Immunoglobulin E and eosinophil-dependent protective immunity to larval Onchocerca volvulus in mice immunized with irradiated larvae

Mice immunized with irradiated Onchocerca volvulus third-stage larvae developed protective immunity. Eosinophil levels were elevated in the parasite microenvironment at the time of larval killing, and measurements of total serum antibody levels revealed an increase in the immunoglobulin E (IgE) level in immunized mice. The goal of the present study was to identify the role of granulocytes and antibodies in the protective immune response to the larval stages of O. volvulus in mice immunized with irradiated larvae. Immunity did not develop in mice if granulocytes, including both neutrophils and eosinophils, were eliminated, nor did it develop if only eosinophils were eliminated. Moreover, larvae were killed in na?ve interleukin-5 transgenic mice, and the killing coincided with an increase in the number of eosinophils and the eosinophil peroxidase (EPO) level in the animals. To determine if EPO was required for protective immunity, mice that were genetically deficient in EPO were immunized, and there were no differences in the rates of parasite recovery in EPO-deficient mice and wild-type mice. Two mouse strains were used to study B-cell function; micro MT mice lacked all mature B cells, and Xid mice had deficiencies in the B-1 cell population. Immunity did not develop in the micro MT mice but did develop in the Xid mice. Finally, protective immunity was abolished in mice treated to eliminate IgE from the blood. We therefore concluded that IgE and eosinophils are required for adaptive protective immunity to larval O. volvulus in mice.     

Immune responses to weakly immunogenic virally induced tumors II. Suppressive effects of the in vivo carried tumor YAC

Unprimed spleen cells from A and C57BL/6 mice could not produce cytotoxic responses to their syngeneic tumors: a Moloney virus-induced in vitro subline YAC-1 and a Rauscher virus-induced in vitro subline RBL5, respectively. Spleen cells from A and C57BL/6 mice immunized with YAC-1 or RBL5 (which cross-react serologically) generated significant syngeneic cytotoxicities after cultivation in vitro. The in vivo carried tumor of A mice, unlike the in vitro sublines, could not stimulate a priming effect. In contrast, YAC stimulated the formation of suppressor cells in both A and C57BL/6 mice. The suppressor cells abrogated the priming effect of the syngeneic tumors, but not the priming effect of the allogeneic tumors. Furthermore, YAC did not suppress normal allogeneic anti-tumor responses. The theoretical and the practical implications of these studies are discussed.     

E-books as a support for young children's language and literacy: the case of Hebrew-speaking children

In this paper, we present a series of studies performed in the last decade that examined the contribution of e-books reading to the language and literacy of young Hebrew-speaking children. Children worked with two e-books designed by the researchers to achieve this aim. We present the effect of reading these e-books on the language and literacy of young children: (a) in general, (b) in different socio-economic statues (SES) groups, (c) among children at risk for learning disabilities (ALD). Language progress was measured by phonological awareness, word meaning, story production and comprehension, and literacy progress was measured by letter naming, word reading and word writing. Results showed that the e-book reading supported all language and literacy skills, except letter naming. The progress of most skills appeared after three reading sessions. Children from middle- and low-SES families benefited from reading the e-books and in some cases, low-SES children were contributed more than those from a middle SES. ALD children improved their vocabulary, phonological awareness and concept about print when provided with an educational e-book. Further research and pedagogical implications for software developers and educators are discussed.     

Impact of dosing regimen of custirsen,an antisense oligonucleotide,on safety,tolerability and cardiac repolarization in healthy subjects

Aims

Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.

Methods

Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.

Results

AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.

Conclusion

Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.     

Blood pressure and cognitive functioning among independent elderly

BACKGROUND: The morbidity and mortality benefits of blood pressure (BP) control for the elderly is well documented. The cognitive consequences of hypertension control in this population, however, are still under debate. We aim to study the association between BP and cognitive performance in the elderly. Specifically, we explore 1) the possibility that BP is differentially associated with various cognitive domains; and 2) the utility of analyzing both BP and cognitive scores as continuous variables to unravel possible nonlinear associations. METHODS: Four hundred ninety-five community living 70 to 85 year olds completed eight cognitive tests that measured memory, concentration, visual retention, verbal fluency, and the mini-mental state examination (MMSE). The performance of each test was analyzed first by comparing four groups (normotensives, normalized hypertensives, untreated hypertensives, and treated but uncontrolled hypertensives). Then, using BP values as continuous variables, linear, U-curve, and J-curve associations were estimated. RESULTS: On all cognitive tests, except for verbal fluency, normotensives performed poorest, treated but uncontrolled hypertensives achieved the highest scores. The MMSE scores and the lighter concentration task were linearly related to BP; J-curve association was observed between memory and visual retention; prolonged concentration was related to pulse pressure alone. CONCLUSIONS: Low BP, as observed among the normotensive subjects, was associated with poor cognitive performance. Mild hypertension appeared to enhance cognitive functioning among the subjects of this study. Moreover, we found support for the hypothesis that the association between BP and different dimensions of cognition take on different patterns.     

Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2

BACKGROUND/AIMS: Lysyl-oxidases catalyze the oxidation of lysine residues in collagen and elastin thereby promoting their polymerization. We have studied here the expression of four lysyl-oxidases in normal and diseased human liver. METHODS: The expression of the different lysyl-oxidases in paraffin embedded liver sections was studied using in-situ hybridization and immunohistochemistry. The enzymatic activity of lysyl-oxidase like protein-2 (Loxl2 or LOR-1) using a previously described lysyl-oxidase assay. RESULTS: We have found that the four lysyl-oxidases which we examined are not significantly expressed in the normal liver. By contrast, Wilson's disease and primary biliary cirrhosis (PBC) patients express lysyl-oxidase (Lox) and lysyl-oxidase like protein-2 (Loxl2 or LOR-1) in hepatocytes, and the expression is accompanied by collagen deposition around the hepatocytes. Lysyl-oxidases are also expressed in additional fibrotic liver diseases such as hepatitis B and C but in these diseases the expression is confined to the fibrotic lesions and collagen does not accumulate around hepatocytes. We have found that Loxl2 is able to oxidize lysine residues of collagen, and behaves in that respect similarly to Lox. The copper chelator D-penicillamine inhibits Loxl2 induced oxidation of collagen but the Lox inhibitor beta-aminopropionitrile did not inhibit the oxidation using a BAPN concentration at which Lox activity was completely inhibited. Loxl2 also catalyzed the oxidation of cell surface proteins on HepG2 hepatoblastoma cells and inhibited their proliferation. CONCLUSIONS: Upregulation of Lox and Loxl2 in hepatocytes of Wilson's disease and PBC patients may contribute to liver damage by various mechanisms. The upregulation of Lox and Loxl2 in Wilson's disease could perhaps be utilized for diagnostic purposes since their expression is up-regulated in hepatocytes even before the onset of fibrosis.     

The viability of the Parenting Representations Interview for assessing and measuring change in parents of adolescents

Parents’ representations include parents’ views of their adolescent, of their own parenting and of the parent–adolescent relationship. Two longitudinal studies of parents and their adolescent sons and daughters support the validity of scales coding mothers in the Parenting Representations Interview-Adolescence (PRI-A). The studies, conducted in Israel during the transition from home to military service, demonstrated that three dimensions derived from the PRI-A: positive representations of adolescents, negative emotionality and inadequate boundaries were associated with adolescents’ AAI variables, relatedness-autonomy behaviors with mothers, and with other indicators, such as adolescents’ wellbeing, romantic intimacy and individuation. Examining parenting representations could help practitioners pinpoint targets for intervention and evaluate the changes that families go through during psychotherapy, as well as the therapeutic process and its outcomes. The findings support the viability of the PRI for use in attachment based interventions for adolescents.