Life goals after brain injury in the light of the dual process approach: empirical evidence and implications for neuropsychological rehabilitation

Sequelae of acquired brain injury endanger the realisation of important life-goals. Discrepancies arise between the importance attached to a goal and the success in realising it. This study investigates goal discrepancies and their influence on patients' subjective well-being (SWB) in different rehabilitation stages. Life-goals, SWB and daily functioning were assessed in 130 neurological inpatients and 42 outpatients by self-report questionnaires. Both patient groups reported greater discrepancies between importance and success of life-goals than a normative sample of healthy controls. In multiple regression modelling, goal discrepancy predicted SWB in the inpatient sample even when controlling for the influence of ABI-related functional limitations. Of significant influence were the discrepancies in the domains of intimacy and achievement. In the respective analysis of the outpatient sample, goal discrepancy was not a significant predictor of SWB when accounting for functional limitations. A post-hoc analysis examined the inter-relation between functional limitations and goal discrepancy. Functional limitations influenced the ratings of successful goal realisation, yet they had less impact on the importance attached to a goal. The findings highlight the importance of patients' life-goals for successful neuropsychological rehabilitation. They indicate a need for further research considering goal adjustment processes in the face of chronic functional impairment.     

Multi-axial loading micromechanics of the cement-bone interface in postmortem retrievals and lab-prepared specimens

Maintaining adequate fixation between cement and bone is important for successful long term survival of cemented total joint replacements. Mixed-mode loading conditions (combination of tension/compression and shear) are present during in vivo loading, but the micromotion response of the interface to these conditions is not fully understood. Non-destructive, multi-axial loading experiments were conducted on laboratory prepared (n=6) and postmortem (n=6) human cement-bone interfaces. Specimens were mounted in custom loading discs and loaded at 0°, 30°, 60°, and 90° relative to the interface plane where 0° represents normal loading to the interface, and 90° represents shear loading along the longitudinal axis of the femur. Axial compliance did not depend on loading angle for laboratory prepared (p=0.96) or postmortem specimens (p=0.62). The cement-bone interface was more compliant under tensile than compressive loading at the 0° loading angle only (p=0.024). The coupled transverse to axial compliance ratio, which is a measure of the coupled motion, was small for laboratory prepared (0.115 ±?0.115) and postmortem specimens (0.142 ±?0.101). There was a moderately strong inverse relationship between interface compliance and contact index (r(2)=0.65). From a computational modeling perspective, the results of the current study support the concept that the cement-bone interface could be numerically implemented as a compliant layer with the same initial stiffness in tension and shear directions. The magnitude of the compliance could be modified to simulate immediate post-operative conditions (using laboratory prepared data set) or long-term remodeling (using postmortem data set).     

Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen

Marginal zone macrophages (MZMs) are a small subset of specialized splenic macrophages known to interact with apoptotic material entering the spleen from circulation. To evaluate whether MZMs regulate immunity to apoptotic material we depleted MZMs and assessed innate and adaptive immune responses to apoptotic cells administered systemically. MZM depletion altered the spatial localization of apoptotic cells, which accumulated in T-cell areas of the lymphoid follicles. MZM depletion also enhanced phagocytosis of apoptotic cells by red pulp (CD68(+)F4/80(+)) macrophages, which expressed increased CD86, MHCII, and CCR7. MZM depletion led to increased production of proinflammatory cytokines and enhanced lymphocyte responsiveness to apoptotic cell antigens. Furthermore, we found that MZM depletion accelerated autoimmune disease progression in mice genetically prone to systemic lupus erythematosus and caused significant mortality in wild-type mice repeatedly exposed to exogenous apoptotic thymocytes. These findings support the hypothesis that MZMs are central in the clearance of apoptotic cells to minimize the immunogenicity of autoantigens.     

Herpesvirus entry mediator regulates hypoxia-inducible factor-1α and erythropoiesis in mice

Erythropoiesis, the production of red blood cells, must be tightly controlled to ensure adequate oxygen delivery to tissues without causing thrombosis or stroke. Control of physiologic and pathologic erythropoiesis is dependent predominantly on erythropoietin (EPO), the expression of which is regulated by hypoxia-inducible factor (HIF) activity in response to low oxygen tension. Accumulating evidence indicates that oxygen-independent mediators, including inflammatory stimuli, cytokines, and growth factors, also upregulate HIF activity, but it is unclear whether these signals also result in EPO production and erythropoiesis in vivo. Here, we found that signaling through herpesvirus entry mediator (HVEM), a molecule of the TNF receptor superfamily, promoted HIF-1α activity in the kidney and subsequently facilitated renal Epo production and erythropoiesis in vivo under normoxic conditions. This Epo upregulation was mediated by increased production of NO by renal macrophages. Hvem-deficient mice displayed impaired Epo expression and aggravated anemia in response to erythropoietic stress. These data reveal that HVEM signaling functions to promote HIF-1α activity and Epo production, and thus to regulate erythropoiesis. Furthermore, our findings suggest that this molecular mechanism could represent a therapeutic target for Epo-responsive diseases, including anemia.     

A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16

Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ～ 6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.     

Enhanced T-cell-independent antitumor effect of cyclophosphamide combined with anti-CD40 mAb and CpG in mice

We have earlier demonstrated T-cell-independent antitumor effects of a combination of anti-CD40 monoclonal antibody (mAb) and CpG oligodeoxynucleotides (CpG) which involved macrophages. As some immunotherapeutic treatments can be potentiated by chemotherapy, we tested if cyclophosphamide (CY) would enhance the antitumor effect of anti-CD40 mAb+CpG. Treatment of B16 melanoma-bearing mice with CY and anti-CD40 mAb+CpG resulted in a significant reduction in tumor growth in immunocompetent mice compared with either CY alone or anti-CD40 mAb with CpG. This enhanced antitumor effect was maintained in severe combined immunodeficiency mice, as measured by both tumor growth and overall survival. Natural killer cells were not required for this antitumor effect as it was also observed in severe combined immunodeficiency/beige mice. Moreover, although CY treatment of immunocompetent mice suppressed natural killer cell activity, it did not negatively affect the antitumor activity of their macrophages when assayed in vitro. Depletion of macrophages in vivo reduced the antitumor effect of CY and anti-CD40 mAb+CpG. These results suggest that therapeutic strategies to activate macrophages may have potential for clinical application in cancer patients receiving chemotherapy.