Dynamics of pigmentation induction by repeated ultraviolet exposures: dose, dose interval and ultraviolet spectrum dependence.

BACKGROUND: The dynamics of ultraviolet (UV)-induced melanogenesis have been well characterized for single UV exposures. However, our knowledge of the effects of repeated UV exposures on the development of new pigmentation is limited. OBJECTIVES: To characterize the dynamics and dose dependence of pigmentation induction by repeated UV exposures using two different UV sources. METHODS: A total of 40 healthy subjects participated in the study: 21 were exposed to a 5% UVB/95% UVA source and 19 were exposed to a 2% UVB/98% UVA source. Skin phototypes 2-3 were represented. Subjects were exposed one to three times per week. The minimal erythemal dose and minimal melanogenic dose of all subjects were determined, and both visual and instrumental observations of the development of pigmentation and erythema were recorded. RESULTS: Dark-brown pigmentation could be produced by a cumulative UV dose of 4200 J m(-2) given as 10 exposures over 5 weeks. However, comparable pigmentation could also be induced by a cumulative dose of 2900 J m(-2) given as eight exposures over 4 weeks. The lowest cumulative dose of 1900 J m(-2) given over 4 weeks produced moderate pigmentation. The 2% UVB source led to earlier and darker pigmentation than the 5% UVB source did for equally erythemogenic doses. CONCLUSIONS: These observations show that the dynamics of melanogenesis induced by repeated exposures depends on UV dose, dose interval and emission spectrum. They also indicate that increasing the UV dose above a certain level of cumulative exposure does not significantly increase the level of UV-induced pigmentation.

Study design in the evaluation of breast cancer imaging technologies.

RATIONALE AND OBJECTIVES: Bringing a new imaging technology to market is a complex process. Beyond conceptualization and proof of concept, obtaining U.S. Food and Drug Administration (FDA) approval for clinical use depends on the documented experimental establishment of safety and efficacy. In turn, safety and efficacy are evaluated in the context of the intended use of the technology. The purpose of this study was to examine a conceptual framework for technology development and evaluation, focusing on new breast imaging technologies as a highly visible and current case in point. MATERIALS AND METHODS: The FDA views technology development in terms of a preclinical and four clinical phases of assessment. With a concept of research and development as a learning model, this phased-assessment concept of regulatory review against intended use was integrated with a five-level version of a hierarchy-of-efficacy framework for evaluating imaging technologies. Study design and analysis issues are presented in this context, as are approaches to supporting expanded clinical indications and new intended uses after a new technology is marketed. CONCLUSION: Breast imaging technologies may be intended for use as replacements for standard-of-care technologies, as adjuncts, or as complementary technologies. Study designs must be appropriate to establish claims of superiority or equivalence to the standard for the intended use. Screening technologies are ultimately judged on their demonstrated effectiveness in decreasing cause-specific mortality through early detection, but they may be brought to market for other uses on the basis of lesser standards of efficacy (eg, sensitivity, specificity, positive and negative predictive value, and stage of disease detected).

A physiologically based pharmacokinetic model for 2,4-toluenediamine leached from polyurethane foam-covered breast implants.

Physiologically based pharmacokinetic (PBPK) modeling was used to assess the low-dose exposure of patients to the carcinogen 2, 4-toluenediamine (2,4-TDA) released from the degradation of the polyester urethane foam (PU) used in Meme silicone breast implants. The tissues are represented as five compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues (e.g., fat), and richly perfused tissues (e.g., muscle). The PBPK model was fitted to the plasma and urine concentrations of 2,4-TDA and its metabolite 4-AAT (4-N-acetyl-2-amino toluene) in rats given low doses of 2, 4-TDA intravenously and subcutaneously. The rat model was extrapolated to simulate oral and implant routes in rats. After adjusting for human physiological parameters, the model was then used to predict the bioavailability of 2,4-TDA released from a typical 4.87-g polyester urethane foam implant found in a patient who weighed 58 kg with the Meme and had the breast implant for 10 years. A quantitative risk assessment for 2,4-TDA was performed and the polyester urethane foam did present an unreasonable risk to health for the patient.

An in vitro evaluation of condoms as barriers to a small virus.

BACKGROUND: Because of the possible presence of small holes, the effectiveness of condoms as barriers to virus transmission is controversial. GOALS: To determine the proportion of condoms that allow virus penetration and the amounts of virus that penetrate. STUDY DESIGN: A sensitive, static test was used to evaluate different condom types as barriers to a small virus, including brand with or without lubrication and ones of different materials. The test included some physiologic-based parameters and some parameters that exaggerated expected actual use conditions. RESULTS: Under test conditions, 2.6% (12 of 470) of the latex condoms allowed some virus penetration; the median level of penetration was 7 x 10(-4) ml. Lubricated condoms performed similarly to nonlubricated ones. Polyurethane condoms yielded results higher than but not statistically different from those for latex condoms. CONCLUSIONS: Few condoms allowed any virus penetration. The median amount of penetration for latex condoms when extrapolated to expected actual use conditions was 1 x 10(-5) ml (volume of semen). Thus, even for the few condoms that do allow virus penetration, the typical level of exposure to semen would be several orders of magnitude lower than for no condom at all.

PIP: Nine brands and 470 samples of latex condoms and two brands and 76 samples of polyurethane condoms bought from retail distributors were tested in vitro for their ability to block the penetration of virus. A sensitive, static test apparatus was designed for and used in the evaluation. The test included some physiological-based parameters as well as some which exaggerated the expected actual use conditions. Both lubricated and nonlubricated condoms were tested. Before testing, however, most of the lubrication was removed from the lubricated condoms through rinsing with Dulbecco's phosphate-buffered saline and blotting with sterile paper towels. The 0X174 bacteriophage of 27 nm particle diameter, 32 nm including its bulky spikes, was used as the proxy challenge virus. Under test conditions, 12 of the latex condoms (2.6%) allowed some virus penetration of median quantity 0.0007 ml. Just two of the latex condoms were responsible for 99.8% of the total penetration among latex condoms overall. The performance of lubricated condoms was similar to that of nonlubricated ones. Four of the polyurethane condoms allowed penetration, but only one condom was responsible for 98.6% of total penetration. The difference in performance between latex and polyurethane condoms is not statistically significant. The median amount of penetration for latex condoms when extrapolated to expected actual use conditions was 0.00001 ml of semen. Therefore, even for the few condoms which allow virus penetration, the typical level of exposure to semen is several orders of magnitude lower than the amount of exposure expected when not using a condom.

Digital acoustical analysis of normal and bimodal Björk-Shiley 60 degrees convexo-concave heart valves.

Fracture of the outlet strut of the Björk-Shiley 60 degrees convexo-concave (BS60CC) valve has been attributed to a bimodal closing pattern in certain valves in which the closing disk rotates about the inlet strut, causing upward displacement of the outlet strut and its eventual fracture. This article reports the in vivo studies of the normal BS60CC valve and the in vitro studies of the normal and bimodal BS60CC valves, using a digital acoustical signal processing technique, in which the individual collisions (impact history) of the occluder disk with the components of the valve body are revealed during each closing cycle. In vitro analysis of the closing acoustical signals of normal BS60CC valves showed impact history cluster width (IHCW) means of 2.07 +/- 0.85 ms (standard error), not significantly different from those of 1.86 +/- 0.58 ms (standard error) observed in 38 clinically normal patients with BS60CC valves (p greater than 0.1). The bimodal valves showed IHCW of 6.14 +/- 0.98 ms (standard error), in vitro, which was significantly greater than those observed in the normal in vitro valve group and in the normal patient population (p less than 0.0001).

Inactivation and mutagenesis of herpes virus by photodynamic treatment with therapeutic dyes.

Dyes which photosensitize membranes may be clinically useful for photodynamic treatment (PDT) of Herpes simplex virus (HSV) infections. It is important to determine whether the enveloped HSV can be inactivated via membrane damage without affecting the genetic material. Selection of appropriate PDT conditions, including the choice of dye, could minimize viral mutagenesis. We determined the mutagenesis caused by PDT employing three membrane-photosensitizing dyes of potential use in cancer photochemotherapy (Photofrin II, polyhematoporphyrin esters, zinc phthalocyanine tetrasulfonates) and a DNA-photosensitizing dye (proflavine sulfate). The effects were compared to those caused by exposure of HSV to ultraviolet radiation (UV). The procedure consisted of incubating HSV with microgram/ml (microM) concentrations of the dye, irradiating the samples with broad spectrum visible/near-UV radiation (Daylight fluorescent lamps) and assaying the survival of the treated HSV. Zinc phthalocyanine was the most potent dye per absorbed photon for inactivating HSV. In parallel with determination of survival, progeny of the surviving virus were grown for determination of mutagenesis. The progeny virus was harvested and subsequently assayed in the presence and absence of 40 micrograms/ml iododeoxycytidine (ICrd) to determine the frequency of mutation to ICrd resistance. Mutation frequencies were determined for progeny from the 1-4% survival level. For PDT with each membrane-photosensitizing dye, only zinc phthalocyanine increased the mutation frequency over the untreated control. This increase was less than 2-fold. Proflavine increased the mutation frequency 2-3 fold over the untreated control. Ultraviolet produced a 15-20 fold increase over the untreated control.(ABSTRACT TRUNCATED AT 250 WORDS)

Residual ethylene oxide determination in polymethyl methacrylate disks and intraocular lenses by headspace gas analysis and N,N-dimethylformamide extraction.

The residue in an ethylene oxide (EO)-exposed polymethyl methacrylate (PMMA) material [flat disk and intraocular lens (IOL)] was determined using three methods: semiautomatic and manual headspace methods and N,N-dimethylformamide (DMF) solvent extraction. Results from the analysis of three different sample configurations at three different EO concentrations are compared. Results from the DMF extraction of PMMA indicate that the headspace methods at 100 degrees C are not exhaustive with respect to recovery of total residual ethylene oxide. Furthermore, the manual headspace method appears to be slightly more effective than the semiautomatic injection headspace method. Sorption of EO and subsequent extraction is related to the surface area-to-volume ratio of the sample, with higher concentrations observed in samples with the high ratio.

Untargeted viral mutagenesis is not found in X-irradiated monkey cells.

The existence of untargeted viral mutagenesis in X-irradiated cells was investigated in a mammalian virus/cell system, where a low level of such viral mutagenesis can be demonstrated in UV-irradiated cells. In the positive control experiment UV-elicited mutagenesis was shown with cell exposures of 5, 10 and 15 J/m2 and a delay of 24 h between cell irradiation and infection with unirradiated herpes simplex virus. Although X-ray doses of 1, 3 and 10 Gy elicit enhanced reactivation of UV-irradiated virus, no untargeted mutagenesis for any X-ray dose at post-irradiation infection times of 0, 24 or 72 h was observed in this study. Thus untargeted mutagenesis of herpes simplex virus was not demonstrated in X-irradiated monkey cells, under conditions where X-ray-enhanced reactivation occurs and where untargeted mutagenesis in UV-irradiated cells occurs.