Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in vitro and induce differentiation and a proinflammatory response

A mutation in the human cystatin C gene leads to familial cerebral amyloid angiopathy. This disease is known as “hereditary cerebral hemorrhage with amyloidosis-Icelandic type” or “hereditary cystatin C amyloid angiopathy.” The mutant cystatin C protein forms aggregates and amyloid, within the central nervous system almost exclusively in connection with the vascular system. It was not known whether immune cells could remove mutant cystatin C protein aggregates. Ex vivo mutant cystatin C protein aggregates, both in solution and dried onto a glass surface, induced adhesion to the substrate, differentiated the THP-1 monocyte cell line and led to a proinflammatory response. Aggregates were also taken up by both THP-1 cells and THP-1 derived macrophages. These are the same responses induced by other amyloidogenic protein species, such as amyloid β protein and amylin, supporting the model of all amyloidogenic proteins being toxic due to common structural motifs. Proinflammatory response induced by the ex vivo mutant cystatin C protein aggregates suggests that vascular inflammation plays an important role in hereditary cerebral hemorrhage with amyloidosis-Icelandic type. Ex vivo protein aggregates of cystatin C might better model cellular behavior than in vitro-generated aggregates or supplement in vitro material.     

Self reported attentional control with the Attentional Control Scale: factor structure and relationship with symptoms of anxiety and depression

The Attentional Control Scale (ACS) is a self-report questionnaire that has been developed to measure individual differences in attentional control. Despite its fairly widespread use, little is known about the psychometric properties of the scale in adult samples. In the present study, factor structure of the ACS and its relationship with symptoms of anxiety and depression was investigated in a total sample of 728 Icelandic university students. Exploratory factor analysis in sample 1 (n = 361), yielded two factors, labeled focusing and shifting. Confirmatory factor analysis in sample 2 (n = 367) showed a reasonable fit of this two factor model. The two factors correlated strongly (0.73). The two subscales showed different predictive validity in a set of hierarchical regression analyses where the focusing subscale made a significant prediction of anxiety scores when depression scores were controlled for, and the shifting subscale significant prediction of depression scores when anxiety scores were controlled for. These findings are discussed in relation to previous studies on attentional and executive control in anxiety and depression.     

Immune response to octavalent diphtheria- and tetanus-conjugated pneumococcal vaccines is serotype- and carrier-specific: the choice for a mixed carrier vaccine

BACKGROUND: Development of protein-conjugated pneumococcal vaccines for infants has led to formulations that are immunogenic in the age group at highest risk for pneumococcal diseases. This study focuses on the search for an optimal formulation. METHODS: In a randomized trial Icelandic infants (n = 160) were immunized at age 3, 4 and 6 months with one of two octavalent pneumococcal conjugate vaccines (serotypes 3, 4, 6B, 9V, 14, 18C, 19F and 23F conjugated to diphtheria toxoid (PncD) or tetanus protein (PncT) followed with a booster of either the same conjugate or 23-valent polysaccharide vaccine at 13 months. Safety data were collected after each vaccination, and IgG responses (enzyme-linked immunosorbent assay) were measured at 3, 4, 6, 7, 13 and 14 months. RESULTS: Both conjugates were safe and caused fewer local reactions than the routine vaccines (P < 0.0001). At 7 months both groups had significant IgG response to all serotypes. The geometric mean concentration range was 0.35 to 4.09 and 0.65 to 3.38 microg/ml for PncD and PncT, respectively, with 88.2 to 100% and 92.4 to 100% of subjects reaching > or = 0.15 microg/ml. The PncD gave better primary responses to serotypes 3, 9V and 18C, whereas PncT gave better response to serotype 4. Similar responses were induced to the other serotypes. Good booster IgG responses were obtained in all vaccine groups; 97.5 to 100% of subjects reached > or = 1 microg/ml. CCONCLUSIONS: Both octavalent pneumococcal conjugates were safe and immunogenic in infants. Based on the results from this and similar trials, a mixed diphtheria and tetanus pneumococcal conjugate vaccine was designed to provide the optimal immune response to each serotype.     

Lean soft tissue contributes more to bone health than fat mass independent of physical activity in women across the lifespan

ObjectivesTo investigate the association between lean soft tissue (LST) and fat mass (FM) on bone health variables in women across the lifespan, while taking into account the influence of objectively measured habitual physical activity (PA).Study designA total of 104 women, 37 young (23.3 ± 2.6 years), 28 middle-age (49.2 ± 5.4 years), and 39 old (68.3 ± 6.4 years) participated in this cross-sectional study. All underwent a DXA scan and wore a pedometer for 7 days.Main outcome measuresBone mineral content (BMC) and BMD of the whole body (WB), lumbar spine (LS) and proximal femur (PF), and body composition (FM and LST) were assessed with DXA and PA (steps/day) was assessed from 7 day pedometer counts.ResultsLST was significantly and positively associated with PF and LS BMD (r = 0.34; 0.67, p < 0.05), and WB, PF and LS BMC (r range = 0.41–0.59, p < 0.05) in all age groups and WB BMD in the middle-age group (r = 0.72, p < 0.05) independent of PA, FM, and hormonal status. FM was not positively associated with any bone variable in any age group when adjusted for PA, LST, and hormonal status. PA was significantly associated with WB BMD in the middle-age group (r = 0.60, p < 0.05), independent of LST, FM, and hormonal status.ConclusionsLST contributes more to bone health in women across the lifespan than FM, independent of PA and hormonal status.     

Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children

Background

Pneumococcal polysaccharide vaccine (PPV) is used in children at high risk of IPD. PPV is generally not considered to induce immunologic memory, whereas pneumococcal conjugate vaccines (PCVs) elicit protective antibody responses in infants and induce immunologic memory. Little is known about the characteristics of immune responses to PCV in children who previously received PCV and PPV in series.

Objective

To characterize immune responses to 13-valent pneumococcal CRM₁₉₇ conjugate vaccine (PCV13; serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in children vaccinated in infancy with 9-valent pneumococcal–meningococcal C-CRM₁₉₇ conjugate combination vaccine (PCV9-MnCC), followed by a toddler dose of PCV9-MnCC or 23-valent pneumococcal polysaccharide vaccine (PPV23).

Methods

Children (n = 89) who received PCV9-MnCC in infancy and PPV23 or PCV9-MnCC at age 12 months in a previous (2002–2003) study were vaccinated at age 7.5 years with PCV13; groups PPV23/PCV13 (n = 50) and PCV9/PCV13 (n = 39). Immunoglobulin (Ig)G antibodies, avidity, and opsonophagocytic activity (OPA) were measured before and at 1 and 4 weeks postvaccination.

Results

One week postvaccination, IgG levels increased significantly for all serotypes in both groups, and >97% of vaccinees achieved IgG ≥0.35 μg/ml 4 weeks after PCV13 vaccination. The PCV9/PCV13 group had higher IgG responses compared with the PPV23/PCV13 group. The upper limits of the 95% confidence intervals of the PPV23/PCV13:PCV9/PCV13 IgG geometric mean concentration ratios were <1.0 for serotypes 1, 4, 5, 9V, 18C, and 23F at 1 week. OPA and avidity results supported these findings.

Conclusions

PPV23 vaccination of toddlers may compromise subsequent responses to pneumococcal conjugate vaccines. The clinical relevance of this finding is unclear.     

DLK1 is a novel regulator of bone mass that mediates estrogen deficiency–induced bone loss in mice

Delta‐like 1/fetal antigen 1 (DLK1/FA‐1) is a transmembrane protein belonging to the Notch/Delta family that acts as a membrane‐associated or a soluble protein to regulate regeneration of a number of adult tissues. Here we examined the role of DLK1/FA‐1 in bone biology using osteoblast‐specific Dlk1‐overexpressing mice (Col1‐Dlk1). Col1‐Dlk1 mice displayed growth retardation and significantly reduced total body weight and bone mineral density (BMD). Micro–computed tomographis (µCT) scanning revealed a reduced trabecular and cortical bone volume fraction. Tissue‐level histomorphometric analysis demonstrated decreased bone‐formation rate and enhanced bone resorption in Col1‐Dlk1 mice compared with wild‐type mice. At a cellular level, Dlk1 markedly reduced the total number of bone marrow (BM)–derived colony‐forming units fibroblasts (CFU‐Fs), as well as their osteogenic capacity. In a number of in vitro culture systems, Dlk1 stimulated osteoclastogenesis indirectly through osteoblast‐dependent increased production of proinflammatory bone‐resorbing cytokines (eg, Il7, Tnfa, and Ccl3). We found that ovariectomy (ovx)–induced bone loss was associated with increased production of Dlk1 in the bone marrow by activated T cells. Interestingly, Dlk1^?/? mice were significantly protected from ovx‐induced bone loss compared with wild‐type mice. Thus we identified Dlk1 as a novel regulator of bone mass that functions to inhibit bone formation and to stimulate bone resorption. Increasing DLK1 production by T cells under estrogen deficiency suggests its possible use as a therapeutic target for preventing postmenopausal bone loss. © 2011 American Society for Bone and Mineral Research.     

Isotypes and Opsonophagocytosis of Pneumococcus Type 6B Antibodies Elicited in Infants and Adults by an Experimental Pneumococcus Type 6B-Tetanus Toxoid Vaccine

Streptococcus pneumoniae is a major respiratory pathogen of infants, children, and the elderly. Polysaccharide vaccines have been useful in adult populations but do not elicit protective immunity in infants and young children. To enhance their immunogenicity, vaccines of pneumococcal polysaccharides conjugated to proteins are being developed. In this study antibody levels and opsonic activities were compared in sera of infants and adults injected with pneumococcal polysaccharide type 6B (Pn6B) conjugated to tetanus toxoid (TT) (Pn6B-TT). Healthy infants were injected with Pn6B-TT; group A was injected at 3, 4, and 6 months of age, and group B was injected at 7 and 9 months of age. A booster injection was given at 18 months. Adults were injected once. Antibodies were measured by enzyme-linked immunosorbent assay and radioimmunoassay, and their functional activities were measured by opsonophagocytosis of radiolabelled pneumococci. In adults, increases in immunoglobulin M (IgM), IgG, IgA, IgG1, and IgG2 to Pn6B were observed. Infants reached adult levels of IgG1 anti-Pn6B after the primary injections. After the booster injection the infant groups had total IgG- and IgM-Pn6B antibody levels similar to those of adults. After the booster injection, IgG1 was the dominant infant anti-Pn6B isotype and at a level higher than in vaccinated adults, but IgA and IgG2 antibodies remained at very low levels. Opsonic activity increased significantly after Pn6B-TT injections; the highest infant sera showed opsonic activity comparable to that of vaccinated adults. Overall, opsonic activity correlated best with total and IgG anti-Pn6B antibodies (r = 0.741, r = 0.653, respectively; n = 35) and was highest in sera with high levels of all Pn6B antibody isotypes. The results indicate the protective potential of a pneumococcal 6B polysaccharide protein conjugate vaccine for young infants.     

Correction to: Peroxidasin Enhances Basal Phenotype and Inhibits Branching Morphogenesis in Breast Epithelial Progenitor Cell Line D492

Journal of Mammary Gland Biology and Neoplasia -     

Community participation and environment of children with and without autism spectrum disorder: parent perspectives

Aim: This study explored parent perspectives of participation patterns and environmental supports and barriers for high-functioning children with autism spectrum disorder (ASD) within their communities compared with a group of children without ASD.

Method: The Participation and Environment Measure for Children and Youth was used to gather online data from parents of 99 children with ASD and 241 children without ASD. Mann–Whitney U test and chi-square tests were used to explore differences between groups and Cohen's d was calculated to examine effect sizes.

Results: Significant differences between children with and without ASD were observed for all participation and environment summary scores. Children with ASD participated less frequently, were less involved, and their parents were less satisfied with their child’s participation in community-based activities. Parents of children with ASD also identified fewer supports for their child’s participation and more environmental barriers than other parents.

Conclusion: Children with ASD participated less in community-related activities than children without ASD as perceived by their parents. Barriers limiting community participation included features of the social and physical environment and limited resources.

Significance: Occupational therapists should focus on decreasing environmental challenges in their efforts to facilitate participation of children with ASD in the community.