Impact of sustained virologic response on risk of type 2 diabetes among hepatitis C patients in the United States.

Data regarding the impact of hepatitis C (HCV) therapy on incidence of type 2 diabetes mellitus are limited. We used the data from the longitudinal Chronic Hepatitis Cohort Study-drawn from four large US health systems-to investigate how response to HCV treatment impacts the risk of subsequent diabetes. Among HCV patients without a history of type 2 diabetes mellitus or hepatitis B, we investigated the incidence of type 2 diabetes from 12 weeks post-HCV treatment through December 2015. Cox proportional hazards models were used to test the effect of treatment status (sustained virologic response [SVR] or treatment failure) and baseline risk factors on the development of diabetes, considering any possible risk factor-by-SVR interactions, and death as a competing risk. Among 5127 patients with an average follow-up of 3.7 years, diabetes incidence was significantly lower among patients who achieved SVR (231/3748; 6.2%) than among patients with treatment failure (299/1379; 21.7%; adjusted hazard ratio [aHR] = 0.79; 95% CI: 0.65-0.96). Risk of diabetes was higher among African American and Asian American patients than White patients (aHR = 1.82 and 1.75, respectively; P < .05), and among Hispanic patients than non-Hispanics (aHR = 1.86). Patients with BMI ≥ 30 and 25-30 (demonstrated higher risk of diabetes aHR = 3.62 and 1.72, respectively; P < .05) than those with BMI < 25; patients with cirrhosis at baseline had higher risk than those without cirrhosis (aHR = 1.47). Among a large US cohort of patients treated for HCV, patients who achieved SVR demonstrated a substantially lower risk for the development of type 2 diabetes mellitus than patients with treatment failure.

Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans.

A recent genome-wide association study in a German population and two subsequent studies in European populations found that a non-synonymous single-nucleotide polymorphism (SNP), rs1049550, within the annexin A11 (ANXA11) gene was associated with susceptibility to sarcoidosis. We sought to identify additional ANXA11 variants independently associated with sarcoidosis, determine whether any sarcoidosis-associated ANXA11 variants were associated with chest radiographic phenotypes, and explore human leukocyte antigen (HLA) SNP-SNP interactions with ANXA11. A total of 209 SNPs spanning 100 kb including the 5' promoter, coding, and 3' untranslated regions of ANXA11 were genotyped for 1689 sarcoidosis cases and 1252 controls. After adjustment for rs1049550, two additional novel ANXA11 sarcoidosis associations were identified only in African Americans--rs61860052 (odds ratio (OR)=0.62; 95% confidence interval (CI)=0.40-0.97) and rs4377299 (OR=1.31; 95% CI=1.06-1.63). These associations were more pronounced in radiologically-classified Scadding stage IV sarcoidosis cases. We also identified a significant SNP-SNP interaction between rs1049550 and a sarcoidosis risk SNP (rs9268839) near the HLA-DRA locus. This further genetic dissection of ANXA11 may provide additional insight into the immune dysregulation characteristic of sarcoidosis pathophysiology.

Properties of blood, porphyrins, and exposure to legacy and emerging persistent organic pollutants in surf scoters (Melanitta perspicillata) overwintering on the south coast of British Columbia, Canada.

The surf scoter (Melanitta perspicillata) is a little-studied species of North American sea duck. Estimates suggest it has experienced a precipitous decline in breeding numbers over the latter half of the past century. To investigate the potential role of contaminant uptake and toxicity in the population decline, this study undertook to measure blood chemistry, porphyrin concentrations, EROD, and organic contaminants in mature surf scoters wintering in the Strait of Georgia, BC, Canada. Hepatic organochlorine pesticide, polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofuran, polychlorinated biphenyl (PCB), polybrominated diphenyl ether, and nonylphenol concentrations were relatively low; for example, SigmaTEQs (toxic equivalents) for PCBs, dioxins, and furans combined ranged from 4.7 ng/kg wet weight in reference-site (Baynes Sound) birds to 11.4 ng/kg wet weight in birds from Vancouver Harbour. Nonetheless, elevated EROD activity indicated that birds in Howe Sound were responding to an Ah-receptor-mediated stressor, which was also affecting hematocrit values and possibly vitamin A status. In addition, a low proportion of lymphocytes in individuals across locations in early spring samples was associated with poor body condition. The apparent loss of fitness just prior to the onset of northerly migrations to breeding grounds is of particular concern. Compromised health of mature birds at this point in the season might impact negatively on the productivity and survival of some individuals, particularly those overwintering in Howe Sound.

Vitamin A and contaminant concentrations in surf scoters (Melanitta perspicillata) wintering on the Pacific coast of British Columbia, Canada.

Surf scoters are part of a community of sea ducks on the western coast of North America that have shown signs of long-term, unexplained declines in breeding bird numbers. Substantial numbers of scoters winter in the major harbours on the west coast, after breeding in the west-central northern boreal forest. To address the potential for contaminants to impact the health and survival of those birds, we investigated the condition and contamination of surf scoters during the winters of 1998-2001 at four foraging locations in the Strait of Georgia region of the Pacific coast of Canada. Vitamin A status was evaluated in liver and plasma samples collected from adults and juveniles, as part of a larger assessment of tissue contamination, body condition and biomarker responses. Individuals collected from a relatively contaminated site, Howe Sound, showed consistently low hepatic concentrations of retinol and retinyl palmitate forms of vitamin A, and gender-specific associations of retinyl palmitate with hepatic EROD activity. The relationship of hepatic retinol to retinyl palmitate was not constant across geographic locations, and a clear, linear relationship between the two forms of vitamin A was only evident in birds from the relatively uncontaminated site. This study also identified strong positive relationships between vitamin A and tissue burdens of cadmium and zinc. The positive association between hepatic retinyl palmitate and renal cadmium is similar to one observed in laboratory rats, in which a mechanism of interference with the controlled release of retinol from the liver was suggested.

Racial differences in the relationship between clinical prostatitis, presence of inflammation in benign prostate and subsequent risk of prostate cancer.

BACKGROUND: Epidemiologic studies, primarily done in white men, suggest that a history of clinically-diagnosed prostatitis increases prostate cancer risk, but that histological prostate inflammation decreases risk. The relationship between a clinical history of prostatitis and histologic inflammation in terms of how these two manifestations of prostatic inflammation jointly contribute to prostate cancer risk and whether racial differences exist in this relationship is uncertain. METHODS: Using a nested design within a cohort of men with benign prostate tissue specimens, we analyzed the data on both clinically-diagnosed prostatitis (NIH categories I-III) and histological inflammation in 574 prostate cancer case-control pairs (345 white, 229 African American). RESULTS: Clinical prostatitis was not associated with increased prostate cancer risk in the full sample, but showed a suggestive inverse association with prostate cancer in African Americans (odds ratio (OR)=0.47; 95% confidence interval (CI)=0.27-0.81). In whites, clinical prostatitis increased risk by 40%, but was only associated with a significant increased prostate cancer risk in the absence of evidence of histological inflammation (OR=3.56; 95% CI=1.15-10.99). Moreover, PSA velocity (P=0.008) and frequency of PSA testing (P=0.003) were significant modifiers of risk. Clinical prostatitis increased risk of prostate cancer almost three-fold (OR=2.97; 95% CI=1.40-6.30) in white men with low PSA velocity and about twofold in white men with more frequent PSA testing (OR=1.91; 95% CI=1.09-3.35). CONCLUSIONS: In our cohort of men with benign prostate specimens, race, and histological inflammation were important cofactors in the relationship between clinical prostatitis and prostate cancer. Clinical prostatitis was associated with a slightly decreased risk for prostate cancer in African American men. In white men, the relationship between clinical prostatitis and prostate cancer risk was modified by histological prostatic inflammation, PSA velocity, and frequency of PSA testing-suggesting a complex interplay between these indications of prostatic inflammation and prostate cancer detection.

Assessment of biological effects of chlorinated hydrocarbons in osprey chicks.

Osprey (Pandion haliaetus) eggs were collected during 1995 and 1996 at seven sites along the Fraser and Columbia River systems of British Columbia, Canada, and Washington and Oregon, USA. Fifty-four eggs were placed into a laboratory incubator. Thirty-eight of the hatched chicks were sacrificed within 24 h. Hatching success did not differ among sites and therefore between treatment and reference areas. Residual yolk sacs of eggs collected downstream of the large bleached-kraft pulp mill at Castlegar contained greater mean concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 2,930 ng/kg lipid) compared with reference sites such as the Nechako River, an upper tributary of the Fraser system (33.7 ng/kg). Total polychlorinated biphenyls (PCBs) in yolk sacs were also higher at Castlegar and in samples from the Columbia River downstream of Portland, Oregon, compared with those from the Nechako River. Concentrations of measured chemicals, including TCDD toxic equivalents (TEQs), total PCBs, p,p'-dichlorodiphenylethylene (p,p'-DDE), and other organochlorines were not different in eggs that failed to hatch compared with calculated whole-egg values for hatched eggs. There were significant biochemical responses; a hepatic cytochrome P4501A (CYP1A) cross-reactive protein was detected in all samples tested and correlated positively with ethoxyresorufin o-deethylase (EROD) activity and yolk sac concentrations of TEQs and total PCBs. Tissue concentrations of vitamin A compounds varied among sites and correlated positively with yolk sac concentrations of TEQs and PCBs. Morphological, histological, and other physiological parameters, including chick growth, edema, deformities, and hepatic and renal porphyrin concentrations, neither varied among sites nor showed concentration-related effects.

Towards molecular understanding of species differences in dioxin sensitivity: initial characterization of Ah receptor cDNAs in birds and an amphibian.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related planar halogenated aromatic hydrocarbons (PHAHs) are highly toxic to most vertebrate animals, but there are dramatic species differences in sensitivity, both within and among vertebrate classes. For example, studies in cultured avian hepatocytes have revealed differential sensitivity of birds to PHAHs [Kennedy et al. (1996). Toxicol. Appl. Pharmacol., 141, 214-230]. Differences in the characteristics or expression of the aryl hydrocarbon receptor (AHR) could contribute to these species differences in PHAH responsiveness. To investigate the molecular mechanism of differential PHAH sensitivity, we have begun to characterize the AHR in white leghorn chicken (Gallus gallus), Pekin duck (Anas platyrhynchos), and common tern (Sterna hirundo), as well as an amphibian, mudpuppy (Necturus maculosus). Partial AHR cDNAs encompassing the helix-loop-helix and PAS domains were cloned and sequenced. Comparison of amino acid sequences in this region indicated a high degree of sequence conservation among the bird species (97% amino acid identity). The percent identity between bird sequences and either mouse or mudpuppy was lower (79%); the mudpuppy AHR was 74% identical to the mouse AHR. Phylogenetic analysis of these and other AHR amino acid sequences showed that the bird and mudpuppy AHRs were more closely related to mammalian and fish AHR1 forms than to fish AHR2. Future studies include the in vitro expression and functional characterization of AHRs from these and other non-mammalian vertebrates.

Vitamin A status of wild mallards (Anas platyrhynchos) wintering in Saskatchewan.

Vitamin A status of wild male mallards (Anas platyrhynchos) overwintering in Saskatchewan, Canada was determined. Vitamin A levels < 0.2 micrograms hepatic retinyl palmitate/g liver, occurred in 6% and 25% of male mallards sampled in 1991 to 1992 and 1992 to 1993, respectively. There was no temporal trend in vitamin A levels over either winter. Squamous metaplastic lesions, commonly associated with vitamin A deficiency in domestic animals, were not observed in any bird; hence, they were not a good indicator of vitamin A status in wild mallards. Serum retinol was not a good indicator of vitamin A status in wild mallards. Many mallards in good body condition had low vitamin A levels; thus, we propose that good body condition and ample fat stores are not indicative of overall health of the bird.

Experimental vitamin A deficiency in mallards (Anas platyrhynchos): lesions and tissue vitamin A levels.

Captive mallards (Anas platyrhynchos), fed an all-grain diet for up to 5 months during the winters of 1991 to 1992 and 1992 to 1993, developed lesions of squamous metaplasia; some had no detectable hepatic vitamin A. Vitamin A deficiency in mallards was defined as hepatic levels of retinyl palmitate < 2 micrograms/g liver. Lesions were found only in ducks with low levels of hepatic vitamin A, but not all ducks with these low levels of hepatic vitamin A had histological lesions. The prevalence of lesions in the esophagus was greatest cranially and caudally and less common in the central region. Palatine salivary glands rarely were affected. Mallards with liver stores > 600 micrograms of hepatic retinyl palmitate per g liver, fed a diet deficient in vitamin A were unlikely to become deficient over a 5 month period. Birds fed an all-grain diet had significantly lower vitamin A concentrations in their liver compared to those fed an all-grain diet with vitamin A added. Liver weight, when corrected for body size, did not affect vitamin A concentration. Serum retinol levels were conserved over a large range of hepatic vitamin A levels but levels below 300 micrograms retinol/l were useful in detecting vitamin A deficiency in captive mallards. Based on the findings, the presence of lesions provides a conservative measure of vitamin A status in ducks and tissue levels should be measured in instances when mallards have questionable vitamin A status.

Changes in adipose tissue distribution during pregnancy in overweight and obese compared with normal weight women.

OBJECTIVE: Differences in body fat distribution contribute to the metabolic abnormalities associated with overweight and obesity; however, such differences have not been adequately explored during pregnancy. Our aim was to compare longitudinal trends in maternal abdominal adipose tissue deposition during pregnancy in overweight/obese compared with normal weight women. STUDY DESIGN: Pregnant women, classified as normal weight (body mass index (BMI) <25 kg m(-2); N=61) or overweight/obese (BMI 25 kg m(-2); N=57), were enrolled in a prospective cohort study starting in the first trimester. Maternal subcutaneous (smin) and preperitoneal (pmax) fat were measured by ultrasound at five time points starting between 6 and 10 weeks gestation. The abdominal fat index (AFI), an established marker of visceral adipose tissue, was calculated as the ratio of pmax to smin. The trajectories of smin, pmax, cumulative fat index (smin plus pmax) and the AFI across pregnancy were analyzed using mixed linear models. RESULTS: The rate of maternal weight gain during pregnancy was significantly lower for overweight/obese women compared with their non-overweight counterparts (P<0.05). Accordingly, the rate of change of pmax and smin differed significantly in normal weight compared with overweight/obese women (P=0.0003 and 0.01, respectively). The cumulative fat index did not change across gestation in normal weight women, whereas it decreased for overweight/obese women (P=0.0005). The log AFI increased across pregnancy in both strata, but significantly more rapidly for normal weight compared with overweight/obese women (P=0.06). CONCLUSIONS: Adipose tissue is preferentially deposited in the more metabolically active visceral compartment as pregnancy progresses. However, this process differs in normal weight compared with overweight/obese women and may contribute to metabolic differences between these groups. Our study is a step toward a more refined description of obesity and its consequences during pregnancy.

Using dried blood spots stored on filter paper to measure cholinesterase activity in wild avian species.

Birds of prey that are poisoned by cholinesterase inhibitors (e.g. organophosphate and carbamate insecticides) are often cared for at animal shelters, rehabilitation centres and wildlife diagnostic facilities. Plasma cholinesterase (ChE) activity is a recognized method of assessing exposure to these insecticides, but standard blood-handling protocols are difficult to follow in non-laboratory settings. The primary objective of this study was to expand upon a method for storing human blood on filter paper without the need for complicated equipment or refrigeration, and to test its utility for measurement of ChE activity in avian blood. ChE activity from whole blood, plasma, and dried blood spots was analysed from 169 wild birds and comparisons made among sample types. ChE activity measured in whole blood haemolysates and dried blood spots were significantly correlated (r = 0.74, p < 0.001), as was ChE activity measured in plasma and dried blood spots (r = 0.68, p < 0.001). This study demonstrated that monitoring pesticide exposure in birds could be conducted using elementary blood sampling, preserving and shipping techniques.

Organochlorines and possible biochemical effects in glaucous gulls (Larus hyperboreus) from Bjørnøya, the Barents Sea.

To study possible biochemical effects of organochlorine contaminants (OCs) in glaucous gulls (Larus hyperboreus), 40 adult individuals were collected from colonies on Bjornoya in the Barents Sea. OCs (four pesticides and nine PCB congeners), microsomal 7-ethoxyresorufin O-deethylase (EROD) activity, microsomal testosterone hydroxylation, highly carboxylated porphyrins (HCPs), retinol, and retinyl palmitate were quantified in liver samples. The hepatic vitamin A stores in glaucous gulls were larger than in herring gulls (Larus argentatus) from other studies conducted in contaminated locations in North America. No significant relationships were found between liver retinoid concentrations and OC levels. The hepatic EROD activity was low compared to other studies on fish-eating birds and only marginally associated with PCB levels. Microsomal testosterone hydroxylase activity was only observed at the 6beta-position and could not be related to OC levels. The low P450-associated enzyme activities in the glaucous gull suggests that they have a low capacity for metabolizing OCs, which may contribute to the high accumulation of OCs in this species. HCPs were only elevated (138 pmol g(-1)) in the sample with highest OC levels, whereas the remaining samples contained low levels of HCPs (<30 pmol g(-1)). The weak association between EROD activity and PCB levels and the low level of HCPs suggest that these biochemical parameters were unaffected by OCs in most of the sampled gulls. Thus, the glaucous gull seems not to be particularly sensitive toward Ah-receptor mediated effects.