NF-κB activity is constitutively elevated in c-Abl null fibroblasts

The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase involved in many cellular processes, including signaling from growth factor and antigen receptors, remodeling the cytoskeleton, and responding to DNA damage and oxidative stress. Many downstream pathways are affected by c-Abl. Elevated c-Abl kinase activity can inhibit NF-κB activity by stabilizing the inhibitory protein IκBα, raising the possibility that c-Abl-deficient cells might have increased NF-κB activity. We examined the levels of NF-κB activity in primary mouse embryonic fibroblasts (MEFs) derived from wild-type and c-Abl knockout mice and found that the knockout MEFs indeed exhibited elevated NF-κB activity in response to stimulation as well as constitutively elevated NF-κB activity. Thus, endogenous c-Abl is a negative regulator of basal and inducible NF-κB activity. Examination of various points of NF-κB regulation revealed that unstimulated c-Abl knockout MEFs do not exhibit an increase in IκBα degradation, p65/RelA nuclear translocation, or DNA binding of NF-κB subunits. They do, however, show reduced levels of the histone deacetylase HDAC1, a negative regulator of basal NF-κB activity. Unstimulated c-Abl knockout MEFs are less responsive to induction of NF-κB activity by trichostatin A, an HDAC inhibitor, suggesting that c-Abl might play a role in the HDAC-mediated repression of basal NF-κB activity.     

The natural history of surgically treated but radiotherapy-naïve nonfunctioning pituitary adenomas

Background and objectives Transsphenoidal surgery is indicated for patients with nonfunctioning pituitary adenomas (NFPAs) causing compressive symptoms. Previous studies attempting to define the rate of recurrence/regrowth of surgically treated but radiation‐naïve NFPAs were somewhat limited by selection bias and/or small numbers and/or lack of consistency of findings between studies. A better understanding of the natural history of this condition could allow stratification of recurrence risk and inform future management. We aimed to define the natural history of a large, mainly unselected cohort with surgically treated, radiotherapy (RT)‐naïve NFPAs and to try to identify predictors of recurrence/regrowth. Design Case‐note analysis of all patients who underwent surgery for NFPA in our hospital between 1980 and 2006 was undertaken. Median follow‐up was 5·7 (range 1–25) years. Patients A total of 212 patients were identified of which 159 were suitable for analysis. 93% did not receive post‐operative RT. Measurement Post‐operative recurrent/regrowth was defined by any increase in tumour remnant size on serial post‐operative pituitary imaging. Results Recurrence/regrowth was documented in 53 patients (33·5%). Multivariate analysis revealed size of the post‐operative tumour remnant and length of follow‐up to be the two major determinants of recurrence/regrowth. The presence of a tumour with an extrasellar remnant was associated with the highest risk of recurrence (odds ratio 3·73 [CI: 1·97–7·09]), while no recurrence was seen in those with no residual tumour post‐operatively and regrowth risk was intermediate for those with remaining intrasellar remnant. Conclusion These results indicate that patients with post‐operative tumour with an extrasellar remnant should be considered routinely for adjuvant RT to reduce the risk of tumour regrowth while those with no residual tumour can be safely observed. Individualized decisions should be made for patients with an intrasellar remnant.     

Regulation of T-cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells

Following recognition of microbial patterns, innate immune receptors provide a rapid innate response and trigger antigen-presenting cell maturation to instruct adaptive immune responses. Here we discuss a family of innate immune receptors for self – the leucocyte immunoglobulin-like receptors (LILRs). These LILRs exert powerful inhibitory effects on antigen-presenting cell phenotype and subsequent T-cell responses, and may act to constrain the effects of Toll-like receptor signalling. Despite their broad ligand specificity, differing affinities of LILRs for individual complexes of peptide–major histocompatiblity complex can determine the nature of their effect on downstream immune responses. Expression and function of LILRs may be skewed in certain conditions such as cancer or human immunodeficiency virus infection, particularly by ectopic expression of human leucocyte antigen-G, a high-affinity LILR ligand. We discuss the relevance of LILR-mediated immune regulation across a range of scenarios from autoimmunity to transplant medicine, infection and cancer.     

Assessing Strengths in Residential Treatment: Looking at the Whole Child

This article outlines the importance of assessing both within-child and environmental strengths for children and adolescents admitted to residential treatment facilities (RTFs). Discussed are the theoretical underpinnings behind strength-based assessment, as well as a number of organizations and initiatives that aim at raising the bar for children's care, creating a holistic viewpoint. Assessments such as the BASC-2, ASEBA, and Vineland-II are well-established measures that have moved to meet these demands, and measures like the BERS-2, RSCA, and DESSA have an overt strengths orientation. The CASA and the DCASC are omnibus strengths measures that can be utilized to fill the “intake gap.”     

Reviews: Is the Calcium Correct? Measuring Serum Calcium in Dialysis Patients

Abnormalities in calcium concentration are frequent in patients receiving dialysis therapy. Most cases of both hypo‐ and hypercalcemia are mild and asymptomatic. There is concern, however, that, on the one hand, hypocalcemia can drive hyperparathyroidism and eventually lead to gland hypertrophy and autonomous function. Hypercalcemia, on the other hand, can be associated with increased extraosseous calcium and phosphate deposition leading to vascular calcification with an attendant mortality and morbidity. Calcium exists in three main forms in the blood: the physiologically active free or ionized fraction (terms often used interchangeably), a protein bound fraction, and a fraction complexed to other anions. Although the ionized calcium can readily be measured using ion‐specific electrodes, it is the total calcium that is most commonly measured because of sample handling and cost concerns. As it is the free or ionized form that is biologically active (and therefore of most relevance), a number of adjustment formulae have been derived to “correct” the total calcium for changes in albumin, protein, and complexing ion concentrations. These formulae show good statistical correlation with measured ionized calcium in populations studied as a whole, but are generally poor predictors of true ionized hypo‐ or hypercalcemia in individual patients. International guideline committees in nephrology recommend frequent assessment of calcium levels in dialysis patients and recommend that these levels be kept within the normal reference range. These guidelines are less clear on which measurement of calcium should be used to guide clinical decision making. This review examines the merits of making any adjustment to the total calcium measurement, and suggests when it is appropriate to measure the ionized or free calcium.