Use of transgenic animals for carcinogenicity testing: considerations and implications for risk assessment

Advances in genetic engineering have created opportunities for improved understanding of the molecular basis of carcinogenesis. Through selective introduction, activation, and inactivation of specific genes, investigators can produce mice of unique genotypes and phenotypes that afford insights into the events and mechanisms responsible for tumor formation. It has been suggested that such animals might be used for routine testing of chemicals to determine their carcinogenic potential because the animals may be mechanistically relevant for understanding and predicting the human response to exposure to the chemical being tested. Before transgenic and knockout mice can be used as an adjunct or alternative to the conventional 2-year rodent bioassay, information related to the animal line to be used, study design, and data analysis and interpretation must be carefully considered. Here, we identify and review such information relative to Tg.AC and rasH2 transgenic mice and p53+/- and XPA-/- knockout mice, all of which have been proposed for use in chemical carcinogenicity testing. In addition, the implications of findings of tumors in transgenic and knockout animals when exposed to chemicals is discussed in the context of human health risk assessment.     

Clonogenicity of normal and malignant hematopoietic progenitor cells after exposure to synthetic alkyl-lymphospholipids

Summary Alkyl-lysophospholipids (ALP) are synthetic analogues of natural lysophosphatidylcholine and represent a new class of anti-tumor agents. They are cytotoxic in vitro with a high selectivity for neoplastic cells which, in contrast to normal cells, lack an alkyl-cleavage enzyme to degrade the adsorbed ALP molecules. As ALP accumulates, it interferes with normal membrane phospholipid turnover and eventually causes disruption of membrane integrity. To evaluate the potential value of ALP in eliminating leukemic cells from remission marrows prior to autologous transplantation, we tested the effect of various ALPs on the clongenicity of normal human marrow cells and on promyelocytic leukemia HL-60. A remarkable difference in the dose response to ALP of normal marrow cells an HL-60 was observed. After an incubation period of 24 h, the same inhibition of clonogenicity in HL-60 occurred at ALP concentrations 4 times lower than in normal marrow cells. Reducing the exposure time to 6 h enhanced the selectivity further: whereas HL-60 colonies were nearly completely inhibited at 16 g ALP/ml, more than 50% of normal CFU-c and BFU-E were recovered after incubation with 48 g/ml. No further increase in selectivity was achieved by changing the incubation temperature. Both thioether- and alkyl-analogues were active and no difference was observed between methoxy- and acylamino-substituted ALPs. We conclude that this selective cytotoxicity makes ALP compounds worth further study as purging agents in autologous bone marrow transplantation programs.Supported by the Deutsche Forschungsgemeinschaft An 111/3     

157. Meniscusläsion und Meniscuschirurgie bei chronisch vorderer Kreuzbandinsuffizienz

Zusammenfassung Am Bergmannsheil Bochum mussten 32 Patienten mit einer muskulär kompensierten chronischen vorderen Kreuzbandinsuffizienz wegen eines Meniscusschadens operiert werden. Insgesamt 37 Meniscusverletzungen verteilten sich auf 20 Korbhenkelrisse, 15 Verletzungen im Bereich des Hinterhomes, je eine Vorderhorn- und eine Transversalruptur. Die 32 Patienten konnten 1–6 Jahre nach erfolgter Meniscuschirurgie nachuntersucht werden. In 12 Fällen fand sich ein gutes Ergebnis. 8 Patienten mit Meniscektomie wiesen ein befriedigendes und 12 ein schlechtes Resultat auf. Die schlechten Ergebnisse fanden sich ausschliesslich bei Läsionen des Meniscushinterhornes und hilateralen Meniscusläsionen (10).     

303. Orientierungshilfen in der diagnostischen und operativen Schulterarthroskopie

Zusammenfassung Plazierung des Arthroskopes, Einstellung der Optik, Zugänge für das Instrumentarium und Interpretation der intraarticulären Befunde sind unabdingbare Voraussetzungen für eine systematische und reproduzierbare Arthroskopie der Schulter. Ein Haltegerät ermöglicht die Positionierung der Schulter in verschiedenen Abduktions- und Anteversionsstellungen. Für die umfassende Exploration und endoskopische Operation am Schultergelenk müssen hinterer, vorderer und oberer Zugang zur Schulter beherrscht werden. Mittels Wechselstab-Technik und weiteren Hilfsinstrumenten ist die Einstellung des Arthroskopes nahezu problemlos möglich. Blutungskomplikationen können durch höheren Durchfluss, Gasinsufflation, elektrochirurgisch oder pharmakologisch beherrscht werden.     

Phacoemulsification devices: a consumer's update

This report extends a previous paper on the various characteristics of the most popular phacoemulsification devices. An evaluation of 11 devices by ten different manufacturers was attempted. Only five manufacturers of six devices agreed to critical evaluation or reevaluation. As in the previous report, the devices were compared for level of patient safety, dependability, efficiency, ease of usage, and operating cost for the first 1,000 cases. At the completion of this study, we ranked the nine devices evaluated over the past 17 months as follows: (1) United Surgical (Optikon) Systems Plus, (2) Optical Micro Systems (OMS), (3) United Surgical (Optikon) Phacotron, (4) CooperVision 10,000, (5) Site XTR, (6) CooperVision KCP, (7) CooperVision 9001, (8) Phakosystems CES 4000 and (9) United Sonics. To enhance the usefulness of this consumer's guide, we asked 40 experienced cataract surgeons what they wanted in the "ideal" phacoemulsification device. The opinions of 27 who responded are included.     

Pseudosickling of hemoglobin Setif

Hemoglobin Setif produces pseudosickling of red cells in vitro; the nature of the process and the conditions that "trigger" it are unknown. Studies of red cells, hemolysates, purified hemoglobin solutions, and artificial mixtures of Hb A and Setif suggest that pseudosickling is produced by intracellular crystallization of insoluble hemoglobin. Increased tonicity of the suspending medium accentuates the process, probably by causing a rise in intracellular hemoglobin concentration. If precipitates from A/Setif mixtures are analyzed, they always contain Hb A, suggesting an unusual mechanism for the process. Despite the fact that osmolality in the renal medulla is similar to that which produces pseudosickling in vitro, carriers do not have renal dysfunction of the type found in patients with sickle cell disease.     

Risk factors for Epstein–Barr virus reactivation after renal transplantation: Results of a large,multi-centre study

Epstein–Barr virus (EBV) reactivation is a very common and potentially lethal complication of renal transplantation. However, its risk factors and effects on transplant outcome are not well known. Here, we have analysed a large, multi-centre cohort (N = 512) in which 18.4% of the patients experienced EBV reactivation during the first post-transplant year. The patients were characterized pre-transplant and two weeks post-transplant by a multi-level biomarker panel. EBV reactivation was episodic for most patients, only 12 patients showed prolonged viraemia for over four months. Pre-transplant EBV shedding and male sex were associated with significantly increased incidence of post-transplant EBV reactivation. Importantly, we also identified a significant association of post-transplant EBV with acute rejection and with decreased haemoglobin levels. No further severe complications associated with EBV, either episodic or chronic, could be detected. Our data suggest that despite relatively frequent EBV reactivation, it had no association with serious complications during the first post-transplantation year. EBV shedding prior to transplantation could be employed as biomarkers for personalized immunosuppressive therapy. In summary, our results support the employed immunosuppressive regimes as relatively safe with regard to EBV. However, long-term studies are paramount to support these conclusions.     

Concentrating stroke care provision in the Czech Republic: The establishment of Stroke Centres in 2011 has led to improved outcomes

This article describes policy processes that have led to the re-organisation of stroke care in the Czech Republic since 2011, which has been part of a broader process of care concentration in several medical fields. Currently, stroke care is provided by 13 Comprehensive and 32 Primary Stroke Centres. The paper explains factors that supported the reform implementation, reviews implications, and discusses future challenges.Mandatory reporting of quality indicators, the introduction of a benchmarking system, integration with pre-hospital emergency care, and the introduction of countrywide patient triage have supported more timely treatment for stroke patients and better quality of care. Data from the Stroke Care Quality Indicators of the Czech Stroke Society show positive trends in many areas: the number of patients treated with intravenous thrombolysis quadrupled in eight years, with 26.4 % of all acute stroke patients receiving thrombolysis in 2018. Czech Republic now ranks third in Europe in the number of thrombolysis per population and second in the number of mechanical thrombectomies per population. The Czech experience provides an example of positive outcomes of concentrated stroke care, while highlighting the importance of proper implementation processes. In particular, it is essential to involve stakeholders and to provide reputational incentives through continuous benchmarking.