Novel strains of Actinobacteria associated with neotropical social wasps (Vespidae; Polistinae, Epiponini) with antimicrobial potential for natural product discovery.

Antimicrobial resistance has been considered a public health threat. The World Health Organization has warned about the urgency of detecting new antibiotics from novel sources. Social insects could be crucial in the search for new antibiotic metabolites, as some of them survive in places that favor parasite development. Recent studies have shown the potential of social insects to produce antimicrobial metabolites (e.g. ants, bees, and termites). However, most groups of social wasps remain unstudied. Here, we explored whether Actinobacteria are associated with workers in the Neotropical Social Wasps (Epiponini) of Costa Rica and evaluated their putative inhibitory activity against other bacteria. Most isolated strains (67%) have antagonistic effects, mainly against Bacillus thuringensis and Escherichia coli ATCC 25992. Based on genome analysis, some inhibitory Actinobacteria showed biosynthetic gene clusters (BGCs) related to the production of antimicrobial molecules such as Selvamycin, Piericidin A1, and Nystatin. The Actinobacteria could be associated with social wasps to produce antimicrobial compounds. For these reasons, we speculate that Actinobacteria associated with social wasps could be a novel source of antimicrobial compounds, mainly against Gram-negative bacteria.

Zebrafish and Artemia salina in vivo evaluation of the recreational 25C-NBOMe drug demonstrates its high toxicity.

The NBOMe (N-2-methoxybenzyl-phenethylamines) family of compounds are synthetic hallucinogens derived from the 2C series. Although this family of compounds has been responsible for multiple cases of acute toxicity and several deaths around the world, to date there are few studies. These compounds act as potent 5-HT2A receptor agonists, including the hallucinogen 25C-NBOMe (2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine). In this study, we first evaluated the toxicity of 25C-NBOMe in two animal models: Artemia salina and zebrafish using the lethality test of Meyer et al. (1982) modified for Artemia salina and the Fish Embryo Toxicity test (FET) for zebrafish (Danio rerio). Subsequently, we determined the behavioral and morphological effects using different concentrations of the 25C-NBOMe. As a result, we found that this substance is highly toxic according to lethality tests in both animal models. We also observe that this hallucinogen induces alterations in swimming and motility patterns in Artemia salina. Similarly, there were alterations in the motor response to a stimulus, as well as abnormal development in the zebrafish. The developmental effects of zebrafish suggest a teratogenic potential for 25C-NBOMe. Therefore, these findings are correlated with side effects, such as motor response abnormalities and muscle deterioration, clinically reported for consumers of this recreational drug. Finally, although recent studies are addressing the neurotoxicity and cardiotoxicity of 25C-NBOMe in cell cultures, to the best of our knowledge, this is the first in vivo report for 25C-NBOMe related to toxicological parameters and their global effects on development. Therefore, it could represent an advance in the study of the substance that contributes to the understanding of the effects on behavior and development in humans.

Use of study-specific MOE-like estimates to prioritize health effects from chemical exposure for analysis in human health assessments.

There are unique challenges in estimating dose-response with chemicals that are associated with multiple health outcomes and numerous studies. Some studies are more suitable than others for quantitative dose-response analyses. For such chemicals, an efficient method of screening studies and endpoints to identify suitable studies and potentially important health effects for dose-response modeling is valuable. Using inorganic arsenic as a test case, we developed a tiered approach that involves estimating study-specific margin of exposure (MOE)-like unitless ratios for two hypothetical scenarios. These study-specific unitless ratios are derived by dividing the exposure estimated to result in a 20% increase in relative risk over the background exposure (RRE20) by the background exposure, as estimated in two different ways. In our case study illustration, separate study-specific ratios are derived using estimates of United States population background exposure (RRB-US) and the mean study population reference group background exposure (RRB-SP). Systematic review methods were used to identify and evaluate epidemiologic studies, which were categorized based on study design (case-control, cohort, cross-sectional), various study quality criteria specific to dose-response analysis (number of dose groups, exposure ascertainment, exposure uncertainty), and availability of necessary dose-response data. Both case-control and cohort studies were included in the RRB analysis. The RRE20 estimates were derived by modeling effective counts of cases and controls estimated from study-reported adjusted odds ratios and relative risks. Using a broad (but not necessarily comprehensive) set of epidemiologic studies of multiple health outcomes selected for the purposes of illustrating the RRB approach, this test case analysis would suggest that diseases of the circulatory system, bladder cancer, and lung cancer may be arsenic health outcomes that warrant further analysis. This is suggested by the number of datasets from adequate dose-response studies demonstrating an effect with RRBs close to 1 (i.e., RRE20 values close to estimated background arsenic exposure levels).

Bayesian hierarchical dose-response meta-analysis of epidemiological studies: Modeling and target population prediction methods.

When assessing the human risks due to exposure to environmental chemicals, traditional dose-response analyses are not straightforward when there are numerous high-quality epidemiological studies of priority cancer and non-cancer health outcomes. Given this wealth of information, selecting a single "best" study on which to base dose-response analyses is difficult and would potentially ignore much of the available data. Therefore, systematic approaches are necessary for the analysis of these rich databases. Examples are meta-analysis (and further, meta-regression), which are well established methods that consider and incorporate information from multiple studies into the estimation of risks due to exposure to environmental contaminants. In this paper, we propose a hierarchical, Bayesian meta-analysis approach for the dose-response analysis of multiple epidemiological studies. This paper is the second of two papers detailing this approach; the first covered "pre-analysis" steps necessary to prepare the data for dose-response modeling. This paper focuses on the hierarchical Bayesian approach to dose-response modeling and extrapolation of risk to populations of interest using the association between bladder cancer and oral inorganic arsenic (iAs) exposure as an illustrative case study. In particular, this paper addresses the modeling of both case-control and cohort studies with a flexible, logistic model in a hierarchical Bayesian framework that estimates study-specific slopes, as well as a pooled slope across all studies. This approach is akin to a random effects model in which no assumption is made a priori that there is a single, common slope for all included studies. Further, this paper also details extrapolation of the estimates of logistic slope to extra risk in a target population using a lifetable analysis and basic assumptions about background iAs exposure levels. In this case, the target population was the general United States population and information on all-cause mortality and incidence and mortality from bladder cancer was used to perform the lifetable analysis. The methods herein were developed for general use in investigating the association between any pollutant and observed health-effects in epidemiological studies. In order to demonstrate these methods, inorganic arsenic was chosen as a case study given the large epidemiological database that exists for this contaminant.

Model averaging methods for the evaluation of dose-response model uncertainty when assessing the suitability of studies for estimating risk.

This paper describes the use of multiple models and model averaging for considering dose-response uncertainties when extrapolating low-dose risk from studies of populations with high levels of exposure. The model averaging approach we applied builds upon innovative methods developed by the U.S. Food and Drug Administration (FDA), principally through the relaxing of model constraints. The relaxing of model constraints allowed us to evaluate model uncertainty using a broader set of model forms and, within the context of model averaging, did not result in the extreme supralinearity that is the primary concern associated with the application of individual unconstrained models. A study of the relationship between inorganic arsenic exposure to a Taiwanese population and potential carcinogenic effects is used to illustrate the approach. We adjusted the reported number of cases from two published prospective cohort studies of bladder and lung cancer in a Taiwanese population to account for potential covariates and less-than-lifetime exposure (for estimating effects on lifetime cancer incidence), used bootstrap methods to estimate the uncertainty surrounding the µg/kg-day inorganic arsenic dose from drinking water and dietary intakes, and fit multiple models weighted by Bayesian Information Criterion to the adjusted incidence and dose data to generate dose-specific mean, 2.5th and 97.5th percentile risk estimates. Widely divergent results from adequate model fits for a broad set of constrained and unconstrained models applied individually and in a model averaging framework suggest that substantial model uncertainty exists in risk extrapolation from estimated doses in the Taiwanese studies to lower doses more relevant to countries like the U.S. that have proportionally lower arsenic intake levels.

Systematic dose-response of environmental epidemiologic studies: Dose and response pre-analysis.

Meta-analysis approaches can be used to assess the human risks due to exposure to environmental chemicals when there are numerous high-quality epidemiologic studies of priority outcomes in a database. However, methodological issues related to how different studies report effect measures and incorporate exposure into their analyses arise that complicate the pooled analysis of multiple studies. As such, there are "pre-analysis" steps that are often necessary to prepare summary data reported in epidemiologic studies for dose-response analysis. This paper uses epidemiologic studies of arsenic-induced health effects as a case example and addresses the issues surrounding the estimation of mean doses from censored dose- or exposure-intervals reported in the literature (e.g., estimation of mean doses from high exposures that are only reported as an open-ended interval), calculation of a common dose metric for use in a dose-response meta-analysis (one that takes into consideration inter-individual variability), and calculation of response "effective counts" that inherently account for confounders. The methods herein may be generalizable to 1) the analysis of other environmental contaminants with a suitable database of epidemiologic studies, and 2) any meta-analytic approach used to pool information across studies. A second companion paper detailing the use of "pre-analyzed" data in a hierarchical Bayesian dose-response model and techniques for extrapolating risks to target populations follows.

Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Model for Inorganic Arsenic Exposure Using Data from Two Diverse Human Populations.

BACKGROUND: Multiple epidemiological studies exist for some of the well-studied health endpoints associated with inorganic arsenic (iAs) exposure; however, results are usually expressed in terms of different exposure/dose metrics. Physiologically based pharmacokinetic (PBPK) models may be used to obtain a common exposure metric for application in dose-response meta-analysis. OBJECTIVE: A previously published PBPK model for inorganic arsenic (iAs) was evaluated using data sets for arsenic-exposed populations from Bangladesh and the United States. METHODS: The first data set was provided by the Health Effects of Arsenic Longitudinal Study cohort in Bangladesh. The second data set was provided by a study conducted in Churchill County, Nevada, USA. The PBPK model consisted of submodels describing the absorption, distribution, metabolism and excretion (ADME) of iAs and its metabolites monomethylarsenic (MMA) and dimethylarsenic (DMA) acids. The model was used to estimate total arsenic levels in urine in response to oral ingestion of iAs. To compare predictions of the PBPK model against observations, urinary arsenic concentration and creatinine-adjusted urinary arsenic concentration were simulated. As part of the evaluation, both water and dietary intakes of arsenic were estimated and used to generate the associated urine concentrations of the chemical in exposed populations. RESULTS: When arsenic intake from water alone was considered, the results of the PBPK model underpredicted urinary arsenic concentrations for individuals with low levels of arsenic in drinking water and slightly overpredicted urinary arsenic concentrations in individuals with higher levels of arsenic in drinking water. When population-specific estimates of dietary intakes of iAs were included in exposures, the predictive value of the PBPK model was markedly improved, particularly at lower levels of arsenic intake. CONCLUSIONS: Evaluations of this PBPK model illustrate its adequacy and usefulness for oral exposure reconstructions in human health risk assessment, particularly in individuals who are exposed to relatively low levels of arsenic in water or food. https://doi.org/10.1289/EHP3096.

The Sonographic Subcentimeter Malignant Thyroid Nodule: What Does It Stand for?

Thyroid cancer management has moved to less extensive surgery in lesions with favorable criteria. Our study evaluated if the sonographic (US) size of thyroid nodules is a reliable criterion to determine the extent of surgery in patients with papillary thyroid carcinoma (PTC). A retrospective study was performed to evaluate thyroid nodules measuring <10 mm in the preop sonogram with a permanent pathology of PTC. Patients were subdivided into two groups based on the US size: A (1-5 mm) and B (6-10 mm). Statistical correlations were made for the presence of the following unfavorable criteria: multifocality, capsular invasion, angio/lymphatic invasion, extrathyroidal invasion, and presence of metastases. A total of 1901 thyroidectomies were performed: 722 (38%) for PTC. 182 (25%) patients met the inclusion criteria. There were 30 patients in Group A (1-5 mm) and 152 patients in Group B (6-10 mm). Five (17%) patients in Group A and 53 (35%) patients in Group B presented unfavorable criteria (P < 0.005). Malignant thyroid nodules with the US size of <5 mm can in theory be candidates for partial thyroidectomy, but 17 per cent of them might still need further surgical intervention. Lesions with the US size of 6 to 10 mm still have a moderate risk of presenting unfavorable pathological criteria.

Relationships between arsenic concentrations in drinking water and lung and bladder cancer incidence in U.S. counties.

Increased risks of lung and bladder cancer have been observed in populations exposed to high levels of inorganic arsenic. However, studies at lower exposures (i.e., less than 100 µg/l in water) have shown inconsistent results. We therefore conducted an ecological analysis of the association between historical drinking water arsenic concentrations and lung and bladder cancer incidence in U.S. counties. We used drinking water arsenic concentrations measured by the U.S. Geological Survey and state agencies in the 1980s and 1990s as proxies for historical exposures in counties where public groundwater systems and private wells are important sources of drinking water. Relationships between arsenic levels and cancer incidence in 2006-2010 were explored by Poisson regression analyses, adjusted for groundwater dependence and important demographic covariates. The median and 95th percentile county mean arsenic concentrations were 1.5 and 15.4 µg/l, respectively. Water arsenic concentrations were significant and positively associated with female and male bladder cancer, and with female lung cancer. Our findings support an association between low water arsenic concentrations and lung and bladder cancer incidence in the United States. However, the limitations of the ecological study design suggest caution in interpreting these results.

Influence of adrenal pathology on perioperative outcomes: a multi-institutional analysis.

BACKGROUND: Endoscopic or open adrenalectomies are performed for variable pathologies. We investigated if adrenal pathology affects perioperative outcomes independent of operative approach. METHODS: A multi-institutional retrospective review of 345 adrenalectomies was performed. A multivariate analysis was utilized. RESULTS: Pathology groups included benign non-pheochromocytoma tumors (50.4%), pheochromocytomas (41%), adrenocortical carcinomas (5.2%), and metastatic tumors (3.4%). Controlling for age, body mass index, tumor size, procedure type, and pathology, pheochromocytomas exhibited greater blood loss (92 mL more, P = .007) and operative times (33 min more, P < .001) than benign non-pheochromocytoma tumors. Metastatic tumors demonstrated longer operative times (53 min more, P = .013). Open adrenalectomy was associated with greater blood loss (396 mL more, P = .001), transfusion requirement (P = .021), operative times (79 min more, P < .001), hospital stay (6.6 days more, P < .001) and complications (P < .001) when compared with endoscopic adrenalectomy. CONCLUSIONS: The type of adrenal pathology appears to influence blood loss and operative time but not complications in patients undergoing adrenalectomy. Open adrenalectomy remains a major driver of adverse perioperative outcomes.

Biomarkers of perchlorate exposure are correlated with circulating thyroid hormone levels in the 2007-2008 NHANES.

Previous epidemiological studies provide conflicting evidence as to whether environmental perchlorate exposure can affect levels of circulating thyroid hormones in the general population. We investigated the statistical relationships between biomarkers of perchlorate exposure and serum thyroid hormone levels in 2007-2008 National Health and Nutrition Evaluation Survey (NHANES) subjects. Generalized additive mixed models (GAMMs) were developed to estimate the relationships between T3 and T4 levels and creatinine-adjusted urinary perchlorate excretion. The models included covariates related to gender, age, ethnicity, income, smoking status, prescription medications, and biomarkers of exposures to other goitrogenic ions and phthalate ester metabolites. Where necessary, relationships between hormone levels and covariates were represented as nonlinear smoothed terms. The effect of the hypothalamic-pituitary-thyroid (HPT) axis on serum hormone levels was taken into account by including a term for thyroid stimulating hormone (TSH) in the models. Regression coefficients for perchlorate were significant and negative in GAMMs predicting total T4 and free T3 levels in males, females, and for the entire cohort when phthalate ester biomarkers and other covariates were included. Coefficients for perchlorate were also significant and negative in regressions predicting free T4 levels in males and in the entire study population. The consistency of these results suggests that HPT axis controls do not completely compensate for small changes in thyroid hormone levels associated with perchlorate and phthalate ester exposures.

Drinking water contribution to aggregate perchlorate intake of reproductive-age women in the United States estimated by dietary intake simulation and analysis of urinary excretion data.

Estimates of perchlorate intake by the US population can be derived from either urinary excretion data or through simulation of dietary intake. Estimates from surveys of urinary excretion (NHANES) are subject to substantial uncertainty owing to the small numbers of subjects for which data are currently available. In addition, current excretion estimates are derived from "spot" urine samples and include a component of short-term (intra-day) variability that may give biased estimates of the variability in average daily intakes. Previous dietary estimates have generally not included any contribution from drinking water, owing to a lack of data related to perchlorate concentrations in water supplies. In this paper, we derive simulation (Monte Carlo) estimates of dietary perchlorate intake distributions for reproductive-age women, which include explicit contributions from drinking water, and compare them to estimates based on urinary excretion. Perchlorate concentrations in water were estimated based on measurements from the US Environmental Protection Agency's UCMR1 database, and from other regional studies of perchlorate contamination. We find that including the drinking water contributions in the dietary simulations yields increases in the population's geometric mean perchlorate intake of 3-8 percent, with a conservative maximum of about 24 percent, compared to intakes estimated based on food intake alone. The intake distributions estimated from dietary and water consumption were found to be very similar to estimates based on creatinine-adjusted perchlorate excretion data from the NHANES, except for having lower population variability. When the dietary simulation data were adjusted to include a contribution from short-term variability similar to that in the "spot" urine samples, the variability in the NHANES and diet-derived estimates were found to be very similar. Our analyses indicate that a reasonable upper-bound estimate for the 95th percentile perchlorate intake among women of reproductive age in the US is on the order of 1.5 x 10(-4) mg/kg/day.

Long-term outcome of patients with elevated parathyroid hormone levels after successful parathyroidectomy for sporadic primary hyperparathyroidism.

HYPOTHESIS: Untreated long-term elevated parathyroid hormone (PTH) levels after successful parathyroidectomy may predict recurrent hyperparathyroidism (HPT). Although elevated PTH levels have been reported in eucalcemic patients after parathyroidectomy for sporadic primary HPT, the long-term clinical significance of this finding remains unclear. DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Five hundred seventy-six consecutive patients with HPT. INTERVENTION: Parathyroidectomy guided by intraoperative monitoring of PTH levels. MAIN OUTCOME MEASURES: Overall incidence of elevated PTH levels (measurements of >or= 70 pg/mL at any time during follow-up) and recurrent HPT (hypercalcemia and elevated PTH levels more than 6 months after parathyroidectomy). RESULTS: Of the 505 patients who underwent successful parathyroidectomy in this series and were followed up for more than 6 months, 337 (66.7%) consistently had PTH levels within the reference range, and 168 (33.3%) had elevated PTH levels. Of the 168 patients with elevated PTH levels, only 8 (4.8%) developed recurrent disease. The earliest recurrence occurred 2 years postoperatively. Factors associated with elevated PTH levels included advanced age, higher preoperative PTH levels, and mild postoperative renal insufficiency. CONCLUSION: Although one-third of the patients had elevated PTH levels after successful parathyroidectomy, most of these patients with elevated PTH levels (95%) will achieve long-term eucalcemia.

Role of surgeon-performed ultrasound in predicting malignancy in patients with indeterminate thyroid nodules.

BACKGROUND: Certain ultrasound features can predict malignancy in patients with thyroid nodules. The purpose of this study was to determine the value of surgeon-performed ultrasound (SUS) in predicting thyroid malignancy in patients with indeterminate fine-needle aspiration (FNA) cytology. METHODS: 477 consecutive patients with dominant thyroid nodules were referred to our institution from 2002 to 2007. Of these, 180/477(38%) were judged to have indeterminate cytology: follicular neoplasm (FN, n = 108), Hürthle neoplasm (HN, n = 29), and suspicious for papillary thyroid cancer (SPTC, n = 43). SUS characteristics for thyroid nodules were recorded in a prospective database prior to thyroidectomy. Variables analyzed included patients' age and sex, nodule size, shape, echogenicity, consistency, borders, multiplicity/multicentricity, and presence of microcalcifications. SUS features of thyroid nodules were correlated with final pathology. The accuracy of individual SUS features as well as the presence of two or more adverse features in predicting malignancy was also examined. RESULTS: There were 144 females and 36 males. Mean age was 52 years (range 17-87 years). Mean tumor size was 2.7 cm (range 0.65-6.6 cm). Overall, final pathology revealed cancer in 92/180 (51%) patients. Malignancy was present in 40/108 (37%) FN, 12/29 (41%) HN, and 40/43 (93%) SPTC. Nodule borders (irregular), shape (height > width), hypoechogenicity, and presence of microcalcifications were significantly associated with malignancy. The presence of 2 or >/=3 adverse SUS thyroid nodule features was associated with a >/=55% or >/=78% risk of malignancy, respectively. CONCLUSION: Adverse thyroid nodule features seen on SUS may predict malignancy and help determine the initial extent of thyroidectomy in patients with indeterminate FNA cytology.

Ileal perforation and reactive hemophagocytic syndrome in a patient with disseminated histoplasmosis: the role of the real-time polymerase chain reaction in the diagnosis and successful treatment with amphotericin B lipid complex.

The following case illustrates an ileal perforation and reactive hemophagocytic syndrome (RHS) resulting from disseminated histoplasmosis in a patient with Human Immunodeficiency Virus (HIV) from Puerto Rico. Although the diagnosis was established by histopathologic findings and a positive bone marrow culture, Histoplasma capsulatum-specific real-time Polymerase Chain Reaction (PCR) allowed to confirm the diagnosis from formalin-fixed, paraffin-embedded tissue. Interestingly, the Histoplasma antigens in both serum and urine samples were falsely negative. Amphotericin B lipid complex (Abelcet), followed by oral itraconazole, led to a successful response and resolution of symptoms. A short review of the clinical signs and symptoms, diagnostic tests, and therapeutic options for disseminated histoplasmosis is done, with emphasis on the role of Histoplasma-specific real-time PCR as a molecular diagnostic tool and the efficacy of treatment with one of the lipid formulations of amphotericin B.