cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein

Using the yeast two hybrid system, a mouse embryo cDNA library was screened for proteins that interact with the C-terminus of the human beta-amyloid precursor protein (beta PP). A fusion protein was identified that interacts specifically with the cytoplasmic domain of beta PP and does not interact with the beta-amyloid region. The protein encoded by this partial mouse cDNA is identical to the C-terminus of the rat Fe65 protein. This mouse protein also interacts with the homologous C-terminal domains of the mouse amyloid precursor-like proteins, APLP1 and APLP2. These conserved cytoplasmic regions contain a common amino acid motif, Asn-Pro-Thr-Tyr, which has previously been shown to influence both the secretion and internalization of beta PP. Fe65 has been implicated in regulatory and cell signaling mechanisms because it contains two different motifs involved in protein binding, a WW domain (a variant of Src homology 3 domains) and a phosphotyrosine interaction domain (PID). Interestingly, the PID domain binds to the same motif present in the conserved cytoplasmic domains of the beta PP and beta PP-like proteins. RNA analyses reveal that Fe65 is predominantly expressed in brain and in the regions most affected by Alzheimer's disease (AD)-associated neuropathology. The human Fe65 mRNA was cloned from a fetal brain cDNA library. The message encodes a protein of 735 amino acids that is 95% identical to the rat Fe65 protein. The human Fe65 gene was mapped on human metaphase chromosomes to band 11p15 using fluorescence in situ hybridization.      

Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia

Background  

Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E₂ and PGD₂.     

A study on the immunological basis of the dissociation between type I-hypersensitivity skin reactions to <Emphasis Type="Italic">Blomia tropicalis</Emphasis> antigens and serum anti-<Emphasis Type="Italic">B. tropicalis</Emphasis> IgE antibodies

Background

Two conditions are used as markers of atopy: the presence of circulating anti-allergen IgE antibodies and the presence of positive skin prick test (SPT) reactions to allergenic extracts. The correlation between these conditions is not absolute. This study aimed at investigating immunological parameters that may mediate this lack of correlation. Individuals whose sera contained anti-B. tropicalis extract IgE antibodies (α-Bt E IgE) were divided into two groups, according to the presence or absence of skin reactivity to B. tropicalis extract (Bt E). The following parameters were investigated: total IgE levels; α-Bt E IgE levels; an arbitrary α-Bt E IgE/total IgE ratio; the proportion of carbohydrate-reactive α-Bt E IgE; the proportion of α-Bt E IgE that reacted with Ascaris lumbricoides extract (Al E); the production of IL-10 by Bt E- and Al E-stimulated peripheral blood cells (PBMC).

Results

Total IgE levels were similar in the two groups, but α-Bt E IgE was significantly higher in the SPT-positive group (SPT+). A large overlap of α-Bt E IgE levels was found in individuals of both groups, indicating that these levels alone cannot account for the differences in SPT outcome. Individuals of the two groups did not differ, statistically, in the proportion of α-Bt E IgE that reacted with carbohydrate and in the production of IL-10 by Bt E- and Al E-stimulated PBMC. Both groups had part of α-Bt E IgE activity absorbed out by Al E, indicating the existence of cross-reactive IgE antibodies. However, the α-Bt E IgE from the SPT-negative individuals (SPT-) was more absorbed with AlE than the α-Bt E IgE from the SPT+ individuals. This finding may be ascribed to avidity differences of the α-Bt E IgE that is present in the two groups of individuals, and could occur if at least part of the α-Bt E IgE from the SPT- individuals were elicited by A. lumbricoides infection.

Conclusion

The present results suggest that a low ratio of specific IgE to total IgE levels (in a minority of individuals), and differences in α-Bt E IgE avidities (which would have high affinities for A. lumbricoides antigens in SPT- than in SPT+ individuals) may play a role in the down-modulation of type-I hypersensitivity reaction against aeroallergens described in helminth-infected individuals.

     

Building social capital with women in a socially disadvantaged community

Individual and community health outcomes are strengthened by friendships and social support networks. Community interventions aimed at improving the social factors that influence the health of individuals and communities increasingly include strategies to develop resilience through building networks and social capital. The study reported here used a cross-sectional survey design, administered at two time points, to measure the effect of a community capacity-building programme implemented by Women's Health Nurses. Data described and where possible measured women's perceptions of their physical and mental well-being, friendships and support networks, community connectedness and participation, safety, and knowledge of and access to local community services. The follow-up survey also measured the impact of specific community development initiatives. Overall, findings of both surveys were consistent, with some notable exceptions. For example, at follow up there was a significant improvement in mental health indicators and fewer women believed their physical or emotional problems imposed a considerable burden on their daily activities. They also believed people from other cultures were more likely to be accepted by neighbours and reported increased involvement in community activities as a direct result of the Villawood Icebreakers Project.     

Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone

Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.     

A case of 75-year-old survivor of unrepaired tetralogy of Fallot and quadricuspid aortic valve

In tetralogy of Fallot (TOF), the most common form of cyanoticcongenital heart disease, only a few patients reach adulthoodwithout surgical correction. We present the case of a man withTOF who survived until the age of 75 years without surgicalintervention and had a very unusual combination of TOF and quadricuspidaortic valve (QAV). QAV, complicated by aortic regurgitation,is an uncommon finding in TOF patients. The hemodynamic consequencesfor both the right and left ventricles are significant. Thiscase provides a rare insight into the late outcome of an elderlypatient with uncorrected TOF.     

Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa

Background  

Angiogenesis, a complex multistep process that comprehends proliferation, migration and anastomosis of endothelial cells (EC), has a major role in the development of pathologic conditions such as inflammatory diseases, tumor growth and metastasis. Brazilian flora, the most diverse in the world, is an interesting spot to prospect for new chemical leads, being an important source of new anticancer drugs. Plant-derived alkaloids have traditionally been of interest due to their pronounced physiological activities. We investigated the anti-angiogenic potential of the naturally occurring guanidine alkaloid pterogynidine (Pt) isolated from the Brazilian plant Alchornea glandulosa. The purpose of this study was to examine which features of the angiogenic process could be disturbed by Pt.     

Socio-demographic, health-related and psychosocial correlates of fear of falling and avoidance of activity in community-living older persons who avoid activity due to fear of falling

Background  

Fear of falling and avoidance of activity are common in old age and are suggested to be (public) health problems of equal importance to falls. Earlier studies of correlates of fear of falling and avoidance of activity did hardly differentiate between severe and mild levels of fear of falling and avoidance of activity which may be relevant from clinical point of view. Furthermore, most studies focused only on socio-demographics and/or health-related variables and hardly incorporated an extensive range of potential correlates of fear of falling including psychosocial variables. This study analyzes the univariate and multivariate associations between five socio-demographic, seven health-related and six psychosocial variables and levels of fear of falling and avoidance of activity in older persons who avoid activity due to fear of falling.     

Critical Appraisal on the Role and Outcome of Emergency Colectomy for Uncomplicated Right-sided Colonic Diverticulitis

Background Emergency colectomy is well accepted for treating complicated right-sided colonic diverticulitis. However, the role of colectomy for uncomplicated diverticulitis is not well defined. The aim of this study was to evaluate the short-term and long-term surgical outcome of uncomplicated right-sided diverticulitis in our locality. Patients and Methods Retrospective chart review of patients operated for right-sided diverticulitis over a 20-year period was conducted. Recurrent attacks of right-sided diverticulitis, re-operation rate and re-hospitalisation rate were the long-term parameters of interest. An updated telephone interview was carried out for all surviving patients. Results Seventy-four patients (35 males and 39 females), median age 35.5 (range 16–70) years, were operated for uncomplicated diverticulitis. Thirty patients underwent colectomy, whereas the others underwent appendectomy with diverticulectomy (n = 8) or appendectomy alone (n = 36). All short-term parameters were less favourable for the colectomy group, including higher complication rate, slower return of gastrointestinal function, higher requirement of parenteral analgesic and longer hospital stay. Without colectomy, only 2 patients developed recurrent diverticulitis necessitating hospitalisation, both of whom resolved on conservative treatment. On the other hand, 1 patient required re-operation after colectomy because of intestinal obstruction. The overall re-hospitalisation rate was comparable between the colectomy and the non-colectomy group (16.7% vs. 13.6%). Conclusions Emergency colectomy can eradicate suspicious lesions and eliminate risk of recurrent diverticulitis but at the expense of higher morbidity rates. As the natural course of uncomplicated right-sided colonic diverticulitis is usually benign, conservative treatment with minimal surgery may be a better therapeutic option.