Regulation of peripheral T cell activation by calreticulin

Regulated expression of positive and negative regulatory factors controls the extent and duration of T cell adaptive immune response preserving the organism's integrity. Calreticulin (CRT) is a major Ca2+ buffering chaperone in the lumen of the endoplasmic reticulum. Here we investigated the impact of CRT deficiency on T cell function in immunodeficient mice reconstituted with fetal liver crt−/− hemopoietic progenitors. These chimeric mice displayed severe immunopathological traits, which correlated with a lower threshold of T cell receptor (TCR) activation and exaggerated peripheral T cell response to antigen with enhanced secretion of inflammatory cytokines. In crt−/− T cells TCR stimulation induced pulsatile cytosolic elevations of Ca2+ concentration and protracted accumulation of nuclear factor of activated T cells in the nucleus as well as sustained activation of the mitogen-activated protein kinase pathways. These observations support the hypothesis that CRT-dependent shaping of Ca2+ signaling critically contributes to the modulation of the T cell adaptive immune response

Health-related quality of life and associated factors after hip fracture. Results from a six-month prospective cohort study

Background: Hip fractures are a major public health problem with increasing relevance in aging societies. They are associated with high mortality rates, morbidity, and loss of independence. The aim of the EMAAge study was to determine the impact of hip fractures on patient-reported health-related quality of life (HRQOL), and to identify potential risk factors for worse outcomes. Methods: EMAAge is a multicenter, prospective cohort study of patients who suffered a hip fracture. Patients or, if necessary, proxies were interviewed after initial treatment and after six months using standardized questionnaires including the EQ-5D-5L instrument, the Oxford Hip Score, the PHQ-4, the Short Nutritional Assessment Questionnaire, and items on patients living situation. Medical data on diagnoses, comorbidities, medications, and hospital care were derived from hospital information systems. Results: A total of 326 patients were included. EQ-5D index values decreased from a mean of 0.70 at baseline to 0.63 at six months. The mean self-rated health on the EQ-VAS decreased from 69.9 to 59.4. Multivariable linear regression models revealed three relevant associated factors with the six-months EQ-5D index: symptoms of depression and anxiety, pre-fracture limitations in activities of daily living, and no referral to a rehabilitation facility had a negative impact. In addition, the six-months EQ-VAS was negatively associated with polypharmacy, living in a facility, and migration background. Conclusions: Hip fractures have a substantial negative impact on patients HRQOL. Our results suggest that there are modifying factors that need further investigation including polypharmacy and migration background. Structured and timely rehabilitation seems to be a protective factor

Malnutrition is associated with six-month mortality in older patients admitted to the emergency department with hip fracture

Background: Hip fractures in older people are a common health problem often associated with malnutrition that might affect outcomes. Screening for malnutrition is not a routine examination in emergency departments (ED). This analysis of the EMAAge study, a prospective, multicenter cohort study, aimed to evaluate the nutritional status of older patients (>= 50 years) with hip fracture, factors associated with malnutrition risk, and the association between malnutrition and the six-months mortality. Methods: Risk of malnutrition was evaluated using the Short Nutritional Assessment Questionnaire. Clinical data as well as data on depression and physical activity were determined. Mortality was captured for the first six months after the event. To assess factors associated with malnutrition risk we used a binary logistic regression. A Cox proportional hazards model was used to assess the association of malnutrition risk with six-month survival adjusted for other relevant risk factors. Results: The sample consisted of N = 318 hip fracture patients aged 50 to 98 (68% women). The prevalence of malnutrition risk was 25.3% (n = 76) at the time of injury. There were no differences in triage categories or routine parameters measured in the ED that could point to malnutrition. 89% of the patients (n = 267) survived for six months. The mean survival time was longer in those without malnutrition risk (171.9 (167.1-176.9) days vs. 153.1 (140.0-166.2) days). The Kaplan Meier curves and the unadjusted Cox regression (Hazard Ratio (HR) 3.08 (1.61-5.91)) showed differences between patients with and patients without malnutrition risk. In the adjusted Cox regression model, risk of death was associated with malnutrition risk (HR 2.61, 1.34-5.06), older age (70-76 years: HR 2.5 (0.52-11.99); 77-82 years: HR 4.25 (1.15-15.62); 83-99 years: HR 3.82 (1.05-13.88)) and a high burden of comorbidities (Charlson Comorbidity Index >= 3: HR 5.4 (1.53-19.12)). Conclusion: Risk of malnutrition was associated with higher mortality after hip fracture. ED parameters did not differentiate between patients with nutritional deficiencies and those without. Therefore, it is particularly important to pay attention to malnutrition in EDs to detect patients at risk of adverse outcomes and to initiate early interventions

Eps8 Regulates Axonal Filopodia in Hippocampal Neurons in Response to Brain-Derived Neurotrophic Factor (BDNF)

A novel signaling cascade controlling actin polymerization in response to extracellular signals regulates filopodia formation and likely also neuronal synapse formation

Dependence of immunoglobulin class switch recombination in B Cells on vesicular release of ATP and CD73 ectonucleotidase activity

Immunoglobulin (Ig) isotype diversification by class switch recombination (CSR) is an essential process for mounting a protective humoral immune response. Ig CSR deficiencies in humans can result from an intrinsic B cell defect; however, most of these deficiencies are still molecularly undefined and diagnosed as common variable immunodeficiency (CVID). Here, we show that extracellular adenosine critically contributes to CSR in human naive and IgM memory B cells. In these cells, coordinate stimulation of B cell receptor and toll-like receptors results in the release of ATP stored in Ca2+-sensitive secretory vesicles. Plasma membrane ectonucleoside triphosphate diphosphohydrolase 1 CD39 and ecto-5′-nucleotidase CD73 hydrolyze ATP to adenosine, which induces CSR in B cells in an autonomous fashion. Notably, CVID patients with impaired class-switched antibody responses are selectively deficient in CD73 expression in B cells, suggesting that CD73-dependent adenosine generation contributes to the pathogenesis of this disease

Regulated delivery of AMPA receptor subunits to the presynaptic membrane

In recent years, a role for AMPA receptors as modulators of presynaptic functions has emerged. We have investigated the presence of AMPA receptor subunits and the possible dynamic control of their surface exposure at the presynaptic membrane. We demonstrate that the AMPA receptor subunits GluR1 and GluR2 are expressed and organized in functional receptors in axonal growth cones of hippocampal neurons. AMPA receptors are actively internalized upon activation and recruited to the surface upon depolarization. Pretreatment of cultures with botulinum toxin E or tetanus toxin prevents the receptor insertion into the plasma membrane, whereas treatment with α-latrotoxin enhances the surface exposure of GluR2, both in growth cones of cultured neurons and in brain synaptosomes. Purification of small synaptic vesicles through controlled-pore glass chromatography, revealed that both GluR2 and GluR1, but not the GluR2 interacting protein GRIP, copurify with synaptic vesicles. These data indicate that, at steady state, a major pool of AMPA receptor subunits reside in synaptic vesicle membranes and can be recruited to the presynaptic membrane as functional receptors in response to depolarization