The CTFA Evaluation of Alternatives Program: an evaluation of in vitro alternatives to the Draize primary eye irritation test. (Phase III) surfactant-based formulations

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.     

Developmental toxicity of 1,2-dichloropropane (PDC) in rats and rabbits following oral gavage

The ST-16 antigenic specificity of the HLA-B locus is defined as a B39 variant of Mexican-Americans. Nucleotide sequencing of cDNA shows the ST-16 allele (B*3905) differs from B*39011 by a single substitution that substitutes tyrosine for aspartic acid at position 74 of the mature class I heavy chain. The complete coding region sequence for the common caucasoid allele encoding the B38 antigen has been determined. This B*3801 allele differs from B*3802 at two nucleotide substitutions within the Bw4 sequence motif. B*3801 and B*3802 may have been derived independently from B*39011 by conversion events with B alleles donating distinctive Bw4 motifs. A novel allele B*39022 derived from a Colombian Indian differs from the B*39021 allele of Japanese origin at two widely separated silent substitutions. Comparison of sequences for the known B16 alleles suggest that B*39021 and B*39022 were independently derived by recombination from B*39013 and B*39011 respectively.     

Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study

Normal women produce small amounts of active androgens. When androgen levels are elevated, such as for example in the polycystic ovary syndrome, this is followed by the development of male physical characteristics and muscle mass, structure and function as well as android adipose tissue distribution and function. Psychological features and stress reactions also seem similar to those of men. Such women have an increased risk of developing hypertension, non-insulin-dependent diabetes mellitus and cardiovascular disease. Recent data have shown that these physical, and psychological characteristics, as well as risk of ill health, are also found in the population of women selected at random. Women in the lowest quintiles of levels of sex-hormone-binding globulin--an indicator inversely related to active androgens--are at risk of developing hypertension, non-insulin-dependent diabetes mellitus and cardiovascular mortality. The mechanism probably includes muscular insulin resistance, following a relative androgen excess. It is thus apparent that androgens, even within the highest levels of the nonselected population of women, are powerful predictors of serious disease development. The population at risk might be as large as about 20% of middle-aged women. This is an area of female disease risk which requires more attention in screening and intervention procedures.     

A Model-based approach for the synthesis of software to firmware adapters for use with automatically generated components

This paper presents the MDE process in use at Elettronica SpA (ELT) for the development of complex embedded systems integrating software and firmware. The process is based on the adoption of SysML as the system-level modeling language and the use of Simulink for the refinement of selected subsystems. Implementations are generated automatically for both the software (C++ code) and firmware parts, and communication adapters are automatically generated from SysML using a dedicated profile and open-source tools for modeling and code generation. The process starts from a SysML system model, developed according to the platform-based design paradigm, in which a functional model of the system is paired to a model of the execution platform. Subsystems are refined as Simulink models or hand-coded in C++. An implementation for Simulink models is generated as software code or firmware on FPGA. Based on the SysML system architecture specification, our framework drives the generation of Simulink models with consistent interfaces, allows the automatic generation of the communication code among all subsystems (including the HW–FW interface code). In addition, it provides for the automatic generation of connectors for system-level simulation and of test harnesses and mockups to ease the integration and verification stage. We provide early results on the time savings obtained by using these technologies in the development process.     

Suppression of tumorigenicity of rat liver epithelial tumor cell lines by a putative human 11p11.2-p12 liver tumor suppressor locus

We have previously identified and mapped a locus within human chromosome 11p11.2-p12 that suppresses the tumorigenic potential of a rat liver tumor cell line (termed GN6TF) which contains well defined chromosomal aberrations involving rat chromosomes 1, 4, 7, and 10. In the present study, we investigated the potential of this human 11p11.2-p12 liver tumor suppressor locus to suppress the tumorigenic potential of two other rat liver tumor cell lines (GN3TG and GP10TA) following microcell-mediated introduction of human chromosome 11. These tumor cell lines are aneuploid and contain chromosomal abnormalities that are similar to the GN6TF tumor line. The tumorigenic potential and other phenotypic characteristics of GN3TG-11neo and GP10TA-11neo microcell hybrid (MCH) cell lines were variable, and dependent upon the status of the introduced human chromosome 11. MCH cell lines that retained the region of 11p11. 2-p12 delineated by microsatellite markers D11S1385 and D11S903 exhibited suppression of tumorigenicity in vivo (decrease in tumorigenicity and/or elongation of latency), whereas, the tumorigenic potential of one MCH line that lacked markers in this region of human 11p11.2-p12, but retained flanking markers, was not changed from that of the parental tumor cell line. The chromosomal interval between microsatellite markers D11S1385 and D11S903 encompasses the previously localized minimal liver tumor suppressor region, suggesting that a common locus is responsible for tumor suppression among the rat liver tumor cell lines examined. The results of the present study have verified the presence of a liver tumor suppressor locus within human 11p11.2-p12, and have identified a substantial number of microsatellite markers that are closely linked to this tumor suppressor region. These chromosomal markers will facilitate positional cloning of candidate genes from this region, and may prove useful for determining the involvement of this locus in the pathogenesis of human liver cancer.     

Carotid artery repair for radiation-associated atherosclerosis is a safe and durable procedure

OBJECTIVE: The development of carotid atherosclerosis after neck irradiation is well documented. There has been concern about the safety and durability of carotid artery repair through a radiated field. The objective of this report is to describe the immediate and long-term results of a series of cases collected in a 13-year interval. METHODS: From 1984 to 1997, 24 patients underwent 26 carotid artery operations. All the patients had undergone prior radiation therapy at a mean interval of 17 years, with an average radiation dose of 6300 rad. Severe scarring of the skin or radiation fibrosis were present in two thirds of the patients, with 4 patients having permanent tracheostomies. The indications for carotid surgery included cerebral or monocular transient ischemic attack (58%), asymptomatic high-grade stenosis (27%), prior stroke (12%), and tumor invasion of the carotid artery (4%). General anesthesia was used with selective shunting on the basis of carotid artery back pressure or electroencephalography monitoring. Patch angioplasty closure was used in 79% of the patients. The operations included standard carotid endarterectomy (n = 20), external carotid endarterectomy (n = 2), carotid patch angioplasty alone (n = 2), aortocarotid bypass grafting (n = 1), and carotid interposition grafting (n = 1). Four patients required skin grafting or myocutaneous flaps. RESULTS: No deaths or strokes occurred within 30 days of the operations. Six patients had transient cranial nerve palsy, and two had wound infections. The patients were followed from 1 to 156 months, with six patients being followed for longer than 18 months. No strokes were seen at late follow-up examination. Duplex scan examination documented one occlusion, in a patient with primary closure, and two restenoses, one of which necessitated reoperation. The remainder of the grafts were widely patent. CONCLUSIONS: Carotid surgery after neck irradiation is safe and durable. The long-term patency rates and the protection against subsequent neurologic events are similar to the results obtained in the absence of radiation therapy. Problems of wound healing were not found in this series.