Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis

Extracellular deposition of amyloid fibrils is responsible for the pathology in the systemic amyloidoses and probably also in Alzheimer disease [Haass, C. & Selkoe, D. J. (1993) Cell 75, 1039-1042] and type II diabetes mellitus [Lorenzo, A., Razzaboni, B., Weir, G. C. & Yankner, B. A. (1994) Nature (London) 368, 756-760]. The fibrils themselves are relatively resistant to proteolysis in vitro but amyloid deposits do regress in vivo, usually with clinical benefit, if new amyloid fibril formation can be halted. Serum amyloid P component (SAP) binds to all types of amyloid fibrils and is a universal constituent of amyloid deposits, including the plaques, amorphous amyloid beta protein deposits and neurofibrillary tangles of Alzheimer disease [Coria, F., Castano, E., Prelli, F., Larrondo-Lillo, M., van Duinen, S., Shelanski, M. L. & Frangione, B. (1988) Lab. Invest. 58, 454-458; Duong, T., Pommier, E. C. & Scheibel, A. B. (1989) Acta Neuropathol. 78, 429-437]. Here we show that SAP prevents proteolysis of the amyloid fibrils of Alzheimer disease, of systemic amyloid A amyloidosis and of systemic monoclonal light chain amyloidosis and may thereby contribute to their persistence in vivo. SAP is not an enzyme inhibitor and is protective only when bound to the fibrils. Interference with binding of SAP to amyloid fibrils in vivo is thus an attractive therapeutic objective, achievement of which should promote regression of the deposits.     

Soluble interleukin-2 receptor levels in lupus nephritis

Soluble interleukin-2 receptor (IL-2R) levels were measured and correlated prospectively with clinical, histologic and serologic findings over a 9-month period in 62 lupus patients. Initially, 39 patients had clinical nephritis and 23 patients did not have nephritis. The 62 lupus patients has significantly higher IL-2R than 15 normal controls, most of this difference attributable to patients with nephritis. During lupus nephritis flare 9 of 10 patients showed significant elevations of IL-2R while only 6 of the 10 patients showed either elevation of anti-DNA antibody or decrease in CH50. During disease remission or stable clinical activity changes in IL-2R levels paralleled changes in anti-DNA antibody and CH50. Nephritis patients with cellular proliferative histology had significantly higher IL-2R levels than those with membranous or mesangial nephropathy. IL-2R correlated strongly with histologic activity and chronicity indices, IgG and C3 deposition whereas anti-DNA antibody and CH50 levels did not. IL-2R levels did not correlate with serum creatinine suggesting that elevations of IL-2R were not simply due to decreased clearance. These observations suggest that serum IL-2R level is a useful marker of disease activity in lupus nephritis and may serve as a helpful adjunct in management of this disorder.     

Variability in cytotoxicity and fluoride release of resin-modified glass-ionomer cements

New-generation glass-ionomer cements contain resin to improve their restorative properties. These resin-modified glass-ionomer cements vary considerably in their chemistry, which could result in corresponding variability in their physical and biological properties. This study investigated the cytotoxicity and the fluoride release of two resin-modified glass ionomers, a conventional glass-ionomer cement, and a resin composite. Samples were prepared and extracted in distilled water for 1, 4, and 7 days; eluates were filtered and tested by means of 3T3 mouse fibroblasts. Cytotoxicity (MTT assay) values were low for all materials and extraction times, indicating minimal cytotoxicity of all materials (less than 30% inhibition). Cytotoxicity of one resin-modified glass ionomer was significantly higher than for the other materials (p < 0.001). One resin-modified glass ionomer and the conventional glass-ionomer cement released significantly more fluoride at each time interval (p < 0.001) than the other resin-modified glass-ionomer cement and the resin composite. Fluoride release and cytotoxicity were correlated (r2 = 0.60; p < 0.001), although the fluoride release does not account for the cytotoxicity observed. Cytotoxicity and fluoride release suggest that one hybrid behaved more like a conventional glass ionomer, and the other like a resin composite. These differences may have implications for material selection in specific clinical situations.     

Chimeric influenza viruses incorporating epitopes of outer membrane protein F as a vaccine against pulmonary infection with Pseudomonas aeruginosa

Peptide 10 (NATAEGRAINRRVE, residues 305-318 of mature protein F) is one of two linear B-cell epitopes within outer membrane protein F of Pseudomonas aeruginosa both of which have been shown to elicit whole cell-reactive antibodies and to afford protection in animal models against P. aeruginosa infection. Influenza A virus was chosen as a vector to present this epitope in a human-compatible vaccine. Various lengths of the peptide 10 epitope ranging from a 5-mer (GRAIN), 7-mer (AINRRVE), 8-mer (TAEGRAIN), 9-mer (GRAINRRVE), 11-mer (AEGRAINRRVE) to a 12-mer (TAEGRAINRRVE) were attempted to be presented into the antigenic B-site of the hemagglutinin (HA) of live recombinant influenza virus. Using PCR, DNA sequences encoding these various peptide 10 lengths were inserted into the HA gene of influenza A/WSN/33 virus. By using a reverse-genetics transfection system, RNA transcribed in vitro from these chimeric HA genes was reassorted into infectious virus. To date chimeric viruses have been rescued and purified containing the peptide 10 5-mer, 7-mer, 8-mer, and 11-mer. RT-PCR and sequencing have confirmed the presence of P. aeruginosa sequences in the HA RNA segment of each chimeric virus. Each of the four chimeric viruses produced to date was used to immunize mice to determine the ability of each chimeric virus to elicit antibodies reactive with whole cells of P. aeruginosa. The immunization protocol consisted of a series of three intranasal inoculations, followed by two intramuscular injections of the chimeric virus. The chimeric virus incorporating the 11-mer elicited IgG antibodies that reacted with various immunotype strains of P. aeruginosa in a whole cell ELISA at titers of 80 to 2,560, whereas the chimeric virus incorporating the 8-mer elicited whole cell-reactive IgG antibodies at titers of 320 to 2,560. These data suggest that these two chimeric viruses may have vaccine efficacy against P. aeruginosa infection. These studies may result in the development of a chimeric influenza virus-protein F vaccine which would prove to be suitable for use in children with cystic fibrosis for the prevention of pulmonary colonization of these children with P. aeruginosa.     

Hemolytic uremic syndromes in childhood

The hemolytic uremic syndrome (HUS) comprises hemolytic anemia, acute renal failure, and thrombocytopenia. It is the most frequent cause of acute renal failure in childhood. Ninety percent of the patients have a diarrheal prodrome, and are referred to as having typical HUS. Approximately 10% exhibit the so-called atypical HUS. Typical HUS is caused by shigatoxin-producing Escherichia coli. The toxin, bound to the globotriosyl ceramide cell receptor and internalized, interferes with protein synthesis, predominantly of endothelial cells. The main target is the kidney, but nearly every organ system can be involved. The most common extrarenal involvement is damage to the central nervous system. The central event is probably an insult to the endothelial cell with consecutive loss of antithrombogenic properties. The von Willebrand factor, activation of platelets via platelet-activating factor, other growth factors (e.g., interleukins 1, 6, 8), nitric oxide, lipopolysaccharides, activated polymorphonucleated neutrophils, and the metabolites of the arachidonic acid cascade (e.g., prostaglandin I2) are believed to be involved in the pathogenic cascade. Controlled therapeutic trials with heparin, dipyridamole, aspirin, and urokinase have not been associated with improved outcome. Antibiotics have not yielded any benefit. Plasma infusions and plasma exchange appear to be efficacious, and are justified in cases of atypical HUS and thrombotic thrombocytopenic purpura. Binding of the toxin to the intestinal lumen, and thereby inhibition of enteral reabsorption, is under investigation.     

Effect of sensory perception of foods on appetite and food intake: a review of studies on humans

OBJECTIVE: How much do the sensory properties of food influence the way people select their food and how much they eat? The objective of this paper is to review results from studies investigating the link between the sensory perception of food and human appetite regulation. CONTENT OF THE REVIEW: The influence of palatability on appetite and food intake in humans has been investigated in several studies. All reviewed studies have shown increased intake as palatability increased, whereas assessments of the effect of palatability using measures of subjective appetite sensations have shown diverging results, for example, subjects either feel more hungry and less full after a palatable meal compared to a less palatable meal, or they feel the opposite, or there is no difference. Whether palatability has an effect on appetite in the period following consumption of a test meal is unclear. Several studies have investigated which sensory properties of food are involved in sensory-specific satiety. Taste, smell, texture and appearance-specific satieties have been identified, whereas studies on the role of macronutrients and the energy content of the food in sensory-specific satiety have given equivocal results. Different studies have shown that macronutrients and energy content play a role in sensory-specific satiety or that macronutrients and energy content are not a factor in sensory-specific satiety. Sensory-specific satiety may have an important influence on the amount of food eaten. Studies have shown that increasing the food variety can increase food and energy intake and in the short to medium term alter energy balance. Further knowledge about the importance of flavour in appetite regulation is needed, for example, which flavour combinations improve satiety most, the possible connection between flavour intensity and satiety, the effect of persistence of chemesthetic sensation on palatability and satiety, and to what extent genetic variation in taste sensitivity and perception influences dietary habits and weight control.     

Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients

Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day. Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen. The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS. Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance. Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidal infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation .