Quantifying the effect of weathering on acute oil toxicity using the PETROTOX model.

Following accidental release into marine environments, crude oil progressively weathers, influencing composition, fate, and toxicity. However, published studies draw conflicting conclusions on the effects of oil weathering on ecotoxicity. Using the PETROTOX model, this study characterized the effect of weathering on acute oil toxicity for four aquatic species. Results indicated that predicted acute toxicity decreased with increased oil weathering, due to reductions in overall concentrations and bioavailability of hydrocarbon constituents.

Binding properties to nicotinic acetylcholine receptors can explain differential toxicity of neonicotinoid insecticides in Chironomidae.

Neonicotinoids are neuroactive insecticides commonly detected in freshwater ecosystems. Recent studies have indicated that these compounds are markedly toxic to Chironomidae, a widespread family of ecologically important aquatic insects. However, despite their sensitivity, the pharmacological mechanisms driving neonicotinoid toxicity have yet to be characterized in these insect species. Here, we used a combination of saturation and competition binding studies to characterize neonicotinoid binding properties to nicotinic acetylcholine receptors (nAChR) in two different Chironomidae (Chironomus riparius and Chironomus dilutus) at two different life stages (larval and adult). Using radiolabeled imidacloprid ([3H]-IMI), we characterized and compared receptor density (Bmax), imidacloprid binding affinity (KD), and receptor binding affinity (Ki) to three different neonicotinoid competitors (imidacloprid, clothianidin, and thiamethoxam). We then compared receptor density and binding affinity parameters derived for Chironomidae to data previously generated for other dipterans and agricultural pests. We found that there were limited differences in neonicotinoid binding between C. riparius and C. dilutus, with both organisms demonstrating high affinities for imidacloprid (KD = 0.22-0.87 nM) and high receptor densities (Bmax = 0.92-6.53 pmol/mg). However, there were significant differences between life-stages, with larvae expressing higher densities of nicotinic acetylcholine receptors and higher imidacloprid affinities than adults. Moreover, there were compound-specific differences in receptor affinity, with larval stages displaying relative affinities (Ki) that generally correlated with acute neonicotinoid toxicity (e.g. clothianidin ≥ imidacloprid >>> thiamethoxam). Finally, compared to other dipterans and agricultural pests, Chironomidae display very high densities of high affinity nicotinic acetylcholine receptors, which likely contribute to their sensitivity. Results indicated that receptor-level differences in neonicotinoid binding may be responsible for ecotoxicological differences amongst distinct insect species, and they likely play a role in life stage-, and compound-level toxicity differences previously observed for Chironomidae. Overall, this study highlights the value of understanding the toxicological mechanisms of action of neonicotinoids in sensitive, non-target aquatic insects, to better predict adverse effects associated with unintentional neonicotinoid exposure.

Neonicotinoid insecticide mixtures: Evaluation of laboratory-based toxicity predictions under semi-controlled field conditions.

Neonicotinoid insecticide mixtures are frequently detected in aquatic environments in agricultural regions. Recent laboratory studies have indicated that neonicotinoid mixtures can elicit greater-than-additive toxicity in sensitive aquatic insects (e.g. Chironomus dilutus). However, this has yet to be validated under field conditions. In this study, we compared the chronic (28- and 56-day) toxicity of three neonicotinoids (imidacloprid, clothianidin, and thiamethoxam) and their mixtures to natural aquatic insect communities. Using experimental in-situ enclosures (limnocorrals), we exposed wetland insects to single-compounds and binary mixtures at equitoxic concentrations (1 toxic unit under the principle of Concentration Addition). We assessed the composition of all emerged insect taxa and the cumulative Chironomidae emergence and biomass over time. In treated limnocorrals, there were subtle shifts in community composition, with greater mean proportions of emergent Trichoptera and Odonata. Cumulative emergence and biomass increased over time and there was a significant interaction between time and treatment. At 28 days, cumulative Chironomidae emergence and biomass were not significantly different between neonicotinoid treatments and controls. However, cumulative emergence in the imidacloprid, clothianidin, and clothianidin-thiamethoxam treatments were 42%, 20%, and 44% lower than predicted from applied doses. At 56 days, effects on cumulative emergence and biomass were significant for imidacloprid, clothianidin, and the clothianidin-thiamethoxam mixture. Contrary to laboratory predictions, mixtures were not more toxic than single compounds under semi-controlled field settings. Furthermore, only clothianidin significantly shifted sex-ratios towards female-dominated populations. Results showed that the responses of natural Chironomidae populations to neonicotinoids and their mixtures cannot be adequately predicted from laboratory-derived single-species models, and although occasional overdosing may have influenced the magnitude of effects, reductions in Chironomidae emergence and biomass can occur at average neonicotinoid concentrations below some current water quality guidelines. Therefore, neonicotinoid guidelines should be revised to ensure that Chironomidae and other sensitive aquatic insects inhabiting agricultural wetlands are adequately protected.

Can chronic exposure to imidacloprid, clothianidin, and thiamethoxam mixtures exert greater than additive toxicity in Chironomus dilutus?

Widespread agricultural use of neonicotinoid insecticides has resulted in frequent detection of mixtures of these compounds in global surface waters. Recent evidence suggests that neonicotinoid mixtures can elicit synergistic toxicity in aquatic insects under acute exposure conditions, however this has not been validated for longer exposures more commonly encountered in the environment. Therefore, we aimed to characterize the chronic (28-day) toxicity of imidacloprid, clothianidin, and thiamethoxam mixtures under different doses and mixture ratios to determine if the assumption of synergistic toxicity would hold under more environmentally realistic exposure settings. The sensitive aquatic insect Chironomus dilutus was used as a representative test species, and successful emergence was used as a chronic endpoint. Applying the MIXTOX modeling approach, predictive parametric models were fitted using single-compound toxicity data and statistically compared to observed toxicity in subsequent mixture tests. Imidacloprid-clothianidin, clothianidin-thiamethoxam and imidacloprid-clothianidin-thiamethoxam mixtures did not significantly deviate from concentration-additive toxicity. However, the cumulative toxicity of the imidacloprid-thiamethoxam mixture deviated from the concentration-additive reference model, displaying dose-ratio dependent synergism and resulting in up to a 10% greater reduction in emergence from that predicted by concentration addition. Furthermore, exposure to select neonicotinoid mixtures above 1.0 toxic unit tended to shift sex-ratios toward more male-dominated populations. Results indicate that, similar to acute exposures, the general assumption of joint additivity cannot adequately describe chronic cumulative toxicity of all neonicotinoid mixtures. Indeed, our observations of weak synergism and sex-ratio shifts elicited by some mixture combinations should be considered in water quality guideline development and environmental risk assessment practices for neonicotinoid insecticides, and explored in further investigations of the effects of neonicotinoid mixtures on aquatic communities.

Increased liver decompensation risk with atypical hepatitis C virus antibody levels.

Knowledge of serum markers of liver decompensation would facilitate care of patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections. HCV load and anti-c33c and anti-NS5 levels did not distinguish 28 HCV- and HIV-positive predecompensation patients from 28 matched control patients, whereas more patients than controls had high anti-c100(p) and low anti-c22(p). In multivariate analysis, decompensation was associated with high anti-c100(p) titer (>/=1:4050; odds ratio [OR], 3. 4; 95% confidence interval [CI], 1.1-11.5) and low anti-c22(p) (<1:36,450; OR, 3.0; 95% CI, 1.0-10.2) and with antibody band strength at 1:50 dilution (anti-c100[p] OR, 7.0; 95% CI, 1. 7-48.9; anti-c22[p] OR, 7.1; 95% CI, 1.7-49.2). With high anti-c100(p) or low anti-c22(p), sensitivity for decompensation was 86%-96% and specificity was 21%-36%; with both markers, sensitivity was 29%-32% and specificity was 93%-96%. Although the mechanisms for these associations are unknown, if these findings are verified in other populations, anti-c100(p) and anti-c22(p) might be valuable surrogate markers for liver decompensation risk.

Central nervous system activation of the indoleamine-2,3-dioxygenase pathway in human T cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

Human T cell lymphotropic virus type I (HTLV-I) is associated with a chronic neurologic disease called HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The potential mechanisms of HAM/TSP pathogenesis were assessed by examination of 2 pathways initiated by interferon-gamma, a predominant cytokine in HAM/TSP. Jamaican HAM/TSP patients (n=17) were compared with patients with other neurologic diseases (ONDs; n=13) with respect to cerebrospinal fluid levels of the following: neopterin; nitrite plus nitrate, a stable indicator of nitric oxide; and tryptophan and kynurenine, metabolites of the indoleamine-2,3-dioxygenase (IDO) pathway. HAM/TSP patients had significantly elevated levels of neopterin (P=.003) and kynurenine (P=.05) and a significantly decreased level of tryptophan (P=.003), compared with patients with ONDs. These results support immune activation within the central nervous system and activation of the IDO pathway. Thus, activation of the IDO pathway may play a role in HAM/TSP.

Risk factors for human T cell lymphotropic virus type II infection among the Guaymi Indians of Panama.

To examine risk factors for human T cell lymphotropic virus type II (HTLV-II) infection, a case-control study was conducted among the Guaymi Indians of Panama. In females, HTLV-II seropositivity was associated with early sexual intercourse (15 years; odds ratio [OR], 2.50; 95% confidence interval [CI], 1.11-6.14) and number of lifetime sex partners. One partner increased risk of seropositivity by 30% (OR, 1.30; CI, 1.05-1.64), and risk increased with number of partners. Similar risk was associated with number of long-term sexual relationships. Among males, intercourse with prostitutes was associated with HTLV-II seropositivity (OR, 1.68; CI, 1.04-2.72). These data support a role for sexual transmission in HTLV-II infection. Association of seropositivity with primary residence in a traditional village (OR, 3.75; CI, 1.02-15.38) and lack of formal education (0 vs. >6 years [OR, 3.89; CI, 1.67-9.82]) observed in males may reflect differences in sexual practices associated with acculturation.

Serum neopterin, beta2-microglobulin, soluble interleukin-2 receptors, and immunoglobulin levels in healthy adolescents.

Serum biomarkers, such as neopterin, beta2-microglobulin (B2M), and soluble interleukin-2 receptors (sIL-2R), are elevated in viral infections, including HIV-1 infection, and in inflammatory conditions, autoimmune disease, and malignancies. For many of these conditions, serum levels correlate with disease activity. Application of these biomarkers in adolescents is limited by a lack of information on the range and determinants of variability (age, sex, race) for serum levels of these important molecules in this age group. To address this question, we analyzed serum samples from a well-characterized heterogeneous population of 111 healthy adolescents. White children had significantly higher serum levels of sIL-2R and IgM and lower levels of IgG (P

Clinical, pathologic, and immunologic features of human T-lymphotrophic virus type I-associated infective dermatitis in children.

OBJECTIVES: To define the clinical and laboratory features associated with infective dermatitis (ID) and confirm its association with human T-lymphotrophic virus type I (HTLV-I). DESIGN: A case series of patients with ID were compared with patients with atopic dermatitis (AD), which is an important disease in the differential diagnosis of ID. SETTING: Patients were recruited from dermatology and pediatric clinics at the University Hospital of the West Indies and the Bustamante Children's Hospital, Kingston, Jamaica. MAIN OUTCOME MEASURES: Clinical and laboratory features of patients with AD were compared with those of patients with ID. PATIENTS: Consecutive patients older than 1 1/2 years diagnosed as having ID (n=50) and AD (n=35) were enrolled based on clinical findings. RESULTS: The mean ages of patients with ID and AD were 6.9 and 7.8 years, respectively. Histologically, both diseases were predominantly chronic dermatitis with propensity for skin colonization with Staphylococcus aureus and beta-hemolytic streptococci; however, the distribution of sites of skin involvement differed. Infection with HTLV-I was the most distinguishing feature among patients with ID, with seropositive results in 100%; only 5 (14%) of the 35 patients with AD had results seropositive for HTLV-I. Infective dermatitis was further characterized by dermatopathic lymphadenitis in 16 (67%) of 24 patients with palpable nodes. Anemia, lymphocytosis, and low albumin and elevated serum globulin levels were more prevalent among patients with ID. Significant elevations of IgA, IgD, and IgG levels were observed among patients with ID compared with those with AD. However, both patients with AD and those with ID had levels of IgD and IgE elevated above the normal range. T-cell subsets among patients with ID revealed T-cell activation with a high percentage of HLA-DR antigen positivity, elevated CD4 (2.4 x 10(9)/L) and CD8 (1.4 x 10(9)/L) cell counts, with an increased CD4/CD8 ratio of 1:73. CONCLUSION: Infective dermatitis is a distinct clinical entity associated with HTLV-I, which plays a role in the pathogenesis and immune perturbations observed.

Incidence of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica and Trinidad.

HTLV-I is sexually transmitted more efficiently from men to women than vice versa, and the majority of HTLV-I endemic areas report a female preponderance of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) cases. The objective of this study was to estimate the gender- and age-specific incidence rates of HAM/TSP in the general population as well as in the HTLV-I-infected population in Jamaica and in Trinidad and Tobago. Incidence rates for HAM/TSP were computed based on all reported incident cases in both countries between 1990 and 1994. Population census reports for 1990 were used to calculate the population at risk. The age-standardized HAM/TSP incidence rate (mean +/- standard error of the mean) in Jamaica was 1.8 +/- 0.2/100,000 person years (PY). Among individuals of African descent in Trinidad and Tobago, the rate was 1.7 +/- 0.4/100,000 PY. As in HTLV-I seroprevalence, the incidence rate of HAM/TSP increased with age through the fifth decade of life and was three times as high in women than in men. The HAM/TSP incidence rate, calculated as a function of the number of HTLV-I-infected persons in each age stratum, is higher in women (24.7/100,000 PY) than in men (17.3/100,000 PY). With HTLV-I infection, the lifetime risk of developing HAM/TSP was estimated to be 1.9% overall and is slightly higher in women (1.8%) than in men (1.3%). Thus, the higher prevalence of HTLV-I in women in endemic areas does not fully explain the preponderance of female HAM/TSP, suggesting that other cofactors must be present. The higher incidence rate in women between the ages of 40 and 59 years, as well as the increase in HAM/TSP incidence rates with age, are indicative of the importance of adult-acquired HTLV-I infection, presumably through sexual transmission.

Temporal variability in immunological parameters: peripheral blood mononuclear cell subsets, serum immunoglobulins, and soluble markers of immune system activation.

T-cell subsets and soluble factors of immune system activation are increasingly used as biologic markers of disease and predictors of disease progression. For example, changes in CD4 cells and CD4:CD8 ratio, sIL-2R, B2M, neopterin, and IgA have been used in predicting AIDS onset and progression. We examined the temporal variability of T-cell subsets, monocytes, natural killer cells, B cells, immunoglobulins, soluble interleukin-2 receptor (sIL-2R), neopterin, and beta-2 microglobulin (B2M) among 135 adults tested at two time points approximately 3 months apart. The purpose of the study was two-fold: (1) to assess the stability of these measures at two points in time, and (2) to investigate which parameters tend to track together over time, i.e., show significant longitudinal correlation. Mean population values for these immunologic parameters remained remarkably stable over the 3-month period. However, individual subjects exhibited significant temporal variability for many parameters. Unlike observations in patients with AIDS, changes in immunoglobulins and other soluble factors were not significantly correlated with changes in cellular subsets over the same period. However, change in B2M was correlated with change in neopterin (r = .35, p < or = .0001), and change in IgA was correlated with changes in IgG and IgM (r = .44, r = .54, P < or = .001 for both). Characterizing this temporal variability in a healthy population provides important information for researchers applying these tests in clinical and epidemiological studies.

Mother-to-child transmission of human T-cell lymphotropic virus type I associated with prolonged breast-feeding.

OBJECTIVES: We assessed the risk of transmitting human T-cell lymphotropic virus type I (HTLV-I) through breast-feeding. STUDY DESIGN/METHODS: To assess the risk of mother-to-child transmission of HTLV-I, 212 HTLV-I-seropositive women and 145 HTLV-I-seronegative women were enrolled in a prospective cohort study conducted in Kingston, Jamaica. Their offspring were examined at regular intervals, and HTLV-I serostatus was determined at each visit. RESULTS: Twenty-eight of the 181 children with at least one postnatal visit born to HTLV-I-seropositive women (and none of the children born to HTLV-I-seronegative women) were persistently seropositive and were considered HTLV-I infected (Kaplan-Meier estimated cumulative incidence, 18%; 95% CI, 12%-24%). Among children observed for at least 24 months, 19 (32%) of 60 children breast fed for 12 months or longer were HTLV-I seropositive, compared with only 8 (9%) of 86 children breast-fed for less than 12 months (relative risk, 3.4; 95% CI, 1.7-6.9). Compared with children weaned at younger ages, transmission of HTLV-I was associated with continued breast-feeding of children who were 12 to 18 months of age (relative hazard, 6.4; 95% CI, 2.1-180.2) and older than 18 months (relative hazard, 18.1; 95% CI, 1.4-29.5). Transmission was also associated with higher maternal antibody titer (a possible marker of virus load), prolonged duration of ruptured membranes during childbirth, and lower maternal income. CONCLUSIONS: These results suggest that limiting the duration of breast-feeding to less than 12 months for children born to HTLV-I-seropositive mothers may significantly reduce mother-to-child transmission of HTLV-I.

Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) and human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are associated with differing patterns of immune dysfunction. Biomarkers of immune activation may correlate with perturbations of immune function associated with these diseases. We conducted a pilot cross-sectional study to assess four candidate biomarkers of immune activation. beta 2-microglobulin, neopterin, tryptophan, and kynurenine levels were assayed in stored sera from asymptomatic, human T-cell leukemia virus type I (HTL V-I)-seronegative (HTLV-I-) and HTLV-I-seropositive (HTLV-I+) individuals, and ATL and HAM/TSP patients previously enrolled in seroepidemiological studies in Jamaica. Mean levels of beta 2-microglobulin, neopterin, and kynurenine were significantly elevated among ATL patients compared to the other study groups. Mean tryptophan levels were significantly lower among ATL and HAM/TSP patients than HTLV-I- and HTLV-I+ groups. No significant differences in biomarkers were found between the HTLV-I- and HTLV-I+ groups. Among HAM/TSP patients, a significant association was found between elevated neopterin levels and symptoms of less than 4 years duration. In Cox proportional hazards regression modeling, neopterin and tryptophan were found to be independent predictors of survival among ATL patients. This study demonstrates a differential pattern of biomarkers of immune activation among ATL and HAM/TSP patients compared to HTLV-I- and HTLV-I+ individuals. Neopterin and tryptophan may be useful clinical indicators of disease severity and prognosis among HAM/TSP and ATL patients.

Risk factors and cofactors for human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica.

Human T-cell lymphotropic virus type I (HTLV-I) has been etiologically associated with a neurologic syndrome called HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as with adult T-cell leukemia/lymphoma. The authors sought to quantify the risk in Jamaica of HAM/TSP associated with HTLV-I infection and cofactors associated with this disease among infected individuals. Between 1988 and 1989, prevalent and incident HAM/TSP patients and controls with other neurologic diseases were enrolled in a retrospective study. A second control group was composed of HTLV-I-seropositive, asymptomatic carriers in Jamaica, ascertained in a separate study conducted in 1988. Although HTLV-I seropositivity was not a component of the case definition for HAM/TSP, all 43 HAM/TSP patients were HTLV-I seropositive compared with two (4.0%) of the controls with other neurologic diseases. Given HTLV-I seropositivity, one cofactor associated with the risk of HAM/TSP was young age at initial heterosexual confidence interval 1.29-12.46 for individuals aged < or = 15; odds ratio = 4.26, 95% confidence interval 1.41-12.90 for individuals aged 16-17 years at initial intercourse). Among individuals who reported this early age at initial sexual intercourse, an increased risk of HAM/TSP was associated with having reported more than five lifetime sexual partners (odds ratio = 2.88, 95% confidence interval 0.90-8.70). Neither an early age at initial sexual intercourse or the number of lifetime sexual partners was a risk factor for adult T-cell leukemia/lymphoma. These data support the hypothesis that HAM/TSP is associated with sexually acquired HTLV-I infection, whereas adult T-cell leukemia/lymphoma is not.

The relative distribution of T cell subsets is altered in Jamaican children infected with human T cell lymphotropic virus type I.

Early childhood infection with human T cell lymphotropic virus type I (HTLV-I) has been suggested to be involved in the pathogenesis of infective dermatitis and adult T cell leukemia/lymphoma. Since only a very small percentage of HTLV-I-infected children develop disease later in life, identification of early interim markers for persons at risk for developing disease would enable monitoring and might provide insight into the pathophysiology of the various diseases associated with HTLV-I infection. A cross-sectional study analyzed T cell subsets in 35 HTLV-I-seronegative and 16 HTLV-I-seropositive Jamaican children 11-31 months old. HTLV-I seropositivity was associated with an increase in the mean percentage of CD4 cells expressing HLA-DR, a marker for T cell activation (P = .02). This increase was positively correlated with duration of infection (r = .74, P = .009). These data demonstrate perturbation of regulatory cells of the immune system in HTLV-I-infected children.

Racial differences in serum immunoglobulin levels: relationship to cigarette smoking, T-cell subsets, and soluble interleukin-2 receptors.

To investigate the influence of race, cigarette smoking, and immunologic parameters on serum immunoglobulins, we analyzed serum IgG, IgA, and IgM levels in 455 healthy adults. The study population ranged in age from 20 to 69 years, including 282 whites and 173 blacks, 181 never-smokers, 93 ex-smokers, and 181 current smokers. Race and smoking were independently associated with alterations in serum IgG levels. Blacks had significantly higher IgG levels than whites (1,587 vs. 1,209 mg/dl; P < 0.001), and never smokers had significantly higher levels than current smokers (1,426 vs. 1,287 vs. mg/dl; P < 0.001). IgA and IgM levels were unrelated to race or smoking. Serum IgG was also found to be directly related to the proportion of HLA-DR+ cells and the level of soluble interleukin-2 receptors (sIL-2R) and inversely related to the proportion of CD4+ cells. Investigation of this racial heterogeneity may provide insights into the pathogenesis of immunologic diseases that exhibit unexplained racial variation.

Endemic transmission of HTLV type II among Kayapo Indians of Brazil.

Serological studies on 926 blood samples from 703 Brazilian Kayapo (Cayapo) Indians showed, by conventional definition of HTLV seropositivity, a 28% prevalence of human T lymphotropic virus (HTLV) infection, the highest yet reported. Immunoblot (WB) and SYNTH-EIA patterns indicate that the predominant infecting agent is type II. Of children under 15 years old, 12% were positive, and of persons over 60, more than 60%. Perinatal and heterosexual modes of transmission offer an adequate explanation of this incidence. Infection in infancy may include infection via breast milk from women other than the mother. Evidence of new infection in adults is apparent at an earlier age in women than in men. This pattern of antibody prevalence was not determined by cohort effects, as demonstrated by tests of serial specimens. Enzyme immunosorbent assay (EIA) absorbencies were not stable in the paired specimens: five serum pairs reverted and mean absorbencies declined over some age ranges. Many specimens with relatively high, but less than positive, EIA results were positive by immunoblot (WB). This suggests that the standard EIA end point does not identify all infected persons. If the WB alone indicates positivity, 47% of the whole population, and more than 80% of the older age groups, are infected with HTLV-II.