammatory diseases upregulated PBR expression with increased binding of its ligand PK11195 is confined mainly to activated microglia in vivo/in situ. Because the functional role of the PBR is unknown, we confirm by immunohistochemistry and PCR (I) that this receptor is expressed on microglia in vitro and (II) that benzodiazepines modulate proliferation of microglial cells and the release of the inflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in cell culture supernatants of primary rat microglia. Compared to lipopolysaccharide-activated controls the release of NO was markedly decreased in cultures treated with benzodiazepines (clonazepam, midazolam, diazepam) and the PBR ligand PK11195. Moreover, release of TNF-alpha and proliferation was significantly inhibited in the benzodiazepine-treated groups. These findings link the in vivo data of elevated PBR levels in neurodegenerative/-inflammatory diseases to a functional role and opens up possible therapeutic intervention targeting the PBR in microglia.

Animals↗
PubMed2002

Cerebral occlusive artery disease in Noonan syndrome.

Noonan syndrome is an autosomal-dominant inherited syndrome with variable expression of multiple malformations including cardiovascular and craniofacial anomalies. While cerebrovascular insults due to cardiogenic emboli, coagulation abnormalities or cerebrovascular malformations have been documented before, intracerebral occlusive artery disease is not well recognized as a cause of stroke in this syndrome. A 6-year-old girl with Noonan syndrome presented with repetitive transient ischemic attacks consisting of dysphasia and right-sided central facial and arm weakness. Neuroimaging showed acute ischemic lesions in the left putamen and caudate nucleus. Multiple intracranial stenoses were found during transcranial Doppler examination and MR angiography. Although hypertrophic cardiomyopathy was documented by transesophageal echocardiography, a cardioembolic origin of the ischemic attacks was unlikely in this case. The symptoms resolved and did not recur after antiplatelet and anticoagulant therapy was initiated. Stenoses of intracranial cerebral arteries should be considered among the causes of stroke in young patients with Noonan syndrome.

Arterial Occlusive Diseases↗
PubMed2001

Cerebrospinal fluid from patients with neurodegenerative and neuroinflammatory diseases: no evidence for rat glial activation in vitro.

To determine the possible contribution of glial cells via oxidative stress/cytokine secretion in the pathogenesis of Parkinson's disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) the concentration of nitric oxide (NO) (by the Griess method) and Interleukin-6 (IL-6) (by enzyme-linked immunosorbent assay) were measured in resting rat microglial and astrocytic cell culture supernatants stimulated by cerebrospinal fluid (CSF) (dilution 1:4, 1:10) from patients with the aforementioned diseases. Neither the concentration of NO (optical density at 450 nm: control, 0.036+/-0.006; MS, 0.034+/-0.008; AD, 0.031+/-0.006; PD, 0.02+/-0.01; lipopolysaccharide (LPS), 0.26+/-0.018) nor the amount of IL-6 (ng/ml: control, 0.112+/-0.026; PD, 0.12+/-0.027; MS, 0.123+/-0.008; ALS, 0.137+/-0.01; LPS, 1.81+/-0.11) differed in any disease group from those of unaffected controls. These findings suggest that the stimuli for inflammatory activation of glia are quite localized and not present in sufficient concentrations in the CSF of affected patients.

Astrocytes↗
PubMed2001

From theory to therapy: implications from an in vitro model of ramified microglia.

Microglia are the principal immune cells in the central nervous system (CNS), characterized by a highly specific morphology and unusual antigenic phenotype. An increasing number of studies have focused on the role of microglia in the pathogenesis of neurodegenerative diseases. To elucidate the function of microglial cells under several neuropathological conditions, we have studied and established a cell culture model that allows us to cultivate microglial cells in their inactive, resting (ramified) phenotype. In the first part of this work, we describe the interaction of microglia cells with their epithelial (astrocytic) microenvironment. The second part reviews experiments with microglia cell cultures to elucidate underlying signalling pathways and summarizes recent advances of our knowledge in microglial molecular pathways that may ultimately lead to neurodegeneration.

Animals↗
PubMed2001

ATP and adenosine induce ramification of microglia in vitro.

Microglial cells in the healthy adult brain possess a characteristic ramified morphology with multiple branched processes, small somata and down-regulated inflammatory properties. In contrast, microglial cells isolated from new-born rat brain inevitably show a non-ramified amoeboid phenotype, which is observed in vivo after pathologic activation or during development. To identify factors that control microglial morphology we investigated the effects of purines alone or in combination with astrocyte-conditioned medium (ACM). Under optimized culture conditions postnatal rat microglial cells developed an amoeboid to ovoid phenotype. Addition of 0.6-1 mM ATP or adenosine induced the outgrowth of numerous processes after 2-3 days that could be observed also in the presence of ACM as previously reported. Culture in ACM plus ATP or adenosine yielded an optimized ramified phenotype. ATP or adenosine, but not ACM alone, also prevented the formation of a flat, amoeboid morphology induced by lipopolysaccharide (LPS); however, at 0.6-1 mM they did not reduce the initial LPS-induced activation of the transcription factor NF-kappaB. By using specific agonists or antagonists the morphological transformations could not be confined to a distinct purinoreceptor subtype, but appeared to be mediated by long-term presence of adenosine in the medium to which phosphorylated purines were rapidly hydrolyzed by microglial cells. Since ACM did not contain sufficient concentrations of ATP or adenosine, purines are not the only ramification-inducing factors present in ACM; however, they are a valuable tool to induce microglial ramification in vitro.

Adenosine↗
PubMed2000

The pathophysiology of parkinsonian tremor: a review.

Parkinsonian tremor is most likely due to oscillating neuronal activity within the CNS. Summarizing all the available evidence, peripheral factors only play a minor role in the generation, maintenance and modulation of PD tremor. Recent studies have shown that not a single but multiple oscillators are responsible. The most likely candidate producing these oscillations is the basal ganglia loop and its topographic organization might be responsible for the separation into different oscillators which, nevertheless, usually produce the same frequency. The neuronal mechanisms underlying these oscillations are not yet clear, but three hypotheses would be compatible with the presently available data from animal models and data recorded in patients. The first is a cortico-subthalamo-pallido-thalamic loop, the second is a pacemaker consisting of the external pallidum and the subthalamic nucleus, and the third is abnormal synchronization due to unknown mechanisms within the whole striato-pallido-thalamic pathway leading to a loss of segregation. Assuming the oscillator within the basal ganglia pathway, the mechanism of stereotactic surgery might be a desynchronization of the activity of the basal ganglia-thalamo-cortical or the cerebello-thalamo-cortical pathway.

Animals↗
PubMed2000

Mechanisms of parenchymal cell death in-vivo after microvascular hemorrhage.

OBJECTIVE: In vitro studies suggest that microhemorrhages with escape of red cells into the tissue may be cytotoxic to parenchymal cells due to oxygen free radical formation. We examined in the rat mesentery the impact of microhemorrhages on parenchymal cell death, as detected by propidium iodide staining, using an intravital approach. METHODS AND RESULTS: Postcapillary venules were punctured with a closed-end micropipette, permitting escape of blood cells and plasma into the mesentery interstitium. Over a period of 2 h, no significant increase in parenchymal cell death was encountered in tissues with hemorrhagic sites compared with nonhemorrhagic control sites. Interstitial microinjections of plasma derived from whole blood incubated for several hours with and without a combination of sodium azide (2 mM) and hydrogen peroxide (1 mM) led to significantly increased levels of cell death compared to control experiments. Interventions against the hydroxyl radical with dimethylthiourea (DMTU, 2 mM) or 2,2'-dipyridyl (DPD, 2 mM), a lipid soluble iron chelator, provided no protective effect against the parenchymal cell death. DMTU slightly delayed tile cytotoxic reaction. CONCLUSIONS: These observations suggest that a newly formed microhemorrhage is not necessarily cytotoxic to parenchymal tissue cells. Interstitial microinjections of plasma, derived from whole blood after prolonged exposure to oxygen free radicals or just aging under in vitro conditions, may be cytotoxic to mesenteric parenchymal cells without effective blockade by interventions against the hydroxyl radical.

2,2'-Dipyridyl↗
PubMed1999

In vitro-staining specificity of the antibody 5-D-4 for microglia but not for monocytes and macrophages indicates that microglia are a unique subgroup of the myelomonocytic lineage.

We have previously shown that (i) the ramified phenotype and (ii) the microglia-specific pattern of membrane currents are induced not only in microglia, but also in monocytes and macrophages if they are cultured in the presence of astrocytes. These findings indicated that microglia are not a separate type of cell of the myelomonocytic lineage, but are induced to take on their unique characteristics by astrocytes. Recently, it was discovered that the antibody 5-D-4 selectively stains ramified microglia in situ. We therefore studied the influence of astrocytes and other epithelial cells on the expression of the keratan sulfate epitope recognized by 5-D-4 in microglia and other myelomonocytic cells. Our findings show that this antigen is exclusively expressed in microglia only if they are induced to ramify by coculture with either astrocytes or epithelial cells. By contrast monocytes and macrophages, even if induced to take on the ramified phenotype do not stain positive with 5-D-4. These findings indicate (i) that 5-D-4 is a specific marker for ramified microglia in vitro, and (ii) that microglia are a separate class of myelomonocytic cells, distinct from monocytes and macrophages.

Animals↗
PubMed1999

Function of the cerebellum in Parkinsonian rest tremor and Holmes' tremor.

We describe a patient who developed Parkinson's disease (PD) 17 years after resection of his right cerebellum because of a Lindau tumor. He showed a classic 4.3-Hz resting tremor on the left side but a 3.1-Hz resting, postural, and intention tremor on the right side compatible with midbrain tremor (Holmes' tremor). We conclude that the generator of the tremor in PD cannot be located within the olivocerebellar loop. The cerebellum, however, seems to modulate the tremor frequency of parkinsonian rest tremor and may prevent the rest tremor from transforming into a postural and goal-directed tremor.

Adult↗
PubMed1999

Animal models of tremor.

Animal models of tremor have been widely used in experimental neurology, because they are an indispensable requirement for understanding the pathophysiology of human tremor disorders and the development of new therapeutic agents. This review focuses on three approaches to produce tremor in animals (application of tremorgenic drugs, experimental central nervous system lesions, study of genetic mutants) and their use in simulating tremor syndromes of humans. Whereas harmaline induces a postural/kinetic tremor in animals that shares some features with human essential tremor/enhanced physiological tremor, MPTP tremor is the best model available for rest tremor in people. The tremor following experimental lesion of the ventromedial tegmentum in primates closely resembles Holmes tremor in humans, whereas cerebellar intention tremor is mimicked by cooling of the lateral cerebellar nuclei. The "campus syndrome," discovered in a breed of Pietrain pigs, might be a useful model of human orthostatic tremor. However, no animal model has yet been generated that exactly recreates all features of any of the known tremor disorders in humans. Problems encountered when comparing tremor in animals and humans include differing tremor frequencies and the uncertainty, if specific transmitter abnormalities/central nervous system lesions seen in animal tremor models are characteristic for their human counterparts. The search for adequate tremor models continues.

Animals↗
PubMed1999

[Improvements in intra-arterial chemotherapy].

BACKGROUND: Intraarterial (i.a.) chemotherapy of head and neck cancer is a worldwide field of clinical research which is still developing. Over the last decade several improvements have been made. This paper relates our own experiences with the so-called bypass method of i.a. chemotherapy and with some recent international developments. METHODS: Between 1989 and 1998, 28 patients with head and neck cancer received Cisplatin intraarterially via the bypass route, 24 of them with a curative intention without any pretreatment. The daily dose was 20 mg and the overall aspired dosage was about 400 mg, given over a period of about 5 weeks, followed by full dose irradiation (> 60 Gy). During these 5 weeks anticoagulation with warfarin was performed. RESULTS: 16 patients received the planned total dose of i.a. Cisplatin. Ten cases of non-life-threatening bone marrow depression and/or 7 cases of slight kidney insufficiency led to premature termination of the chemotherapy. Due to anticoagulation no technical failures occurred (early thrombosis of the cannulated artery), as we had experienced in the past. In 12 of 24 cases a complete remission was observed. CONCLUSION: The bypass method is a technically well-developed method of i.a. infusion if performed by experienced personnel.

Adult↗
PubMed1997

Ramification of microglia, monocytes and macrophages in vitro: influences of various epithelial and mesenchymal cells and their conditioned media.

Microglial cells are able to switch between an "active" amoeboid and a ramified "resting" morphology during development and after experiencing lesions. We have previously shown that in vitro microglial morphology is controlled by their cellular environment, i. e. cells become ramified in astrocyte coculture but amoeboid on monolayers of fibroblasts. In the present study we have extended the analysis of the control of macrophage morphology by maintaining macrophages of different origins in coculture with different epithelial or mesenchymal cells and their conditioned media. Microglia, monocytes and spleen macrophages seeded onto monolayers of astrocytes, kidney epithelia or hepatoma cells developed the ramified morphology but remained amoeboid in fibroblast coculture. Ramification was also induced by media conditioned by these cells as well as by phorbolic esters, i.e. activators of protein kinase C. In double coculture assays, even small numbers of fibroblasts were able to override the "epithelial" influence. Likewise, microglia remained amoeboid, when incubated on several constituents of the extracellular matrix. These results indicate that macrophage ramification is an active process initiated by diffusible factors secreted by various epithelial cells, possibly acting upon a protein-kinase-C-related receptor. We interprete the modification of macrophage morphology as a functional adaptation to the surrounding type of tissue that is enforced by its constituent cells. Thus, the specific morphologies of microglia, hepatic von Kupffer's cells or peritubular kidney macrophages could be explained by similar epithelium-macrophage interaction.

Animals↗
PubMed1996

Multimerization of thyroglobulin (TG) during extracellular storage: isolation of highly cross-linked TG from human thyroids.

Thyroglobulin (TG) is the major soluble protein of the thyroid and is known to be extracellularly stored for future liberation of thyroid hormones. We have developed techniques for the isolation of an insoluble storage form of human TG present in the follicle lumen. The application of these techniques yielded insoluble and translucent colloid globules varying in size (50-500 microns) and shape and consisting primarily of densely packed TG. Intact colloid globules exhibited the imprints of the apical cell surfaces of thyrocytes that had surrounded the colloid globules in situ. Hence, in size and surface morphology, isolated colloid globules represent authentic lumenal content. Based on the total protein of single colloid globules and their volume, an average protein concentration of 590 mg/mL was calculated. The presence of protein disulfide isomerase in colloid globules and in the secretory product of cultured thyrocytes suggests its involvement in the extracellular multimerization of human TG. Native colloid globules increased their volume considerably upon reduction of disulfide bonds; they were completely dissolved by treatment with dithiothreitol and SDS. The results show that part of extracellular human TG undergoes multimerization, primarily by the formation of intermolecular disulfide bonds, thus allowing the storage of TG at excessively high, previously unknown, concentrations.

Adult↗
PubMed1994

Incidence, diagnosis, and treatment of ureteric stenosis in 1298 renal transplant patients.

Of 1130 patients who had undergone a total of 1298 kidney transplantations, 40 developed a stenosis of the ureter (3.1%). In all of the transplants, the anastomosis between the ureter and the urinary bladder was established as extravesical ureteroneocystostomy. Up until 1984, in cases where an obstruction in the urinary tract was suspected, the diagnosis was made by an i.v. pyelogram or by nuclear scans of the transplant. Thereafter, in 28 patients, in cases of sonographically suspected stenosis of the ureter, the diagnosis was established by means of a simplified Whitaker test. Nearly one-half of the stenoses of the ureter developed within the first 3 months after transplantation. In five patients (12.5%) the stenosis developed significantly later, 3-10 years after kidney transplantation. Seventy percent of the stenoses were localized in the distal third of the ureter. About 75% of the surgically explored stenoses could be corrected by resection and reimplantation of the ureter. During the post-operative follow-up, restenosis occurred in three patients. At present, 62% of all patients whose ureteric stenoses were corrected have well-functioning kidney transplants.

Adolescent↗
PubMed1991

[20 years kidney transplantation. Experience of a practice].

Between September, 1969, and May, 1990, 1,086 kidney transplantations were performed in Freiburg. In the majority of cases, the transplantations were allografts and had been made possible by close cooperation with the Eurotransplant Foundation. The results of this long-term study show that the transplant function rates at one year in the period under observation were comparable. Only the introduction of the immunosuppressive agent cyclosporine A brought about any improvement. On the basis of the results achieved at our center, the HLA system had an influence on transplantation function rate only in the case of the DR system. However, this does not mean that, for organ matching, the HLA system should no longer be complied with, since multicentric studies have substantiated its importance. High-risk groups, such as diabetics and elderly patients who undergo a transplantation achieve the same good results as the low-risk groups, provided that each case is carefully considered on its individual merits.

Adolescent↗