Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary

As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.     

Factors associated with weight changes in successful quitters participating in a smoking cessation program

Objective

To identify possible predictors of post-cessation weight gain in smoking abstainers.

Patients and methods

A sample of 607 successful abstainers seen at the Centre for Tobacco-Dependent in Prague, Czech Republic, between 2005 and 2010, was included in this analysis. This sample was followed up for 1 year and included 47.9% women (N = 291) with the mean age of 48 years (18–85).

Findings

Post-cessation weight gain occurred in 88.6% of the 607 abstainers. The mean weight gain after one year post-quit was 5.1 kg (95% confidence interval 4.7–5.5 kg). Baseline characteristics associated with increased weight gain included a higher baseline smoking rate (p < 0.001), more severe cigarette dependence (p = 0.003), less physical activity (p = 0.008), and a report of increased appetite on the baseline assessment of withdrawal symptoms (p < 0.001).

Conclusions

Smokers who are more dependent and have minimal physical activity are at increased risk for post-cessation weight gain. For these smokers, incorporating interventions targeting the weight issue into tobacco dependence treatment is recommended. Further research should be done to identify reasons for this important quitting complication.     

Gastro 2013 APDW/WCOG Shanghai Working Party Report: Chronic diarrhea: Definition,classification, diagnosis

Diarrhea is best defined as passage of loose stools often with more frequent bowel movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish stool form and to identify loose stools. Laboratory testing of stool consistency has lagged behind. Acute diarrhea is likely to be due to infection and to be self‐limited. As diarrhea becomes chronic, it is less likely to be due to infection; duration of 1 month seems to work well as a cut‐off for chronic diarrhea, but detailed scientific knowledge is missing about the utility of this definition. In addition to duration of diarrhea, classifications by presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or inflammatory) may help the canny clinician refine the differential diagnosis of chronic diarrhea. In this regard, a careful history remains the essential part of the evaluation of a patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques is useful, and biopsy of the small intestine and colon for histological assessment provides key diagnostic information. Endomicroscopy and molecular pathology are only now being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut is increasing; aside from a handful of well‐described infections because of pathogens, little is known about alterations in the microbiome in chronic diarrhea. Serological tests have well‐defined roles in the diagnosis of celiac disease but have less clearly defined application in autoimmune enteropathies and inflammatory bowel disease. Measurement of peptide hormones is of value in the diagnosis and management of endocrine tumors causing diarrhea, but these are so rare that these tests are of little value in screening because there will be many more false‐positives than true‐positive results. Chemical analysis of stools is of use in classifying chronic diarrhea and may limit the differential diagnosis that must be considered, but interpretation of the results is still evolving. Breath tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth, and intestinal transit are fraught with technical limitations that decrease sensitivity and specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond empirical trials of bile acid sequestrants.     

A phase II trial evaluating the efficacy of high-dose Radioiodinated Tositumomab (Anti-CD20) antibody,etoposide and cyclophosphamide followed by autologous transplantation,for high-risk relapsed or refractory non-hodgkin lymphoma

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.     

Father–child interaction: associations with self-control and aggression among 4.5-year-olds

Examined correlates of positive father caregiving and harsh control among 721 (350 girls) four-year-old children through analysis of NICHD Study of Early Child Care data and 7050 (3450 girls) four-year-old children through analysis of Early Childhood Longitudinal Study – Birth Cohort data. Findings from both samples suggest that, for both boys and girls, father positive care is associated with lower levels of impulsivity and higher ratings of inhibitory control. For girls, father positive care is associated with lower ratings of aggression. For boys, these findings suggest self-regulation moderates associations between father positive care and aggression. Some support was obtained for models of both moderation and mediation in the prediction of children's peer-based behaviour.     

Simplified Microarray System for Simultaneously Detecting Rifampin,Isoniazid, Ethambutol,and Streptomycin Resistance Markers in Mycobacterium tuberculosis

We developed a simplified microarray test for detecting and identifying mutations in rpoB, katG, inhA, embB, and rpsL and compared the analytical performance of the test to that of phenotypic drug susceptibility testing (DST). The analytical sensitivity was estimated to be at least 110 genome copies per amplification reaction. The microarray test correctly detected 95.2% of mutations for which there was a sequence-specific probe on the microarray and 100% of 96 wild-type sequences. In a blinded analysis of 153 clinical isolates, microarray sensitivity for first-line drugs relative to phenotypic DST (true resistance) was 100% for rifampin (RIF) (14/14), 90.0% for isoniazid (INH) (36/40), 70% for ethambutol (EMB) (7/10), and 89.1% (57/64) combined. Microarray specificity (true susceptibility) for first-line agents was 95.0% for RIF (132/139), 98.2% for INH (111/113), and 98.6% for EMB (141/143). Overall microarray specificity for RIF, INH, and EMB combined was 97.2% (384/395). The overall positive and negative predictive values for RIF, INH, and EMB combined were 84.9% and 98.3%, respectively. For the second-line drug streptomycin (STR), overall concordance between the agar proportion method and microarray analysis was 89.5% (137/153). Sensitivity was 34.8% (8/23) because of limited microarray coverage for STR-conferring mutations, and specificity was 99.2% (129/130). All false-susceptible discrepant results were a consequence of DNA mutations that are not represented by a specific microarray probe. There were zero invalid results from 220 total tests. The simplified microarray system is suitable for detecting resistance-conferring mutations in clinical M. tuberculosis isolates and can now be used for prospective trials or integrated into an all-in-one, closed-amplicon consumable.