Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

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DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human

Objective

Obesity is associated with low-grade inflammation and the infiltration of immune cells in insulin-sensitive tissues, leading to metabolic impairment. Epigenetic mechanisms control immune cell lineage determination, function and migration and are implicated in obesity and type 2 diabetes (T2D). The aim of this study was to determine the global DNA methylation profile of immune cells in obese and T2D individuals in a cell type-specific manner.

Material and methods

Fourteen obese subjects and 11 age-matched lean subjects, as well as 12 T2D obese subjects and 7 age-matched lean subjects were recruited. Global DNA methylation levels were measured in a cell type-specific manner by flow cytometry. We validated the assay against mass spectrometry measures of the total 5-methylcytosine content in cultured cells treated with the hypomethylation agent decitabine (r = 0.97, p < 0.001).

Results

Global DNA methylation in peripheral blood mononuclear cells, monocytes, lymphocytes or T cells was not altered in obese or T2D subjects. However, analysis of blood fractions from lean, obese, and T2D subjects showed increased methylation levels in B cells from obese and T2D subjects and in natural killer cells from T2D patients. In these cell types, DNA methylation levels were positively correlated with insulin resistance, suggesting an association between DNA methylation changes, immune function and metabolic dysfunction.

Conclusions

Both obesity and T2D are associated with an altered epigenetic signature of the immune system in a cell type-specific manner. These changes could contribute to the altered immune functions associated with obesity and insulin resistance.     

Usefulness of Rapid Desensitization Therapy for Severe Rash Caused by Molecularly Targeted Drugs Used in the Treatment of Non-small-cell Lung Cancer

Molecular-targeted drugs (MTDs), such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase inhibitors, are used to treat non-small-cell lung cancer (NSCLC). The incidence of rash caused by EGFR-TKIs and discontinuation of MTDs because of rash are issues. Rapid desensitization therapy (RDT) was performed in five patients who developed severe rash after introduction of MTDs and was successful in four, all of whom showed no rash relapse. RDT may thus be useful for treating rash in patients receiving MTDs for NSCLC.     

Predictors of Treatment Engagement in Ethnically Diverse,Urban Children Receiving Treatment for Trauma Exposure

Keeping traditionally underrepresented children and their families engaged in treatment until completion is a major challenge for many community‐based mental health clinics. The current study used data collected as part of the National Child Traumatic Stress Network Core Data Set to examine whether racial/ethnic disparities exist in treatment duration and completion in children seeking treatment for trauma exposure. We then explored whether disparities persist after accounting for other variables associated with children's social contexts and the treatment setting. The sample included 562 ethnically diverse children receiving services from a child abuse prevention and treatment agency in Southern California. The results indicated that African American children had significantly shorter trauma‐informed treatment duration and higher rates of premature termination than Spanish‐speaking Latino children. These disparities persisted even with other variables associated with treatment duration and completion (e.g., child's age, level of functional impairment, and receipt of group and field services) in the model. Implications and future directions for research and practice are discussed.     

Cancer-specific health-related quality of life in children with brain tumors

Purpose

To understand the influence of disease and treatment on the health-related quality of life (HRQOL) of children with brain tumors, compared to the HRQOL of children with other cancers, from the viewpoints of children and parents.

Methods

A total of 133 children aged 5–18 years and 165 parents of children aged 2–18 completed questionnaires of the Pediatric Quality of Life Inventory Cancer Module (Pain and Hurt, Nausea, Procedural Anxiety, Treatment Anxiety, Worry, Cognitive Problems, Perceived Physical Appearance, and Communication scales); higher scores indicate a better HRQOL. The Cancer Module scores, weighted by age and treatment status, were compared to those obtained in a previous study of children with other cancers (mostly leukemia).

Results

The weighted mean scores for Pain and Hurt (effect size d = 0.26) and Nausea (d = 0.23) from child reports and the scores for Nausea (d = 0.28) from parent reports were higher for children with brain tumors than scores for children with other cancers. The scores for Procedural Anxiety (d = ?0.22) and Treatment Anxiety (d = ?0.32) from parent reports were lower for parents of children with brain tumors than the scores for parents of children with other cancers. The child-reported Pain and Hurt score of the Cancer Module was higher (d = 0.29) and in less agreement (intraclass correlation coefficient = 0.43) with scores from the Brain Tumor Module, indicating that assessments completed with the Cancer Module misesteem pain and hurt problems in children with brain tumors.

Conclusions

The profiles of cancer-specific HRQOL in children with brain tumors differ from those of children with other cancers; we therefore suggest that these children receive specific psychological support.     

Improved synthesis and application of conjugation-amenable polyols from d-mannose

A series of polyhydroxyl sulfides and triazoles was prepared by reacting allyl and propargyl d-mannose derivatives with selected thiols and azides in thiol–ene and Huisgen click reactions. Conformational analysis by NMR spectroscopy proved that the intrinsic rigidity and linear conformation of the mannose derived polyol backbone is retained in the final click products in solution. Single crystal X-ray structure determination of one of the compounds prepared further verified that the linear conformation of the polyol segment is also retained in the solid state. In addition, an improved method for direct Barbier-type propargylation of unprotected d-mannose is reported. The new reaction protocol, involving tin-mediated propargylation in an acetonitrile-water mixture, provides access to multigram quantities of the desired, valuable alkyne polyol without relying on protecting group manipulations or chromatographic purification.

An improved method for the propargylation of d-mannose and application of the rod-like polyol and its allylated analogue in click reactions is described.