Idiopathic cholangiopathy in a biliary cast syndrome necessitating liver transplantation following head trauma

The development of total biliary casts is very unusual, especially in patients who have not undergone liver transplantation. The aetiology of these casts is uncertain but several factors are believed to play a role, including periods of fasting, haemolysis, cholangitis and recent surgery. Resultant bile stasis and/or gallbladder hypocontractility promote sludge and subsequent stone formation. Here we present the case of a previously well 66-year-old woman who developed a total biliary cast several weeks after being involved in a road traffic accident during which she sustained head injuries but no obvious liver insult. This cast was removed at laparotomy but the patient had resultant diffuse biliary tree abnormalities and persistent cholestasis and subsequently required a liver transplant. The possible aetiologies of biliary cast formation and subsequently cholangiopathy necessitating transplantation in this patient are described.     

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.     

Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy

Increased production of reactive oxygen species (ROS) is implicated in the development of left ventricular hypertrophy (LVH). Phagocyte-type NADPH oxidases are major cardiovascular sources of ROS, and recent data indicate a pivotal role of a gp91phox-containing NADPH oxidase in angiotensin II (Ang II)-induced LVH. We investigated the role of this oxidase in pressure-overload LVH. gp91phox-/- mice and matched controls underwent chronic Ang II infusion or aortic constriction. Ang II-induced increases in NADPH oxidase activity, atrial natriuretic factor (ANF) expression, and cardiac mass were inhibited in gp91phox-/- mice, whereas aortic constriction-induced increases in cardiac mass and ANF expression were not inhibited. However, aortic constriction increased cardiac NADPH oxidase activity in both gp91phox-/- and wild-type mice. Myocardial expression of an alternative gp91phox isoform, Nox4, was upregulated after aortic constriction in gp91phox-/- mice. The antioxidant, N-acetyl-cysteine, inhibited pressure-overload-induced LVH in both gp91phox-/- and wild-type mice. These data suggest a differential response of the cardiac Nox isoforms, gp91phox and Nox4, to Ang II versus pressure overload.     

Doctors’ perspectives on the barriers to appropriate prescribing in older hospitalized patients: a qualitative study

Aims

Older patients commonly suffer from multimorbidites and take multiple medications. As a result, these patients are more vulnerable to potentially inappropriate prescribing (PIP). PIP in older patients may result in adverse drug events (ADEs) and hospitalizations. However, little has been done to identify why PIP occurs. The objectives of this study were (i) to identify hospital doctors'' perceptions as to why PIP occurs, (ii) to identify the barriers to addressing the issues identified and (iii) to determine which intervention types would be best suited to improving prescribing.

Methods

Semi-structured interviews based on the Theoretical Domains Framework (TDF), a tool used to apply behaviour change theories, were conducted with 22 hospital doctors. Content analysis was conducted to identify domains of the TDF that could be targeted to improve prescribing for older people. These domains were then mapped to the behaviour change wheel to identify possible intervention types.

Results

Content analysis identified five of the 12 domains in the TDF as relevant: (i) environmental context and resources, (ii) knowledge, (iii) skills, (iv) social influences and (v) memory/attention and decision processes. Using the behaviour change wheel, the types of interventions deemed suitable were those based on training and environmental restructuring.

Conclusion

This study shows that doctors feel there is insufficient emphasis on geriatric pharmacotherapy in their undergraduate/postgraduate training. An intervention providing supplementary training, with particular emphasis on decision processes and dealing with social influences would be justified. This study has, however, uncovered many areas for potential intervention in the future.