Clinical chemistry of common apolipoprotein E isoforms

Apolipoprotein E plays a central role in clearance of lipoprotein remnants by serving as a ligand for low-density lipoprotein and apolipoprotein E receptors. Three common alleles (apolipoprotein E(2), E(3) and E(4)) give rise to six phenotypes. Apolipoprotein E(3) is the ancestral form. Common apolipoprotein E isoforms derive from nucleotide substitutions in codons 112 and 158. Resulting cysteine-arginine substitutions cause differences in: affinities for low-density lipoprotein and apolipoprotein E receptors, low-density lipoprotein receptor activities, distribution of apolipoprotein E among lipoproteins, low-density lipoprotein formation rate, and cholesterol absorption. Accompanying changes in triglycerides, cholesterol and low-density lipoprotein may promote atherosclerosis development. Over 90% of patients with familial dysbetalipoproteinaemia have apolipoprotein E(2)/E(2). Apolipoprotein E(4) may promote atherosclerosis by its low-density lipoprotein raising effect. Establishment of apolipoprotein E isoforms may be important for patients with diabetes mellitus and several non-atherosclerotic diseases. Apolipoprotein E phenotyping exploits differences in isoelectric points. Isoelectric focusing uses gels that contain pH 4-7 ampholytes and urea. Serum is directly applied, or prepurified by delipidation, lipoprotein precipitation or dialysation. Isoelectric focusing is followed by immunofixation/protein staining. Another approach is electro- or diffusion blotting, followed by protein staining or immunological detection with anti-apolipoprotein E antibodies and an enzyme-conjugated second antibody. Apolipoprotein E genotyping demonstrates underlying point mutations. Analyses of polymerase chain reaction products are done by allele-specific oligonucleotide probes, restriction fragment length polymorphism, single-stranded conformational polymorphism, the primer-guided nucleotide incorporation assay, or denaturating gradient gel electrophoresis. Detection with primers that either or not initiate amplification is performed with the amplification refractory mutation system. Disparities between phenotyping and genotyping may derive from isoelectric focusing methods that do not adequately separate apolipoprotein E posttranslational variants, storage artifacts or faint isoelectric focusing bands.     

Interleukin-2 enhancement of cytotoxicity by humanized monoclonal antibody M195 (anti-CD33) in myelogenous leukemia

The mass childhood immunization programme has traditionally been viewed as a safe and effective preventative measure by health promoters, primary health care professionals and governments. This consensus has meant that immunization has rarely been viewed as ethically problematic. A number of recent changes in the context of the delivery of health care, particularly the emphasis on consumerism and the effect of the marketization of services, makes timely an examination of ethical, social and political issues. This article examines four main grounds for problematizing the mass childhood immunization programme. These are: clinical research evidence about the safety and efficacy of vaccines; the masking of wider social and political determinants of ill health; the contradictory strictures about collective and individual rights in relation to immunization; and the uniqueness of childhood immunization as a physical intrusion into a healthy body. The implications of these ethical issues are discussed in relation to informed consent and the need for a 'greenfield' review that includes the views of dissenting parents, lawyers and moral philosophers, as well as health professionals.     

Development of the bi-directional ultrasound system for base of tongue imaging

The use of conventional ultrasound systems to image the upper airway has been limited because ultrasound energy is attenuated by the air column. In an attempt to study upper airway geometry, we developed a computer controlled bi-directional ultrasound system which combines two conventional ultrasound devices with computer image processing to yield images of upper airway structures. Human studies and cadaver studies were performed to evaluate the system. Images acquired by the bi-directional ultrasound system were comparable to images from 3D volume rendered CT scans. This system may provide valuable data in the study of upper airway physiology and pathology.     

ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes

Acyl-CoA:cholesterol acyltransferase (ACAT) is the enzyme largely responsible for intracellular cholesterol esterification. A systemic inhibitor of ACAT is believed to be able to slow or even reverse the atherosclerotic process. Towards that goal, a series of cyclic sulfides, derived from the hetero-Diels-Alder reaction of thioaldehydes with 1,3-dienes, and bearing carboxamide substituents, were prepared and evaluated for in vitro (in several tissues and species) and ex vivo ACAT inhibition. Minor changes in subsequent structure were found to have a significant effect in optimization of the biological activity of this series of compounds.     

Acute aortic dissection: association with patent ductus arteriosus

The Cuban recombinant vaccine against the hepatitis B virus was applied to a group of individuals over 65 from a geriatric home in Havana City. Dose of 20 ìg were administered within a scheme from 0.1 to 6 months in order to study its immunogenicity, which was evaluated at 2, 7, and 12 months after the first dose. 47.1% of protective titres and geometrical mean of 6.04 UI/L were obtained after 60 days. 100% of seroconversion (UI/L) and seroprotection (10 UI/L) and geometric mean of 136.93 UI/L were obtained when the immune response was evaluated on the 7th month. Finally, after a year, seroconversion and seroprotection were also of 100%, and the geometric mean was of 204.61 UI/L. It was proved the high immunogenic power of this vaccine, which makes it recommendable to protect this age group from the hepatitis B virus.     

Herd immunity to filarial infection is a function of vector biting rate

Despite the existence of an impressive body of work on human immune responses against filarial infections, the occurrence of a protective response to infection remains unclear. Here, we use a combined modelling and comparative data analysis framework to address this issue for human infections with the filarial parasite, Wuchereria bancrofti. By analogy with previous work, the analysis involves the comparison of observed field patterns of infection with epidemiological patterns predicted by a mathematical model of parasite immunity. Unlike most other human helminths, which are transmitted by ingestion or dermal penetration, exposure to infection with lymphatic filariasis can be measured explicitly in terms of vector mosquito biting rates, thereby also allowing, probably for the first time, examination of the suggested role of exposure in generating herd immunity to macroparasites. Observed field patterns in this study were derived from 19 different published studies, which gave parallel estimates of community exposure rates and the corresponding age--prevalence patterns of infection, while predictions of the epidemiological impact of herd immunity were obtained using a catalytic model framework. The results provide the first conclusive evidence to date that variations in the observed age--prevalence patterns of infection in filariasis can be effectively explained by the occurrence of an exposure-driven acquisition of herd immunity. We discuss this result in terms of implications for the new World Health Organization-led initiative for the global control of this parasitic disease.     

Lead differentially modifies cytokine production in vitro and in vivo

An imbalance between helper T cell type 1 (Th1) and helper T cell type 2 (Th2) activation can result in immunodysregulations leading to impaired cell-mediated immunity with an increased incidence of infectious disease or cancer and/or aberrant humoral immunity that may culminate with an autoimmune disease. Mercury, a heavy-metal toxicant, is known to induce renal autoimmunity characterized by a predominant Th2 response. Lead, another metal toxicant, causes enhanced B cell activities and impairs host resistance to several bacterial and viral infections. In addition, Pb was reported to enhance Th2 proliferation and inhibit Th1 proliferation. The differential effects of Pb on Th subset activation have been further investigated. In vitro IL-4 production by a Th2 clone was significantly increased by the addition of PbCl2, whereas IFN gamma production by a Th1 clone was decreased by the addition of PbCl2. When BALB/c mice were subcutaneously exposed to PbCl2, ex vivo Il-4 production by anti-CD3-stimulated splenic T cells was enhanced, but IFN gamma production was inhibited. Additionally, the plasma IL-4 and IgE levels of Pb-exposed mice were increased, and the plasma IFN gamma levels were significantly lowered in the absence of any additional exogenous antigen. In vitro, ex vivo, and in vivo treatment with HgCl2 produced similar findings. This study is the first report of the preferential activation of a Th2 response by Pb in vivo and suggests that PB, like Hg, may induce autoimmune responses by upsetting the balance between Th1- and Th2-like cells, which could enhance production of antibodies to self antigens.