Ceaseless vigilance for chemical safety.

An outline is presented of action taken during the last half-century to combat the hazards associated with the proliferation of chemicals in the environment. Particular reference is made to the work of the International Programme on Chemical Safety, established in 1980 by WHO, the International Labour Organisation and the United Nations Environment Programme.

Oral immunization of rainbow trout with antigen microencapsulated in poly(DL-lactide-co-glycolide) microparticles.

The model protein antigen, human gamma globulin (HGG) was microencapsulated in poly(DL-lactide-co-glycolide) microparticles and administered orally to rainbow trout. Oncorhynchus mykiss (Walbaum, 1792). Using a Western blotting technique it was demonstrated that the dynamics of passage through the gut were different for the microencapsulated and soluble antigen. The association of HGG with microparticles increased the retention time of the antigen in the stomach and delayed its entry into the intestinal region. After the delivery of microencapsulated HGG, antigen was detected in gut contents in fragmented form which suggested that some of the antigen was present at the particle surface and therefore susceptible to proteolysis. However, a greater amount of intact antigen was detected in the posterior intestine and in the bloodstream of fish, which were administered with microparticle-associated than soluble antigen, indicating that the antigen was partially protected. Immunization with microencapsulated HGG resulted in the detection of specific antibody in the serum but levels were not significantly greater than after the delivery of soluble antigen. However, specific antibody was detected in the intestinal mucus of fish which were administered with the microencapsulated antigen after boosting with soluble HGG but not in fish which were primed with the soluble antigen.

Particle uptake and translocation across epithelial membranes.

Oral delivery of drugs and vaccines has many advantages over other routes of administration. For example, for vaccination, enteric delivery may result in the induction of a mucosal immune response against pathogens which colonise and invade the mucosa. However, the oral delivery of peptide or protein drugs or antigens is beset with problems, such as gastrointestinal breakdown of labile molecules, low level of macromolecular absorption and, for vaccines, the poor immune response usually elicited by orally administered soluble antigens. Investigations are therefore in progress to develop means of increasing intestinal absorption and decreasing digestion of orally administered molecules. Molecules can be incorporated into biodegradable microparticles to reduce the effect of gut secretions and to enable the absorption of bioactive agents in an unaltered form. The uptake of microparticulates through the gut wall is accepted as a true biological phenomenon but the mechanism and route of uptake have not been established. Furthermore, in general, only small numbers of microparticles are translocated across epithelial membranes, possibly making these systems inappropriate for drug or vaccine delivery. This paper reviews particle uptake across the gastrointestinal tract and describes studies carried out to determine whether a humoral response can be elicited following oral administration of an antigen associated with biodegradable poly(DL lactide-coglycolide) microparticles. The use of lipid delivery vehicles to enhance microparticle uptake and the selective transport of microspheres across M cells is also described.

Single dose, polymeric, microparticle-based vaccines: the influence of formulation conditions on the magnitude and duration of the immune response to a protein antigen.

Ovalbumin-loaded poly (D,L-lactide co-glycolide) [OVA-loaded PLG] microparticles, produced by emulsion/solvent evaporation stimulated the production of high serum IgG antibody levels after a single subcutaneous (s.c.) administration in mice and the duration of the immune response paralleled the degradation rate of the carrier. Formulations based on slow resorbing PLG maintained relatively constant peak antibody levels for 26 weeks and high titres for over 1 year at a level approximating the peak response to the faster resorbing, OVA-loaded particles which was of lower duration. Vaccine formulations prepared by simple mixing of blank PLG microparticles and OVA exhibited low primary immune responses which were only elevated by boosting. OVA-loaded PLG microparticles exhibited a substantial surface protein component amounting to ca 40% and 60% of the total protein loading for slow resorbing and fast resorbing PLG, respectively. These findings suggest that sustained presentation of surface protein to the immune system was a major factor in the induction and long-term maintenance of high antibody titres following a single s.c. administration of OVA-loaded microparticles.

Selective transport of microparticles across Peyer's patch follicle-associated M cells from mice and rats.

M cells are specialized structures in the Peyer's patch follicle-associated epithelium capable of taking up bacteria, viruses and other pathogens for later presentation to the gut-associated lymphoid tissue. The present work studies how coating microspheres with different proteins affects their ability to be taken up by M cells under near physiological conditions in vivo. The later appearance of microspheres in intestinal lymph has also been measured by flow cytometry. The protein preparations used in these experiments included bovine serum albumin (bSA), human immunoglobulin G (hIgG), secretory immunoglobulin A (hIgA), bovine growth hormone (bGH) and bGH complexed with an IgG antibody raised against bGH (bGH-Ab). Selectivity in binding of these microspheres to M cells, determined by confocal microscopy, was bGH < bSA < hIgG (mice) and bGH < bGH-Ab (rats and mice). A similar selectivity was seen for microsphere entry into M cells (bGH < bSA < hIgG; bGH < bGH-Ab). The appearance of protein-coated microspheres in rat mesenteric lymph showed a similar selectivity to that found for binding and entry into M cells (bGH < bGH-Ab). This latter selectivity was also found for hIgA-coated microspheres (bSA < hIgA). Preservation of transport selectivity throughout transcytosis highlights the unique importance of the M cell surface as being the primary site determining which type of antigen can be presented subsequently to the gut immune system. The possibility that this is a transient or phasic property of the M cell surface and that this could have physiological relevance is also discussed.

Aspects of the design and delivery of microparticles for vaccine applications.

Mortality and morbidity data continue to indicate there is a compelling need for the derivation of a new generation of vaccine delivery systems that can be usefully applied via injection and also mucosally. One technology that has potential for design as an effective vaccine delivery system is the formulation of biodegradable microparticles from the polymers and poly lactide co-glycolide (PLGA) in particular. The potential advantages of the delivery of vaccines within such microparticles is discussed. The potential for eliciting and optimising immunity after the mucosal delivery of biodegradable microparticles is also discussed.

Locus of control and degree of compliance in hemodialysis patients.

An experiment was conducted to test the hypothesis that dialysis patients with an internal locus of control orientation will show a higher rate of compliance to medication and dietary restrictions than those patients with an external locus of control. The results strongly supported the hypothesis. The possibility of interventions to modify patient locus of control is discussed, as is the use of this widely studied personality variable in predicting patient compliance.

Self-hemodialysis. The optimal mode of dialytic therapy.

Maintenance hemodialysis is presently the mainstay of treatment for the majority of patients with end-stage renal disease. There has been disagreement, however, as to what form the delivery of dialysis should take-self-dialysis, at home, or in-center, as opposed to in-center, limited-care dialysis. This review of the recent literature strongly supports self-dialysis as the optimal form of therapy, since the cost is less, and survival and rehabilation are better than with limited-care dialysis. We conclude that a greater effort should be expended to encourage and even direct patients toward this form of therapy.

Progression from minimal or focal to diffuse proliferative lupus nephritis.

Histologic classification of renal glomerular lesions in 46 patients with systemic lupus erythematosus revealed 17 as having either focal proliferative (10 patients) or minimal mesangial proliferative (7 patients) glomerulonephritis. Six of the 17 have progressed to a diffuse proliferative glomerular lesion on subsequent renal biopsies, 9 months to 5 years later. Five had clinical deterioration at the time of follow-up biopsies; currently one is undergoing hemodialysis and four others have decreased renal function. Although a comparison of those who progressed with those who are stable revealed greater proteinuria in some of those who progressed, no other clinical features of the initial illness were different in the two groups, nor were differences between the two groups noted on light microscopic examination of initial renal biopsies. However, ultrastructurally, electron-dense deposits, especially those subendothelial in location, were noted along glomerular capillary basement membranes more frequently and in greater number in those who progressed. These findings suggest that lupus patients with a mild proliferative glomerulonephritis may have clinical and histologic progression of the renal disease, and those who progress cannot be clearly defined by clinical or light microscopic features. Ultrastructural demonstration of subendotheial deposits suggests a greater likelihood of subsequent progressive disease.

Dialysis-induced muscle cramps: treatment with hypertonic saline and theory as to etiology.

We postulate that plasma or muscle cell hypo-osmolality may be the major factor or co-factor causing muscle cramps during dialysis, rather than plasma volume contraction alone. The transient hyperosmolality induced with hypertonic saline is therapeutic because it reverses this abnormal state. We feel that the bolus administration of hypertonic saline is of great value in the therapy of dialysis-induced cramps and may be the treatment of choice. It is a rapid and effective means of relieving cramps at no risk to the patient, and without compromising ultrafiltration.