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Biomedical subjects

B Sommer

Publications and source records attributed to B Sommer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Transgenic approaches to model Alzheimer's disease.

Two transgenic mouse lines were generated which express human APP751 containing familial Alzheimer's disease (AD) mutations in brain neurons. These mice develop pathological features reminiscent of AD. The degree of pathology depends on both expression levels and specific mutations. In mice with more advanced pathology (APP 23), typical plaques appear at six months which increase with age and are Congo Red positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. A quantitative analysis of degenerative changes by state-of-the-art unbiased stereological methods revealed a significant reduction in neuronal cell bodies of the CA1 field of the hippocampus when compared to controls. This reduction is directly related to plaque load. When subjected to analysis in the Morris water maze, 18 month old APP 23 mice show a significant increase in platform finding latency throughout the entire trial when compared to non-transgenic littermates.

Alzheimer Disease↗
PubMed2000

Liporecycling: a technique for facial rejuvenation and body contouring.

BACKGROUND: Soft tissue augmentation using autologous fat is a standard method in facial rejuvenation and in refinement of body contouring. Different procedures by different authors have been described, each with its specific advantages and disadvantages. OBJECTIVE: The purpose of this article is to describe a method of harvesting, processing, and reinjection of fat that provides new aspects and advantages compared to previously described procedures. METHODS: We report about a new method of autologous fat grafting. Fat is harvested during machine-assisted liposuction in tumescent local anesthesia with microcannulas, processed in a special open manner, and reinjected through a 24-gauge needle for intra- and subdermal augmentation. RESULTS: Short- and long-term results are equivalent to other methods of fat cell grafting. CONCLUSION: Advantages of the described method include easy harvesting during conventional machine-assisted liposuction, the possibility of removing undesired bands of fibrous tissue from the graft, and easy passage through a 24-gauge needle. Thus sub- and intradermal augmentation is possible with the same material and syringe.

Adipose Tissue↗
PubMed2000

Current concepts of fat graft survival: histology of aspirated adipose tissue and review of the literature.

BACKGROUND: Controversy remains about the longevity of correction in autologous fat grafts and its relation to adipocyte survival. Reported long-term fat graft survival rates differ widely, depending on harvesting method, means of reinjection, injection site, and evaluation methods. OBJECTIVE: To demonstrate histologic findings of aspirated adipose tissue and compare the findings to the reports in the literature. METHODS: Review of the literature and the histology of transplanted fat 7 years after subcutaneous implantation and trypan blue staining to determine the vitality of defrosted adipocytes. RESULTS: Fat cells survive aspiration with a suction machine or syringe equally well. Use of a liposuction cannula or 14-gauge needle gives comparable results. Local anesthesia or tumescent local anesthesia is recommended for the donor site, preferably with addition of epinephrine. CONCLUSION: Clinical longevity of correction after autologous fat transfer is determined by the degree of augmentation resulting from the amount of fibrosis induced and the number of viable fat cells. Survival of aspirated fat cell grafts depends mainly on the anatomic site, the mobility and vascularity of the recipient tissue, or underlying causes and diseases, and less on harvesting and reinjection methods.

Adipose Tissue↗
PubMed1999

Expression of metabotropic glutamate receptor subtype mRNA (mGluR1-8) in human cerebellum.

The expression of metabotropic glutamate receptor (mGluR) mRNAs in the human cerebellar neocortex was investigated using in situ hybridization. mGluR1, 3 and 4 mRNAs were most abundant and widely distributed, whereas mGluR2, 5 and 7 mRNA expression was circumscript. mRNAs coding for mGluR1, 3, 4 and 7 were expressed in Purkinje cells. mGluR1 and 4 mRNAs detectable in granule cells and mGluR1, 2, 3, 4 and 7 mRNAs in Golgi cells. mGluR5 mRNA was detectable in putative Bergmann glia as well as mGluR3 mRNA, which was widely expressed in glial cells. mGluR8 mRNA expression was very low in a subset of stellate/basket cells of the molecular layer whereas mGluR6 mRNA was not detectable in the cerebellar cortex.

Aged↗
PubMed1999

Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid.

Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer's disease pathology, namely the extracellular deposition of amyloid plaques. Here, we describe significant deposition of amyloid beta (Abeta) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to that observed in human aging and Alzheimer's disease. Amyloid deposition occurred preferentially in arterioles and capillaries and within individual vessels showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was associated with local neuron loss, synaptic abnormalities, microglial activation, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of Abeta in cerebrospinal fluid, and regional localization of CAA in APP23 mice suggest transport and drainage pathways rather than local production or blood uptake of Abeta as a primary mechanism underlying cerebrovascular amyloid formation. APP23 mice on an App-null background developed a similar degree of both plaques and CAA, providing further evidence that a neuronal source of APP/Abeta is sufficient to induce cerebrovascular amyloid and associated neurodegeneration.

Aging↗
PubMed1999

Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.

Administration, Oral↗
PubMed1999

Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice.

A characteristic feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To study the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid deposition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal termination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growth-associated protein GAP-43 and showed light and electron microscopic characteristics of axonal terminals. Our findings suggest that (1) cerebral amyloid deposition has neurotropic effects and is the main cause of aberrant sprouting in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.

Amyloid beta-Protein Precursor↗
PubMed1999

Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning.

Gene-targeted mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A-/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+ transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.

Action Potentials↗
PubMed1999

NGD 94-1 as an agonist at human recombinant dopamine D4.4 receptors expressed in HEK293 cells.

The atypical antipsychotic, clozapine has some selectivity for dopamine D4 receptors and is a silent antagonist at these receptors. NGD 94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl)-piperazin-1-yl-methyl]-imidazole ) is a highly selective dopamine D4 receptor ligand recently introduced as a putative antipsychotic mimicking the dopamine D4 receptor antagonist effects of clozapine. We show that NGD 94-1 is not silent. It behaved as an agonist in human embryonic kidney 293 cells expressing human recombinant dopamine D4.4 receptors. This questions the clinical use of NGD 94-1.

Cells, Cultured↗
PubMed1999

[Tumescent technique for local anesthesia. Use and prospectives of aa new anesthetic method].

The tumescent technique for local anesthesia (TLA) involves the infiltration of the subcutaneous fatty tissue with a large volume of a diluted local anesthetic. This large added volume increases the tension in the tissue, creating more favorable conditions for the action of the analgesic and for dermatological operative measures. Originally developed for use in the area of liposuction, TLA has since proved to have advantages over other forms of analgesia in numerous other dermatological indications. Overall, TLA is an effective and practical analgesic technique associated with comparatively few side effects that has been shown to be very useful in surgery of the skin.

Adipose Tissue↗
PubMed1999

Differential display of human marrow stromal cells reveals unique mRNA expression patterns in response to dexamethasone.

Human bone marrow stromal cells (hBMSC) are pluripotent cells that have the ability to differentiate into bone, cartilage, hematopoietic-supportive stroma, and adipocytes in a process modulated by dexamethasone (DEX). To characterize changes in hBMSC in response to DEX, we carried out differential display experiments using hBMSC cultured for 1 week in the presence or absence of 10(-8) M DEX. When RNA from these cells was used for differential display, numerous cDNA bands were identified that were up-regulated and down-regulated by DEX. The cDNA bands were reamplified by PCR and directly used to screen an hBMSC cDNA library. Seven clones were isolated and characterized by DNA sequencing and found to encode the following genes: transforming growth factor-beta-induced gene product ((beta)ig-h3), calphobindin II, cytosolic thyroid-binding protein, 22-kDA smooth muscle protein (SM22), and the extracellular matrix proteins osteonectin/SPARC, type III collagen, and fibronectin. To confirm that these genes were regulated by DEX, the cells were treated continuously with this hormone for periods ranging from 2 to 30 days, and steady-state mRNA levels were measured by Northern blot analysis. All genes showed some level of regulation by DEX. The most profound regulation by DEX was observed in the (beta)ig-h3 gene, which showed a relative 10-fold decrease in mRNA levels after 6 days of treatment. Interestingly, (beta)ig-h3 expression was not altered by DEX in fibroblasts from other human tissues, including thymus stromal fibroblasts, spleen stromal fibroblasts, and foreskin fibroblasts. In summary, differential display of DEX-treated hBMSC revealed unique patterns of gene expression and has provided new information about phenotypic changes that accompany the differentiation of hBMSC toward osteogenesis. J. Cell. Biochem. 76:231-243, 1999. Published 1999 Wiley-Liss, Inc.

Annexin A6↗
PubMed1999

Efficient gene transfer into normal human skeletal cells using recombinant adenovirus and conjugated adenovirus-DNA complexes.

In order to assess efficient DNA gene transfer into human primary cell cultures derived from the skeleton we tested two viral-based procedures. First, replication-deficient recombinant adenoviruses (ADV) were used to infect post-confluent human marrow stromal fibroblasts (HMSF) and human trabecular bone (HTB) cells. Both cell types were readily infected by modified adenoviral vectors carrying a reporter gene making this virus an attractive candidate to facilitate DNA gene transfer. In a second approach we coincubated DNA with ADV that had polylysine (PLL) covalently attached. With this ADV/PLL/DNA complex, very efficient gene transfer into multilayered HMSF and HTB cell cultures was observed, and DNA coincubated with unmodified ADV failed to be effectively transferred. These data imply that the covalently bound PLL more effectively binds exogenous DNA, resulting in a highly efficient internalization event in both cell types. Thus, this latter method has many advantages over conventional ADV gene transfer procedures. It is simple, rapid, and it does not require engineering of DNA into the viral genome, thereby allowing transfer of large fragments of DNA.

Adenoviridae↗
PubMed1999

Association of microglia with amyloid plaques in brains of APP23 transgenic mice.

Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD, the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between beta-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-beta precursor protein (betaPP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14- to 18- month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1- and phosphotyrosine-positive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice, early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally, bundles of amyloid fibrils, sometimes surrounded by an incomplete membrane, were observed within the microglial cytoplasm. However, microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal, contributory, or consequential to cerebral amyloidosis, our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived betaPP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived betaPP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice.

Animals↗
PubMed1999

Receptor density as a factor governing the efficacy of the dopamine D4 receptor ligands, L-745,870 and U-101958 at human recombinant D4.4 receptors expressed in CHO cells.

1. The relationships between the density of dopamine D4.4 receptors and the agonist efficacies of L-745,870 (3-(4-[4-chlorophhenyl]piperazin-1-yl)-methyl-1H-pyrrolo [2, 3-b]pyridine) and U-101958 ((1-benzyl-piperidin-4-yl)-(3-isopropoxy-pyridin-2-yl)-methyl-a min e) were investigated in Chinese hamster ovary (CHO) cells, after treatment with the gene expression enhancer, sodium butyrate. 2. In CHO cells expressing D4.4 receptors (CHO/D4 cells), dopamine inhibited forskolin-stimulated cyclic AMP accumulation (Emax 56+/-1% inhibition, pEC50 7.4+/-0.1, n=10). U-101958 behaved as a partial agonist (39+/-7% the efficacy of dopamine, pEC50 8.1+/-0.3, n=4), whereas L-745,870 had no detectable agonist effect. 3. Receptor density, as estimated by [3H]-spiperone saturation binding was 240+/-30 fmol mg-1 protein (n=8) in CHO/D4 cell homogenates. It reached 560+/-150 (n=6), 1000+/-190 (n=4) and 840+/-120 (n=4) fmol mg-1 protein after treatment with sodium butyrate (5 mM) for 6, 18 and 48 h, respectively. 4. The increase in receptor density was associated with a gradual enhancement of the agonist effects (increased Emax and pEC50 values) of dopamine. The efficacy of U-101958 (relative to dopamine) doubled and L-745,870 was turned into a partial agonist (efficacy 49% relative to dopamine, pEC50 8. 6+/-0.2, n=6, after 48 h treatment with sodium butyrate). These agonist effects of U-101958 and L-745,870 could be antagonized by spiperone (0.1 microM) but not by raclopride (10 microM). 5. The results show that U-101958 and L-745,870 are partial agonists at human dopamine D4.4 receptors expressed in CHO cells. Their efficacy is governed by receptor density. Agonist effects of these two compounds in vivo cannot be excluded under circumstances of increased receptor levels.

Aminopyridines↗
PubMed1999

Brain-derived neurotrophic factor exerts opposing effects on beta2-adrenergic receptor according to depolarization status of cerebellar neurons.

To investigate the molecular mechanisms underlying brain-derived neurotrophic factor (BDNF)-controlled synaptic plasticity, we studied beta2-adrenergic receptor (beta2-AR) expression in cultured cerebellar granule cells. We show that, depending on the state of depolarization, BDNF exerts opposite effects on beta2-AR expression. In neurons maintained in low K+ medium (5 mM K+) that will enter apoptosis, BDNF increases beta2-AR and beta2-AR transcripts. In contrast, in depolarized neurons (high K+ medium, 25 mM K+) BDNF represses beta2-AR expression. The use of reporter genes (driven by the beta2-AR promoter or restricted regulatory elements) revealed that BDNF exerts its opposite effects at the transcriptional level by recruiting a cyclic AMP response element (CRE) and the trans-acting factor CRE binding protein. These results provide the first evidence that a neurotrophin, e.g., BDNF, may exert an opposite effect on receptor expression and function (beta2-AR) according to the depolarization status of the neuron. Based on this finding, we propose that BDNF not only mediates neuronal survival, but is also involved in the modulation of the general sensitivity of the neuron to external signals, thus maintaining its optimal functional integration within the neuronal network.

Animals↗
PubMed1999

Expression and signaling of group I metabotropic glutamate receptors in astrocytes and microglia.

Stimulation of astrocytes with the excitatory neurotransmitter glutamate leads to the formation of inositol 1,4,5-trisphosphate and the subsequent increase of intracellular calcium content. Astrocytes express both ionotropic receptors and metabotropic glutamate (mGlu) receptors, of which mGlu5 receptors are probably involved in glutamate-induced calcium signaling. The mGlu5 receptor occurs as two splice variants, mGlu5a and mGlu5b, but it was hitherto unknown which splice variant is responsible for the glutamate-induced effects in astrocytes. We report here that both mRNAs encoding mGlu5 receptor splice variants are expressed by cultured astrocytes. The expression of mGlu5a receptor mRNA is much stronger than that of mGlu5b receptor mRNA in these cells. In situ hybridization experiments reveal neuronal expression of mGlu5b receptor mRNA in adult rat forebrain but a strong neuronal expression of mGlu5a mRNA only in olfactory bulb. Signals for mGlu5a receptor mRNA in the rest of the brain were diffuse and weak but consistently above background. Activation of mGlu5 receptors in astrocytes yields increases in inositol phosphate production and transient calcium responses. It is surprising that the rank order of agonist potency [quisqualate > (2S,1 'S,2'S)-2-(carboxycyclopropyl)glycine = trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD) > glutamate] differs from that reported for recombinantly expressed mGlu5a receptors. The expression of mGlu5a receptor mRNA and the occurrence of 1S,3R-ACPD-induced calcium signaling were found also in cultured microglia, indicating for the first time expression of mGlu5a receptors in these macrophage-like cells.

Animals↗
PubMed1999

Tumescent liposuction in Germany: history and new trends and techniques.

Due to the developments and changes of tumescent solution, infiltration technique, and cannulas, we perform tumescent liposuction today using up to 6-8 l tumescent solution. Total aspirate measures up to 9 l, pure fat aspired up to 5 l. Tumescent liposuction of extended areas can still be done as an outpatient procedure. The condition of patients intra- and postoperatively as well as results has improved and the predictability of outcome is more certain.

Germany↗