Impact of the informed consent process on patients' understanding of varicose veins and their treatment.

AIM: It is particularly important that patients have reasonable understanding of the risks, benefits and nature of elective surgery. This study sought to analyse this level of understanding in patients undergoing varicose vein surgery METHODS: Eighty two patients completed a questionnaire in the vascular outpatient clinic and were asked to complete a telephone questionnaire following the clinic. RESULTS: Pain (n = 46) was the primary reason patients considered varicose vein surgery followed by appearance (n = 32). Most patients felt that varicose veins placed them at high risk of leg ulcers (n = 46) and DVT (n = 41). A high level of expectation that surgery would significantly affect pain and flares was recorded. While the outpatient visit did not materially change these misconceptions, an educational leaflet significantly enhanced the recall of complications (p = 0.028) in patients who remembered receiving a leaflet. CONCLUSION: Patients attending varicose vein clinics have an unrealistic expectation of the benefits of surgery and fail to understand the benign nature of their condition. The outpatient process has little effect on patient-held beliefs.

Batten disease: evaluation of CLN3 mutations on protein localization and function.

Juvenile neuronal ceroid lipofuscinosis (JNCL), Batten disease, is an autosomal recessive lysosomal storage disease associated with mutations in CLN3. CLN3 has no known homology to other proteins and a function has not yet been described. The predominant mutation in CLN3 is a 1.02 kb genomic deletion that accounts for nearly 85% of the disease alleles. In this mutation, truncation of the protein by a premature stop codon results in the classical phenotype. Additional missense and nonsense mutations have been described. Some missense substitutions result in a protracted phenotype, with delays in the onset of classical clinical features, whereas others lead to classical JNCL. In this study, we examined the effect of naturally occurring point mutations on the intracellular localization of CLN3 and their ability to complement the CLN3-deficient yeast, btn1-Delta. We also examined a putative farnesylation motif thought to be involved in CLN3 trafficking. All of the point mutations, like wild-type CLN3, were highly associated with lysosome-associated membrane protein II in non-neuronal cells and with synaptophysin in neuronal cell lines. In the yeast functional assay, point mutations correlating with a mild phenotype also demonstrated CLN3 activity, whereas the mutations associated with severe disease failed to restore CLN3 function completely. CLN3 with a mutation in the farnesylation motif trafficked normally but was functionally impaired. These data suggest that these clinically relevant point mutations, causative of Batten disease, do not affect protein trafficking but rather exert their effects by impairing protein function.

Phenotypic reversal of the btn1 defects in yeast by chloroquine: a yeast model for Batten disease.

BTN1 of Saccharomyces cerevisiae encodes an ortholog of CLN3, the human Batten disease gene. We have reported previously that deletion of BTN1, btn1-Delta, resulted in a pH-dependent resistance to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP). This phenotype was caused by btn1-Delta strains having an elevated ability to acidify growth medium through an elevated activity of the plasma membrane H(+)-ATPase, resulting from a decreased vacuolar pH during early growth. We have determined that growing btn1-Delta strains in the presence of chloroquine reverses the resistance to ANP, decreases the rate of medium acidification, decreases the activity of plasma membrane H(+)-ATPase, and elevates vacuolar pH. However, an additional effect of this phenotypic reversal is that activity of plasma membrane H(+)-ATPase is decreased further and vacuolar pH is increased further as btn1-Delta strains continue to grow. This phenotypic reversal of btn1-Delta can be considered for developing a therapy for Batten disease.

Toxicological significance of DNA adducts: summary of discussions with an expert panel.

A workshop was held to discuss the uses of data on DNA adduct measurement in humans and in experimental systems in vitro and in vivo. The discussions focused principally on the understanding of the toxicological significance of DNA adducts as provided by information from animal models. An Expert Panel concluded that human DNA adduct data have utility in several aspects of risk assessment. The presence and amount of specific adducts that can be correlated with a chemical exposure are relevant for hazard identification and risk evaluation. Data from experimental systems have established dose-response relationships between the level of adducts and exposure, but these remain complex and depend on metabolic fate. Although structure-activity relationships have been useful retrospectively to explain the DNA-reactive nature of some chemicals or classes of chemicals, there are currently no means outside the laboratory to specifically predict the adduct-producing potency of a compound. Analysis of DNA adducts in tissues of laboratory animals and humans has revealed sensitive subpopulations, a finding that has important relevance for human risk assessment. Adduct analysis may be one of the best tools available to characterize exposures to DNA from complex mixtures for purposes of epidemiological investigation. Consensus statements were developed based on presentations by R. Gupta, W. Lutz, R. Nath, and B. Singer [see Regul. Toxicol. Pharmacol. 23(1), 1996] and subsequent discussions. First, rigorous scientific criteria should be met for the detection and characterization of specific DNA adducts in vitro and in target tissues in vivo. Second, the use of adduct data in risk extrapolation has the greatest value when there is characterization of adduct structure, an understanding of the role of repair in DNA adduct removal, and demonstration of biological relevance for each adduct. Third, the detection of DNA adducts in a tissue does not necessarily indicate a specific tumorigenic risk for that tissue. Fourth, the mutagenic potency for specific adducts varies by several orders of magnitude. Fifth, the role of DNA adducts induced by exogenous agents must be placed in perspective of endogenously produced adducts. The biological significance of a type of DNA adduct is related to several factors, including the efficiency of conversion to mutation, the amounts of similar endogenous adducts, and the variety of exogenous DNA adducts found in DNA from humans. The biological relevance of DNA adducts may be deduced from the dose-response relationships for adducts and tumors at physiologically relevant doses as well as from data showing mutations in targets such as oncogenes or tumor suppressor genes. There is convincing evidence in the literature for an association between some specific DNA adducts, mutation, and the carcinogenic process. As a general conclusion, the Panel suggested that the current technological capabilities for detection of DNA adducts exceed our ability to define the biological significance of adducts as it relates to toxicity or health outcome. DNA adducts are likely to play an important role in human risk for cancer induction and progression, but the quantitative aspects of this relationship remain to be determined.

Multiple chemical sensitivities: a symposium on the state of the science.

Multiple chemical sensitivities (MCS) defies diagnostic categorization because of its pansystemic manifestations, its lack of consistent symptomatology, and its absence of specific, measurable endpoints, either physical stigmata or laboratory findings. Controlled studies have been few and difficult to perform. Moreover, the phenomenon resists systematic investigation for two reasons. First, it has coalesced into a movement championed by zealous proponents and organized adherents. Second, it has gained support in the courts, the legislatures, and the regulatory agencies which have provided special protection and monetary awards to this phenomenon before science and medicine have defined it as a medical disorder. One hotly contested issue in the MCS debate is the relative role of organic versus psychological contribution to the symptoms of MCS patients. This is a critical issue most importantly because it determines approaches to treatment, secondarily because it affects regulatory action, disability determination, and compensability. The interest of the ISRTP in this phenomenon derives from the significant regulatory impact of this diagnosis on OSHA standards, EPA regulations, and FDA standards. The symposium was convened to explore the quality of the science underlying MCS with respect to diagnosis, and, particularly, to cause. The general objective of the symposium was to discuss the state of the science regarding MCS and its implications in regulatory toxicology and public health. The panel of speakers represented a variety of disciplines including toxicology, immunology, occupational medicine, psychiatry, psychology, epidemiology, and public health. The symposium was attended by a diverse audience representing the medical, scientific, business, legal, and regulatory communities. The majority of speakers critically questioned the characterization of MCS as a clinical entity, in light of historical comparisons to earlier false diagnoses, toxicological implausibility, and clinical inconsistencies.

A critique of the use of the maximum tolerated dose in bioassays to assess cancer risks from chemicals.

The maximum tolerated dose (MTD) regimen for testing substances for their ability to induce cancer and other chronic diseases in laboratory rodents has been required by governmental authorities for several decades. Cancer researchers originally suggested the MTD approach and it was then adopted by the FDA and EPA. The intention was to detect the ability of any substance under any circumstances, including the most extreme, to induce cancer in laboratory rodents. We question the validity of using the MTD in animal bioassays to evaluate risk for human cancer. The paradox is that the safer the chemical, the higher the MTD, but the higher the MTD, the more likely that biochemical distortions will result and cause cellular injury, abnormal cell replication, toxic hyperplasia, and toxicity-induced cancer. All chemicals are toxic at some dose, whether relevant to anticipated human exposure or vastly exceeding it. New approaches to cancer-testing lifetime bioassays are needed. A minimally toxic dose is defined and suggested to avoid specific tissue toxicity detected by clinical or pathology examination in animals subchronically exposed to the test compound for 90 days. The highest subtoxic dose that can be tolerated by test animals over a long period of time is suggested as being more appropriate for carcinogenicity bioassays.