Rolle der Winkelstabilität bei der intramedullären Stabilisierung

Zusammenfassung Winkelstabile Plattenfixateur-interne-Systeme haben in den letzten 20 Jahren zunehmend an Bedeutung gewonnen. Die aus der Winkelstabilität resultierende flächenhafte Krafteinleitung und gleichmäßigere Kraftverteilung führen zu einer besseren Knochenbruchheilung insbesondere im metaphysischen Bereich und bei Osteoporose. Bei Marknagelsystemen ist die Winkelstabilität bislang nur partiell verwirklicht. Der vorgestellte winkelstabile Tibiamarknagel realisiert an jedem einzelnen Bolzen eine Winkelstabilität mit dem einliegenden intramedullären Kraftträger. Von Februar 2002–August 2004 wurden 21 Patienten mit ihm behandelt. In 13 Fällen wurden Frakturen stabilisiert, 6 Patienten hatten Fehlstellungen, 2 Patienten Pseudarthrosen. Zum Nachuntersuchungszeitpunkt waren alle Behandlungen abgeschlossen. Postoperative Komplikationen traten nicht auf. In allen Fällen wurde eine vollständige Durchbauung erreicht. In 6 Fällen fand sich radiologisch eine verzögerte Knochenbruchheilung. Die ersten klinischen Erfahrungen mit dem winkelstabilen Tibiamarknagel zeigen, dass dieser aufgrund der höheren Primärstabilität insbesondere im metaphysären Knochenbereich mit kurzen Fragmenten sowie bei Osteoporose Vorteile gegenüber anderen nichtwinkelstabilen oder nur partiell winkelstabilen Marknagelsystemen erbringt. Die verzögerten Knochenbruchheilungen bedürfen weiterer klinischer und biomechanischer Untersuchungen.     

Dependence and cross-dependence in the guinea-pig myenteric plexus

Summary Chronic activation of opioid receptors results in the development of tolerance and dependence. Tolerance may be confined to a single receptor type and thus has been termed selective tolerance. The present investigation reveals that prolonged activation of an inhibitory acting receptor type not only results in dependence associated with this receptor but also brings about cross-dependence. Cross-dependence involves both opioid receptors as well as non-opioid receptors, e. g. adrenoceptors. The experimental design employed did not permit conclusions to be drawn about whether those receptors exhibiting cross-dependence also developed tolerance. Regardless of the receptors and their specific subsequent transduction systems, all the receptors which showed dependence and cross-dependence proved sensitive to pertussis toxin, suggesting a critical function of GTP-binding proteins for the development of not only opioid dependence but also for drug dependence in general. Since multiple transmitter receptors may converge on the same ion channel, the concept of convergent dependences may be linked to GTP-binding proteins. However, no conclusions can be drawn with regard to the precise biochemical mechanisms underlying dependence. Send offprint requests to R. Schulz at the above address     

Rationale for clinical trials of opiate antagonists in treating patients with personality disorders and self-injurious behavior

A subgroup of patients with personality disorders from the DSM-III-R (American Psychiatric Association 1987) "flamboyant" cluster is characterized by repetitive self-injurious behavior (SIB) apparently not motivated by suicidal intent. After describing the clinical and demographic characteristics of these patients, the clinical and preclinical evidence suggesting the involvement of endogenous opiate systems in this behavior is reviewed. Patients with personality disorders and SIB have been found to have elevated levels of plasma beta-endorphin. However, the available evidence is not sufficient to show whether this is a cause of or a consequence of SIB. Behavioral stereotypies resulting in self-injury in animals and SIB in mentally retarded patients have been shown to be abolished by opiate antagonist administration in a significant proportion of both groups. The available evidence suggests that clinical trials of oral opiate antagonist drugs should be undertaken because of the promise such drugs have in the treatment of this sometimes life-threatening disorder.     

Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3

OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.     

ErbB2 and the antimetastatic nm23/NDP kinase in regulating serum induced breast cancer invasion

The erbB2 gene is often found amplified and/or overexpressed in breast cancer in which it has clinical relevance as prognostic and predictive factor. It is involved in growth regulation and has a role in the initial phases of cell proliferation, while in vivo and in vitro studies have suggested an involvement also in cell invasion and metastases. It is not clear if these two roles are mutually exclusive and little is known about the mechanisms by which erbB2 may be involved in the control of these processes. Our previous data on patient series suggested that erbB2 might be regulated in different ways depending on the neoplastic status of the cells and that it might be involved in different regulatory pathways. To test this hypothesis we have measured the serum-dependent regulation of erbB2 as a function of the expression of the antimetastatic gene, nm23, in a panel of breast cancer cell lines. The experimental model consisted of three cell lines having different proliferative and invasive potentials: a non-metastatic estrogen receptor (ER) positive cell line, MCF-7; a highly metastatic ER negative cell line, MDA-MB435; and the MDA-MB435 cell line transfected with the nm23-H1 antimetastatic gene (clone H1-177) which has lost the ability to invade and metastasize. We first analysed the serum concentration dependence of invasion and proliferation after 3-4 days of serum deprivation confirming the proliferative and invasive potential of the three cell lines. Modulation of erbB2 expression by different concentrations of serum was then studied. ErbB2 expression in MCF-7 cells showed a complex pattern due to serum modulation, whereas, it was not longer regulated by serum in the MDA-MB435 cell line. In H1-177 cells the erbB2 response to serum was restored and it was very similar to that observed in MCF-7. These data showed a tight association between nm23 and the regulation of erbB2 expression by serum factors suggesting that the role of erbB2 in invasion might be dependent on nm23 expression.     

Estimates of global research productivity in virology

The quantity and quality of published research in the field of Virology by different world regions was estimated in this study. Using the PubMed database, articles from journals included in the "Virology" category of the "Journal Citation Reports" database of the Institute for Scientific Information for the period 1995-2003 were retrieved. The world was divided into nine regions based on geographic, economic, and scientific criteria. Data on the country of origin of the research was available for 33,425 out of 33,712 articles (99.2% of all articles from the included journals). USA exceeds all other world regions in research production for the period studied (42% of total articles), with Western Europe ranking second (35.7%). The mean impact factor in articles published in Virology journals was highest for the USA (4.60), while it was 3.90 for Western Europe and 3.22 for the rest of the world (seven regions combined). USA and Canada ranked first in research productivity when both gross national income per capita (GNIPC) and population were taken into account. The results of this analysis show a distressing fact; the absolute and relative production of research in the field of Virology by the developing regions is very low, although viral diseases cause considerable morbidity and mortality in these areas. It is evident from this study that developing regions need more help from the developed regions to enhance research infrastructure.     

Morphological features in human cortical brain microvessels after head injury: a three-dimensional and immunocytochemical study

We studied the morphology of cortical microvessels in the brains of 10 patients who had died after receiving a traumatic head injury (THI). Scanning electron microscopy (SEM) of vascular corrosion casts, confocal microscopy of histological sections after immunocytochemistry, and detection of apoptosis by terminal dUTP nick end labeling (TUNEL) were used. Microvascular casts showed an angioarchitectonic distribution that was defined as normal according to results obtained in a previous, nontraumatic series of subjects. However, when we compared them with previous works, the cast surface of some of the microvessels showed three types of morphological alterations: longitudinal folds, sunken surfaces with craters, and a significant flattening with reduction of lumen. The vessels that were primarily affected were the arterioles and capillaries of the middle and deep cortical vascular zones. Immunostaining with the monoclonal antibody MAS-336 against endothelial cells also showed the presence of longitudinal folds with a thinning of the vascular lumen, cytoplasmic round bodies, and a thickening of the endothelial cell membrane. The TUNEL technique revealed a positive staining of some endothelial cells. The structural alterations we observed indicate that microvessels undergo endothelial cell damage after THI. We suggest that this kind of lesion and the secondary functional injury to the blood-brain barrier (BBB) could play an important role in the development of the secondary lesions that these patients show in the subacute phase.     

Controlling the statistics of action: obstacle avoidance

Task optimization in the presence of signal-dependent noise (TOPS) has been proposed as a general framework for planning goal-directed movements. Within this framework, the motor command is assumed to be corrupted by signal-dependent noise, which leads to a distribution of possible movements. A task can then be equated with optimizing some function of the statistics of this distribution. We found the optimal trajectory for obstacle avoidance by minimizing the mean-squared error at the end of the movement while keeping the probability of collision with the obstacle below a fixed limit. The optimal paths accurately predicted the empirical trajectories. This demonstrates that controlling the statistics of movements in the presence of signal-dependent noise may be a fundamental and unifying principle of goal-directed movements.     

Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice

We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals.