The new tapestry of risk assessment

Neurotoxicology is entering a new phase in how it views and practices risk assessment. Perhaps more than any of the other disciplines that comprise the science of toxicology, it has been compelled to consider a daunting array of factors other than those directly coupled to chemical and dose, and the age and sex of the subject population. In epidemiological investigations, researchers are increasingly cognizant of the problems introduced by allegedly controlling for variables classified as confounders or covariates. In essence, they reason, the consequence is blurring or even concealing interactions of exposure with modifiers such as the individual's social ecology. Other researchers question the traditional practice of relying on values such as NOAELs when they are abstracted from a biological entity that in reality represents a multiplicity of intertwined systems. Although neurotoxicologists have come to recognize the complexities of assessing risk in all its dimensions, they still face the challenge of communicating this view to the health professions at large.     

Microsatellite instability in pediatric and adult high-grade gliomas

About 15% of sporadic gastrointestinal and endometrial tumors show the microsatellite instability (MSI) phenotype because of loss of DNA mismatch repair (MMR) function. The incidence of MSI in tumors of the central nervous system still remains controversial. Previous studies reported a particular high frequency of MSI (approximately 25%) in young patients suffering from high-grade gliomas. Based on these data and the fact that in different tumor entities MMR deficiency defines a subgroup of tumors with distinct pathogenesis and particular clinicopathological features that may have impact on prognosis and therapy, we screened 624 gliomas from 71 young and 553 adult patients for MMR deficiency by MSI analysis using three highly sensitive diagnostic markers. Alterations of MMR protein expression was examined by immunohistochemistry. A malignant glioma from an adult patient displayed MSI and concomitant loss of nuclear MSH2 and MSH6 protein expression (0.16%; 1/619). No evidence for MSI or loss of MMR protein expression was observed in 71 gliomas from young patients (0%; 0/71) including 41 high-grade astrocytic tumors. Overall, we observed a much lower incidence of MSI among high-grade pediatric gliomas than initially reported and suggest that MMR deficiency does not play a major role in the pathogenesis of glial neoplasms.     

'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage

Sepsis is a deadly disease characterized by considerable derangement of the proinflammatory, anti-inflammatory and coagulation responses. Protease-activated receptor 1 (PAR1), an important regulator of endothelial barrier function and blood coagulation, has been proposed to be involved in the lethal sequelae of sepsis, but it is unknown whether activation of PAR1 is beneficial or harmful. Using a cell-penetrating peptide (pepducin) approach, we provide evidence that PAR1 switched from being a vascular-disruptive receptor to a vascular-protective receptor during the progression of sepsis in mice. Unexpectedly, we found that the protective effects of PAR1 required transactivation of PAR2 signaling pathways. Our results suggest therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis.     

Informed and patient-centered decision-making in the primary care visits of African Americans with depression

Objective

We examined the prevalence and extent of informed decision-making (IDM) and patient-centered decision-making (PCDM) in primary care visits of African Americans with depression.

Role of Dendritic Cells in the Pathogenesis of Whipple's Disease

Accumulation of Tropheryma whipplei-stuffed macrophages in the duodenum, impaired T. whipplei-specific Th1 responses, and weak secretion of interleukin-12 (IL-12) are hallmarks of classical Whipple''s disease (CWD). This study addresses dendritic cell (DC) functionality during CWD. We documented composition, distribution, and functionality of DC ex vivo or after in vitro maturation by fluorescence-activated cell sorting (FACS) and by immunohistochemistry in situ. A decrease in peripheral DC of untreated CWD patients compared to healthy donors was due to reduced CD11c^high myeloid DC (M-DC). Decreased maturation markers CD83, CD86, and CCR7, as well as low IL-12 production in response to stimulation, disclosed an immature M-DC phenotype. In vitro-generated monocyte-derived DC from CWD patients showed normal maturation and T cell-stimulatory capacity under proinflammatory conditions but produced less IL-12 and failed to activate T. whipplei-specific Th1 cells. In duodenal and lymphoid tissues, T. whipplei was found within immature DC-SIGN⁺ DC. DC and proliferating lymphocytes were reduced in lymph nodes of CWD patients compared to levels in controls. Our results indicate that dysfunctional IL-12 production by DC provides suboptimal conditions for priming of T. whipplei-specific T cells during CWD and that immature DC carrying T. whipplei contribute to the dissemination of the bacterium.     

Imaging of the brain in polytraumatized patients comparing 64-row spiral CT with incremental (sequential) CT

Introduction

Up to now, due to a better image quality, for brain imaging the substantially slower sequential examination mode has been preferred during CT in polytraumatized patients. We aimed to re-evaluate modern ultrafast 64-row spiral CT regarding image quality in brain imaging of polytraumatized patients.

Methods

In 30 polytraumatized patients, both 64-row spiral and sequential CT of the brain were performed within 24 h. Retrospectively, two radiologists subjectively evaluated the delineation of the internal capsule, the pons, the medial rectus muscle of the orbita, the differentiation of grey/white matter, and the extent of artifacts at the inner skull. Image noise was also evaluated objectively. Statistics were performed using Cohen's kappa and a two-sided t-test.

Results

Perfect or clear agreements were noted regarding the delineation of the inner skull, the medial rectus muscle, the internal capsule, and grey/white matter differentiation. Due to beam hardening artifacts at the level of the pons, no agreement and no superiority of one of the CT-methods was noted. No differences were obtained regarding the objective evaluation of image noise.

Discussion

Image quality is generally equivalent. Since 64-row spiral CT can substantially save examination time we recommend to perform a spiral examination of the brain in polytraumatized patients.