Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and D-dimer

BACKGROUND: Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the "frailty syndrome," defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. METHODS: Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 +/- 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. RESULTS: Caregivers had higher mean levels of IL-6 (1.38 +/- 1.42 vs 1.00 +/- 0.92 pg/mL, p =.032) and of D-dimer (723 +/- 530 vs 471 +/- 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (beta =.20, p =.029) and of borderline significance for IL-6 (beta =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (beta =.50, p <.001) and IL-6 (beta =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. CONCLUSIONS: The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus

The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C(-/-) mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C(-/-) mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C(-/-) C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C(-/-) mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3(rd) ventricle in JAM-C(-/-) C57BL/6 mice. Taken together, our study suggests that JAM-C(-/-) C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C.

Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 16 cases

OBJECTIVE: To describe the prevalence, main characteristics, and treatment of severe autoimmune cytopenias [autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenic purpura (AITP)] in patients with chronic hepatitis C virus (HCV) infection. METHODS: Retrospective chart review of patients with chronic HCV infection seen at our institution. Two additional departments contributed eight more patients to assess therapy of HCV-related autoimmune cytopenias. RESULTS: Eight patients (seven AITP, one AIHA) fulfilled the inclusion criteria in our population of 4345 HCV-infected patients. The number of patients with AITP was much greater than would be expected by chance (P<0.0001). Patients with HCV-related AITP were older and demonstrated more immunological markers than a group of 40 controls. Eight additional patients (six AITP, two Evans syndrome) were included. We only assessed the response for AITP patients because of the single case of AIHA. Patients with AITP had a poor response to initial corticosteroids [one complete response (CR), three partial response (PR), and four failures]. Intravenous immunoglobulins led to transient efficacy in three of four patients. In second-line therapy, five of seven patients responded to splenectomy. Rituximab proved effective in increasing platelets in two patients. Of eight patients treated with antiviral therapy (IFN-alpha+/-ribavirin), five responded (three CR, two PR). CONCLUSION: AITP occurs more commonly in patients with chronic HCV infection than would be expected by chance. HCV-positive AITP requires a treatment strategy different from that used in HCV-negative AITP. On the basis of the results from our study and a literature analysis, we propose an algorithm for treatment of severe HCV-related autoimmune cytopenias.

C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE

Interleukin 17-producing T helper cells (T(H)-17 cells) are important in experimental autoimmune encephalomyelitis, but their route of entry into the central nervous system (CNS) and their contribution relative to that of other effector T cells remain to be determined. Here we found that mice lacking CCR6, a chemokine receptor characteristic of T(H)-17 cells, developed T(H)-17 responses but were highly resistant to the induction of experimental autoimmune encephalomyelitis. Disease susceptibility was reconstituted by transfer of wild-type T cells that entered into the CNS before disease onset and triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of choroid plexus in mice and humans. Our results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.

Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09

Treatment allocation by epidermal growth factor receptor mutation status is a new standard in patients with metastatic nonesmall-cell lung cancer. Yet, relatively few modern chemotherapy trials were conducted in patients characterized by epidermal growth factor receptor wild type. We describe the results of a multicenter phase II trial, testing in parallel 2 novel combination therapies, predefined molecular markers, and tumor rebiopsy at progression. Objective: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced nonesmall-cell lung cancer are promising for further investigation. Methods: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. Results: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16.

Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.

BACKGROUND & AIMS Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.

Impairments of peripheral motion change detection during smooth pursuit eye movements

Introduction: In team sports the ability to use peripheral vision is essential to track a number of players and the ball. By using eye-tracking devices it was found that players either use fixations and saccades to process information on the pitch or use smooth pursuit eye movements (SPEM) to keep track of single objects (Schütz, Braun, & Gegenfurtner, 2011). However, it is assumed that peripheral vision can be used best when the gaze is stable while it is unknown whether motion changes can be equally well detected when SPEM are used especially because contrast sensitivity is reduced during SPEM (Schütz, Delipetkose, Braun, Kerzel, & Gegenfurtner, 2007). Therefore, peripheral motion change detection will be examined by contrasting a fixation condition with a SPEM condition. Methods: 13 participants (7 male, 6 female) were presented with a visual display consisting of 15 white and 1 red square. Participants were instructed to follow the red square with their eyes and press a button as soon as a white square begins to move. White square movements occurred either when the red square was still (fixation condition) or moving in a circular manner with 6 °/s (pursuit condition). The to-be-detected white square movements varied in eccentricity (4 °, 8 °, 16 °) and speed (1 °/s, 2 °/s, 4 °/s) while movement time of white squares was constant at 500 ms. 180 events should be detected in total. A Vicon-integrated eye-tracking system and a button press (1000 Hz) was used to control for eye-movements and measure detection rates and response times. Response times (ms) and missed detections (%) were measured as dependent variables and analysed with a 2 (manipulation) x 3 (eccentricity) x 3 (speed) ANOVA with repeated measures on all factors. Results: Significant response time effects were found for manipulation, F(1,12) = 224.31, p < .01, ηp2 = .95, eccentricity, F(2,24) = 56.43; p < .01, ηp2 = .83, and the interaction between the two factors, F(2,24) = 64.43; p < .01, ηp2 = .84. Response times increased as a function of eccentricity for SPEM only and were overall higher than in the fixation condition. Results further showed missed events effects for manipulation, F(1,12) = 37.14; p < .01, ηp2 = .76, eccentricity, F(2,24) = 44.90; p < .01, ηp2 = .79, the interaction between the two factors, F(2,24) = 39.52; p < .01, ηp2 = .77 and the three-way interaction manipulation x eccentricity x speed, F(2,24) = 3.01; p = .03, ηp2 = .20. While less than 2% of events were missed on average in the fixation condition as well as at 4° and 8° eccentricity in the SPEM condition, missed events increased for SPEM at 16 ° eccentricity with significantly more missed events in the 4 °/s speed condition (1 °/s: M = 34.69, SD = 20.52; 2 °/s: M = 33.34, SD = 19.40; 4 °/s: M = 39.67, SD = 19.40). Discussion: It could be shown that using SPEM impairs the ability to detect peripheral motion changes at the far periphery and that fixations not only help to detect these motion changes but also to respond faster. Due to high temporal constraints especially in team sports like soccer or basketball, fast reaction are necessary for successful anticipation and decision making. Thus, it is advised to anchor gaze at a specific location if peripheral changes (e.g. movements of other players) that require a motor response have to be detected. In contrast, SPEM should only be used if a single object, like the ball in cricket or baseball, is necessary for a successful motor response. References: Schütz, A. C., Braun, D. I., & Gegenfurtner, K. R. (2011). Eye movements and perception: A selective review. Journal of Vision, 11, 1-30. Schütz, A. C., Delipetkose, E., Braun, D. I., Kerzel, D., & Gegenfurtner, K. R. (2007). Temporal contrast sensitivity during smooth pursuit eye movements. Journal of Vision, 7, 1-15.