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Biomedical subjects

M Korte

Publications and source records attributed to M Korte.

At least 19 recordsLinked to original sources
PubMed2003

[Familial hyperactivity of angiotensin-converting enzyme (ACE)].

An extremely high level of serum angiotensin-converting enzyme (ACE) activity was found in eight individuals, women aged 31, 60, 42 and 67 years, and men aged 50, 47, 23 and 50 years. They had consulted a specialist due to a wide range of non-specific complaints or abnormalities (fatigue, dyspnoea, arthralgia, kidney stones with high urinary calcium, neurological symptoms and an elevated blood alkaline phosphatase activity level). As each of these complaints could be a symptom of sarcoidosis, the ACE activity was measured. However, sarcoidosis was not diagnosed in any of these patients. A subsequent analysis revealed that all eight individuals had family members with a similar elevation of ACE. Therefore, the increase in ACE activity was familial. Patients with this disorder have serum ACE levels of between 3 and 7 times the upper limit of normal, whereas in the case of sarcoidosis, serum ACE levels rarely exceed three times this limit. Familial ACE hyperactivity is not accompanied by clinical symptoms. It is caused by a point mutation in the ACE gene, which results in the cell-bound ACE being more readily loosened from the cell surface into the circulatory system.

Adult↗
PubMed2001

Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity.

During development, Eph receptors mediate the repulsive axon guidance function of ephrins, a family of membrane attached ligands with their own receptor-like signaling potential. In cultured glutamatergic neurons, EphB2 receptors were recently shown to associate with NMDA receptors at synaptic sites and were suggested to play a role in synaptogenesis. Here we show that Eph receptor stimulation in cultured neurons modulates signaling pathways implicated in synaptic plasticity, suggesting cross-talk with NMDA receptor-activated pathways. Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity. In EphB2(-/-) hippocampal slices, protein synthesis-dependent long-term potentiation (LTP) was impaired, and two forms of synaptic depression were completely extinguished. Interestingly, targeted expression of a carboxy-terminally truncated form of EphB2 rescued the EphB2 null phenotype, indicating that EphB2 kinase signaling is not required for these EphB2-mediated functions.

Age Factors↗
PubMed2000

Shc-binding site in the TrkB receptor is not required for hippocampal long-term potentiation.

Recent evidence shows that neurotrophins are not only involved in neuronal survival and differentiation but also in modulating synaptic strength in the developing and adult nervous system. To understand how neurotrophins induce changes in synaptic strength, we have investigated signaling pathways downstream of the TrkB receptor, which binds brain-derived neurotrophic factor (BDNF) or NT-4/5. To test whether the Shc-site activated signaling pathway, which has been shown to be important for neuronal survival in vivo, also plays a role in processes like long-term potentiation (LTP), we have generated a mouse strain carrying a mutation in the Shc-binding site of the TrkB receptor. In hippocampal slices from these mice we investigated whether basal synaptic transmission, early-LTP (E-LTP) or late-LTP (L-LTP) were affected by this mutation. We found that homo- and heterozygous mutant mice show no difference in the induction-rate or magnitude of E-LTP and L-LTP induced by theta-burst or tetanus stimulation, suggesting that the Shc-binding site in the TrkB receptor and its downstream activated signaling cascade is not involved in hippocampal synaptic plasticity.

Animals↗
PubMed2000

Cerebral taurine release mechanisms in vivo: pharmacological investigations in rats using microdialysis for proof of principle.

Cerebral taurine acts as neurotransmitter, as neuromodulator, or as osmoregulator. To investigate its release mechanisms in vivo, we combined the microdialysis technique with a variety of experimental paradigms. Taurine release was stimulated by either NMDA, NO or a hypotonic solution locally with or without the addition of the NMDA antagonists APV or Ketamine, or the NO synthase inhibitor L-NAME. Alternatively, the neuroprotective drug lubeluzole was applied i.v. NMDA, NO or the hypotonic solution stimulated the release of taurine. NMDA-mediated taurine release was inhibited by either APV, Ketamine or the NO synthase inhibitor L-NAME. Lubeluzole had no effect. Under the hypotonic conditions only lubeluzole was effective. These data confirm in vivo that the NMDA-induced taurine release is mediated via the NO cascade. By contrast, the release after a hypotonic stimulus is not related to the NO cascade. Instead, Na(+)- and/or Ca(2+)-mediated events might have been attenuated by lubeluzole.

Animals↗
PubMed1999

Essential role for TrkB receptors in hippocampus-mediated learning.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.

Animals↗
PubMed1999

Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma.

Natural killer-like T lymphocytes termed cytokine-induced killer (CIK) cells have been shown to eradicate established tumours in a severe combined immune deficient (SCID) mouse/human lymphoma model. Recently, we demonstrated that CIK cells transfected with cytokine genes possess an improved proliferation rate and a significantly higher cytotoxic activity as compared to non-transfected cells. Here, in a phase I clinical protocol, autologous CIK cells were generated from peripheral blood obtained by leukapheresis in patients with metastatic renal cell carcinoma, colorectal carcinoma and lymphoma. CIK cells were transfected with a plasmid containing the interleukin-2 (IL-2) gene via electroporation. Transfected cells generated IL-2 in the range of 330-1800 pg 10(-6) cells 24 h(-1) with a mean of 836 pg 10(-6) cells 24 h(-1). Ten patients received 1-5 intravenous infusions of IL-2-transfected CIK cells; five infusions with transfected CIK cells were given. In addition, the same patients received five infusions with untransfected CIK cells for control reasons. In three patients, WHO grade 2 fever was observed. Based on polymerase chain reaction of peripheral blood transfected cells could be detected for up to 2 weeks after infusion. There was a significant increase in serum levels of interferon gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor beta (TGF-beta) during treatment. Interestingly, there was also an increase in CD3+ lymphocytes in the blood of patients during therapy. In accordance, a partial increase in cytotoxic activity in peripheral blood lymphocytes (PBLs) was documented when patient samples before and after therapy were compared. Concerning clinical outcome, six patients remained in progressive disease, three patients showed no change by treatment, and one patient with lymphoma developed a complete response. In conclusion, we were able to demonstrate that CIK cells transfected with the IL-2 gene can be administered without major side-effects and are promising for future therapeutic trials.

Adolescent↗
PubMed1997

Rapid gene transfer into cultured hippocampal neurons and acute hippocampal slices using adenoviral vectors.

Primary cultures of hippocampal neurons were infected with an adenovirus coding for beta-galactosidase. Expression could be detected as early as 4 h after infection and steadily increased to high levels at 24 h without evidence for a functional impairment of the infected neurons. Similarly, adenovirus-mediated gene transfer into acute hippocampal slices was detectable 4 h after infection and could be localized to discrete areas of the CA1 region by microinjection of the virus stock solution. Infected slices were still suitable for electrophysiological experiments.

Adenoviridae↗
PubMed1996

Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice.

Long-term potentiation (LTP) has been shown to be impaired in mice deficient in the brain-derived neurotrophic factor (BDNF) gene, as well as in a number of other knockout animals. Despite its power the gene-targeting approach is always fraught with the danger of looking at the cumulative direct and indirect effects of the absence of a particular gene rather than its immediate function. The re-expression of a specific gene at a selective time point and at a specific site in gene-defective mutants presents a potent procedure to overcome this limitation and to evaluate the causal relationship between the absence of a particular gene and the impairment of a function in gene-defective animals. Here we demonstrate that the re-expression of the BDNF gene in the CA1 region almost completely restores the severely impaired LTP in hippocampal slices of BDNF-deficient mice. The results therefore provide strong evidence for the direct involvement of BDNF in the process of LTP.

Adenoviridae↗
PubMed1996

The involvement of brain-derived neurotrophic factor in hippocampal long-term potentiation revealed by gene targeting experiments.

Brain-derived neurotrophic factor (BDNF) is a member of the NGF gene family, which has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently begun to receive attention. To determine whether BDNF has a function in processes like long-term potentiation (LTP), we produced a strain of mice with a deletion in the coding sequence of the BDNF-gene. We then used hippocampal slices from these mice to investigate whether LTP is affected by this mutation. Mutant mice showed significantly weaker LTP in the CA1 region. The magnitude of the potentiation as well as the percentage of cases in which LTP could be induced successfully was clearly reduced whereas important pharmacological and morphological control parameters in the hippocampus of these animals were unaffected. Adenoviral vectors were used to re-express BDNF in acute slices of BDNF-knock-out mice. In most cases LTP could be rescued with this approach. These results suggest that BDNF has an important functional role in the expression of LTP in the hippocampus.

Animals↗
PubMed1995

Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor.

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) gene family, has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently begun to receive attention. To determine whether BDNF has a function in processes such as long-term potentiation (LTP), we produced a strain of mice with a deletion in the coding sequence of the BDNF gene. We then used hippocampal slices from these mice to investigate whether LTP was affected by this mutation. Homo- and heterozygous mutant mice showed significantly reduced LTP in the CA1 region of the hippocampus. The magnitude of the potentiation, as well as the percentage of cases in which LTP could be induced successfully, was clearly affected. According to the criteria tested, important pharmacological, anatomical, and morphological parameters in the hippocampus of these animals appear to be normal. These results suggest that BDNF might have a functional role in the expression of LTP in the hippocampus.

Animals↗
PubMed1993

Effects of small doses of dioxins on the immune system of marmosets and rats.

There is no doubt that TCDD is capable of inducing effects on a variety of components and functions of the immune system in a variety of species. In fact, such changes seem to belong to the most sensitive variables affected by TCDD. Some of the biological effects, induced at rather high doses of TCDD exhibiting general toxicity (> 3 micrograms TCDD/kg body wt), may be considered unspecific or the result of the pronounced thymus involution. However, other effects (such as that on lymphocyte subtype patterns in marmosets or a reduced resistance of mice to influenza viruses) have been reported to occur at dose levels far from those leading to thymic involution or general toxicity. It should be remembered that the pathognomonic relevance for man of subtle modifications in the pattern of lymphocyte surface receptors is largely unknown. Until now, such deviations are considered rather as biological phenomena than indications or causes of specific diseases. Nevertheless, such changes represent clear-cut biological effects induced by TCDD. Since effects of TCDD on components and defined functions of the immune system have been revealed in several species, it would be surprising if humans were largely resistant to such effects, but reliable data in humans with high exposures to defined dioxins verified by an appropriate quantification of the exposure are scarce as of now. Data published so far have not revealed pronounced alterations of such variables. However, no studies of well-defined human populations with quantified body burdens have been performed with modern methods (such as flow cytometry) analyzing a wide variety of surface receptors. Performance of such studies is essential for a better and reliable risk assessment, and the technology is available. Some of the effects observed (such as the changes in the pattern of lymphocyte subpopulations) must certainly be considered as biological effects induced by TCDD, and the situation is similar to the induction of hepatic monooxygenases, which are also observable in this dose range. However, the relevance of such changes with respect to adverse health effects in humans is presently difficult to judge in the absence of clear-cut functional deficits demonstrated so far either in vivo or in vitro.

Animals↗
PubMed1993

Auditory spatial tuning of cortical neurons is sharpened in cats with early blindness.

1. The specificity for the location of a sound source in azimuth was measured in single neurons of the anterior ectosylvian (AE) region of the cat's cortex, which includes the anterior auditory field (AAF) and the anterior ectosylvian auditory field (AEA). 2. The influence of visual experience on auditory spatial tuning of these neurons was determined by comparing responses in cats with binocular deprivation from birth with those in normal control cats. 3. Spatial tuning was measured under near free-field conditions by presenting broadband sounds through a speaker in seven different azimuthal locations, from -60 to +60 degree at 20 degree intervals. Elevation was constant at the cats' ears. 4. In normal cats, a little over one-half of the neurons in the AE region (82/146 = 56%) showed some degree of azimuthal spatial tuning, as defined by at least a 2:1 ratio of responses between best and worst location. The rest (44%) were omnidirectional. 5. In binocularly deprived cats, a significantly higher proportion (70/82 = 86%) of the neurons in the AE region were spatially tuned. Only 14% were omnidirectional. Median spatial tuning width was significantly sharper than in normal cats. 6. We conclude that visual deprivation from birth induces intermodal changes that enhance the response specificity of neurons in the auditory cortex. These modifications may constitute the neural basis of behavioral compensation for early blindness.

Animals↗
PubMed1993

Auditory compensation for early blindness in cat cerebral cortex.

Single-neuron activity was recorded in the caudal part of the anterior ectosylvian (AE) cortex of cats that had been deprived of vision for several years by means of binocular lid suture shortly after birth and in normal control animals. Over 300 neurons were tested in each group with auditory, visual, and somatosensory stimuli. We confirmed the existence of an anterior ectosylvian visual area (AEV) in the fundus and ventral bank of the AE sulcus. Neurons in AEV had purely visual responses in normal cats. In visually deprived cats, by contrast, only a minority of cells in this area still responded to visual stimulation. Instead, most cells reacted vigorously to auditory and, to some extent, somatosensory stimuli. The few remaining visual neurons were also driven by auditory or somatosensory stimuli. No increase in the number of unresponsive neurons was found. It appears, therefore, that a cortical region that normally represents visual activity can become driven by auditory or somatosensory activity as a result of visual deprivation. Our results imply that early blindness causes compensatory increases in the amount of auditory cortical representation, possibly by an expansion of nonvisual areas into previously visual territory. In particular, they provide evidence for the existence of neural mechanisms for intermodal compensatory plasticity in the cerebral cortex of young animals. The changes described here may also provide the neural basis for a behavioral compensation for early blindness described elsewhere.

Acoustic Stimulation↗
PubMed1992

Crossmodal changes in the somatosensory vibrissa/barrel system of visually deprived animals.

Cats deprived of vision from birth adapt remarkably well to their situation and show little behavioral impairment. They seem to compensate for their lack of vision by relying more on their auditory and tactile senses. We report here that the facial vibrissae, which are most important for tactile orientation in many animals, show supernormal growth in both cats and mice that have been deprived of vision from birth. Furthermore, the whisker representation in the somatosensory cortical barrel field shows a concomitant enlargement in binocularly enucleated mice: individual barrels are expanded in size by up to one-third. The increased use of the vibrissae in visually deprived animals may stimulate both their own growth and, via activation of the respective neural pathways, the expansion of their central representation.

Animals↗
PubMed1992

Abnormal thymus development and impaired function of the immune system in rats after prenatal exposure to aciclovir.

Aciclovir (synonym: acyclovir) causes abnormal thymus development in rats. After treatment on day 10 of gestation a weight reduction of the organ is obvious in 21-day-old fetuses which persists postnatally. Adult male rats exposed in utero to one or three injections of 100 mg aciclovir/kg body wt given to the dam on day 10 of pregnancy showed a reduction of the thymus weight to 333 +/- 158 mg and 276 +/- 61 mg (control: 428 +/- 92 mg; n = 10). Corresponding alterations were detectable in female offspring. Liver weight was also decreased and spleen weight (in relation to body wt) was significantly increased in the offspring after the three exposures. In a host resistance model with Trichinella spiralis the function of the immune system of rats prenatally exposed to aciclovir was examined. Six weeks postnatally 10-12 randomly selected male rat offspring of one control and two treatment groups (1 or 3 injections of 100 mg aciclovir/kg body wt on day 10 of gestation) were infected orally with 500 Trichinella spiralis muscle larvae. Before and several times after the infection blood was taken from a tail vein or obtained by decapitation for examination of the antibody titers (IgM, IgG, IgA, IgE) to antigens of T. spiralis. Six weeks after the infection the weight of relevant organs was determined and tongue preparations were used for T. spiralis muscle larvae counting. Aciclovir exposed animals showed a different immune response than control rats. IgM titers in both treatment groups were higher than in controls two weeks after the infection but not different by the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗