Die Beanspruchung des menschlichen Ellenbogengelenks

Zusammenfassung Bei 80 Objekten werden die Gelenkflächen des menschlichen Ellenbogengelenks untersucht. Die Trochlea und das Capitulum humeri sowie das Caput radii zeigen keine nennenswerten Unterschiede in der Ausdehnung der mit typischem Gelenkknorpel bedeckten Flächen. Dagegen lassen sich für die Ulnazange drei charakteristische Formgruppen abgrenzen: In 3 Fällen kann eine einheitliche Knorpelfläche beobachtet werden. Bei etwa zwei Drittel der untersuchten Objekte liegt im mittleren Bereich der Incisura trochlearis in horizontaler Richtung ein 2–5 mm breiter knorpelfreier Streifen, der den Gelenkknorpel in 2 vollständig getrennte Flächen unterteilt. Das restliche Drittel der Objekte besitzt eine unvollständige Trennung der Gelenkfläche. Unter Berücksichtigung der Vorstellungen von Pauwels über die causale Histogenese der mesenchymalen Stützgewebe sowie der Materialverteilung im Knochengewebe in Abhängigkeit von der einwirkenden Spannungsgröße werden die morphologischen Befunde den für die jeweiligen Skeletelemente von Pauwels ermittelten Spannungsdiagrammen gegenübergestellt. An der Trochlea und dem Capitulum humeri und am Caput radii findet sich eine geradezu ideale Übereinstimmung in der Ausdehnung der Knorpelfläche und der Knochendichte unter den Gelenkflächen mit den entsprechenden Spannungsdiagrammen. An der Ulna trifft dies nur für einen geringen Teil der Objekte zu. Für die unterschiedliche Ausgestaltung der Incisura trochlearis werden zwei mögliche Ursachen diskutiert: 1. die Resultierende R verharre während des Bewegungsablaufes in einzelnen Positionen innerhalb der Incisura trochlearis verschieden lange; 2. der Krümmungsradius der Trochlea humeri sei größer als derjenige im mittleren Bereich der Ulnazange, so daß hier wegen des fehlenden Kontaktes der Gelenkflächen keine Druckübertragung möglich ist.

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The stress of the human elbow jointI. Functional morphology of the articular surfaces

Summary The articular surfaces of 80 human elbow joints are analysed. The trochlea and capitulum humeri and the caput radii of the investigated individuals show no particular differences in the extent of their surfaces covered with typical articular cartilage. On the other hand the form of the incisura trochlearis is rather variable. Three characteristic formgroups are to be discerned. In three objects a continuous cartilage surface has been observed. In 50 of the investigated joints there is a small intersection free from cartilage in the midst of the incisura trochlearis, dividing the articular cartilage in two isolated surfaces. In the rest of the analysed objects the articular surface is divided only partially. According to Pauwels' hypothesis on the causal histogenesis of the mesenchymal supporting tissues and of the density distribution of the bone dependence upon the magnitude of the local unit stress the morphological findings in the single investigated parts of the elbow joint are confronted with the corresponding stress diagram as described by Pauwels. In the trochlea and capitulum humeri and in the caput radii a nearly ideal correspondence of the extent of the articular surface and the density of the bone tissue with the unit stress diagrams are found. In the ulna this correspondence exists only in few of the analysed objects. For the different form of the incisura trochlearis two possible explanations are discussed: 1, during the motion the resultant of forces may stay for a different time in their single positions in the incisura trochlearis; 2. the curvature radius of the trochlea humeri may be greater than that one of the incisura trochlearis in the central area. So no pressure occurs in this part of the articular surface.

Mit freundlicher Unterstützung durch die Deutsche Forschungsgemeinschaft.     

Determination of specific oxygen uptake rates in human hematopoietic cultures and implications for bioreactor design

Oxygen plays an important role in the cultivation of primary cellsex vivo. In this study, we used hermetically sealed tissue culture well inserts equipped with oxygen electrodes to measure the oxygen utilization of cultured human bone marrow mononuclear cells (BM MNCs). The oxygen uptake rate (OUR) of BM MNCs was determined during a 14-day culture in which both adherent and nonadherent cells were present. Early in the culture, the cells exhibited very low OURs. The specific OURs (uptake rate per cell) were at approximately 0.005 μmol/10⁶ cells/hr shortly after the initiation of culture. The OUR then increased as the cultures developed. After about 8 to 10 days of cultivation the specific OURs had increased to 0.038±0.006 and 0.025±0.005 μmol/10⁶ cells/hr for adherent and nonadherent cells, respectively, after which no further increase was observed. Based on these oxygen uptake rate data, a mathematical model of oxygen diffusion was formulated and use to investigate issues associated with hematopoietic bioreactor design, including initial cell density, medium depth, reactor configuration, and oxygen partial pressure.In situ OUR measurements confirmed predicted oxygen limitations based on the mathematical model and the experimentally determined OURs. High-density hematopoietic cultures present design challenges in terms of sufficient and uniform delivery of oxygen to an active hematopoietic culture. These challenges can be met by using parallelplate bioreactors with thin liquid layers.     

KCNE1 reverses the response of the human K+ channel KCNQ1 to cytosolic pH changes and alters its pharmacology and sensitivity to temperature

Previous studies have shown that heteromultimeric KCNQ1/KCNE1 (KvLQT1/minK) channels and homomultimeric KCNQ1 (KvLQT1) channels exhibit different current properties, e.g. distinct kinetics and different sensitivities to drugs. In this study we report on the divergent responses to internal pH changes and further characterize some of the current properties of the human isoforms of KCNQ1 and KCNE1 expressed in Chinese hamster ovary (CHO) cells or Xenopus laevis oocytes. Decreasing the bath temperature from 37 degrees C to 20 degrees C increased the half-activation time by a factor of 5 for KCNQ1/KCNE1 currents (IKs) but by only twofold (not significant) for KCNQ1 currents (IK) in CHO cells. Acidification of cytosolic pH (pHi) increased IKs but decreased 1K whereas intracellular alkalinization decreased I(Ks) but increased IK. pHi-induced changes in intracellular Ca2+ activity ([Ca2+]i) did not correlate with the current responses. At 20 degrees C mefenamic acid (0.1 mM) significantly augmented IKs but slightly decreased IK. It changed the slow activation kinetics of I(Ks) to an instantaneous onset. The form of the current/voltage (I/V) curve changed from sigmoidal to almost linear. In contrast, at 37 degrees C, mefenamic acid also increased I(Ks) but slowed the activation kinetics and shifted the voltage activation to more hyperpolarized values without markedly affecting the sigmoidal shape of the I/V curve. The potassium channel blockers clotrimazole and tetrapentylammonium (TPeA) inhibited I(Ks) with a lower potency than I(K). These results show that coexpression of KCNE1 reversed pH regulation of KCNQ1 from inhibition to activation by acidic pHi. In addition, KCNE1 altered the pharmacological properties and sensitivity to temperature of KCNQ1. The pH-dependence of I(Ks) might be of clinical and pathophysiological relevance in the pathogenesis of ischaemic cardiac arrhythmias.     

Transgenic rat model of Huntington's disease

Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.     

Shashi XLMR syndrome: report of a second family

This report describes a family with mental retardation in two brothers. The pedigree is consistent with either X-linked mental retardation or autosomal recessive inheritance. The clinical features consist of coarse face, prominent lower lip, large testes, and obesity. This same constellation of findings was observed in a family with X-linked mental retardation (XLMR) reported by Shashi et al. [2000: Am J Hum Genet 66:469-479]. Furthermore, haplotype analysis was consistent with localization of the Shashi XLMR syndrome in Xq26-q27. Thus, the family likely represents a second occurrence of the Shashi XLMR syndrome.     

Analysis of the α/β T-cell receptor repertoire by competitive and quantitative family-specific PCR with exogenous standards and high resolution fluorescence based CDR3 size imaging

The characterization of the human T-cell receptor (TCR) repertoire in various physiological and pathological conditions has become an important tool in studies of the immune response. Therefore, a number of PCR based strategies for the semiquantitative analysis of the TCR repertoire have been described. Family specific amplification of TCR cDNA has been employed in a number of studies often with contradictory results. We have developed a strategy utilizing exogenous standards with homologous primer binding sites for the quantitative analysis of the α/β T-cell receptor repertoire. This system allows the detection of even minute differences in T-cell populations based on quantitative PCR (Q-PCR) and competitive PCR (C-PCR). Results presented here demonstrate that expansions of T-cell subsets as defined by the specificity of the variable gene segments can be readily monitored when exceeding 1% of the total repertoire. In addition, the proposed method reveals direct information of CDR3 size heterogeneity and can be used to estimate the T-cell repertoire complexity and monitor clonal expansions. We discuss variables such as cell number and experimental conditions influencing accuracy and reproducibility of the analyses. We have used this protocol based on non-radioactive techniques for characterization of the fine specificity of the T-cell repertoire in peripheral and organ-infiltrating T-lymphocytes. The analyses revealed information about polyclonal or clonal expansion of T-cells in vivo and in vitro following various stimuli such as superantigenic stimulation of T-cell subsets as well as antigen-driven shaping of the α/β T-cell repertoire in autoimmune and infectious diseases.     

Pharmacological control of leukotriene and prostaglandin production from mouse peritoneal macrophages

Leukotriene and prostaglandin production by mouse peritoneal macrophages was investigated. It could be shown that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate initiated the release of prostaglandin E₂ but had little effect on the release of leukotriene C₄-like immunoreactivity. The divalent cation ionophore A 23187 at concentrations between 10^–6 and 10^–8 mol/l initiated prostaglandin as well as leukotriene release. This prostaglandin and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs including benoxaprofen inhibited prostaglandin release but simultaneously enhanced leukotriene production. The analgesics paracetamol and 4-methylaminoantipyrine had similar effects at high concentrations. The experimental compound BW 755 c inhibited prostaglandin and leukotriene production while the antithrombotic compound nafazatrom inhibited the production of leukotriene C₄-like immunoreactivity but enhanced prostaglandin E₂ production. Nordihydroguaiaretic acid inhibited prostaglandin and leukotriene production. The results show that the metabolism of arachidonic acid in macrophages via the cyclooxygenase or the lipoxygenase pathway is dependent on the stimulus applied. Both pathways can be inhibited conjointly or selectively by drugs. Our results do not provide evidence that differences in anti-inflammatory activity claimed for some of the drugs tested can be explained by differential inhibition of either pathway. The experimental system described may be used for assessing the potency of drugs to inhibit the lipoxygenase and the cyclooxygenase pathway of arachidonic acid metabolism.