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To provide an overview of the epidemiologic parameters of emerging adverse effects associated with antiretroviral therapy for human immunodeficiency virus (HIV) disease. All available antiretroviral agents are associated with significant adverse drug effects. Of particular interest are newly emerging suspected adverse drug effects which were not generally noted in pre-marketing trials nor captured under current standard clinical care practices. Suspected antiretroviral toxicities meeting these criteria include: HIV-associated lipodystrophy which can include peripheral lipoatrophy, lipohypertrophy and metabolic abnormalities; hyperlactatemia and lactic acidosis; and metabolic bone abnormalities such as decreased bone mineral density, osteoporosis and osteonecrosis. Results of prospective and observational studies reported to date suggest that these abnormalities, while aetiologically complex, are likely attributable to treatment factors and may be intricately interrelated. The medical management of these symptoms remains unsatisfactory given the unexplored efficacy of traditional approaches in the HIV positive population. While the pathogenic mechanism of these disorders remains obscure, a theory of tissue-specific mitochondrial toxicity has been proposed. With the continued introduction of novel therapies and standard treatment with combination therapy, new adverse events will continue to emerge among persons being treated for HIV disease. Beyond their immediate clinical implications, these events may contribute to changing patterns of antiretroviral utilisation including therapy initiation, adherence and cessation.

The objectives of this paper are to: assess the impact of exposure to current levels of environmental contaminants in the Canadian Arctic on human health; identify the data and knowledge gaps that need to be filled by future human health research and monitoring; examine how these issues have changed since our first assessment [Van Oostdam, J., Gilman, A., Dewailly, E., Usher, P., Wheatley, B., Kuhnlein, H. et al., 1999. Human health implications of environmental contaminants in Arctic Canada: a review. Sci Total Environ 230, 1-82]. The primary exposure pathway for contaminants for various organochlorines (OCs) and toxic metals is through the traditional northern diet. Exposures tend to be higher in the eastern than the western Canadian Arctic. In recent dietary surveys among five Inuit regions, mean intakes by 20- to 40-year-old adults in Baffin, Kivalliq and Inuvialuit communities exceeded the provisional tolerable daily intakes (pTDIs) for the OCs, chlordane and toxaphene. The most recent findings in NWT and Nunavut indicate that almost half of the blood samples from Inuit mothers exceeded the level of concern value of 5 microg/L for PCBs, but none exceeded the action level of 100 microg/L. For Dene/Métis and Caucasians of the Northwest Territories exposure to OCs are mostly below this level of concern. Based on the exceedances of the pTDI and of various blood guidelines, mercury and to a lesser extent lead (from the use of lead shot in hunting game) are also concerns among Arctic peoples. The developing foetus is likely to be more sensitive to the effects of OCs and metals than adults, and is the age groups of greatest risk in the Arctic. Studies of infant development in Nunavik have linked deficits in immune function, an increase in childhood respiratory infections and birth weight to prenatal exposure to OCs. Balancing the risks and benefits of a diet of country foods is very difficult. The nutritional benefits of country food and its contribution to the total diet are substantial. Country food contributes significantly more protein, iron and zinc to the diets of consumers than southern/market foods. The increase in obesity, diabetes and cardiovascular disease has been linked to a shift away from a country food diet and a less active lifestyle. These foods are an integral component of good health among Aboriginal peoples. The social, cultural, spiritual, nutritional and economic benefits of these foods must be considered in concert with the risks of exposure to environmental contaminants through their exposure. Consequently, the contamination of country food raises problems which go far beyond the usual confines of public health and cannot be resolved simply by risk-based health advisories or food substitutions alone. All decisions should involve the community and consider many aspects of socio-cultural stability to arrive at a decision that will be the most protective and least detrimental to the communities.

The immunotoxic effects of tributyltin chloride (TBTC) were examined in the offspring of Sprague-Dawley rats exposed in utero from day 8 of gestation, through lactation and post-weaning until pups reached the age of 30 days (male and female), 60 days (female) and 90 days (male). Daily oral (gavage) doses of 0.025, 0.25 and 2.5 mg/kg body weight/day were administered in olive oil 7 days/week. Immunologic endpoints were investigated at the termination of each study. Statistically significant results (P0.05) included the following: At 30 days, the mean percent and absolute natural killer (NK) cell numbers were increased in male and female rats treated with the high TBTC dose. At 60 days, female rats had increased mean serum IgM levels at the low and high TBTC doses, increased mean percentage CD4(+)8(+) (immature) T lymphocytes at the middle and high doses, a non-linear dose-response increase in NK cell activity at the 50:1 and 100:1 effector:target cell ratios (pairwise comparisons significant at the low dose compared with control), and increased mean numbers of L. monocytogenes colony-forming bacteria on Day 2 post-infection (significant for trend) and Day 3 post infection (pairwise comparisons significant only in the middle dose). The 90-day male rats had decreased mean serum IgA levels at the middle dose group; increased IgM levels at the high dose group, increased IgG levels at the middle and high doses; decreased IgG2(a) in the high dose compared to the control; a dose-related increase in the mean percentage NK cell numbers (pairwise comparisons significant at the high dose compared with the control) and increased mean NK cell activity (pairwise comparisons significant at all dose groups compared with the control). The delayed-type hypersensitivity response to oxazolone was increased in the low and middle doses and decreased in the high dose. Thymus atrophy was observed in the high TBTC dose across all ages. Thus, in utero and post-natal treatment of F1 rats with low levels of TBTC affected some aspects of humoral and cell mediated immunity as well as the number and function of cells which are involved in the host's immunosurveillance mechanisms against tumours and viral infections.

The effects of fumonisin B1 (FB1) on the immune system of Sprague-Dawley rats were investigated. Groups of male and female rats (10 rats/group) were gavaged daily for 14 days with doses of 0, 5, 15, and 25 mg/kg body wt/day and the primary (IgM) response to sheep red blood cells expressed as plaque-forming cell numbers/10(6) spleen mononuclear leukocytes (PFC/10(6) splenocytes) and PFC/spleen was determined. There was a significant dose-related linear trend toward decreased PFC/10(6) splenocytes (p = 0.003) and PFC/spleen cells (p = 0.001) in the male rats. Body weights, expressed as a percentage of the control, were significantly reduced (p = 0.002) in the male rats administered 15 and 25 mg/kg doses. The PFC numbers in female rats were not affected significantly by treatment (p0.05). For the remaining immunotoxicity studies, groups of male rats (10 rats/group) were gavaged with FB1 doses of 0, 1, 5, and 15 mg/kg body wt/day for 14 days. There was a weakly significant dose-related trend toward increased numbers of serum immunoglobulin class G (p = 0.04). Also a significant dose-related increase (p = 0.013) in Listeria monocytogenes numbers was observed in the spleen at 24 hr postinfection. Treatment did not have a significant effect on organ weights, hematology, mitogen-induced lymphocyte transformation, calcium mobilization, the numbers of leukocytes and T-lymphocyte subsets, the natural killer cell activity, and phagocytosis (p/= 0. 05). These observations suggested that FB1 may have indirect consequences for human health and warrant further investigations.

Male rats were gavaged with fumonisin B1 (FB1) once daily for 11 consecutive days at doses of 0, 1, 5, 15, 35, and 75 mg FB1/kg body weight. Urine osmolality (at 5-75 mg FB1/kg) and organic ion transport in kidney slices (at 5-75 mg FB1/kg) were reduced. Urinary excretion of protein (at 15-75 mg FB1/kg) and of the enzymes LDH (at 5-75 mg FB1/kg), NAG (at 5-75 mg FB1/kg) and GGT (at 15-75 mg FB1/kg) were increased. These findings were indicative of glomerular and tubular toxicity. Histopathologic changes in the kidney consisted of necrosis of tubular epithelia of variable extent accentuated in the inner cortex. These changes were present at 1 and 5 mg FB1/kg and were more pronounced at 15-75 mg FB1/kg. Serum enzymes indicative of hepatotoxicity (ALT, GGT) were elevated compared to controls at 75 mg FB1/kg only. There were noticeable increases in mitotic figures in hepatocytes at 35-75 mg FB1/kg, while single cell necroses were increasingly numerous from 15-75 mg FB1/kg. The kidneys were considered to be the primary target organs in this study.

The original criteria for modifying a radical mastoidectomy were: (1) an intact pars tensa and a defective pars flaccida with cholesteatoma; (2) normal or near normal hearing; and (3) an intact, functional ossicular chain. We propose a fourth criterion: that the cholesteatoma site be delineated lateral to the body of the incus. Control of the disease process is easily assured if the lesion is in that area. Our recommended fourth criterion is based on the results of a five-year study of fifty-two cases that met the original criteria. The cholesteatoma reoccurred in the middle ear in only one case. In six cases, periodic care is necessary because of retraction to the grafted attic area. The procedure and technique used in these patients and the excellent results are discussed in this article.