Biomedical subjects

J Wiltfang

Publications and source records attributed to J Wiltfang.

At least 109 records · Page 6Linked to original sources

PubMed1999

Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. Rapid communication.

The spectrum of action of flupirtine includes analgesia, muscle relaxation and neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonism has been discussed as a possible mechanism of action of this compound with little direct evidence. The objective of the present study was to develop a plausible model to explain flupirtine's spectrum of action. A four-stage strategy was selected for this purpose: Firstly, the serum concentration of flupirtine under therapeutic conditions was determined on the basis of the current literature. The second stage involved assessing the known in-vitro effects in light of the therapeutic active concentration. Using whole cell patch clamp recordings from cultured rat superior colliculus neurones interactions between flupirtine and NMDA receptors were assessed. Only very high concentrations of flupirtine antagonized inward currents to NMDA (200 microM) at -70 mV with an lC50 against steady-state responses of 182.1+/-12.1 microM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA receptor antagonism probably has little relevance for the clinical efficacy of flupirtine as the concentrations needed were far higher than those achieved in clinical practice. However, the activation of a G-protein-regulated inwardly rectifying K+ channel was identified as an interesting molecular target site of flupirtine. In the next stage, the central nervous spectrum of action of experimental K+ channel openers (PCO) was considered. As far as they have been studied, experimental K+ channel openers display a spectrum of action comparable to that of flupirtine. In the final stage, a global model was developed in which flupirtine stabilizes the resting membrane potential by activating inwardly rectifying K+ channels, thus indirectly inhibiting the activation of NMDA receptors. The model presented here reconciles the known functional NMDA receptor antagonism of flupirtine with the activation of K+ channels that occurs at therapeutic concentrations, thus providing an understanding of flupirtine's spectrum of action. This makes flupirtine the prototype of a clinically applicable substance group with analgesic, muscle-relaxant and neuroprotective properties.

Aminopyridines↗

PubMed1999

[Clinical studies on the pathophysiology of odontogenic abscesses].

In 26 patients with abscesses in the maxillofacial area, the electrolyte concentrations, pH and osmotic and hydrostatic pressures of the pus fluid were measured and calculated. The main cations identified were sodium (134 +/- 38 mmol/l) and potassium (37 +/- 16 mmol/l) and as anions chloride (183 +/- 46 mmol/l) and bicarbonate (10 +/- 4 mmol/l). The pH value of the pus liquid was 6.164 +/- 0.233. The calculated mean osmotic pressure of the pus liquid was 7910 +/- 1455 mm Hg, whereas the measured physical pressure inside the abscess was 49 +/- 13 mm Hg. Both pressure types show time-dependent pressure curves. With time, the real pressure inside the abscess cavity increases, whereas the osmotic pressure decreases. There was no relationship between the two pressure types and the different species of microorganisms responsible for the inflammation. The results of the study reveal that abscesses can be regarded as osmotically active systems, and the mechanism by which the abscess is formed might be as follows. After penetration of virulent microorganisms into the tissue space, the area of acute inflammation is walled off by the collection of inflammatory cells. Destruction of tissue by products of the polymorphonuclear leucozytes takes place and results in liquefactive necrosis and a hypertonic abscess cavity. The inwards-directed flow of tissue fluids into the cavity via the abscess membrane causes volume expansion and generates pressure, two facts that can explain the swelling dynamics and typical symptoms of abscesses in the maxillofacial area.

Humans↗

PubMed1999

[Biodegradable miniplates (lactosorb) in cranio-osteoplasty--experimental results with the rapidly maturing, juvenile minipig].

As a passive intracranial transmission (PIT- effect) has been described for metallic osteosyntheses materials in the infant growing skull. Thereby the use of resorbable plates and screws might be an alernative fixation device in infant craniofacial surgery. For evaluating the biological behaviour, craniotomies were performed in the frontoorbital region of four infant minipigs, six weeks of age and 6.1 kg of weight. After turning and orthotopical repositioning the full thickness bone graft were fixed with resorbable plates and screws made of LactoSorb on the left side after epiperiosteal, on the right side after subperiosteal preparation. The animals were sacrificed after 3, 6, 9 and 18 months. Histologically, a PIT- effect was detected similar to metallic microplates and screws being significant diminished after epiperiosteal preparation and plate positioning. The biodegradation was not affected by intraosseous translocation. Even in case of intrasinuidal transmission no inflammatory reactions werde observed. No contraindications for the clinical use of this specific PLLA-PGA copolymer could be found when implanted in the rapidly growing craniofacial bone surfaces.

Animals↗

PubMed1999

Cisternal S100 protein and neuron-specific enolase are elevated and site-specific markers in intractable temporal lobe epilepsy.

In the brain, S100 protein and neuron-specific enolase (NSE) are mainly found in glial cells and neurons, respectively. We investigated concentrations of S100 protein and NSE in cisternal cerebrospinal fluid obtained during implantation of foramen ovale electrodes in eight patients with temporal lobe epilepsy (TLE). In addition, the meningeal markers cystatin-C and beta-trace as well as total protein were measured. Patients with trigeminal neuralgia (TN) undergoing glycerol rhizotomy served as controls. S100 protein and NSE levels ipsilateral to the site of seizure onset were significantly higher than in TN. Contralateral TLE values were also markedly but not significantly elevated. The meningeal markers cystatin-C and beta-trace protein as well as total protein did not differ in TLE and TN. We conclude that interictal temporal lobe dysfunction corresponds with neuronal and glial marker elevations in the extracellular space and that site-specific elevations may predict the site of seizure origin biochemically.

Adult↗

PubMed1999

The resorbable miniplate system Lactosorb in a growing cranio-osteoplasty animal model.

In the surgical treatment of craniosynostosis and craniofacial dysostosis in the growing child, passive intraosseous translocation (PIT effect) with intracranial displacement of metal plates and screws may be a problem. In an animal experiment, a possible PIT effect using resorbable PLA/PGA miniplates (Lactosorb, W. Lorenz, FL, USA) following cranio-osteoplasty were investigated in four young Göttingen minipigs. In addition to the mechanical properties, the processes of degradation and of sub- vs supraperiosteal application of the miniplates were evaluated. During degradation the resorbable PLA/PGA miniplates performed like metal plates as they also displayed passive intraosseous translocation in the growing animal model. However, in the experimental PLA/PGA miniplating the internal calvarial bone was not affected. Degradation took 12-18 months and was not delayed by bony incorporation. Mechanical properties proved to be sufficient in craniofacial surgery. Supraperiosteal plating delayed the PIT effect during the first 3 months after surgery. In the growing skull resorbable plates seem to be a promising therapeutic approach. However, prior to a general recommendation results of long-term clinical studies have to be evaluated.

Absorbable Implants↗

PubMed1999

Elevated serum levels of astroglial S100beta in patients with liver cirrhosis indicate early and subclinical portal-systemic encephalopathy.

Portal-systemic encephalopathy is the prototype among the neuropsychiatric disorders that fall under the term Hepatic Encephalopathies. Ammonia toxicity is central to the pathophysiology of Portal-systemic encephalopathy, and neuronal ammonia toxicity is modulated by activated astrocytes. The calcium-binding astroglial key protein S100beta is released in response to glial activation, and its measurement in serum only recently became possible. Serum S100beta was determined by an ultrasensitive ELISA in patients (n=36) with liver cirrhosis and transjugular intrahepatic portosystemic stent-shunt. Subclinical portal-systemic encephalopathy and overt portal-systemic encephalopathy were determined by age-adjusted psychometric tests and clinical staging, respectively. Serum S100beta, was specifically elevated in the presence of subclinical or early portal-systemic encephalopathy, but not arterial ammonia. S100 levels elevated above a reference value (S100beta < or = 110pg/ml) or the cut off value determined in our group of patients (112pg/ml) predicted subclinical portal-systemic encephalopathy with a specificity and sensitivity of 100 and 56.5%, respectively. Serum S100beta was significantly dependent on liver dysfunction (Child-Pugh score), but was more closely related to cognitive impairments than the score. Serum S100beta seems to be a promising biochemical surrogate marker for mild cognitive impairments due to portal-systemic encephalopathy.

Astrocytes↗

PubMed1999

Prothrombin concentration in the cerebrospinal fluid is not altered in Alzheimer's disease.

Prothrombin, known to be expressed in brain and to possess growth modulating properties, has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). We studied prothrombin concentration in lumbar CSF (L-CSF) in patients with AD (n = 25), neurologic disease controls (NDC; n = 33) covering a wide range of neurologic disorders, and subjects with Guillain-Barre syndrome (GBS; n = 4) as well as in samples of non-pathological ventricular CSF (V-CSF; n = 4). The results were evaluated with respect to CSF flow rate, as indicated by the albumin quotient (Q(Alb)). The concentrations of prothrombin in L-CSF in NDC (mean: 0.46 mg/l, range: 0.21-0.96), and AD (mean: 0.6 mg/l, range: 0.19-1.2) were in the normal range reported previously. Expectedly, prothrombin concentration in L-CSF of GBS was increased (mean: 6.3 mg/l, range: 2.3-9.7) corresponding to the increased Q(Alb) in this group (mean 54.6x10(-3), range: 17-88.1). The concentrations of both prothrombin and albumin were 5.5-fold higher in L-CSF than in V-CSF (mean Q(Alb) : 1.1x10(-3), mean concentration of prothrombin: 0.088 mg/l). In conclusion, CSF prothrombin in all conditions evaluated here is exclusively derived from blood.

Adolescent↗

PubMed1999

Isoform pattern of 14-3-3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

Two-dimensional polyacrylamide gel electrophoresis of CSF has been used in the diagnosis of Creutzfeldt-Jakob disease (CJD). One of the two diagnostic protein spots was identified as isoform(s) of the 14-3-3 family of abundant brain proteins. This has led to the development of one-dimensional 14-3-3 sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot, which is currently used to support the diagnosis of CJD. In the present study employing western blot analysis, we have identified the panel of 14-3-3 isoforms that appear in the CSF of 10 patients with CJD compared with 10 patients with other dementias. The results clearly show that the 14-3-3 isoforms beta, gamma, epsilon, and eta are present in the CSF of patients with CJD and can be used to differentiate other dementias. 14-3-3eta also gave a baseline signal in all patients with other dementias, including six patients with Alzheimer's disease. The presence of 14-3-3eta in the CSF of a patient with herpes simplex encephalitis was particularly noteworthy. This study has determined that isoform-specific 14-3-3 antibodies against beta, gamma, and epsilon should be considered for the neurochemical differentiation of CJD from other neurodegenerative diseases.

14-3-3 Proteins↗

PubMed1999

[Neuronal potassium channel opening with flupirtine].

The spectrum of action of flupirtine includes analgesic, muscle-relaxant and neuroprotective properties. The substance's mechanism of action has yet to be fully explained. Over the past few years, however, evidence has accumulated that flupirtine interacts with the glutamatergic N-Methyl-D-Aspartate (NMDA) receptor. Although it was not possible to demonstrate a direct effect on the NMDA receptor, all of the findings pointed to an indirect influence on the NMDA receptor in the sense of a functional NMDA antagonism. It was thus postulated that a site of action "up- or downstream" of the NMDA receptor is influenced. Such a site of action proved to be the G-protein-activated inwardly rectifying K+ channels (GIRK), the opening of which leads to a stabilization of the resting membrane potential of neuronal cells and thus causes an indirect inhibition of the NMDA receptor. At therapeutically relevant concentrations, flupirtine is a neuronal potassium channel opener. This mechanism may explain the spectrum of action of flupirtine. Selective neuronal potassium channel opening (SNEPCO) thus proves to be a new principle of action, making flupirtine the prototype of a new substance class with analgesic, muscle-relaxant and neuroprotective properties. The experimental basis for this working hypothesis and the resulting model concepts are presented from the perspective of a four-stage approach.

Aminopyridines↗

PubMed1999

Late increase of serum S100 beta protein levels in hamsters after oral or intraperitoneal infection with scrapie.

Following recent reports of elevated serum S100 beta protein (S100 beta) levels in patients with genetic and sporadic Creutzfeldt-Jakob disease and in rodents parenterally infected with scrapie, the suitability of serum S100 beta as a preclinical marker for transmissible spongiform encephalopathies was assessed in time-course studies. Syrian hamsters were orally and intraperitoneally challenged with scrapie and assayed for serum S100 beta levels at various times after infection. Although elevated serum S100 beta levels were consistently observed in terminally ill animals for both routes of infection, the experiments failed to detect significantly increased S100 beta serum concentrations prior to the manifestation of clinical symptoms. Thus, in this animal model, serum S100 beta does not appear to be an appropriate marker for the preclinical detection of scrapie, but it may provide a convenient laboratory aid for the diagnosis of transmissible spongiform encephalopathy in naturally or accidentally infected animals and humans.

Administration, Oral↗

PubMed1999

Kinetics of serum neuron-specific enolase and prolactin in patients after single epileptic seizures.

PURPOSE: To investigate and compare the temporal profile of serial levels of neuron-specific enolase (NSE) and prolactin in serum from patients after single epileptic seizures. METHODS: Measurement of NSE and prolactin by sensitive immunoassays in 21 patients with complex partial seizure (CPSs: n = 11) and secondarily generalized tonic-clonic seizures (SGTCSs; n = 10) during continuous video-EEG monitoring at four different time points (1, 3, 6, and 24 h after ictal event). Statistical analysis was performed by using a repeated-measures analysis of variance (ANOVA) model. RESULTS: Mean+/-SD values for NSE levels (ng/ml) were 12.5 +/-4.4 (1 h), 10.8+/-3.8 (3 h), 11.1+/-4.9 (6 h), and 8.2+/-1.9 (24 h). The corresponding prolactin levels (mU/L) were 1,311+/-1,034, 232+/-158, 237+/-175, and 251+/-98. There was a significant decrease of NSE and prolactin levels over time (p < 0.001). The pair-wise comparison of NSE levels showed significant differences between the time points 1 vs. 24 h (p < 0.001), 3 vs. 24 h (p = 0.007), and 6 vs. 24 h (p = 0.009). In contrast, serum prolactin levels showed a significant difference between 1 vs. 3 h (p < 0.001) only. Most of the NSE levels remained normal after CPSs and SGTCSs. At 1 h after the seizure, only 33% of the subjects had increased NSE, whereas abnormal prolactin levels occurred with a sensitivity of 80%. CONCLUSIONS: In contrast to prolactin, serum NSE is not a sensitive marker of individual seizures. Only some individuals showed an increase of NSE beyond the prolactin-sensitive time frame after a single seizure, and mean NSE levels were not significantly increased compared with those of normal controls.

Adult↗

PubMed1999

Persistence of haloperidol in human brain tissue.

OBJECTIVE: After discontinuation of neuroleptic drugs, their antipsychotic and antiparkinsonian effects are still present for a prolonged period. It is not known whether the extended effects of neuroleptic drugs in humans are due to the continued presence of drug in brain tissue or to long-lasting drug-induced physiologic changes. The aim of this study was to directly examine haloperidol concentrations in human brain tissue in relation to drug-free time. METHOD: Haloperidol concentrations were measured in five regions (temporal cortex, cingulate gyrus, caudate nucleus, dentate nucleus, corpus callosum) of the postmortem brains of 11 patients previously treated with haloperidol. Haloperidol was analyzed by means of high-performance liquid chromatography with ultraviolet detection. The half-life in brain tissue was estimated by a population kinetic analysis. RESULTS: Haloperidol concentrations in the human brain tissue were 10-30 times higher than optimal serum concentrations used in the treatment of schizophrenia. Haloperidol concentrations appeared to be homogeneously distributed across different brain areas within a single patient. There was no apparent relation between duration of treatment and mean haloperidol concentration. Higher doses of haloperidol seemed to be related to higher concentrations in brain tissue. The elimination half-life from brain tissue was calculated to be 6.8 days. CONCLUSIONS: The results may have implications for clinical treatment decisions and the design of clinical research protocols. Patients exposed to haloperidol cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.

Antipsychotic Agents↗

PubMed1999

First results on daytime submandibular electrostimulation of suprahyoidal muscles to prevent night-time hypopharyngeal collapse in obstructive sleep apnea syndrome.

Daytime submandibular electrostimulation (dSE) of suprahyoidal muscles was applied to prevent sleep-associated collapse of the tongue into the hypopharyngeal airway. By placing the stimulatory electrodes intra- and extraorally, recruitment of stimulated muscle fibers at low current densities was improved. The significant impact of electrostimulation on suprahyoidal muscle force was initially demonstrated in healthy controls as compared to placebo-treated volunteers. The morphology of suprahyoidal muscles was not affected by this treatment. A patient with obstructive sleep apnea syndrome initially presented with a respiratory disturbance index (RDI) of 13.2, an oxygen desaturation index of 23 and a minimal oxygen saturation of 75%. After two weeks of placebo treatment (TENS-stimulation), respiratory parameters remained unchanged. Two weeks of dSE treatment, however, improved the RDI to 3.9, the oxygen desaturation index from 23 to 2.8 and the minimal oxygen saturation from 75% to 88%. 3D-sonography showed considerable hypertrophy of the stimulated muscles. These results indicate that dSE may prevent episodes of apnea induced by sleep-associated hypopharyngeal collapse of the tongue.

Adult↗

PubMed1998

Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: prospective case-control study.

OBJECTIVE: To analyse serum concentrations of brain specific S100 protein in patients with Creutzfeldt-Jakob disease and in controls. DESIGN: Prospective case-control study. SETTING: National Creutzfeldt-Jakob disease surveillance unit. SUBJECTS: 224 patients referred to the surveillance unit with suspected Creutzfeldt-Jakob disease and 35 control patients without dementia. MAIN OUTCOME MEASURE: Serum concentration of S100 protein in patients with Creutzfeldt-Jakob disease, in patients with other diseases causing dementia, and in the control group. RESULTS: Of the 224 patients with suspected Creutzfeldt-Jakob disease, 65 were classed as definitely having the disease after neuropathological verification, an additional 6 were classed as definitely having the disease as a result of a genetic mutation, 43 as probably having the disease, 36 as possibly having the disease, and 74 patients were classed as having other disease. In the 108 patients classed as definitely or probably having Creutzfeldt-Jakob disease the median serum concentration of S100 was 395 pg/ml (SD 387 pg/ml). This was significantly higher than concentrations found in the 74 patients classed as having other diseases (median 109 pg/ml; SD 177 pg/ml; P = 0.0001). At a cut off point of 213 pg/ml sensitivity for the diagnosis of the disease was 77.8% (95% confidence interval 68.8% to 85.2%) and specificity was 81.1% (70.3% to 89.3%). There was a significant difference in survival at different concentrations of S100 in Kaplan-Meier curves (P = 0.023). CONCLUSION: Measurement of serum concentrations of S100 is a valuable tool which can be used more easily than tests on cerebrospinal fluid in the differential diagnosis of Creutzfeldt-Jakob disease. More studies are needed to determine whether serial testing of serum S100 improves diagnostic accuracy.

Biomarkers↗

PubMed1998

Decrease of S100 beta protein in serum of patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown origin characterized by loss of upper and lower motor neurons and concomitant astrogliosis. We have investigated the S100 beta protein levels in serum as a marker for astroglia of patients with ALS (n = 41) in comparison to a control group (n = 32). Additionally we have investigated 12 patients at different follow-up time points (minimum 6 months). We could not observe a significant difference of S100 beta protein in patients with ALS in comparison to our control group (P = 0.11) but we could clearly see a decrease of S100 beta levels in the further course of the disease. As S100 beta is also seen as a protein with nerve growth factor activity we assume that the fall of serum levels may reflect the loss of nerve growth stimulation in patients with ALS and suppose that repetitive measurements of S100 beta in serum can be used as an objective marker for disease progression.

Aged↗

PubMed1998

Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease.

The analysis of 14-3-3 protein in cerebrospinal fluid (CSF) was shown to be highly sensitive and specific for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, the predictive value of this test in the clinical diagnosis of, and its relation to, sporadic, genetic, and iatrogenic CJD cases have yet to be established. CSF samples of suspect CJD cases seen in the prospective German surveillance study were tested for the presence of 14-3-3 protein by using a modified western blot (WB) technique. WB detected 14-3-3 protein in 95.4% of definite and 92.8% of probable cases. In two patients classified initially as not having CJD the test was positive, and both were later proved to have definite CJD. The positive predictive value is 94.7% and the negative predictive value is 92.4%. False-positive results in a single CSF analysis were seen in patients with herpes simplex encephalitis, hypoxic brain damage, atypical encephalitis, intracerebral metastases of a bronchial carcinoma, metabolic encephalopathy, and progressive dementia of unknown cause. WB analysis for 14-3-3 protein was positive in only 5 of 10 cases of familial forms of spongiform encephalopathies. CSF analysis for 14-3-3 protein should thus be performed in any case suspect for CJD.

14-3-3 Proteins↗

PubMed1998

Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations.

A prospective study of hepatic encephalopathy (HE) including neuropsychiatric and psychometric evaluation, electroencephalography, and determination of arterial ammonia levels was performed in 55 cirrhotic patients treated consecutively by transjugular intrahepatic portosystemic shunt (TIPS). The cumulative HE rate increased from 23.6% within the 3-month interval before TIPS to 50. 9% within the first 3-month interval post-TIPS (P = .003). Significant and independent predictors of HE post-TIPS were the presence of HE pre-TIPS and reduced liver function. The cumulative HE rate declined in the second 3-month interval post-TIPS and reached the pre-TIPS level. Chronic forms of HE exceeding grade I were not observed. In a subgroup of 22 nonencephalopathic TIPS patients, the prevalence of subclinical HE did not change after TIPS. Among individual psychometric tests, the block design test gave the highest proportion of pathological results (about 50%), whereas selective reminding gave the lowest (10%-25%). Electroencephalography (EEG) showed a temporary increase of pathological results at 1 month after TIPS, when patients with overt HE (grade I) were included (proportion of 21.1% before vs. 57.1%, P = .005). Arterial ammonia concentration increased from a mean of 94 +/- 26 microgram/dL to 140 +/- 28 microgram/dL at 3 months after TIPS (P < .001). Elevated ammonia levels persisted. TIPS led to a temporary increase of HE incidence within 3 months. The decline of the HE rate beyond 3 months despite a sustained increase of arterial ammonia levels could not entirely be explained by reduction of shunt flow, nor by alteration of liver function. Instead, cerebral adaptation to gut-derived neurotoxins might be anticipated.

Adolescent↗

PubMed1998

The role of glutamate in dementia.

Glutamate is an excitatory neurotransmitter, but may also act as an endogenous neurotoxin. There is good evidence for an involvement of the glutamatergic system in the pathophysiology of dementia. The glutamatergic transmission machinery is quite complex and provides a gallery of possible drug targets. There are good arguments both for an agonist and an antagonist strategy. When following the antagonist strategy, the goal is to provide neuroprotective effects via glutamate receptor antagonisms without inhibiting the physiological transmission that is required for learning and memory formation. When following the agonist strategy, the goal is to activate glutamatergic transmission without neurotoxic side effects. Several available antidementia drugs may modulate the glutamatergic transmission.

Animals↗