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Background Chronic abdominal pain (CAP) carries a significant burden of disease. The last edition of the Rome Criteria (Rome IV) allows the diagnosis of functional gastrointestinal disorders (FGIDs) according to symptoms-based criteria; however, patients continue to experience a delay in their diagnosis and to be submitted to different interventions before the establishment of a positive diagnosis. Objective We aimed to characterize etiology, clinical features, and interventions in a pediatric cohort of patients with CAP secondary to FGIDs, who were referred to our tertiary care university-affiliated hospital, in Brazil. Methods A retrospective descriptive study of children and adolescents (aged 20 years and younger) referred to our institution, from January/2013 to December/2018, for CAP, and who fulfilled criteria for FGIDs classified according to Rome IV criteria. Results Three hundred twenty-eight patients with CAP were screened, of which 67.9% (223 patients) fulfilled the criteria for FGIDs and were included in the study. Sixty percent were female, with a mean age of 8.3 years. At the time of referral, the mean duration of symptoms was 2.8 years. Length/height for age and weight for age mean z-scores were -0.08±1.87 and -0.38±1.62, respectively. Functional abdominal pain not otherwise specified was overall the most common diagnosis (70.4%). Before establishing the diagnosis of FGIDs, multiple pharmacological interventions were described, while after, the mainstay of therapy was education/reassurance and dietary interventions. Thirty-two percent of patients did not further require specialized follow-up. Conclusion Even at the tertiary care level, FGIDs were still the most common etiology of chronic abdominal pain, particularly functional abdominal pain not otherwise specified. Despite the relatively long duration of symptoms at referral, cessation of specialized care follow-up was possible in approximately a third of the cases. RESUMO Contexto A dor abdominal crônica (DAC) pode acarretar importante morbidade. A última edição dos Critérios de Roma (Roma IV) permite o diagnóstico de distúrbios gastrointestinais funcionais (DGIFs) de acordo com critérios baseados em sintomas; no entanto, esses pacientes continuam a apresentar atraso no diagnóstico e a serem submetidos a diferentes intervenções antes do estabelecimento de um diagnóstico. Objetivo Caracterizar a etiologia, características clínicas e intervenções de crianças com DAC que não são mantidas na atenção primária e que foram encaminhadas ao nosso hospital universitário de nível terciário, no Brasil. Métodos Estudo retrospectivo descritivo de crianças e adolescentes (com idade igual ou inferior a 20 anos) encaminhados a nossa instituição, entre janeiro/2013 e dezembro/2018, por DAC e que preenchiam os critérios para DGIFs conforme o consenso de Roma IV. Resultados Trezentos e vinte e oito pacientes com DAC foram triados, 67,9% (223 pacientes) preencheram os critérios para DGIFs e foram analisados. Sessenta por cento do sexo feminino, com idade média de 8,3 anos. A duração média dos sintomas no encaminhamento era de 2,8 anos. Os escores z médios de estatura para idade e peso para idade foram -0,08±1,87 e -0,38±1,62, respectivamente. Dor abdominal funcional sem outra especificação foi o diagnóstico mais comum (70,4%). Antes do diagnóstico de DGIFs, múltiplas intervenções farmacológicas foram descritas, enquanto depois, a base da terapia foi a educação, passar segurança à família e intervenções dietéticas. Trinta e dois por cento dos pacientes apresentaram resolução dos sintomas e receberam alta do acompanhamento especializado. Conclusão Mesmo no nível terciário, as desordens gastrointestinais funcionais ainda constituem a etiologia mais comum da DAC, particularmente a dor abdominal funcional não especificada. Apesar da duração longa dos sintomas, alta do serviço especializados foi possível em aproximadamente um terço dos casos.

On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and ΔWhile the HID included both human and animal data, this set of three reviews will highlight the animal-derived data pertaining to somatic development (Part I), neurodevelopmental effects (Part II), and proposed neurodevelopmental mechanisms of action (Part III).Endogenous cannabinoids (eCBs) and their receptors serve many critical functions in normal development. ΔIn reaching its decision to list cannabis and Δ

This review summarizes the most common potential pathways of neurodevelopmental toxicity due to perinatal exposure to Δ

This paper presents a sketch of the segmental and prosodic phonology of Omagua, a highly endangered Tupi-Guarani language of Peru, based on original fieldwork. After reviewing the classification, h...

Many nitrosamines are potent carcinogens, with more than 30 listed under California’s Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California’s Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.

We developed an integrated, modular approach to predicting chemical toxicity relying on in vitro assay data, linkage of molecular targets to disease categories, and software for ranking chemical activity and examining structural features (chemotypes). We evaluate our approach in a proof-of-concept exercise to identify and prioritize chemicals of potential carcinogenicity concern. We identified 137 cancer pathway-related assays from a subset of U.S. EPA's ToxCast platforms. We mapped these assays to key characteristics of carcinogens and found they collectively assess 5 of 10 characteristics. We ranked all 1061 chemicals screened in Phases I and II of ToxCast by their activity in the selected cancer pathway-related assays using Toxicological Prioritization Index software. More chemicals used as biologically active agents (eg, pharmaceuticals) ranked in the upper 50% versus lower 50%. Twenty-three chemotypes are enriched in the top 5% (n = 54) of chemicals; these features may be important for their activity in cancer pathway-related assays. The biological coverage of the ToxCast assays related to cancer pathways is limited and short-term assays may not capture the biology of some key characteristics. Metabolism is also minimal in the assays. The ability of our approach to identify chemicals with cancer hazard is limited with the current input data, but we expect that our approach can be applied with future iterations of ToxCast and other data for improved chemical prioritization and characterization. The novel approach and proof-of-concept exercise described here for ranking chemicals for potential carcinogenicity concern is modular, adaptable, and amenable to evolving data streams.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro. We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention. See all articles in this CEBP Focus section, “Environmental Carcinogenesis: Pathways to Prevention.”

Purpose of Review Cannabis exposure during critical windows of development may have intergenerational physiological consequences disrupting epigenetic programming and marks. This review examines the literature relating to pre-gestational and prenatal cannabinoid exposure and its effect on genes and molecular pathways related to the development of psychiatric disease. Recent Findings Developmental cannabis exposure alters epigenetic processes with functional gene consequences. These include potentially heritable alterations in genes and molecular pathways critical for brain development and associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia, addiction, and other psychiatric diseases. Summary Cannabis consumption and mental health illness in adolescents and young adults are increasing in the United States (U.S.), and recent studies suggest that cannabis consumption during critical periods of brain development could contribute to mental health illness through epigenetic mechanisms. These findings warrant future studies and consideration by regulators and health communicators.

A 66-year-old man with cryptogenic cirrhosis secondary to nonalcoholic steatohepatitis presented for orthotopic liver transplantation. Following organ reperfusion, the patient developed vasoplegic syndrome, with arterial blood pressures of approximately 60-70/30-40 mm Hg (mean arterial pressure [MAP] 90 minutes. He required high-dose norepinephrine and vasopressin infusions, as well as i.v. bolus doses of norepinephrine and vasopressin to reach a goal MAP> 60 mm Hg. There was minimal response to a 2 mg/kg i.v. bolus of methylene blue. Following the administration of 5 g of i.v.hydroxocobalamin, the patient had a profound improvement in arterial blood pressure, with subsequent discontinuation of the vasopressin infusion and rapid reduction of norepinephrine infusion from 20 to 2 μg/min. While there have been several reports of the efficacy of hydroxocobalamin for vasoplegia after cardiopulmonary bypass, there have been only limited cases of hydroxocobalamin used in liver transplantation, and none with high-dose administration. We present a case of vasoplegic syndrome during liver transplantation that was refractory to high-dose vasopressors and methylene blue but responsive to high-dose i.v. hydroxocobalamin.

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.