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Biomedical subjects

P Rieckmann

Publications and source records attributed to P Rieckmann.

At least 73 records · Page 4Linked to original sources
PubMed1998

[Juvenile cerebral ischaemia caused by designer drugs].

HISTORY AND CLINICAL FINDINGS: A 29-year-old man reported two episodes, 3 months apart, of dysarthria, each lasting for several hours. It was associated with hypaesthesia over the cheeks. Neurological examination several hours later was unremarkable. On direct questioning the patient reported that he had been taking marihuana and cocaine immediately before each episode. There was also a history of regular abuse of various drugs over several years by this socially well integrated young man. INVESTIGATIONS: Cranial computed tomography, cranial magnetic resonance imaging and cerebral scintigraphy indicated multiple cortical and subcortical ischaemic lesions of different sizes and ages. ECG, long-term ECG monitoring, transoesophageal echocardiography and upper abdominal sonography were normal. Cerebrospinal fluid revealed a slightly abnormal blood-brain barrier (5.3 g/l protein, albumin ratio of 7.3). Auto-antibody titres and coagulation and serological tests for neurotropic bacteria and viruses were normal. Urinary drug screening was positive for cannabinoids. DIAGNOSIS, TREATMENT AND COURSE: We assume that the patient had transitory cocaine-induced ischaemic attacks (TIA) and clinically silent cerebrovascular accidents (CVA). He was discharged without specific treatment after being informed of the severe neurological sequelae of his drug abuse. CONCLUSIONS: The rising abuse of "designer drugs" is of increasing diagnostic significance in TIA-like symptoms and CVAs in young adults, which may be of haemorrhagic or ischaemic aetiology. Thromboembolic, vasospastic or vasculitic factors play a pathogenetic role. Early performance of appropriate blood and urine tests is of great diagnostic importance.

Adult↗
PubMed1998

Serum levels of macrophage-derived protein MRP-8/14 are elevated in active multiple sclerosis.

Serum concentrations of two macrophage-derived calcium-binding proteins, MRP-8 and MRP-8/14, were studied in 28 patients with relapsing multiple sclerosis (MS). Serum levels were determined with a commercially available sandwich ELISA and the one-tailed Mann-Whitney U test was used for statistical analysis. Median serum levels of MRP-8/14 were significantly higher in MS patients (5150 ng/ml) compared to 26 healthy controls (1482 ng/ml) and significantly higher in MS patients within an acute relapse (6690 ng/ml) compared to MS patients with stable disease (3050 ng/ml). MRP-8 levels were not elevated in MS patients. These results may indicate an early activation of macrophages in the formation of demyelinating MS plaques. In addition, increased serum levels of MRP-8/14 may prove to be a useful paraclinical disease activity parameter in MS patients.

Acute Disease↗
PubMed1998

A method for preventing artifactual binding of cRNA probes to neurons caused by in situ hybridization.

When in situ hybridization was used for the detection of mRNA for the beta-trace protein (beta-trace; prostaglandin-D-synthase) in sections of rat and porcine brains, unspecific binding reactions of sense and antisense probes to neurons were observed. The beta-trace fragment which served as a template for the synthesis of cRNA probes was blunt end-cloned in the vector pCR-Script SK (+). It was demonstrated that the unspecific signals were caused by artifactual binding of two portions of the cRNA which correspond to sequences of the multicloning site of this vector. These sequences are localized between the SrfI restriction site (or the insert) and the promoter for the T7 RNA polymerase. Thus, artifactual binding could be prevented using riboprobes synthesized by T3 RNA polymerase instead of T7 RNA polymerase. Because of the relatively weak transcription efficiency of T3 RNA polymerase, as compared with T7 RNA polymerase, a blocking procedure was established which allowed successful in situ hybridization with T7 RNA polymerase-synthesized probes. Blocking was performed using synthetic oligonucleotides deduced from the two sequences of the multicloning site which were found to be responsible for artifactual binding.

Animals↗
PubMed1998

Synergistic immunomodulatory effects of interferon-beta1b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis.

Subcutaneous application of interferon-beta1b (IFN-beta1b) is an established therapy for patients with relapsing-remitting multiple sclerosis (RRMS), but early side effects are still a major concern. In vitro studies with myelin basic protein (MBP)-specific T-cell lines revealed a synergistic suppressive effect of IFN-beta1b and the phosphodiesterase inhibitor pentoxifylline (PTX) on proliferation and the production of tumor necrosis factor-alpha (TNF-alpha), lymphotoxin (LT), and interferon-gamma (IFN-gamma). In an initial, open labeled prospective trial, the cytokine messenger RNA (mRNA) expression of blood mononuclear cells from MS patients, receiving either IFN-beta1b alone or in combination with oral PTX, was determined by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Patients treated with IFN-beta1b alone reported more side effects during the first 3 months of treatment and had upregulated TNF-alpha as well as IFN-gamma mRNA expression during the first month, which was not detected in patients receiving both drugs. A synergistic effect of both drugs was observed on the upregulation of interleukin (IL)-10 mRNA, which was accompanied by an increase in IL-10 serum levels. Both in vitro and in vivo data suggest that co-treatment of IFN-beta1b with PTX is a promising approach to correct the disturbed cytokine balance in MS patients.

Adjuvants, Immunologic↗
PubMed1998

Identification of macrophage populations expressing tumor necrosis factor-alpha mRNA in acute multiple sclerosis.

Macrophages are involved in central nervous system (CNS) demyelination in multiple sclerosis (MS) and other demyelinating diseases. Macrophages seen in MS lesions form a heterogeneous population with respect to their stage of activation and differentiation. We have analyzed macrophages from active demyelinating lesions of a patient who died from fulminant MS of Marburg's type to define the functional heterogeneity of different macrophage populations in acute demyelination. We examined tumor necrosis factor-alpha (TNF-alpha) mRNA expression in macrophages defined by different activation markers. The majority of TNF-alpha mRNA-positive cells were macrophages positive for the pan-macrophage marker KiM1P. A subgroup of TNF-alpha mRNA-positive macrophages was stained by the early activation marker MRP14. In contrast, macrophages positive for the acute activation marker 27E10 were entirely negative for TNF-alpha mRNA. In conclusion, macrophages in acute demyelinating CNS lesions are heterogeneous as shown by staining for different activation markers. This heterogeneity is also of functional relevance as certain subpopulations are involved in TNF-alpha mRNA expression, while others are not. This may be important for directing therapeutic strategies against well-defined pathogenic macrophage populations.

Acute Disease↗
PubMed1998

A longitudinal prospective study of soluble adhesion molecules in acute stroke.

BACKGROUND AND PURPOSE: Activation of endothelial cells is a consequence of cerebral ischemia and leads to the expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, which can be released into the blood. This study aimed to define the kinetics of soluble adhesion molecule serum levels after cerebral ischemia and their correlation with the extent of neurological deficits, clinical outcome, and infarct volume as measured on CT scans. Methods-Plasma levels of soluble (s) ICAM-1, sVCAM-1, and sE-selectin were repeatedly determined by ELISA in 38 patients during a period of 14 days after acute cerebral ischemia. RESULTS: Soluble adhesion molecule levels demonstrated considerable variability. Overall, concentrations revealed characteristic and significant changes after completed strokes but not after transient ischemic attacks. In patients with completed stroke (n=26) but not in patients with transient ischemic attacks (n=12), sICAM-1 peaked within 24 hours (P=0.04), sVCAM-1 reached a maximum after 5 days (P=0.02), and sE-selectin levels decreased after 5 days (P=0.002). There was no clear-cut correlation of soluble adhesion molecule levels with infarct volume or clinical disability. The initial increase of sE-selectin levels was higher in more disabled patients (P=0.02). sICAM-1 levels were higher in patients with signs of infection (n=9; P=0.03). CONCLUSIONS: As a result of large interindividual variability influenced by ischemia-independent factors, soluble adhesion molecules are not reliable candidates as surrogate markers in acute cerebral ischemia. The characteristic profile of individual soluble adhesion molecules after completed stroke supports prior hypotheses of their involvement in the pathogenesis of acute cerebral ischemia, but this needs to be clarified in detail.

Acute Disease↗
PubMed1998

Correlation of soluble adhesion molecules in blood and cerebrospinal fluid with magnetic resonance imaging activity in patients with multiple sclerosis.

Several studies have reported a positive correlation between levels of soluble adhesion molecules in serum or cerebrospinal fluid and cranial MRI activity. We performed a cross-sectional study in 46 patients with newly diagnosed MS and determined levels of soluble intercellular adhesion molecule-I (sICAM-I) as well as vascular cell adhesion molecule-I (sVCAM-I) in correlation to the number and area of gadolinium enhancing lesions on cranial magnetic resonance images (MRI). The data revealed a significant positive correlation between sVCAM-I serum levels and gadolinium enhancing lesions. In addition, CSF to serum ratios for sICAM-I and sVCAM-I correlated to MRI activity. In patients with a single enhancing lesion (SEL) there was a negative correlation between the QsCAM and the distance of the SEL to the ventricles. As these adhesion molecules are stable and markers of disease activity in MS, we further investigated sVCAM-I serum levels during treatment with interferon beta-Ib (Betaferon). Significant increases in serum levels for sVCAM-I in patients receiving Betaferon were associated with a favourable treatment response after 1 year in 17 out of 19 patients and correlated to decreased MRI activity, whereas stable or reduced sVCAM-I levels occurred more often in non-responders (five out of six patients). Therefore it can be hypothesized that soluble adhesion molecules are released from cerebral endothelial cells as an early immunoregulatory activity of the immune system to reduce cellular traffic across the blood brain barrier and this is further enhanced by IFN-beta treatment.

Adjuvants, Immunologic↗
PubMed1997

Quantification of cytokine mRNA expression by RT PCR in samples of previously frozen blood.

In order to facilitate cytokine mRNA detection in blood cells, we have developed a highly reproducible and easily performed RNA isolation method for use with whole blood. Previously frozen human whole blood samples were lysed in guanidine thiocyanate solution to isolate total RNA. After reverse transcription a PCR method was applied to detect beta-actin and cytokine mRNA expression (interleukin-(IL)2, IL4, IL10, tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma)). The presence of cDNA was confirmed by agarose gel electrophoresis and quantitated on-line using sequence-specific fluorochrome labeled internal oligonucleotide probes. This quantitative method is based on the cleavage of fluorescent dye labeled probes by the 5' --> 3' endonuclease activity of the Taq DNA polymerase during PCR and measurement of fluorescence intensity by a Sequence Detector System. The signal generated was directly proportional to the starting copy number of target molecules in the sample over 6 log concentrations and quantitative analysis of cDNA concentrations was performed in comparison to beta-actin or cytokine cDNA standards. mRNAs coding for beta-actin and TNF alpha were readily detectable in cDNAs prepared from the whole blood of eight healthy donors, while the other cytokines were expressed in lower amounts (IFN gamma, IL10) or were undetectable (IL2, IL4). The assay described is highly reproducible, requires no post PCR manipulation of the amplicons and permits the analysis of several hundred PCR reactions per day. Using this method it is possible to detect and quantify cytokine mRNA expression reliably in small amounts of previously frozen blood even after storage of samples for at least several months.

Cytokines↗
PubMed1997

Soluble adhesion molecules (sVCAM-1 and sICAM-1) in cerebrospinal fluid and serum correlate with MRI activity in multiple sclerosis.

We performed a prospective study to correlate quantiative brain magnetic resonance imaging activity (gadolinium-diethylenetriaminepentaacetic acid enhancement) to cerebrospinal fluid and serum levels of soluble adhesion molecules in 46 patients with newly diagnosed multiple sclerosis (MS) and 30 control subjects with other diseases of the central nervous system. In all patients, magnetic resonance imaging of the brain and lumbar puncture were performed on the same day. In 32 (70%) of 46 MS patients, 8 (80%) of 10 patients with acute viral encephalitis, but none of the control subjects with noninflammatory diseases, gadolinium-enhancing lesions were detected. There was a significant correlation between the cerebrospinal fluid/serum ratios for soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 as well as serum levels for both molecules and the area of gadolinium-enhancing lesions. No obvious correlation was observed between magnetic resonance imaging findings and cerebrospinal fluid cell count, protein concentration, or intrathecal immunoglobulin production. In patients with a single periventricular gadolinium-enhancing lesion (n = 16), we observed a strong negative correlation between the distance from the lateral ventricles and the cerebrospinal fluid/serum ratios for soluble intercellular adhesion molecule-1/albumin and soluble vascular cell adhesion molecule-1/albumin. These results suggest that intrathecal production of the two soluble adhesion molecules, as well as serum levels for soluble vascular cell adhesion molecule-1, in patients with MS reflect magnetic resonance imaging activity of typical periventricular lesions.

Adult↗
PubMed1997

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in B-lymphocyte function.

Two cytokines important in the regulation of B-cell function are tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). They act at different steps in B-cell differentiation and can be produced by the B cells themselves upon appropriate stimulation. Crosslinking of surface Ig and signaling through CD22 or CD40 lead to increased secretion of both cytokines. Neutralization of TNF-alpha or IL-6 biologic activity in B-cell cultures results in a significant reduction in B-cell proliferation and Ig secretion. Increased production of these cytokines is found in several diseases associated with aberrant B-cell function. This review will focus on the role of TNF-alpha and IL-6 in normal and pathophysiological conditions of B-cell function.

Antibodies, Monoclonal↗
PubMed1997

Pathogenesis of immune-mediated demyelination in the CNS.

Collective evidence from studies in the animal model experimental autoimmune encephalomyelitis and pathological and immunological studies on MS patients suggest that this most common inflammatory demyelinating disorder of the central nervous system results from primarily T-lymphocyte driven aberrant immune responses to a number of myelin and possibly non-myelin antigens. These include MBP, PLP, MOG, MAG, CNP and S 100. Autoreactive T-cells reactive with these antigens circulate in blood and upon activation can travel across the blood-brain-barrier to initiate a local immunoflammatory response provided they encounter a microglial cell that displays antigenic epitopes in the context of MHC class II gene products and accessory molecules. Demyelination probably results from antibody-induced complement activation. Repeated inflammatory episodes eventually exhaust the reparative capacities of oligodendrocytes and damage axons. As the disease evolves, an initialy focussed immune response may diversify due to a process termed epitope spreading. The initial event of T lymphocyte activation remains elusive, but molecular mimicry, cross-recognition of structures shared between microbes and myelin, appears to be crucial.

Animals↗
PubMed1997

Limited efficacy of pentoxifylline as anti-inflammatory agent in experimental pneumococcal meningitis.

Dexamethasone appears to show some adverse side-effects as adjunctive anti-inflammatory agent in bacterial meningitis. For this reason, we tested the anti-inflammatory and neuroprotective effect of pentoxifylline administered 15 min before starting antibiotic treatment with ceftriaxone (n = 10) versus antibiotic therapy alone (n = 9) in the rabbit model of pneumococcal meningitis. Pentoxifylline lowered the medians of leucocyte density, tumour necrosis factor-alpha (TNF-alpha) and lactate in the cerebrospinal fluid (CSF), but only leucocyte migration into the subarachnoid space was significantly inhibited 8 h after initiation of therapy (P = 0.01). CSF protein, brain water content, and the entry of ceftriaxone into CSF were not influenced by pentoxifylline. The density of neuronal apoptoses in the dentate gyrus was slightly lower in animals receiving pentoxifylline than in those treated with ceftriaxone only. The median concentration of neuron-specific enolase in CSF was lower in the pentoxifylline-treated group, but the difference was not significant. In conclusion, pentoxifylline showed some anti-inflammatory activity in pneumococcal meningitis, but the substance failed significantly to reduce neuronal damage.

Animals↗
PubMed1996

Gene polymorphism at position -308 of the tumor-necrosis-factor-alpha (TNF-alpha) in multiple sclerosis and it's influence on the regulation of TNF-alpha production.

Tumor-necrosis-factor alpha (TNF-alpha) is a major mediator of the inflammatory immune response and may play an important role in the pathogenesis and progression of Multiple Sclerosis (MS). Increased TNF-alpha levels of cerebrospinal fluid (CSF) and peripheral blood were found in patients with chronic progressive MS and patients with acute relapses, but not in the stable form of the disease. Considering the association of different TNF-alpha alleles with diverse autoimmune diseases we sequenced the TNF-alpha promotor region (-674 to +201) of 23 patients with relapsing/remitting MS, of 27 patients with chronic progressive MS (21 patients had primary progressive course and six patients had a secondary progressive course) and of 22 healthy controls, who had no history of MS in their families. In three of 21 patients (14%) with primary chronic progressive MS a homozygous point-mutation at position -308 could be demonstrated where guanine (G) was substituted by adenosine (A). This mutation could neither be detected in patients with relapsing/remitting MS nor in healthy controls. However, 40% of the patients with relapsing/remitting MS and 43% of the primary chronic progressive MS patients were heterozygous at position -308 for G/A, whereas only 32% of healthy controls showed this heterogeneity. The genetic variations were demonstrated by polymerase chain reaction (PCR)-amplification of the TNF-alpha promotor-region and consecutive direct automatic sequencing. Functional analysis of the promoter region using the chloramphenicol-acetyltransferase (CAT) assay revealed spontaneous production with the homozygous mutation at -308 only.

Adenosine↗
PubMed1996

Cell-mediated immune response of macaques immunized with low doses of simian immunodeficiency virus (SIV).

Many uninfected people at high risk of HIV infection developed an HIV-specific cellular immune response despite their lack of seroconversion. Therefore, they must have been exposed to HIV without subsequent infection. It has been concluded from these data, that cell-mediated immunity (CMI) rather than humoral immunity might confer protection to HIV infection. Therefore, we tried to induce such a strong CMI in macaques by different immunization strategies. Five or seven animals were immunized with high or low doses of a whole SIV split vaccine. The lower dose of the vaccine provoked a stronger T-helper cell (TH) proliferation than the higher dose, which led to a pronounced humoral immune response. To induce a strong CMI without any specific antibody response, five macaques were inoculated with low doses of infectious SIV. None of these animals seroconverted but each animal developed a SIV-specific TH response. Interestingly, we could neither detect an SIV-specific CTL activity in the animals nor did we find typical TH1- or TH2-like cytokine profiles investigating stimulated bulk-cultures from SIV-exposed animals by RT-PCR. 24 weeks after the first low dose SIV exposure the animals were boosted by a second low dose of SIV followed by a subsequent intravenous challenge with a high dose of SIV 12 weeks later. Unexpectedly, none of the animals was found to be protected against infection and the development of AIDS-like symptoms.

Animals↗