Roxithromycin, Clarithromycin, and Azithromycin Attenuate the Injurious Effects of Bioactive Phospholipids on Human Respiratory Epithelium in Vitro

The effects of the bioactive phospholipids (PL), platelet-activating factor (PAF), lyso-PAF, and lysophosphatidylcholine (LPC) on the beat frequency and structural integrity of human ciliated respiratory epithelium were studied in vitro, in the presence or absence of polymorphonuclear leukocytes (PMNL), the antimicrobial agents, roxithromycin, clarithromycin, and azithromycin and the antioxidative enzymes catalase and superoxide dismutase (SOD). All three PL caused dose-dependent slowing of ciliary beat frequency (CBF) and epithelial damage (ED) at concentrations 1 g/ml, which were unaffected by inclusion of the antimicrobial agents and antioxidative enzymes. When epithelial strips were exposed to the combination of PMNL and PL, there was significant potentiation of ciliary dysfunction and ED, which was ameliorated by pretreatment of the PMNL with the antimicrobial agents or by inclusion of catalase, but not SOD. These results demonstrate that LPC, PAF, and lyso-PAF cause epithelial damage by direct mechanisms which are oxidant-independent, as well as by indirect mechanisms involving phagocyte-derived reactive oxidants. Macrolides and azalide antimicrobial agents may have beneficial effects on airway inflammation in asthma and microbial infections by protecting ciliated epithelium against oxidative damage inflicted by PL-sensitized phagocytes.     

Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting

Malaria infection induces the production of serum antibodiesto a variety of malaria antigens but the prevalence of antibodiesto any particular antigen ins typically mucb less than 100%.It has been assumed that non-responsiveness to defined antigensin malaria immune subjects is due to HLA mediated restricutionof the Immune response. In this study we have investigated therole of HLA and non-HLA genes in the antibody response to twomerozoite surface antigens (MSP1 and MSP2) and a sexual stageantigen (Pfs260/230) opf P{lasmodium falcpartum, and concludethat host genotype is not a major determinant of responsiveness.Although antibody levels vary in accordance with seasonal variationsin malaria transmission in semi-immune children, antibiody levelsremain stable in clncall immine adults.     

Anti-IgE and Con A-induced histamine release from mast cells of four rat strains: Correlation with total serum IgE

Anti-IgE- and Con A-induced histamine release from serosal mast cells were compared to each other and to total serum levels of IgE in non-immunized, alum-injected, and Silica gel-injected rats of the BN, Fischer, PVG, and SD strains. The results indicate that the degree of anti-IgE-and Con A-induced release is strain-dependent and varies with immunization conditions. Furthermore, there is a gross but not complete correlation between the degree of serosal mast cell histamine release induced by the two secretagogues. However, Con A- or anti-IgE-induced release could significantly be correlated to serum levels of total IgE only in the Fischer strain but not in the BN or the PVG strains. In the SD strain, Con A-induced release correlated to serum IgE levels in Silica gel-injected but not in alum-injected animals.Subsidiary of AB Astra, Sweden.     

Phase I testing of a malaria vaccine composed of hepatitis B virus core particles expressing Plasmodium falciparum circumsporozoite epitopes

We report the first phase I trial to assess the safety and immunogenicity of a malaria vaccine candidate, ICC-1132 (Malarivax), composed of a modified hepatitis B virus core protein (HBc) containing minimal epitopes of the Plasmodium falciparum circumsporozoite (CS) protein. When expressed in Escherichia coli, the recombinant ICC-1132 protein forms virus-like particles that were found to be highly immunogenic in preclinical studies of mice and monkeys. Twenty healthy adult volunteers received a 20- or a 50-microg dose of alum-adsorbed ICC-1132 administered intramuscularly at 0, 2, and 6 months. The majority of volunteers in the group receiving the 50-microg dose developed antibodies to CS repeats as well as to HBc. Malaria-specific T cells that secreted gamma interferon were also detected after a single immunization with ICC-1132-alum. These studies support ICC-1132 as a promising malaria vaccine candidate for further clinical testing using more-potent adjuvant formulations and confirm the potential of modified HBc virus-like particles as a delivery platform for vaccines against other human pathogens.     

Using the literature in developing McGill's guidelines for interactions between residents and the pharmaceutical industry.

Evidence suggests that the pharmaceutical industry exerts a large influence on residents' education and practice. Yet existing guidelines by professional bodies do not cover the specifics of residents' interactions with the pharmaceutical industry. At the psychiatry residency program of the McGill University Health Center, the authors set out to systematically evaluate areas of concern for residents and to develop guidelines for use by residents during and outside their training. Areas of concern included educational activities, training, fundraising, and other specific resident-industry interactions. In 1998, a committee of residents and faculty systematically evaluated areas of concern and, based on a review of the literature and discussions with experts, in 2000 developed guidelines for use by McGill's psychiatry program residents. The process for guideline development and methods for their implementation in 2001 are described. Education and training of residents on resident-industry interactions were included early in the curriculum. Guidelines were developed to address limitations on fundraising activities; restriction of direct gifts to residents; the appropriateness and awarding of industry fellowships; and the handling of drug samples, meals, and other presentations to residents. While guidelines for residents are useful adjuncts for guiding residents' interactions with the pharmaceutical industry, the authors conclude that they need to be reinforced with education and sensitization by faculty.     

Neuroimaging of typical and atypical development: a perspective from multiple levels of analysis

To date, research involving functional neuroimaging of typical and atypical development has depended on several assumptions about the postnatal maturation of the brain. We consider evidence from multiple levels of analysis that brings into question these underlying assumptions and advance an alternative view. This alternative view, based on an "interactive specialization" approach to postnatal brain development, indicates that there is a need to: obtain data from early in development; focus more on differences in interregional interactions rather than searching for localized, discrete lesions; examine the temporal dynamics of neural processing; and move away from deficits to image tasks in which atypical participants perform as well as typically developing participants.     

Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) defines a group of otherwise healthy elderly subjects with a markedly elevated risk of developing Alzheimer's disease (AD). In the search for biomarkers of MCI, we assessed whether MCI shares neurochemical abnormalities with AD in areas affected early in the course of the disease. As a secondary study aim, we tested to what extent neurochemical findings reflect neuropsychological deficits. Proton spectroscopy was performed in 19 MCI patients, 18 AD patients and 22 age and gender matched controls (CON) within the parietal gray and white matter (PWM and PGM) and the hippocampus (HIP). The cognitive test battery used included measures compiled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). The N-acetyl-aspartate to creatine ratio (NAA/Cr) was significantly reduced in the HIP of MCI and AD compared with CON (p < 0.05). Only AD patients showed parietal abnormalities, namely significantly elevated myoinositol (mI/Cr and mI/NAA) in PGM, reduced NAA/Cr and elevated mI/NAA in PWM. MCI subjects were significantly impaired in categorical verbal fluency (VF) (p < 0.001) and delayed verbal recall (DVR) (p < 0.001). VF was positively correlated with hippocampal NAA/Cr (p < 0.05) and parietal mI/NAA (p < 0.05). In summary, this study demonstrates shared neurobiological hippocampal abnormalities in MCI and AD, whereas parietal lobe neurochemical profiles and functions were normal in MCI. Thus, biological evidence is provided that MCI represents a precursor stage of AD. Moreover, multivoxel 1H MRS may enable an objective staging of the neurodegenerative process underlying the age-dependent cognitive deficits eventually leading to dementia.     

Experimental pneumococcal meningitis: impaired clearance of bacteria from the blood due to increased apoptosis in the spleen in Bcl-2-deficient mice

Necrotic and apoptotic neuronal cell death can be found in pneumococcal meningitis. We investigated the role of Bcl-2 as an antiapoptotic gene product in pneumococcal meningitis using Bcl-2 knockout (Bcl-2(-/-)) mice. By using a model of pneumococcal meningitis induced by intracerebral infection, Bcl-2-deficient mice and control littermates were assessed by clinical score and a tight rope test at 0, 12, 24, 32, and 36 h after infection. Then mice were sacrificed, the bacterial titers in blood, spleen, and cerebellar homogenates were determined, and the brain and spleen were evaluated histologically. The Bcl-2-deficient mice developed more severe clinical illness, and there were significant differences in the clinical score at 24, 32, and 36 h and in the tight rope test at 12 and 32 h. The bacterial titers in the blood were greater in Bcl-2-deficient mice than in the controls (7.46 +/- 1.93 log CFU/ml versus 5.16 +/- 0.96 log CFU/ml [mean +/- standard deviation]; P < 0.01). Neuronal damage was most prominent in the hippocampal formation, but there were no significant differences between groups. In situ tailing revealed only a few apoptotic neurons in the brain. In the spleen, however, there were significantly more apoptotic leukocytes in Bcl-2-deficient mice than in controls (5,148 +/- 3,406 leukocytes/mm2 versus 1,070 +/- 395 leukocytes/mm2; P < 0.005). Bcl-2 appears to counteract sepsis-induced apoptosis of splenic lymphocytes, thereby enhancing clearance of bacteria from the blood.     

A Log Ratio-Based Analysis of Individual Changes in the Composition of the Oral Microbiota in Different Dietary Phases

Background: Investigating the influence of nutrition on oral health has a long scientific history. Due to recent technical advances like sequencing techniques for the oral microbiota, this topic has gained scientific interest again. A basic challenge is to understand the influence of nutrition on the oral microbiota and on the interaction between the oral bacteria, which is also statistically challenging. Methods: Log-transformed ratios of two bacteria concentrations are introduced as the basic analytic tool. The framework is illustrated by application in an experimental study exposing eleven participants to different nutrition schemes in five consecutive phases. Results: The method could be sufficiently used to analyse the interrelation between the bacteria and to identify some bacterial groups with the same as well as different reactions to additional dietary components. It was found that the strongest changes in bacterial concentrations were achieved by the additional consumption of dairy products. Conclusion: A log ratio-based analysis offers insights into the relation of different bacteria while taking specific features of compositional data into account. The presented methods allow becoming independent of the behaviour of other bacteria, which is a disadvantage of common analysis methods of compositions. The results indicate that modulations of the oral biofilm microbiota due to nutrition change can be attained.