Gastrointestinal haemorrhage due to erosion of the duodenal wall by a biliary stent

Complications from improperly placed biliary stents are not uncommon. Free loose wires from the ends of an uncovered stent can irritate and damage adjacent mucosal surfaces. Effective management can be achieved via percutaneous placement of a second stent to alter the orientation of the original stent.     

Interaction between blood type,smoking and factor V Leiden mutation and risk of venous thromboembolism: a Danish case‐cohort study

See also Lowe GDO. Epidemiology of venous thromboembolism: the need for large (including prospective) studies and meta‐analyses. This issue, pp 2186–8 and Rosendaal FR. Etiology of venous thrombosis: the need for small original studies. This issue, pp 2189–90.     

How Zebrafish Can Drive the Future of Genetic-based Hearing and Balance Research

Over the last several decades, studies in humans and animal models have successfully identified numerous molecules required for hearing and balance. Many of these studies relied on unbiased forward genetic screens based on behavior or morphology to identify these molecules. Alongside forward genetic screens, reverse genetics has further driven the exploration of candidate molecules. This review provides an overview of the genetic studies that have established zebrafish as a genetic model for hearing and balance research. Further, we discuss how the unique advantages of zebrafish can be leveraged in future genetic studies. We explore strategies to design novel forward genetic screens based on morphological alterations using transgenic lines or behavioral changes following mechanical or acoustic damage. We also outline how recent advances in CRISPR-Cas9 can be applied to perform reverse genetic screens to validate large sequencing datasets. Overall, this review describes how future genetic studies in zebrafish can continue to advance our understanding of inherited and acquired hearing and balance disorders.     

Importance of monoamine oxidase A in the bioactivation of neurotoxic analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic neurotoxin that causes biochemical, pharmacological, and pathological deficits in experimental animals similar to those seen in human parkinsonian patients. All of the deficits can be prevented by treating mice with selective inhibitors of monoamine oxidase B (MAO-B), including deprenyl, prior to MPTP administration. We now report that the dopaminergic neurotoxicity of two potent MPTP analogs, namely the 2'-methyl and 2'-ethyl derivatives (2'-MeMPTP and 2'-EtMPTP), cannot be prevented by deprenyl pretreatment. However, the neurotoxicity of these two analogs can be prevented by pretreatment with a combination of deprenyl and the selective MAO-A inhibitor clorgyline at doses that are sufficient to almost completely inhibit both MAO-B and MAO-A activities. Moreover, the neurotoxicity of 2'-EtMPTP (but not of 2'-MeMPTP and MPTP) can be significantly attenuated by clorgyline alone. There was a parallel between the capacity of the MAO inhibitors to decrease the brain content of the pyridinium species after administration of the tetrahydropyridines and the capacity of the MAO inhibitors to protect against the neurotoxic action of the tetrahydropyridines. The data support the conclusion that both 2'-MeMPTP and 2'-EtMPTP are bioactivated to pyridinium species to a significant extent by MAO-A. Further, it appears that the formation of the pyridinium species plays an important role in the neurotoxic process.     

Interleukin-1-induced leukocyte extravasation across rat mesenteric microvessels is mediated by platelet-activating factor

Although our understanding of the molecular interactions that mediate the adhesion of leukocytes to venular endothelial cells has greatly expanded, very little is known about the mechanisms that mediate the passage of leukocytes across the vessel wall in vivo. The aim of the present study was to investigate the role of endogenously formed platelet-activating factor (PAF) in the process of leukocyte extravasation induced by interleukin-1 (IL-1). To determine at which stage of emigration PAF was involved, we studied the behavior of leukocytes within rat mesenteric microvessels by intravital microscopy. Rats were injected intraperitoneally with saline, recombinant rat IL-1 beta (IL-1 beta), or the peptide N-formyl-methionyl-leucyl- phenylalanine (FMLP) 4 hours before the exteriorization of the mesenteric tissue. In animals treated with IL-1 beta there was a significant increase in the number of rolling and adherent leukocytes within venules (20- to 40-micron diameter) and in the number of extravasated leukocytes in the tissue. Pretreatment of rats with the PAF receptor antagonist UK-74,505 had no effect on the leukocyte responses of rolling and adhesion, but significantly inhibited the migration of the leukocytes across the vessel wall induced by IL-1 beta (76% inhibition). A structurally unrelated PAF antagonist, WEB-2170, produced the same effect (64% inhibition). However, in contrast, UK- 74,505 had no effect on the leukocyte extravasation induced by FMLP, indicating selectivity for the response elicited by certain mediators. These results provide the first line of direct evidence for the involvement of endogenously formed PAF in the process of leukocyte extravasation induced by IL-1 in vivo.     

The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.     

Expression of CD27 and its ligand, CD70, on chronic lymphocytic leukemia B cells

Crosslinking the CD27 antigen on T cells provides a costimulatory signal that, in concert with T-cell receptor crosslinking, can induce T- cell proliferation and cellular immune activation. We find that chronic lymphocytic leukemia (CLL) B cells from most patients coexpress both membrane-bound and soluble CD27, along with its newly identified ligand, CD70. The expression of soluble CD27 may preclude leukemic B cells from stimulating T cells via CD70, thereby potentially impairing their ability to function as effective antigen-presenting cells. We find that leukemic B-cell expression of soluble and membrane-bound CD27 can be downmodulated through a CD40-dependent signal. This signal also induces enhanced expression of CD70 on both normal and leukemic B cells. We find that tumor necrosis factor (TNF)-alpha, or the Th1 cytokine interferon (IFN)-gamma, also can induce downmodulation of CD27, whereas Th2-associated cytokines interleukin-4 (IL-4) or IL-10 can enhance leukemic B-cell expression of this accessory molecule. The modulation of CD27 induced by these conditions is accompanied by reciprocal changes in the expression levels of CD70, suggesting that these accessory molecules may be engaged in reciprocal receptor-ligand downmodulation. Consistent with this, we observe that co-culture of CLL B cells with transfected murine plasmacytoma cells that express human CD70 affects downmodulation of CD27 and enhanced expression of CD70 on leukemic B cells, but does not affect expression of CD27 mRNA. However, we find that CD40-crosslinking, in addition to reducing the level of CD27 protein, also reduces leukemic B-cell expression of CD27 mRNA. This argues that the changes in the expression levels of CD27 following CD40-signaling are not simply due to induced increases in the expression levels of CD70. Finally, we demonstrate that reciprocal changes in expression of CD27 and CD70 may contribute to the enhanced antigen-presenting capacity of CLL B cells after CD40-dependent leukemic B-cell activation. These findings expand the understanding of the regulation of costimulatory molecules important in antigen presentation and also have implications for the immunobiology of and therapy for CLL.     

What's wrong with fear conditioning?

Fear conditioning is one of the prime paradigms of behavioural neuroscience and a source of tremendous insight in the fundamentals of learning and memory and the psychology and neurobiology of emotion. It is also widely regarded as a model for the pathogenesis of anxiety disorders in a diathesis-stress model of psychopathology. Starting from the apparent paradox between the adaptive nature of fear conditioning and the dysfunctional nature of pathological anxiety, we present a critique of the human fear conditioning paradigm as an experimental model for psychopathology. We discuss the potential benefits of expanding the human fear conditioning paradigm by (1) including action tendencies as an important index of fear and (2) paying more attention to “weak” (i.e., ambiguous) rather than “strong” fear learning situations (Lissek et al., 2006), such as contained in selective learning procedures. We present preliminary data that illustrate these ideas and discuss the importance of response systems divergence in understanding individual differences in vulnerability for the development of pathological anxiety.