A methodology for successfully producing global translations of patient reported outcome measures for use in multiple countries.

The production of accurate and culturally relevant translations of patient reported outcome (PRO) measures is essential for the success of international clinical trials. Although there are many reports in publication regarding the translation of PRO measures, the techniques used to produce single translations for use in multiple countries (global translations) are not well documented. This article addresses this apparent lack of documentation and presents the methodology used to create global translations of the Chronic Liver Disease Questionnaire-Hepatitis C Virus (CLDQ-HCV).

A comparative review of health-related quality-of-life measures for use in HIV/AIDS clinical trials.

With the advent of highly active antiretroviral therapy (HAART), HIV-infected patients are living longer and are concerned not only with a treatment's ability to extend their life but also with the quality of the life they are able to lead. Regulatory authorities are also paying closer attention to the use of health-related quality-of-life (HR-QOL) measures in clinical trials and to the subsequent claims that are made based on the results. This paper reviews existing HR-QOL measures reported in the HIV/AIDS literature since 1990 and identifies those most worthy of consideration for use in future clinical trials.

Validation of a patient-administered questionnaire to measure the severity and bothersomeness of lower urinary tract symptoms in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment questionnaire.

Objective: To develop and validate a self-administered questionnaire to assess the 'severity' and 'bothersomeness' of the most frequently reported signs and symptoms of uncomplicated urinary tract infection (uUTI).

Subjects And Methods: The UTI Symptoms Assessment questionnaire (UTISA) is a 14-item instrument asking about the severity and bothersomeness of seven key uUTI symptoms. It was developed after comprehensive literature and data review and administration in draft form to a sample of 30 women with uUTI.

Validation of a patient-administered questionnaire to measure the activity impairment experienced by women with uncomplicated urinary tract infection: the Activity Impairment Assessment (AIA).

Background: To validate a questionnaire to assess the activity impairment associated with uncomplicated urinary tract infection (uUTI).

Methods: The Activity Impairment Assessment (AIA) assesses the amount of time an individual's work or regular activities have been impaired as a result of their UTI. The measure was completed by 276 women with uUTI who had participated in a prospective, open-label, non-comparative multi-centre clinical trial of CIPRO XR (extended-release ciprofloxacin).

The effect of butylated hydroxytoluene on selected immune surveillance parameters in rats bearing enzyme-altered hepatic preneoplastic lesions.

Selected immune function parameters were examined in male Fischer 344 rats following (a) induction of enzyme-altered preneoplastic liver foci (EAF), and (b) growth modulation of EAF by 30-day feeding with the food antioxidant butylated hydroxytoluene (BHT). Glutathione S-transferase-P (GSTP)-positive EAF were observed in livers of rats receiving diethylnitrosamine (DEN), 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH) (Solt-Farber procedure), with or without BHT treatment. The induction of EAF and/or 0.

Carcinogen risk assessment: a necessary dilemma?

Carcinogen risk assessment is the process by which an attempt is made to estimate human risk due to carcinogens, from the results of animal studies. It is based upon a number of prudent default assumptions, that is, assumptions that cannot be proved scientifically because either the basic concept is philosophical in nature or because the amount of scientific evidence required is too costly to obtain even on a world-wide basis. Recently, scientific effort has shown that more and more examples have been described suggesting these examples do not behave in the way indicated by the default assumptions.

Cancer risk assessment at the crossroads: the need to turn to a biological approach.

Mathematically based carcinogen risk assessment is based on a number of prudent default assumptions which are becoming progressively less tenable as new scientific evidence is adduced. For example, the assumptions that all rodent carcinogens will be carcinogenic in humans and that there is no safe dose of any carcinogen may, in specific examples, be shown to be untrue. The mechanisms by which carcinogens exert their effects, especially the induction of DNA lesions, DNA repair of these lesions, and cell proliferation, are considered; it is suggested that with recently developed experimental techniques they might be employed to develop a more biologically based approach to risk assessment and might avoid at least, some of the pitfalls associated with the present mathematically based carcinogen risk assessment models.

The effect of different levels of dietary alpha-linolenic and other fatty acids on mammary gland ductular cell proliferation in female Swiss Webster mice.

In previous work we have shown that changing the fatty acid composition of a constant amount of fat in a modified AIN-76A diet affected the level of ductular cell proliferation in the mammary glands of young virgin female Swiss Webster mice. In particular, linoleic acid concentrations of 5-10% of the total fat in the diet led to variable but appreciably higher levels of proliferation than did higher levels of linoleic acid. In this report it is shown that feeding low levels of the total fat as alpha-linolenic acid (0-5%) resulted in a similar effect.

The effect of butylated hydroxytoluene on the growth of enzyme-altered foci in male Fischer 344 rat liver tissue.

Butylated hydroxytoluene (BHT) is a synthetic, food-use, phenolic antioxidant. It has previously been demonstrated to be operationally non-genotoxic and, in addition, failed to induce biologically significant increases in cellular proliferation in the liver, urinary bladder and thyroid gland on feeding to young adult Wistar rats. Nevertheless, it has been reported to enhance the yield of liver tumors when fed to rats or mice that developed an appreciable background incidence of these tumors without treatment.

Mechanistic and other considerations in cancer prevention.

Possibilities for the prevention of cancer, particularly in relation to the food supply, are considered. It is suggested that the growing realization that cancer may be induced by more than one mechanism combined with a present lack of knowledge of the nature and level of naturally-occurring carcinogens in food crops, makes successful prevention in humans exceedingly difficult.

Marketing and psychophysics: cornflakes and Stevens' power function.

Although major firms do not publish their pricing and packaging strategies, an analysis of 83 pairs of boxes of breakfast cereals using Stevens' Law showed that firms price their products on the perception of size rather than by actual size. By contrast, laundry detergents are priced by actual weight and volume.

Effect of addition of dried healthy or diseased parsnip root tissue to a modified AIN-76A diet on cell proliferation and histopathology in the liver, oesophagus and forestomach of male Swiss Webster mice.

Umbelliferous crop plants, including the parsnip (Pastinaca sativa L.), elaborate enhanced levels of furocoumarins, including psoralens, when subjected to biotic or abiotic stress. These furocoumarins are recognized to lead to phototoxicity.

International Commission for Protection Against Environmental Mutagens and Carcinogens. Oxidative DNA damage--the effects of certain genotoxic and operationally non-genotoxic carcinogens.

A wide variety of oxidative DNA lesions are commonly present in untreated human and animal DNA. One of these lesions, 8-hydroxydeoxyguanosine, has been shown to lead to base mispairing (mutation) on DNA replication. Other lesions remain to be investigated in this respect.

Food safety: are human activities really worse than nature's?

Those chemicals that are added to food during modern processing are most stringently examined for toxic effects and, if they demonstrate toxicity, are strictly controlled. Despite this, a considerable proportion of the North American human cancer burden has been associated with diet and nutrition. The possible contributions of excess calories, excess and wrongly balanced fats, natural contaminants, and naturally occurring carcinogens within the food supply to this horrendous burden of cancer is considered.

Effect of varying the type of fat in a semi-purified AIN-76A diet on cellular proliferation in the mammary gland and intestinal crypts in female Swiss Webster mice.

Young virgin female Swiss Webster mice were fed AIN-76A semi-purified diets containing equal weights of different fats for approximately 30 days. Using [3H]thymidine radioautography, it was established that mice fed 100% lard or high levels of fish oils (menhaden oil or cod liver oil) developed elevated cellular proliferation in the duct cells of the mammary gland and an increased number of labeled cells/crypt in the crypts of the colo-rectum accompanied by an increase in the size of the proliferative compartment. A possible inverse correlation between the level of [3H]thymidine labeling in the mammary gland, but not in the colo-rectum, and the linoleic acid content of individual diets may help to explain the significance of these observations.

Calories, fat, fibers, and cellular proliferation in Swiss Webster mice.

Increased cellular proliferation has been associated with the enhanced expression of several key stages in carcinogenesis. A standard protocol was used to investigate the effect of specific dietary regimens on cellular proliferation. Young adult Swiss Webster mice were fed for 30 days with modified AIN-76A semi-purified diets designed to illustrate the effects of the levels of dietary or calorie restriction, different fibers and bulking agents, and different fats on cellular proliferation.

Classification of carcinogens: polemics, pedantics, or progress?

Rodent carcinogens may, for physiological or other reasons, induce cancer by a variety of mechanisms which vary in their ability to affect humans. While the current approach of some regulatory agencies to carcinogen risk assessment and regulation may possibly be justified with most genotoxic carcinogens, this is not true with all nongenotoxic carcinogens. Mechanisms attributable to high dose toxicity occasioned by misuse of the maximum tolerated dose concept, imbalancing of homeostasis, unphysiological conditions, and induced cellular proliferation are reviewed.

Early indicators of potential neoplasia produced in the rat forestomach by non-genotoxic agents: the importance of induced cellular proliferation.

Forestomach neoplasia induced by the apparently non-genotoxic carcinogens, butylated hydroxyanisole and propionic acid, appears to arise by way of sustained high levels of cellular proliferation. Several other inducers of enhanced cellular proliferation, or the consequential incidence of hyperplastic lesions, have been identified in the rodent forestomach but the requisite carcinogenicity bioassays remain undone. In other tissues, such as the male rat kidney, the rodent thyroid follicular cell and the bladder epithelium, there is also evidence supporting the concept that sustained enhanced cellular proliferation may be an important early marker for non-genotoxic carcinogens.

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC publication No. 19. The classification of carcinogens identified in the rodent bioassay as potential risks to humans: what type of substance should be tested next?

The relevance of rodent cancer bioassay data to humans is discussed in relation to the needs of regulatory agencies. The usefulness of in vivo and in vitro genotoxicity testing in this connection is also discussed. In the case of rodent carcinogens that do not elicit genotoxicity, it is suggested that homeostatic imbalance, cell proliferation, and other processes may play a major role in tumor development and its importance to the possible ability of the test agent to induce human cancer.

An appreciation of the maximum tolerated dose: an inadequately precise decision point in designing a carcinogenesis bioassay?

Cancers arise in specific tissues. One difficulty with the present definitions of the Maximum Tolerated Dose (MTD), as they pertain to the rodent cancer bioassay, is that they base MTD on relatively crude parameters associated with the well-being of the entire animal rather than with the lack of specific tissue toxicity. Additional factors that could be included in the MTD definition, or could be separately determined, are addressed.