Higher executive abilities following a blood transfusion in children and young adults with sickle cell disease

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non‐SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3‐7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ²(1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.     

Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer

Background To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.Methods Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.Results Two patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete ‘punctate’ areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high ‘punctate’ IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.Conclusions These results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.Subject terms: Prognostic markers, Colorectal cancer     

Expression of hybrid class I genes of the major histocompatibility complex in mouse L cells.

The class I genes of the major histocompatibility complex of the mouse can be divided into two categories: those encoding the transplantation antigens and those encoding the Qa and Tla antigens. The inbred BALB/c mouse has 28 potential Qa/Tla genes. The sites of tissue expression, developmental regulation, and functions of these genes are virtually unknown. We have used the technique of exon shuffling to construct hybrid genes between each of three Qa region genes (Q5, Q7, and Q8) and two other class I genes (H-2Ld and Q6). The hybrid genes have been transfected into mouse L cells, in which intact transplantation antigen genes generally are expressed and in which intact Qa genes generally are not expressed. Analysis of expression of the hybrid gene constructs indicates that the 5' half of two of the Qa genes (Q5 and Q8) can readily be expressed in the context of a hybrid molecule, whereas the 3' half prevents cell-surface expression. The exon shuffling approach described here will be useful in characterizing Qa/Tla genes and in identifying or producing new reagents to study the Qa/Tla gene products, their tissue distribution, their developmental stages of expression, and, ultimately, their functions.     

Intrathecal neostigmine and sufentanil for early labor analgesia.

BACKGROUND: Recent efforts to improve the combined spinal epidural (CSE) technique have focused on adding opioids to other classes of analgesics. In this study, the authors used intrathecal neostigmine in combination with intrathecal sufentanil to investigate the usefulness of neostigmine for reducing side effects and prolonging the duration of sufentanil. METHODS: One hundred six healthy pregnant women in labor were enrolled in this study, which was divided into four phases. In all phases, patients received a CSE anesthetic while in the lateral position. In phase I, three groups of six women each received intrathecal neostigmine, 5, 10, or 20 microg, in an open-label, dose-escalating safety assessment. In phase II, 24 women received intrathecal sufentanil alone to establish an ED50 (dose that produces > 60 min of labor analgesia in 50% of patients). In phase III, an ED50 was established for sufentanil combined with a fixed dose of neostigmine (10 microg). In phase IV, 40 women received either twice the ED50 of sufentanil alone or twice the ED50 of sufentanil plus neostigmine, 10 microg. RESULTS: Neostigmine alone had no adverse effects on maternal vital signs, fetal heart rate, or Apgar scores. Neostigmine, 20 microg, produced analgesia in one patient and severe nausea and vomiting in another. The ED50 for intrathecal sufentanil alone was 4.1 +/- 0.31 microg, and the ED50 for intrathecal sufentanil combined with neostigmine, 10 microg, was 3.0 +/- 0.28 microg. The duration of analgesia and side effects from double these ED50s (sufentanil, 9 microg, or sufentanil, 6 microg, plus neostigmine, 10 microg) were similar between groups. CONCLUSIONS: The 10-microg intrathecal neostigmine dose alone produced no analgesia or side effects, but reduced the ED50 of intrathecal sufentanil by approximately 25%. Additionally, doses approximately double these ED50s each produced a similar duration of analgesia and side effects, indicating intrathecal neostigmine shifts the dose-response curve for intrathecal sufentanil to the left.     

Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.     

Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia

In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X_L. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.