Infection of Human Coronary Artery Endothelial Cells by Group B Streptococcus Contributes to Dysregulation of Apoptosis, Hemostasis, and Innate Immune Responses

Early onset sepsis due to group B streptococcus leads to neonatal morbidity, increased mortality, and long-term neurological deficencies. Interaction between septicemic GBS and confluent monolayers of human coronary artery endothelial cells (HCAECs) was analyzed by genome wide expression profiling. In total, 124 genes were differentially expressed (89 upregulated, 35 downregulated) based on a more than 3-fold difference to control HCAEC. Regulated genes are involved in apoptosis, hemostasis, oxidative stress response, infection, and inflammation. Regulation of selected genes and proteins identified in the gene array analysis was confirmed by Real-time RT-PCR assay (granulocyte chemotactic protein 2), ELISA (urokinase, cyclooxygenase 2, granulocyte chemotactic protein 1), and western blotting (Heme oxygenase1, BCL2 interacting protein) at various time points between 4 and 24 hours. These results indicate that GBS infection might influence signalling pathways leading to impaired function of the innate immune system and hemorrhagic and inflammatory complications during GBS sepsis

Monitoring lower limb biomechanical asymmetry and psychological measures in athletic populations - A scoping review

Background: Lower limb biomechanics, including asymmetry, are frequently monitored to determine sport performance level and injury risk. However, contributing factors extend beyond biomechanical and asymmetry measures to include psychological, sociological, and environmental factors. Unfortunately, inadequate research has been conducted using holistic bio-psycho-social models to characterize sport performance and injury risk. Therefore, this scoping review summarized the research landscape of studies concurrently assessing measures of lower limb biomechanics, asymmetry, and introspective psychological state (e.g., pain, fatigue, perceived exertion, stress, etc.) in healthy, competitive athletes. Methods: A systematic search of Medline, Embase, CINAHL, SPORT Discus, and Web of Science Core Collections was designed and conducted in accordance with PRISMA guidelines. 51 articles were included in this review. Results: Significant relationships between biomechanics (k = 22 studies) or asymmetry (k = 20 studies) and introspective state were found. Increased self-reported pain was associated with decreased range of motion, strength, and increased lower limb asymmetry. Higher ratings of perceived exertion were related to increased lower limb asymmetry, self-reported muscle soreness, and worse jump performance. Few studies (k = 4) monitored athletes longitudinally throughout one or more competitive season(s). Conclusion: This review highlights the need for concurrent analysis of introspective, psychological state, and biomechanical asymmetry measures along with longitudinal research to understand the contributing factors to sport performance and injury risk from bio-psycho-social modeling. In doing so, this framework of bio-psycho-social preventive and prognostic patient-centered practices may provide an actionable means of optimizing health, well-being, and sport performance in competitive athletes

Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder

Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B

PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system

Cyclic AMP induces IPC leukemia cell apoptosis via CRE-and CDK-dependent Bim transcription

The IPC-81 cell line is derived from the transplantable BNML model of acute myelogenic leukemia (AML), known to be a reliable predictor of the clinical efficiency of antileukemic agents, like the first-line AML anthracycline drug daunorubicin (DNR). We show here that cAMP acted synergistically with DNR to induce IPC cell death. The DNR-induced death differed from that induced by cAMP by (1) not involving Bim induction, (2) being abrogated by GSK3β inhibitors, (3) by being promoted by the HSP90/p23 antagonist geldanamycin and truncated p23 and (4) by being insensitive to the CRE binding protein (CREB) antagonist ICER and to cyclin-dependent protein kinase (CDK) inhibitors. In contrast, the apoptosis induced by cAMP correlated tightly with Bim protein expression. It was abrogated by Bim (BCL2L11) downregulation, whether achieved by the CREB antagonist ICER, by CDK inhibitors, by Bim-directed RNAi, or by protein synthesis inhibitor. The forced expression of BimL killed IPC-81WT cells rapidly, Bcl2-overexpressing cells being partially resistant. The pivotal role of CREB and CDK activity for Bim transcription is unprecedented. It is also noteworthy that newly developed cAMP analogs specifically activating PKA isozyme I (PKA-I) were able to induce IPC cell apoptosis. Our findings support the notion that AML cells may possess targetable death pathways not exploited by common anti-cancer agents

Classifying individuals with and without patellofemoral pain syndrome using ground force profiles - Development of a method using functional data boosting.

BACKGROUND:Predictors of recovery in patellofemoral pain syndrome (PFPS) currently used in prognostic models are scalar in nature, despite many physiological measures originally lying on the functional scale. Traditional modelling techniques cannot harness the potential predictive value of functional physiological variables. RESEARCH QUESTION:What is the classification performance of PFPS status of a statistical model when using functional ground reaction force (GRF) time-series? METHODS:Thirty-one individuals (control = 17, PFPS = 14) performed maximal countermovement jumps, on two force plates. The three-dimensional components of the GRF profiles were time-normalized between the start of the eccentric phase and take-off, and used as functional predictors. A statistical model was developed using functional data boosting (FDboost), for binary classification of PFPS statuses (control vs PFPS). The area under the Receiver Operating Characteristic curve (AUC) was used to quantify the model's ability to discriminate the two groups. RESULTS:The three predictors of GRF waveform achieved an average out-of-bag AUC of 93.7 %. A 1 % increase in applied medial force reduced the log odds of being in the PFPS group by 0.68 at 87 % of jump cycle. In the AP direction, a 1 % reduction in applied posterior force increased the log odds of being classified as PFPS by 1.10 at 70 % jump cycle. For the vertical GRF, a 1 % increase in applied force reduced the log odds of being classified in the PFPS group by 0.12 at 44 % of the jump cycle. SIGNIFICANCE:Using simple functional GRF variables collected during functionally relevant task, in conjunction with FDboost, produced clinically interpretable models that retain excellent classification performance in individuals with PFPS. FDboost may be an invaluable tool to be used in longitudinal cohort prognostic studies, especially when scalar and functional predictors are collected