Executive function in children with sickle cell anemia on transfusion: NIH toolbox utility in the clinical context.

Objective: The aim of this study was to establish the utility of the NIH Toolbox as a cognitive screener of executive functions in the clinical context. Additionally, we aimed to investigate whether age and time on transfusion were related to executive function performance. Method: Twenty-eight children and adolescents with sickle cell anemia (SCA) between 8 and 18 years (M = 13.28, SD = 3.05) on transfusion treatment were included. Participants completed five NIH Toolbox tasks (three executive function tasks and two non-executive function control tasks). Results: Mean scores on one of the three executive function measures (inhibitory control) fell below the average range (M = 81.36, SD = 14.01) with approximately 70% of children from both groups below the average range. Scores for processing speed (M = 86.82, SD = 22.01) and cognitive flexibility (M = 85.75, SD = 12.67) were low averages. As expected, scores on non-executive measures (language and memory) fell within the average range. No significant differences were observed between children with silent stroke and no stroke on executive function measures. Older age (p < .01) and length of time on transfusion (p < .05) predicted lower inhibitory control scores. Conclusions: Findings provide evidence for poor development of inhibitory control with age in this patient population. As the NIH Toolbox successfully highlighted expected deficits in this patient population, this study supports the use of this tool as a brief screening measure for children with SCD. The clinical and theoretical implications of the findings are discussed.

Sickle cell disease: time for a targeted neonatal screening programme.

Ireland has seen a steady increase in paediatric sickle cell disease (SCD). In 2005, only 25% of children with SCD were referred to the haemoglobinopathy service in their first year. A non-funded screening programme was implemented. This review aimed to assess the impact screening has had. All children referred to the haemoglobinopathy service born in Ireland after 2005 were identified. Data was collected from the medical chart and laboratory system. Information was analysed using Microsoft Excel. 77 children with SCD were identified. The median age at antibiotic commencement in the screened group was 56 days compared with 447 days in the unscreened group, p = < 0.0003. 22 (28%) of infants were born in centre's that do not screen and 17 (81%) were over 6 months old at referral, compared with 14 (21%) in the screened group. 6 (27%) of those in the unscreened group presented in acute crisis compared with 2 (3%) in the screened population. The point prevalence of SCD in Ireland is 0.2% in children under 15 yr of African and Asian descent. We identified delays in referral and treatment, which reflect the lack of government funded support and policy. We suggest all maternity units commence screening for newborns at risk of SCD. It is a cost effective intervention with a number needed to screen of just 4 to prevent a potentially fatal crisis.

Inflammation and cancer: macrophage migration inhibitory factor (MIF)--the potential missing link.

Macrophage migration inhibitory factor (MIF) was the original cytokine, described almost 50 years ago and has since been revealed to be an important player in pro-inflammatory diseases. Recent work using MIF mouse models has revealed new roles for MIF. In this review, we present an increasing body of evidence implicating the key pro-inflammatory cytokine MIF in specific biological activities related directly to cancer growth or contributing towards a microenvironment favouring cancer progression.

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours.

Toll-like receptor (TLR) agonists are potent activators of innate immune responses, activating dendritic cell (DC) maturation and inflammatory cytokine secretion by innate immune cells and as a consequence they promote adaptive immune response when coadministered with foreign antigens. There is also some evidence from mouse models that TLR ligands can help to break tolerance to self-antigens and promote immune responses to tumour antigens. Therefore, they have been exploited as adjuvants for tumour vaccines or as immunotherapeutics against cancer. Clinical evaluation of TLR agonists has resulted in a licensed immunotherapeutic for basal cell carcinoma, but there have also been disappointing results from clinical trials, with one pharmaceutical company recently halting its clinical programme. A major obstacle to the development of any active immunotherapeutic approach to cancer is the immunosuppressive environment of the growing tumour, including the induction of tolerogenic DCs and regulatory T (Treg) cells, which suppress the development of protective effector T-cell responses. This can be compounded by the use of TLR ligands as immunotherapeutics. A problem with TLR agonists that has not been fully appreciated is that they can generate suppressive as well as inflammatory responses in innate immune cells and can promote the induction of regulatory as well as effector T cells. This is part of a normal mechanism for limiting collateral damage during infection or sterile inflammation, but can constrain their ability to induce protective antitumour immunity, especially in the immune suppressed environment of the tumour. Alternatively, manipulating the TLR-activated innate immune responses to selectively blocking immunosuppressive arm, as well as that induced by the tumour, may hold the key to enhancing their efficacy as tumour immunotherapeutics and as adjuvants for cancer vaccines.

CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways.

Proteins possessing the caspase recruitment domain (CARD) motif have been implicated in pathways leading to activation of caspases or NF-kappaB in the context of apoptosis or inflammation, respectively. Here we report the identification of a novel protein, CARDINAL, that contains a CARD motif and also exhibits a high degree of homology to the C terminus of DEFCAP/NAC, a recently described member of the Apaf-1/Nod-1 family. In contrast with the majority of CARD proteins described to date, CARDINAL failed to promote apoptosis or NF-kappaB activation. Rather, CARDINAL potently suppressed NF-kappaB activation associated with overexpression of TRAIL-R1, TRAIL-R2, RIP, RICK, Bcl10, and TRADD, or through ligand-induced stimulation of the interleukin-1 or tumor necrosis factor receptors. Co-immunoprecipitation experiments revealed that CARDINAL interacts with the regulatory subunit of the IkappaB kinase (IKK) complex, IKKgamma (NEMO), providing a molecular basis for CARDINAL function. Thus, CARDINAL is a novel regulator of NF-kappaB activation in the context of pro-inflammatory signals.