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Background: The population of people living with HIV is aging, and with aging come emergent comorbidities, including osteoporosis, for which screening and treatment are becoming increasingly important. Osteoporosis prevalence among those living with HIV is 3 times greater than among HIV-uninfected controls., Objective: To assess and describe osteoporosis risk factors, screening, diagnosis, and treatment for people 50 years of age or older living with HIV and receiving care at a multidisciplinary HIV primary care clinic., Methods: A retrospective chart review of people 50 years of age or older living with HIV was conducted at the John Ruedy Clinic in Vancouver, British Columbia, between June 1, 2016, and June 1, 2019. Patients who had had fewer than 2 yearly follow-up appointments were excluded., Results: A total of 146 patients were included in the analysis; most were male ( n = 134, 92%), and the median age was 55 years. Patients had a median of 3 osteoporosis risk factors (in addition to age and HIV infection), and 145 patients had at least 1 risk factor. All screening for osteoporosis was conducted by dual-energy X-ray absorptiometry (DXA). Thirty-nine (27%) of the patients were screened with DXA, 92 (63%) were not screened, and 15 (10%) already had a diagnosis of osteoporosis. The DXA screening identified osteoporosis in an additional 10 patients and osteopenia in 22 patients. Treatments for patients with osteoporosis included bisphosphonates ( n = 15, 60%) and vitamin D or calcium (or both), without any other medications ( n = 4, 16%). In the overall study population, 32 (22%) of the patients were taking calcium and 46 (32%) were taking vitamin D., Conclusions: Many patients aged 50 years or older and receiving HIV care at the John Ruedy Clinic had or were at risk for osteoporosis. An opportunity exists to increase screening and treatment of these individuals. A multidisciplinary team may be crucial in achieving this goal., Competing Interests: Competing interests: None declared., (2022 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

A 90-day gavage study was conducted with 0.0, 0.02, 0.075, 0.25, 1.0 and 4.0 mg/kg bw/day dose groups of 3-methylfuran to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including changes in gross anatomy, histopathology, clinical biochemistry and hematology. There were significant changes in the serum clinical biochemistry markers related to liver injury where males were more affected than the females for most parameters analysed. The serum liver injury marker γ-glutamyltransferase, alanine and aspartate aminotransferases were significantly increased in males in the 4.0 mg/kg dose group. Alkaline phosphatase was increased in females and males. There were increases in both gross and histological lesions in the liver of both sexes in addition to statistical differences in female liver weights at the 4.0 mg/kg bw/day dose. Significant increases in spleen weights were found in both genders. This was accompanied by a dose-dependent atrophy of both B- and T-cell regions in which the males were more affected. There were no significant changes in male kidney weights but there was microscopically decreased protein in the proximal tubules and crowding of their nuclei in the 4.0 mg/kg bw/day dose group. There were also significant changes in the kidney serum biomarkers including various electrolytes, blood urea nitrogen, creatinine and uric acid. A small, but significant increase in female kidney weights was observed and which increase was accompanied by changes in electrolytes, kidney specific markers and a dose-dependent increase in mineralization. In both genders, amylase decreased whereas lipase increased but these were not accompanied by any histological changes in the pancreas. Histopathological changes in the liver were observed consistently in male and female rats in the 0.25 mg/kg dose group and higher. Hence, a lowest observed adverse effect level (LOAEL) of 0.25 mg/kg bw/d and a no observed adverse effect level (NOAEL) of 0.075 mg/kg bw/day are proposed for 3-methylfuran-induced hepatic lesions in this study. Benchmark dose modelling based on a BMR of 10% change in lesion incidence, generated BMDLs 10 of 0.08 mg/kg bw/day in male rats and 0.05-0.17 mg/kg bw/day in female rats for increased incidence of liver lesions., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARα and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal thyroid hormone (TH) homeostasis, in the livers of adult male rats exposed in feed to 50mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes, and global gene expression changes consistent with the involvement of PPARα and CAR/PXR. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122-5p and miR-21-5p were the most decreased, in PFOS-treated rats. Expression of the miR-23b-3p/27b-3p/24-3p cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes suggests involvement of epithelial to mesenchymal transition (EMT), which is a primary process of tumor cell motility and cancer metastasis. Our analysis also revealed transcripts that may mediate PFOS-induced effects on TH homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signaling, suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, the study suggests an important role for miRNAs in PFOS-induced hepatotoxicity and provides insight into the effects of PFOS on TH homeostasis., (Copyright © 2015. Published by Elsevier B.V.)

Background: HIV-infected patients on antiretroviral therapy frequently develop dyslipidemias and, despite therapy with potent lipid-lowering agents, a high percentage does not achieve guideline recommended lipid targets. In this study, we examined the efficacy of combination treatment with a statin and the cholesterol transport blocker, ezetimibe, vs. monotherapy with a statin in HIV-infected patients not achieving lipid goals., Methods: This was a 12-week, prospective, randomized, open-label clinical trial. Patients were eligible if they had an apolipoprotein B (apoB) >0.80 g/L despite therapy with rosuvastatin 10 mg daily for a minimum of 12 weeks. Patients were randomized to take ezetimibe 10 mg/rosuvastatin 10 mg or rosuvastatin 20 mg for 12 weeks. Percentage and absolute change in apoB (primary outcome), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apoliporpotein A1 (apoA1), apoB/apoA1, TC/HDL-C, atherogenic index of plasma (API), and high-sensitivity C-reactive protein (hsCRP) were compared. Changes in safety parameters (such as AST, ALT, CK) and clinical symptoms were also assessed., Results: Forty-three patients (23 on ezetimibe 10 mg/rosuvastatin 10 mg and 20 on rosuvastatin 20 mg) completed the trial. Baseline characteristics did not differ between the groups. Significant improvements in apoB were seen with both ezetimibe plus rosuvastatin (mean of -0.17 g/L, p < 0.001) and rosuvastatin 20 mg (mean of -0.13 g/L, p = 0.03) treatment groups, but did not differ between groups (p = 0.53). Significant between-group differences were observed for mean TC (-1.01 mmol/L vs. -0.50 mmol/L, p = 0.03), TG (-0.62 mmol/L vs -0.17 mmol/L, p = 0.03), and non-HDL-C (-0.97 mmol/L vs. -0.53 mmol/L, p = 0.03) all in favour of the ezetimibe plus rosuvastatin group. Two patients, both in the rosuvastatin 20 mg group, experienced mild myalgias; neither discontinued the study., Conclusions: The addition of ezetimibe to rosuvastatin appears to be safe in patients with HIV. Furthermore, the combination of ezetimibe and rosuvastatin improved TG, AIP and non-HDL cholesterol levels more than a dose increase in rosuvastatin in patients with HIV-associated dyslipidemia.

There is disagreement internationally across major regulatory jurisdictions on the relevance and utility of whole food (WF) toxicity studies on GM crops, with no harmonization of data or regulatory requirements. The scientific value, and therefore animal ethics, of WF studies on GM crops is a matter addressable from the wealth of data available on commercialized GM crops and WF studies on irradiated foods. We reviewed available GM crop WF studies and considered the extent to which they add to the information from agronomic and compositional analyses. No WF toxicity study was identified that convincingly demonstrated toxicological concern or that called into question the adequacy, sufficiency, and reliability of safety assessments based on crop molecular characterization, transgene source, agronomic characteristics, and/or compositional analysis of the GM crop and its near-isogenic line. Predictions of safety based on crop genetics and compositional analyses have provided complete concordance with the results of well-conducted animal testing. However, this concordance is primarily due to the improbability of de novo generation of toxic substances in crop plants using genetic engineering practices and due to the weakness of WF toxicity studies in general. Thus, based on the comparative robustness and reliability of compositional and agronomic considerations and on the absence of any scientific basis for a significant potential for de novo generation of toxicologically significant compositional alterations as a sole result of transgene insertion, the conclusion of this review is that WF animal toxicity studies are unnecessary and scientifically unjustifiable.

Background: The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health., Methods: Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the study's Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies., Results: Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada., Conclusions: The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals., (© 2013 John Wiley & Sons Ltd and Her Majesty the Queen in Right of Canada. Reproduced with the permission of the Minister of Health.)

The fungal toxin fumonisin B1 (FB1) is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition. Based on this mechanism of action and on lack of evidence of genotoxicity, FB1 is considered a non-genotoxic carcinogen. The p53 heterozygous (p53+/-) mouse is a cancer-prone model used for carcinogenesis. The effects of chronic dietary FB1 exposure were characterized in p53+/- mice to confirm non-genotoxicity using a model which is more sensitive to genotoxic than non-genotoxic carcinogens and to clarify the relationship between p53 expression, altered sphingolipid metabolism, and FB1-induced carcinogenesis. Responses to FB1 were similar in p53+/- and p53+/+ mice after 26 weeks exposure to 0, 5, 50 or 150 mg FB1/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150 mg/kg FB1. For a 10% increase in hepatic megalocytosis, the estimated 95% lower confidence limit of the benchmark dose (BMDL10) ranged from 0.15 and 1.11 mg FB1/kg bw/day. Based on similar responses in p53+/- and p53+/+ mice, p53 and related pathways play a secondary role in responses to FB1 toxicity and carcinogenesis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Metabolic complications common to the HIV-positive population may increase the risk for cardiovascular disease. Asymptomatic peripheral arterial disease (PAD) is associated with increased cardiovascular risk. The ankle-brachial pressure index (ABI) is a screening tool commonly used for the detection of asymptomatic PAD. The prevalence of asymptomatic PAD based on ABI in HIV-positive patients is unknown. This study was cross-sectional in design and assessed PAD by measuring the systolic ABI as determined by a handheld 8-MHz Doppler probe with the patient at rest in a supine position. A brief medical history including pertinent risk factors was obtained. One hundred and sixty-seven HIV-positive patients were evaluated (97.6% male; mean age 52.0 years; 31.2% current smokers, 29.4% former smokers, 26.3% diabetes mellitus). Asymptomatic PAD (ABI < or = 0.9) was found in four patients (2.4%, 95% CI: 0.3-4.5%). Smoking was a significant predictor of PAD. Patients with a positive test for PAD had at least two major risk factors for the disease including smoking, a history of disease in another vascular bed, dyslipidemia, diabetes, and hypertension. All patients with a positive test for PAD had a high risk (>20%) for cardiovascular disease according to the Framingham risk score. Three of the four patients with positive tests had previously diagnosed vascular disease (CAD, stroke). Three patients presenting with PAD were evaluated and all had a positive ABI. The prevalence of PAD compared to previous studies on PAD in HIV was low and identified only those patients with high cardiovascular risk based on other features. ABI was not useful in detecting occult vascular disease in HIV-positive patients and offers no additional information to that derived from cardiovascular risk stratification.

Rodent studies have shown that furan is a hepatocarcinogen. Previous studies conducted with high doses showed tumors at nearly 100% incidence at all doses. In this paper, a ninety-day gavage experiment conducted with lower doses (0.0, 0.03, 0.12, 0.5, 2.0, and 8.0 mg/kg bw) to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including gross changes and histopathology, clinical biochemistry, hematology, and immunotoxicology is reported. As indicated by changes in serum biomarkers, increased liver weights and gross and histological lesions, the liver is the major target organ affected by furan. There were no changes in body weights, food consumption, or histology in other organs. Some of the serum electrolyte markers, including phosphorus, were altered. There was a significant increase in serum thyroxine and triidothyronine in males. This increase was not accompanied by histological thyroid changes. Immunophenotypic analysis showed that thymic lymphocyte maturation was altered in male rats. Although altered clinical biochemistry and hematological parameters were observed at a dose of > 0.5 mg/kg bw, mild histological lesions in the liver were observed at > 0.12 mg/kg bw. Based on this finding, a furan dose of 0.03 mg/kg bw was proposed as the no-observed adverse effect level for hepatic toxicity.

Objective: Cardiovascular disease (CVD) is the leading cause of death in people with type 2 diabetes. Apolipoprotein B (apoB) is known to be a better marker of CVD risk than low-density lipoprotein cholesterol (LDL-C). This study investigated apoB levels in people with type 2 diabetes., Methods: We obtained blood samples from 507 consenting people with type 2 diabetes who were not receiving lipid-lowering medication and who had no previous history of CVD. Subjects were divided into 3 groups: men (M), women <50 years old (W1) and women ≥50 years old (W2). Primary analysis examined lipid parameters, specifically apoB. Secondary analysis involved classifying patients according to the Canadian Diabetes Association's apoB, LDL-C and triglyceride (TG) targets., Results: We found a total mean apoB level of 0.92 g/L. Among patients who failed to achieve the LDL-C target, 28% of M, 39% of W1 and 30% of W2 met the apoB target. The proportions of individuals categorized as being above the LDL-C and apoB targets were significantly different in all 3 groups (p<0.01). When LDL-C was below target and TG was <1.5 mmol/L, 100% of M and W1 and 93% of W2 met the apoB target., Conclusions: The discordance between the proportions of patients meeting LDL-C and apoB targets may lead to patients being erroneously classified. ApoB and LDL-C correlate very well when TG is <1.5 mmol/L, but not when ≥1.5 mmol/L. Approximately one-third of patients met both LDL-C and apoB goals. Thus, not all patients with type 2 diabetes should be considered to be at a high risk of CVD., (Copyright © 2009 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Perfluorooctanesulfonate (PFOS) is a stable and environmentally persistent metabolic or degradation product of perfluorooctanyl compounds that were manufactured for a variety of industrial and consumer applications. PFOS itself was sold for use as a surfactant. The structurally related contaminants perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), and N-ethyl perfluorooctane sulfonamide (N-EtPFOSA) were shown to suppress immune responses in laboratory rodents. Relatively low doses of PFOS were found to be immunosuppressive in mice. To assess effects of PFOS on the rat immune system at doses known to alter hepatic function, changes in the morphology and function of immune tissues and cells were measured in adult rats exposed to PFOS in their diet for 28 d at levels ranging from 2 to 100 mg PFOS/kg diet (corresponding to approximately 0.14 to 7.58 mg/kg body weight [bw]/d) and compared to those receiving control diet. Body weight reductions were significant in male and female rats exposed to 50 and 100 mg PFOS/kg diet. Liver/body weight was significantly increased in females exposed to 2 mg PFOS/kg diet and in males exposed to 20 mg PFOS/kg diet. Female rats exposed to 100 mg PFOS/kg diet exhibited a significant increase in spleen weight relative to body weight; these changes lacked a histologic correlate and were not observed in males. While thymus weights relative to body weights were not affected, numbers of apoptotic lymphocytes rose in thymus with increasing dietary PFOS. There was a significant dose-related increase in total peripheral blood lymphocyte numbers in female but not male rats. In both genders the percentages of cells within lymphocyte subclasses were altered. There was a significant trend toward increasing T and T-helper (Th) cells and decreasing B cells with higher PFOS dose. Serum total immunoglobulin (Ig) G1 levels were significantly reduced in males exposed to 2 and 20 mg PFOS/kg diet. The ability of male and female rats to mount delayed-type hypersensitivity (DTH) responses to the T-cell-dependent antigen keyhole limpet hemocyanin (KLH) was not altered by PFOS. There was a significant trend toward elevated KLH-specific IgG in serum from male rats exposed to increasing levels of PFOS in diet. Splenic T- and B-cell proliferation in response to ex vivo mitogen exposure was unaffected by exposure to dietary PFOS. In conclusion, changes in immune parameters in rat did not manifest as functional alterations in response to immune challenge with KLH and may be secondary to hepatic-mediated effects of PFOS in this model.

Perfluorooctanesulfonate (PFOS) is one of a class of industrial chemicals known as perfluoroalkyl acids, which have a wide variety of uses as surfactants and stain repellants. The presence of fluorochemical residues in human blood, plasma, or serum from sample populations worldwide is indicative of widespread human exposure. Previous studies demonstrated that PFOS alters fatty acid metabolism in the liver of rodents and that this leads to peroxisome proliferation. This study was undertaken to (1) confirm the effects of PFOS on rat liver, (2) identify additional target organs and systems, and (3) further explore the biochemical and molecular changes associated with PFOS exposure. The results confirmed that liver was a primary target for PFOS. Hepatomegaly, decreased serum triglycerides and cholesterol, and increased expression of the genes for acyl-coenzymeA oxidase 1 (ACOX1) and cytochrome P-450 4A22 (CYP4A22) were indicative of exposure to a peroxisome proliferator. Changes in liver fatty acid profiles included increased total monounsaturated fatty acid levels and decreased total polyunsaturated fatty acids, as well as an increase in linoleic acid levels and a decrease in longer chain fatty acids. These changes were similar to those induced by relatively weak peroxisome proliferators. Disruptions in hepatic fatty acid metabolism may contribute to changes in red blood cell membranes, resulting in increased lysis and cell fragility. Serum thyroid hormone levels were decreased in PFOS-treated rats, while the kidney and cardiovascular systems were not significant targets. Residue analyses indicated that PFOS accumulation in tissues was dose dependent, appearing preferentially in the liver at lower doses but increasing in serum and other organs relative to liver at higher doses.

Background: Highly active antiretroviral therapy (HAART) with protease inhibitors (PI) is successful in suppressing viral replication, but may lead to a range of metabolic abnormalities associated with cardiovascular disease (CVD)., Objectives: The first objective of the study was to compare baseline demographic and clinical characteristics between PI users and non-PI users referred to a specialized metabolic clinic during 1999-2003. The second objective was to assess the associations of prescription drugs and fish oil with dyslipidaemia and to determine whether or not patients achieved treatment targets during 6 months of treatment., Methods: A retrospective analysis was performed using two sets of charts based on standardized forms with entries for personal data, drug treatment and clinical history. Anonymous linkage with the British Columbia HIV/AIDS Drug Treatment Program and the hospital laboratory was performed to gather information about HAART prescriptions and blood work., Results: In total, 237 patients were included in the study. There were few differences in any demographic or clinical factors between PI users and non-PI users. Compared with controls not taking lipid-lowering drugs or fish oil (n=48), statins appeared to be the only agent that was significantly associated with a reduced total cholesterol concentration (-15.6%; P=0.009). Fibrate treatment was associated with the largest reduction of triglyceride concentration (-37.4%; P=0.012), closely followed by fish oil (n=18;-32%; P=0.027). Six-month treatment success rates ranged between 17 and 43% of patients for total cholesterol (<5.2 mmol/L) and between 15 and 44% of patients for triglycerides (<2.3 mmol/L)., Conclusions: Despite the apparent lowering of blood lipids with drug and fish oil treatments, a majority of patients in these treatment groups (56.5-83.3%) still had elevated concentrations after 6 months.

Background: We sought to determine N-terminal pro-Brain Natriuretic Peptide (NTproBNP) levels among a population of individuals with type 2 diabetes, and to correlate these levels with diabetes medications and patient demographics., Methods: We analyzed data from 506 patients with type 2 diabetes. We compared NT-proBNP levels of these patients with those from the general population. We also sought to determine whether patients' NT-proBNP levels were correlated with diabetes medications, age, gender, creatinine, hemoglobin A1C levels, BMI, blood pressure, and lipid levels., Results: Increasing doses of sulfonylureas were associated with increasing levels of NT-proBNP. However, patients on combined sulfonylurea and metformin therapy had lower NT-proBNP levels than those on sulfonylureas alone. Neither thiazolidinediones nor insulin were associated with NT-proBNP levels. The majority of patients with type 2 diabetes had similar NT-proBNP levels compared to a reference group from the general population. In no age category did NT-proBNP levels differ significantly between men and women. Levels of NT-proBNP were positively associated with age (p<0.0001), systolic blood pressure (p<0.01) and creatinine levels (p<0.0001), and negatively associated with diastolic blood pressure (p<0.001). Levels of NT-proBNP were not associated with A1C, BMI, triglycerides, and high density lipoprotein (p=NS)., Conclusions: Levels of NT-proBNP are associated with increasing sulfonylurea dosage, age, blood pressure, and creatinine levels. There is unlikely to be clinically significant differences in NT-proBNP levels between patients with type 2 diabetes and a normal population.

Fish consumption is the most important source of human exposure to methylmercury (MeHg). Since fish is also a rich source of n-3 polyunsaturated fatty acids, this study was conducted to examine the effects of dietary fats on MeHg-induced acute toxicity in rats. Weanling male Sprague Dawley rats were administered semi-purified casein-based isocaloric diet containing soy oil, seal oil, docosahexaenoic acid (DHA), fish oil, or lard for 28 days. Rats were then gavaged with 0, 1, or 3 mg MeHg/kg body weight (BW) per day and fed the same diet for 14 consecutive days. On 43rd day of the experiment, rats were sacrificed and blood samples were collected and analyzed for hematology. Liver and spleen were removed, fixed, and examined for pathological changes. Blood, feces, liver, and brain were analyzed for total mercury and/or MeHg contents. Serum samples were analyzed for clinical markers of hepatic injury and immunoglobulin. Total mercury contents in all tissues measured increased with dose. Mercury excretion in feces increased with dose and duration of MeHg treatment. Both diets and MeHg showed significant effects and interacted significantly on many of the toxicological endpoints measured. Many of the effects of MeHg were diet-dependent. For example, in the rats fed the lard diet, 3mg MeHg/kg BW significantly increased relative liver and spleen weight as compared with vehicle control; whereas in rats fed the fish oil, soy oil, seal oil, or DHA, this effect of MeHg was less obvious or absent, suggesting a protective effect of these diets. MeHg at 3mg/kg BW significantly decreased serum albumin level in all except DHA dietary groups, implying a protection by the DHA diet on this parameter. Only in the lard dietary group, did 3mg MeHg/kg BW significantly increase serum bilirubin level, indicating an enhancing effect of this diet on MeHg toxicity. MeHg suppressed the adaptive immune system and stimulated the innate immune system in rats in a diet-dependent fashion. The seal oil diet provided more resistance, while the fish oil diet rendered greater sensitivity to these effects of MeHg on the immune system. These results imply significant modulating effects of dietary fats on MeHg toxicity which may translate into more severe or protective clinical outcomes. Therefore, dietary fats are important factors to be considered in the risk assessment of MeHg exposure.

Background: Acne vulgaris may occur as part of immune reconstitution in human immunodeficiency virus (HIV)-seropositive patients on highly active antiretroviral therapy (HAART). Tetracyclines are a common acne treatment. Hypertriglyceridemia has not been reported as a side effect of this drug class., Objective: We report a case of an HIV-seropositive man on HAART (CD4 count 450 cells/microL) who developed isolated hypertriglyceridemia (> 13 mmol/L) after three separate challenges with minocycline or tetracycline, improving each time therapy was discontinued., Results: Based on a review of the literature, this is the first reported case of hypertriglyceridemia with minocycline or tetracycline therapy. No published reports have examined the safety of tetracyclines in the setting of HIV or HAART., Conclusion: A strong temporal association between tetracycline use and hypertriglyceridemia was found without an alternate explanation for the observed lipid profile. Given the common use of tetracyclines in dermatology, we feel that this is an important observation to report.

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.

Hunger and food insecurity are important factors that may affect an individual's nutritional state and should therefore be assessed in nutrition surveillance activities. The objective of this study was to determine the level of food insecurity and hunger among HIV-positive persons accessing antiretroviral therapy in British Columbia. A cross-sectional study was performed in the BC HIV/AIDS drug treatment program, a province-wide source of free-of-charge antiretroviral medications. In 1998-1999, participants completed a questionnaire focusing on personal information, health, and clinical status. Food and hunger issues were evaluated with the Radimer/Cornell questionnaire. Overall, 1213 responding men and women were classified as food secure (52%), food insecure without hunger (27%), or food insecure with hunger (21%). In both categories of food insecurity, individuals were significantly more likely to be women, aboriginals, living with children, and to have less education, a history of recreational injection drug and/or alcohol abuse, and an unstable housing situation (P < 0.05). In logistic multivariate modeling, income < or = Can$10,000 [adjusted odds ratio (AOR) 3.78, 95% CI (2.53-5.65)], shared household with children [AOR 3.68, 95% CI (1.98-6.84)] and unemployment [AOR 3.15, 95% CI (1.94-5.13)] were the strongest predictors of hunger. In HIV-positive individuals, the occurrence of food insecurity was nearly 5 times higher than in the general Canadian population. The results should stimulate further research to identify to what extent hunger-associated factors are reversible with interventions built on nutritional and/or social strategies.

Background: Protease inhibitors are known to alter the lipid profiles in subjects treated for HIV/AIDS. However, the magnitude of this effect on plasma lipoproteins and lipids has not been adequately quantified., Objective: To estimate the changes in plasma lipoproteins and triglycerides occurring within 12 months of initiating PI-based antiretroviral therapy among HIV/AIDS afflicted subjects., Methods: We included all antiretroviral naive HIV-infected persons treated at St-Paul's Hospital, British Columbia, Canada, who initiated therapy with protease inhibitor antiretroviral (ARV) drugs between August 1996 and January 2002 and who had at least one plasma lipid measurement. Longitudinal associations between medication use and plasma lipids were estimated using mixed effects models that accounted for repeated measures on the same subjects and were adjusted for age, sex, time dependent CD4+ T-cell count, and time dependent cumulative use of non-nucleoside reverse transcriptase inhibitors and adherence. The cumulative number of prescriptions filled for PIs was considered time dependent. We estimated the changes in the 12 months following any initiation of a PI based regimen., Results: A total of 679 eligible subjects were dispensed nucleoside analogues and PI at the initiation of therapy. Over a median 47 months of follow-up (interquartile range (IQR): 29-62), subjects had a median of 3 (IQR: 1-6) blood lipid measurements. Twelve months after treatment initiation of PI use, there was an estimated 20% (95% confidence interval: 17% - 24%) increase in total cholesterol and 22% (12% - 33%) increase in triglycerides., Conclusions: Twelve months after treatment initiation with PIs, statistically significant increases in total cholesterol and triglycerides levels were observed in HIV-infected patients under conditions of standard treatment. Our results contribute to the growing body of evidence implicating PIs in the development of blood lipid abnormalities. In conjunction with the predominance or men, high rates of smoking, and aging of the treated HIV-positive population, elevated lipoproteins and triglycerides may mean that patients such as these are at elevated risk for cardiovascular events in the future.

The chlordane constituent trans-nonachlor and its metabolite oxychlordane are among the most persistent chlordane-related contaminants and are found in tissues and milk from humans ingesting diets high in Arctic marine mammal fat. Although chlordane is no longer registered in North America, there is a need for toxicological data on chlordane-related contaminants found in food and the environment which are either structurally different or relatively more abundant than the constituents of the original chlordane mixture. Thus, a feeding study was undertaken to provide toxicological data on trans-nonachlor. Male and female Sprague-Dawley rats were exposed to 0, 5, 13 or 50 ppm trans-nonachlor in feed for 90 days and clinical, hematological and histopathological changes were assessed in each rat. Female rats were less able than males to metabolize and eliminate trans-nonachlor and, as a result, accumulated more trans-nonachlor in their adipose tissues. trans-Nonachlor, like technical chlordane and other organochlorines, induced liver microsomal enzymes in a pattern similar to phenobarbital. Endocrine effects included functional and morphological changes in the thyroid and adrenals. In male rats exposure to trans-nonachlor was associated with changes in endpoints indicative of increased oxidative stress, which may be related to both direct action on cellular targets or to secondary effects resulting from cytochrome P450 induction. The results indicate that subchronic trans-nonachlor exposure in rats induced hepatic changes with far-reaching metabolic and endocrine effects. Differences in target organ responses in male and female rats indicate that the sex-related metabolic differences affecting trans-nonachlor bioaccumulation and elimination merit further study.

Objective: To describe two cases of human immunodeficiency virus (HIV)-infected patients who had diabetes mellitus, which resolved after initiation of antiretroviral therapy., Methods: We present the clinical and laboratory findings and describe the clinical course of these two patients., Results: A 48-year-old HIV-infected black woman presented with multiple infections and hyperglycemia. After her acute infections were treated and she was feeling well, she continued to have diabetes that necessitated insulin therapy. Administration of a protease inhibitor-based antiretroviral regimen resolved her diabetes and eliminated the need for insulin or oral therapy. Our second patient, a 37-year-old HIV-infected black man, presented with polyuria and polydipsia and a hemoglobin A1c value of 11%. He received antiretroviral therapy, and his diabetes resolved after a period of 2 1/2 months., Conclusion: Protease inhibitor-based antiretroviral therapy is associated with diabetes mellitus in up to 6% of HIV-infected patients. Although most HIV-infected patients in whom diabetes develops have this disorder after initiation of protease inhibitor therapy, the current two cases illustrate patients in whom diabetes resolved after use of antiretroviral therapy. This finding supports the presence of other mechanisms that affect glucose metabolism in patients infected with HIV and suggests that control of HIV infection may have a role in controlling diabetes.

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 (P<0.05) 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 authors present an introduction to the basics of lipid metabolism including an overview of the structure and function of lipoproteins and a description of the pathways of lipid metabolism. Dyslipidemia is an important risk factor in the context of cardiovascular disease, and appropriate intervention can have a significant impact on clinical outcomes. The information presented herein will help to provide a foundation of knowledge on which to base the assessment and treatment of dyslipidemic patients. A better understanding of lipid metabolism will help health care professionals to provide better care in the realm of dyslipidemia management., (Copyright 2003 CHF, Inc.)

Due to widespread usage of the pesticide chlordane until the 1980's, this toxic and persistent mixture has accumulated in the food chain. The Arctic acts as a global sink for these and other persistent organic pollutants, which bioaccumulate in the marine and freshwater food chains. As a result, humans consuming diets high in Arctic fish and marine mammal fat can ingest higher levels of chlordane contaminants than humans consuming "southern" diets. The most abundant constituents of the chlordane mixture are trans-chlordane, cis-chlordane, trans-nonachlor, cis-nonachlor and heptachlor; oxychlordane is the major metabolite of the chlordanes and nonachlors. In humans the predominant chlordane-related contaminants detected in breast milk and adipose tissues are trans-nonachlor and oxychlordane. The present studies were undertaken to provide toxicological data on oxychlordane for the purpose of clarifying target organ toxicity and risks to human health associated with ingesting contaminated foods. Female rats were gavaged with oxychlordane at doses ranging from 0.01 to 10 mg/kg body weight/day for up to 28 days. In terms of general toxicity oxychlordane had a steep dose-response curve: 10 mg/kg oxychlordane was acutely toxic and 1 mg/kg oxychlordane caused no measurable effects. Weight loss, reduced feed consumption and thymic atrophy were the hallmarks of acute oxychlordane toxicity. At lower doses rats showed signs of hepatic changes indicative of microsomal enzyme induction. Oxychlordane was more bioaccumulative and was toxic at levels approximately 8 times lower than trans-nonachlor and cis-nonachlor. Thus, ingestion of trans-nonachlor and related chlordane contaminants in foods results in the formation of a metabolite that is more toxic and bioaccumulative than the parent contaminants.

Respiratory allergy and allergy to foods continue to be important health issues. There is evidence to indicate that the incidence of food allergy around the world is on the rise. Current estimates indicate that approximately 5% of young children and 1-2% of adults suffer from true food allergy (Kagan 2003). Although a large number of in vivo and in vitro tests exist for the clinical diagnosis of allergy in humans, we lack validated animal models of allergenicity. This deficiency creates serious problems for regulatory agencies and industries that must define the potential allergenicity of foods before marketing. The emergence of several biotechnologically derived foods and industrial proteins, as well as their potential to sensitize genetically predisposed populations to develop allergy, has prompted health officials and regulatory agencies around the world to seek approaches and methodologies to screen novel proteins for allergenicity.

The immunotoxicity of cis- and trans-nonachlor and chlordane were investigated in adult male and female Sprague-Dawley rats following a 28-day oral (gavage) treatment. Rats were randomly assigned to six experimental groups: cis-nonachlor, females; trans-nonachlor, females; technical chlordane females; cis-nonachlor, males; trans-nonachlor, males; technical chlordane, males. The immunologic endpoints included: quantification of the total serum immunoglobulin (Ig) levels and subclasses and flow cytometric analysis of peripheral blood leukocytes and T-lymphocyte subsets, evaluation of the lymphoproliferative activity of splenocytes in response to concanavalin A (Con A) and Salmonella typhimurium (STM) mitogens, and natural killer (NK) cell activity of splenocytes. Satellite experiments to examine the delayed-type hypersensitivity (DTH) response to oxazolone, and resistance to Listeria monocytogenes were set up for female rats treated with cis- or trans-nonachlor. Statistically significant (P<0.05) effects included: increased serum immunoglobulin M (IgM) levels in the chlordane-treated females at the 25 mg/kg dose (pairwise comparison); increased serum IgG(1) and IgG(2c) in the cis-nonachlor-treated males at the 2.5 and 25 mg/kg doses and increased serum IgG(2a) levels at all doses; increased serum IgG(2b) at the 25 mg/kg dose and decreased (dose-related) serum IgM levels in the cis-nonachlor-treated male rats; increased (linear trend) IgG(1) and IgG(2a) in the cis-nonachlor-treated females with effects on IgG(2a) significant at the 25 mg/kg dose compared with control; increased serum IgG(2a) in the trans-nonachlor-treated male and female rats at the 2.5 mg/kg dose; increased absolute numbers (linear trend) of peripheral white blood cells, B lymphocytes, natural killer (NK) cells, T-suppressor/cytotoxic lymphocytes, and the double positive (T-helper/inducer, T-suppressor/cytotoxic) cells in the trans-nonachlor-treated females; increased (non-linear trend) lymphoproliferative activity in the Con A-stimulated splenocytes and decreased (linear trend) activity in the S. typhimurium mitogen-stimulated splenocytes of the cis-nonachlor-treated females; reduced resistance to L. monocytogenes in the cis-nonachlor (day 3, P=0.034)- and trans-nonachlor (day 2, P=0.0001)-treated females, and reduced (linear trend) NK cell activity in the cis-nonachlor-treated males. The present data indicated that the chlordane compounds tested in this study had significant effects on a number of immunologic endpoints. In comparison to technical chlordane, cis- and trans-nonachlors were more immunotoxic. Therefore, an evaluation of the risk these chlorinated compounds may pose to human health should consider the potential effects different chlordane compounds may have on the immune system.

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 (p > 0.05). 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., (Copyright 1997 Society of Toxicology.)

A subchronic rat study with paired-water control was conducted to resolve the question of whether monochloramine at 200 ppm in drinking water can cause reduced body weight gain and other changes observed in earlier investigations. Male Sprague-Dawley rats (93 +/- 5 g) were divided into three groups of 10 rats each: the treatment group was fed drinking water containing 200 ppm monochloramine, the control group was fed bicarbonate-buffered water ad libitum, and the paired-water control rats were given a daily volume of bicarbonate-buffered water equal to that consumed by the monochloramine treatment group. Compared to the control group, rats in the treatment group consumed an average of 42% less fluid and 16% less food over the 13-week treatment period and had 15-20% lower final body weight gain. Similar degrees of reduction in food consumption and body weight gain were observed in the paired-water rats. A decreased liver to body weight ratio occurred in the treatment and paired-water groups. Increased inorganic phosphate, albumin, total protein, and urea nitrogen were detected in sera from both the treatment group and the paired-water groups. The paired-water animals had lower levels of white blood cells and lymphocytes, while the paired-water and monochloramine-treated groups had reduced monocyte counts. Except for a slightly increased response to Con A observed in splenic lymphocytes of the monochloramine-treated rats (versus the paired-water), no significant changes were found in mitogen responsiveness to T cell, B cell, and B plus T cell mitogens or in splenic natural killer (NK) cell activities. There were no significant changes in serum levels of IgG, IgA, and IgM. The following biochemical parameters showed no significant variations among the three groups: serum thyroxin, liver phase I (PROD, EROD, and MROD) and phase II (UDPGT and GST) drug-metabolizing enzyme activities; serum and liver thiobarbituric acid-reactive substances (TBARS); bronchoalveolar lavage fluid protein and N-acetylgluosaminidase (NAGA) activity; and urinary ascorbic acid, protein, and NAGA activity. Histopathological examination revealed minimal to mild adaptive changes in the liver of the paired-water and monochloramine-treated rats and in the thyroid of the monochloramine-treated animals. No treatment-related cytological changes were found in red cells and bone marrow. The results indicate that the reduced body weight gain and the minor biochemical, hematological, immunological, and histopathological changes associated with subchronic exposure to 200 ppm monochloramine in drinking water (equivalent to an intake of 21.6 mg/kg/day) were largely related to the reduced water intake and food consumption and not caused by monochloramine.

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 toxicity of purified fumonisin B1 (FB1) administered ip was examined in male Sprague-Dawley rats. FB1 was injected at 7.5 or 10 mg/kg body weight/day for 4 consecutive days. This resulted in significant reductions in body weight, food consumption and faeces production. Polyuria without a compensatory increase in water consumption was observed in treated rats. Erythrocytosis, elevated haematocrits and haemoglobin levels were attributed to dehydration. Nephrotoxicity in treated rats was evident by clinical changes including elevated blood urea nitrogen and by subtle changes in kidney morphology. Histopathology and serum biochemistry also indicated that the liver was an important target organ in FB1-treated rats. A small increase in liver glutathione concentration was also evident in rats receiving 10 mg FB1/kg body weight. Effects on the immune system included reduced thymus weight, disseminated thymic necrosis and consistently elevated serum immunoglobulin M levels. Circulating phagocytic cell numbers were elevated in treated rats, probably owning to tissue damage associated with ip dosing. The liver and kidneys appear to be target organs of FB1 in Sprague-Dawley rats.

Complex and interrelated biological processes are at work in the expression of the host response to sepsis. To a large degree, these processes reflect drastic changes in the molecular workings of cells of the body. The protean nature of sepsis reflects this molecular adaptation. Studies are continuing to accrue that describe aspects of this process in tissue culture, animal models, and man. However, without an understanding of the basic mechanisms of molecular biology, the understanding of this important and expanding literature is limited. This review describes the basic molecular processes involved in replication of deoxyribonucleic acid (DNA) and transcription of DNA to ribonucleic acid (RNA) in the nucleus, translation of messenger RNA into proteins and the posttranslational modifications of these proteins in the cytoplasm. It uses the process of endotoxin-induced cellular activation as its model and highlights important aspects of DNA promoter and enhancer processes in this activation. Specific examples of known promoter genes and genomic translation are described. This review serves as a "primer" for the subsequent three review articles in this series that will follow it in preceding issues.