Fusobacterium pneumonia and death following uvulo-palato-pharyngoplasty

A case with a fatal outcome caused by infection with Fusobacterium species was seen in a patient recently operated on for heavy snoring with uvulo-palato-pharyngoplasty (UPPP). The mechanism of infection is discussed. It is concluded that a febrile episode seen in patients less than 2 weeks postoperatively should be considered a serious symptom and be treated intensively after thorough examination. © 1994 John Wiley & Sons, Inc.     

Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a

Subunit intranasal vaccines offer the prospect of inducing combined systemic-mucosal immunity against mucosally transmitted infections such as human immunodeficiency virus. However, although human studies have demonstrated the induction of active immunity, secretory immunoglobulin A (sIgA) responses are variable, and no study has demonstrated protection by accepted vaccine-licensing criteria as measured by direct toxin-neutralizing activity. Using the genetically inactivated mutant diphtheria toxoid CRM(197) in a bioadhesive polycationic polysaccharide chitosan delivery system, we found that a single nasal immunization was well tolerated and boosted antitoxin neutralizing activity in healthy volunteers, which could be further boosted by a second immunization. The neutralizing activity far exceeded accepted protective levels and was equivalent to that induced by standard intramuscular vaccine and significantly greater than intranasal immunization with CRM(197) in the absence of chitosan. A striking but unexpected observation was that although unilateral intranasal immunization induced circulating antitoxin antibody-secreting cells, a nasal antitoxin sIgA response was seen only after the second immunization and only in the vaccinated nostril. If these data are reproduced in larger studies, an intranasal diphtheria vaccine based on CRM(197)-chitosan could be rapidly licensed for human use. However, a restricted sIgA response suggests that care must be taken in the priming-boosting strategy and clinical sampling techniques when evaluating such vaccines for the induction of local mucosal immunity.     

Is MED13L-related intellectual disability a recognizable syndrome?

Introduction

MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.

The effect of infused fat emulsions on reticuloendothelial function in the rabbit

The effect of the infusion of different fat emulsions (Intralipid and MCT/LCT mixtures) on the reticuloendothelial function of the rabbit has been investigated. Emulsions containing 20% dispersed triglyceride were administered over 6 h to a total of 3 g/kg body weight. The extent of blockade of the reticuloendothelial system was measured using a labelled probe in the form of technetium-99m labelled albumin microspheres. Scintigraphic and blood and organ level determinations demonstrated that all emulsions caused an impairment of reticuloendoethlial function, but this was small.     

Surface Modification of Poly(lactide-co-glycolide) Nanospheres by Biodegradable Poly(lactide)-Poly(ethylene glycol) Copolymers

The modification of surface properties of biodegradable poly(lactide-co-glycolide) (PLGA) and model polystyrene nanospheres by poly(lactide)-poly(ethlene glycol) (PLA:PEG) copolymers has been assessed using a range of in vitro characterization methods followed by in vivo studies of the nanospheres biodistribution after intravenous injection into rats. Coating polymers with PLA:PEG ratio of 2:5 and 3:4 (PEG chains of 5000 and 2000 Da, respectively) were studied. The results reveal the formation of a PLA: PEG coating layer on the particle surface resulting in an increase in the surface hydrophilicity and decrease in the surface charge of the nanospheres. The effects of addition of electrolyte and changes in pH on stability of the nanosphere dispersions confirm that uncoated particles are electrostatically stabilized, while in the presence of the copolymers, steric repulsions are responsible for the stability. The PLA:PEG coating also prevented albumin adsorption onto the colloid surface. The evidence that this effect was observed for the PLA:PEG 3:4 coated nanospheres may indicate that a poly(ethylene glycol) chain of 2000 Da can provide an effective repulsive barrier to albumin adsorption. The in vivo results reveal that coating of PLGA nanospheres with PLA:PEG copolymers can alter the biodistribution in comparison to uncoated PLGA nanospheres. Coating of the model polystyrene nanospheres with PLA:PEG copolymers resulted in an initial high circulation level, but after 3 hours the organ deposition data showed values similar to uncoated polystyrene spheres. The difference in the biological behaviour of coated PLGA and polystyrene nanospheres may suggest a different stability of the adsorbed layers on these two systems. A similar biodistribution pattern of PLA:PEG 3:4 to PEG 2:5 coated particles may indicate that poly(ethylene glycol) chains in the range of 2000 to 5000 can produce a comparable effect on in vivo behaviour.     

Nasal drug delivery--possibilities, problems and solutions.

This paper discusses the problems associated with nasal drug delivery and how it is possible, sometimes by means of quite simple concepts, to improve transport across the nasal membrane. In this way it is feasible to deliver efficiently challenging drugs such as small polar molecules, peptides and proteins and even the large proteins and polysaccharides used in vaccines or DNA plasmids exploited for DNA vaccines. The transport of drugs from the nasal cavity directly to the brain is also described and examples of studies in man, where this has been shown to be feasible, are discussed. Recent results from Phase I/II studies in man with a novel nasal chitosan vaccine delivery system are also described. Finally, the author's thoughts about the future for nasal drug delivery are also depicted.     

Nasal clearance in health and disease.

This paper reviews the anatomical and physiological factors of importance for nasal drug delivery and discusses in particular the influence of the nasal mucociliary clearance mechanism on the nasal absorption of drugs. The effect of nasal pathological conditions on the mucociliary clearance mechanism and the possible effect of such disease states on nasal drug transport are also discussed. Strategies for the exploitation of bioadhesive drug delivery systems and especially nasal absorption enhancers for the improvement of nasal drug delivery are evaluated to include considerations of the mechanism of action and correlation between the degree of bioadhesion and absorption enhancement and transport of drugs across the nasal membrane. A range of studies involving bioadhesive/absorption enhancer systems are detailed. A selected bioadhesive material, chitosan, which has been shown to have excellent absorption enhancer properties for a variety of drugs is discussed in some detail.     

Concurrent uveoretinitis and pineocytoma in a child suggests a causal relationship.

Uveoretinitis was observed in a 9-year-old girl 6 months prior to the clinical appearance of a pineal tumour. Surgical removal was not successful but biopsy revealed a parenchymal neoplasm with differentiated pinealocytes and absent mitotic activity. Some of the tumour cells contained S-antigen, rhodopsin, and serotonin. Systemic glucocorticoid therapy followed by radiation therapy caused considerable reduction in size of the tumour and a complete normalisation of all eye symptoms. This report demonstrates for the first time that a pineocytoma can occur together with uveoretinitis in humans. The latter resembles the experimentally induced autoimmune uveoretinitis described in animals. It is speculated that the retinitis might reflect an autoimmune response to S-antigen present in some tumour cells of the pineocytoma.     

Nasal delivery of chitosan-DNA plasmid expressing epitopes of respiratory syncytial virus (RSV) induces protective CTL responses in BALB/c mice

Respiratory syncytial virus (RSV), an important pathogen of the lower respiratory tract, is responsible for severe illness both in new born and young children and in elderly people. Due to complications associated with the use of the early developed vaccines, there is still a need for an effective vaccine against RSV. Most pathogens enter the body via mucosal surfaces and therefore vaccine delivery via routes such as the nasal, may well prove to be superior in inducing protective immune responses against respiratory viruses, since both local and systemic immunity can be induced by nasal immunisation. Previously we have shown that intradermal immunisation of a plasmid DNA encoding the CTL epitope from the M2 protein of RSV induced protective CTL responses. In the present study, the mucosal delivery of plasmid DNA formulated with chitosan has been investigated. Chitosan is a polysachharide consisting of copolymers of N-acetylglucosamine and glucosamine that is derived from chitin, a material found in the shells of crustacea. Intranasal immunisation with plasmid DNA formulated with chitosan induced peptide- and virus-specific CTL responses in BALB/c mice that were comparable to those induced via intradermal immunisation. Following RSV challenge of chitosan/DNA immunised mice, a significant reduction (P<0.001) in the virus load was observed in the lungs of immunised mice compared to that in the control group. These results indicate the potential of immunisation with chitosan-formulated epitope-based vaccines via the intranasal route.     

The Effect of Blood Sampling Site and Physicochemical Characteristics of Drugs on Bioavailability After Nasal Administration in the Sheep Model

Purpose. Investigate the effect of blood sampling site and physicochemical characteristics of drugs on the pharmacokinetic (PK) parameters obtained after intravenous and nasal administration in sheep and compare results with computer simulations. Methods. Three drugs, insulin, morphine, and nicotine, were administered nasally and by intravenous (IV) injection to sheep, and serial blood samples collected concurrently from the carotid artery (insulin, morphine) or cephalic vein (nicotine) and jugular vein. Plasma drug concentrations were measured, and pharmacokinetic and statistical analyses performed, to evaluate sampling site differences. Results. After nasal insulin, bioavailabilities calculated from the two blood sampling site data were comparable. In contrast, apparent bioavailabilities following nasal morphine or nicotine were significantly higher when sampling was from the jugular vein. These results were supported by computer simulations. These observations are attributed to the greater effects of noninstantaneous mixing of drugs for jugular vein sampling following nasal dosing, compared to the other sampling sites, which is significant for drugs that are rapidly and well absorbed and that have a high volume of distribution (V_d). Conclusion. The results clearly show that the characteristics of the drug and the blood sampling site can have a significant effect on the pharmacokinetic results obtained after nasal administration in sheep.