A clinical study on the tolerability of a liposomal povidone-iodine nasal spray: implications for further development.

PURPOSE OF STUDY: This phase I study assessed tolerability and local effect of a liposome dispersion with povidone-iodine (polyvinylpyrrolidone-iodine, PVP-I) as nasal spray. PROCEDURES: Three groups received liposomal dispersion with PVP-I (2.2, 4.4 and 0% as control) in single and repeated use (3 days, three times a day). A set of functional and cytological tests as well as safety assessments were performed. RESULTS: No safety-relevant finding or serious adverse events were reported, no evidence for cyto- nor genotoxicity obtained. No clinically relevant changes in mucosa appearance, nor in olfactory sense, nor in ciliary activity (sensitive indicator of local tolerance) occurred and no complaints about nasal airflow obstruction were observed. All liposomal formulations had a positive effect on the nasal mucosa, challenged by allergy in some volunteers. CONCLUSIONS AND MESSAGE: Application of liposomal PVP-I spray to the nasal mucosa does not result in any demonstrable limitation of the nasal function nor in detectable damage to the multilayer ciliated epithelium of the nose. Improvement of various parameters of nasal function under liposomal PVP-I suggest improved mucociliary clearance. Explanation could be humidification, improved surfactant (phospholipid) level and/or sufficient mucolytic activity of iodide due to local application of the constituents.

Mucosal antibody response induced with a nasal virosome-based influenza vaccine.

A vaccination against influenza that elicits both a systemic antibody and a mucosal IgA response would improve on the protective efficacy of currently available vaccines. Previous studies have shown the safety and efficacy of virosomes as delivery systems in vaccination. This study was a controlled, randomised, double-blind, single centre, phase II trial assessing an intranasal virosome vaccine, adjuvanted with heat-labile toxin (HLT) from enterotoxigenic Escherichia coli, versus an intranasal without HLT and comparing it open to an intramuscular vaccine in a total of 88 healthy adults. The development of a new technique enabled for the first time the detection of neutralising IgA antibodies in very dilute nasal wash samples. It was demonstrated that intranasally administered inactivated influenza vaccine, adjuvanted with HLT, not only elicits a spectrum of humoral and cell-mediated responses in healthy adults, critical for the protection and recovery from influenza virus infection, but is also highly effective in eliciting IgA neutralising antibodies at the mucosa. Intranasal virosome-formulated, HLT-adjuvanted, influenza vaccine was effective and well tolerated in this study. Its potential to offer a high level of mucosal protection, not provided by conventional parenteral vaccination, could play a significant role in preventing morbidity and mortality associated with influenza.

The nose as bacterial reservoir: important differences between the vestibule and cavity.

UNLABELLED: The difference between the spectra of potential bacterial pathogens (PBPs) in the nasal vestibule and cavity has not been taken into account in clinical studies. PURPOSE: Since one can anticipate different flora in different kinds of mucosae, the authors compared bacterial species in the vestibule with those of the cavity. SUBJECTS AND METHOD: A total of 534 healthy male clerical workers in a downtown Lucerne office building were examined with fractionated swabs. RESULTS: PBPs, notably Staphylococcus aureus, were found in 412 subjects and surprisingly, differences in flora of the two sites were noted in 130 of them: PBPs were observed in the vestibule and not in the cavity in 85 of the subjects, and in 45 of them, the reverse was true. CONCLUSION: The practical implications of these findings are considerable regarding infection control in patients at increased infection risk.

Epithelial changes in seasonal allergic rhinitis throughout the year: evidence of coexistent air pollution and local secretory IgA deficiency?

To determine possible epithelial changes in seasonal allergic rhinitis, we examined epithelial cells in cytology swab preparations of 38 non-smoking patients, exclusively sensitized to grass pollen, throughout the year, and surgical material of 8 patients. Cytologically, we found a marked goblet cell hyperplasia during the period of grass pollen exposure, while meta- and dysplasia were found throughout the year. Immunohistochemically, a lack of secretroy IgA in the altered epithelium was detected. These results were not obtained in the control group of 60 healthy non-smokers. Since we have recently found the same epithelial changes of meta- and dysplasia in smokers, these findings may point to non-specific toxic damage of the nasal epithelium possibly caused by other air pollutants. The altered epithelium may lead to an impairment of the local secretory IgA defence system and thereby to an increased allergen uptake.

The comet assay of nasal epithelia: measurement of DNA damage for the assessment of genotoxic air pollution.

OBJECTIVES: The alkaline single cell gel electrophoresis or "comet" assay allows measurement of DNA damage in single cells with a high degree of sensitivity, e.g., for investigations of the effect of environmental agents with DNA-damaging potential. This study aimed to adapt this test to respiratory cells of the human nasal mucosa to examine the genotoxic effect of air pollution (cigarette smoke). STUDY DESIGN: In a prospective study, nasal epithelia of 16 cigarette smokers were examined by the adapted comet assay and the results were correlated with the results of the Papanicolaou-stained nasal cytology, carried out in a blinded fashion. The control group comprised 20 non-smoking men. All subjects under investigation were healthy office workers. METHODS: Nasal epithelia were harvested from the maxilloturbinates. One part of cells was Papanicolaou stained and evaluated by cytopathologists. The comet assay was performed on the other part of the cells. The examiners were blinded to the study and control groups. RESULTS: Among cigarette smokers, a significant correlation between cytopathological cell nucleus changes (metaplasia and dysplasia) and the DNA migration (tail lengths) in the comet assay was found as a sign of DNA damage. This was not found in nonsmoking control persons. CONCLUSIONS: These results confirm the sensitivity of the comet assay and the hypothesis that cell nucleus changes in conventional nasal cytology are associated with DNA damage.

Phase 1 evaluation of intranasal virosomal influenza vaccine with and without Escherichia coli heat-labile toxin in adult volunteers.

Virosomal vaccines were prepared by extracting hemagglutinin (HA) and neuraminidase from influenza virus and incorporating it in the membranes of liposomes composed of phosphatidylcholine. Two intranasal spray vaccine series were prepared: one series comprised 7.5 micrograms of HA of each of three strains recommended by the World Health Organization and 1 microgram of Escherichia coli heat-labile toxin (HLT), and the other contained the HA without HLT. In addition, a third vaccine preparation contained 15 micrograms of HA and 2 micrograms of HLT. The parenteral virosomal vaccine contained 15 micrograms of HA without additional adjuvant. The immunogenicity of a single spray vaccination (15 micrograms of HA and 2 micrograms of HLT) was compared with that of two vaccinations (7.5 micrograms of HA with or without 1 microgram of HLT) with an interval of 1 week in 60 healthy working adults. Twenty volunteers received one parenteral virosomal vaccine. Two nasal spray vaccinations with HLT-adjuvanted virosomal influenza vaccine induced a humoral immune response which was comparable to that with a single parenteral vaccination. A significantly higher induction of influenza virus-specific immunoglobulin A was noted in the saliva after two nasal applications. The immune response after a single spray vaccination was significantly lower. It could be shown that the use of HLT as a mucosal adjuvant is necessary to obtain a humoral immune response comparable to that with parenteral vaccination. All vaccines were well tolerated.

[The nose in internal medicine]. / Die Nase in der Inneren Medizin.

Compared with the lower respiratory tract, the nose reacts with greater physiological sensitivity to environmental stimuli by means of secretion, obstruction and sneezing. When a certain level of nasal reaction is exceeded, we have what is called vasomotoric rhinopathy. Systemic illnesses can also be reflected in the nose. Timely recognition can prevent life-threatening situations such as arise in Wegener's granulomatosis or rhinoliquorrhoea. In rhinitic complaints thought should also be given to the possible side effects of medication. Antihypertensive products and hormonal contraceptives are those most frequently responsible. The suffering experienced by a patient with chronically blocked nasal breathing is often underestimated. A variety of possible causes are reviewed.

Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin.

BACKGROUND: Control of the nuclear localization of specific proteins is an important mechanism for regulating many signal transduction pathways. Upon activation of the Wnt signaling pathway, beta-catenin localizes into the nucleus and interacts with TCF/LEF-1 (T-cell factor/lymphocyte enhancer factor-1) transcription factors, triggering activation of downstream genes. The role of regulated nuclear localization in beta-catenin signaling is still unclear. Beta-catenin has no nuclear localization sequence (NLS). Although it has been reported that beta-catenin can piggyback into the nucleus by binding to TCF/LEF-1, there is evidence that its import is independent of TCF/LEF-1 in vivo. Therefore, the mechanism for beta-catenin nuclear localization remains to be established. RESULTS: We have analyzed beta-catenin nuclear import in an in vitro assay using permeabilized cells. Beta-catenin docks specifically onto the nuclear envelope in the absence of other cytosolic factors. Docking is not inhibited by an NLS peptide and does not require importins/karyopherins, the receptors for classical NLS substrates. Rather, docking is specifically competed by importin-beta/beta-karyopherin, indicating that beta-catenin and importin-beta/beta-karyopherin both interact with common nuclear pore components. Nuclear translocation of beta-catenin is energy dependent and is inhibited by nonhydrolyzable GTP analogs and by a dominant-negative mutant form of the Ran GTPase. Cytosol preparations contain inhibitory activities for beta-catenin import that are distinct from the competition by importin-beta/beta-karyopherin and may be involved in the physiological regulation of the pathway. CONCLUSIONS: Beta-catenin is imported into the nucleus by binding directly to the nuclear pore machinery, similar to importin-beta/beta-karyopherin or other importin-beta-like import factors, such as transportin. These findings provide an explanation for how beta-catenin localizes to the nucleus without an NLS and independently of its interaction with TCF/LEF-1. This is a new and unusual mechanism for the nuclear import of a signal transduction protein. The lack of beta-catenin import activity in the presence of normal cytosol suggests that its import may be regulated by upstream events in the Wnt signaling pathway.

[The power of odors--pathogenic or unpleasant]. / Macht der Gerüche--krank machend oder belästigend.

Modern toxicological studies have prompted us to rethink the role of olfaction and odours in our world. Our sense of smell is able to discriminate between an almost unlimited number of compounds of different chemical composition at extremely low threshold levels. Olfaction is classified as a chemical sense because of the bimolecular excitation process between the stimulant and receptor molecule. Receptor molecules of the olfactory epithelium have a variable region of the molecule which can differentiate between an unlimited number of aromatics. The sense of smell--the oldest phylogenetic sense--is therefore in very intensive contact with the "chemical" environment. Virtually all of the aromatic products which we are exposed to are highly complex chemical mixtures of numerous individual components which have a toxic potential little investigated to date. The perception of odours can be interpreted as a warning--a protective mechanism necessary for survival. At the same time, however, the exaggerated use of perfumes is held to be indicative of a highly cultured status. Unlike any other sense, that of smell is directly connected to archaic areas of the paleocortex region of the cerebral hemisphere, so that an odour will fill us with joy or abhorrence outside of our control. Odours cannot, therefore, be analyzed rationally without eliciting instinctive reactions, positive or negative, which result in acceptance or rejection. The highly developed memory for odour types is believed to be coupled to the route of the olfactory tract. The use of olfactometry today enables odours to be reliably quantified and characterized in a reproducible manner.

Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus.

beta-Catenin, a cytoplasmic protein known for its association with cadherin cell adhesion molecules, is also part of a signaling cascade involved in embryonic patterning processes such as the determination of the dorsoventral axis in Xenopus and determination of segment polarity in Drosophila. Previous studies suggest that increased cytoplasmic levels of beta-catenin correlate with signaling, raising questions about the need for in- teraction with cadherins in this process. We have tested the role of the beta-catenin-cadherin interaction in axis formation. Using beta-catenin deletion mutants, we demonstrate that significant binding to cadherins can be eliminated without affecting the signaling activity. Also, depletion of the soluble, cytosolic pool of beta-catenin by binding to overexpressed C-cadherin completely inhibited beta-catenin-inducing activity. We conclude that binding to cadherins is not required for beta-catenin signaling, and therefore the signaling function of beta-catenin is independent of its role in cell adhesion. Moreover, because beta-catenin signaling is antagonized by binding to cadherins, we suggest that cadherins can act as regulators of the intracellular beta-catenin signaling pathway.

Extracorporeal shock wave treatment raises blood pressure in borderline hypertensive rats.

The long-term sequelae on kidney function and blood pressure of renal shock wave treatment were studied in normotensive Wistar rats, contralaterally nephrectomized Wistar rats and borderline hypertensive F1-hybrids bred from stroke-prone spontaneously hypertensive rats and Wistar-Kyoto rats. Renal shock wave treatment raised arterial blood pressure in borderline hypertensive, but not in normotensive, rats. A concomitant impairment of ipsilateral renal function or perfusion was not seen despite macroscopic and microscopic evidence of a loss of functioning parenchyma. We conclude that extracorporeal shock wave treatment, by way of its detrimental effects on the kidney, has the potential to provoke arterial hypertension in rats, provided that a genetic predisposition exists.

The state of actin assembly regulates actin and vinculin expression by a feedback loop.

Actin filaments are major determinants of cell shape, motility and adhesion, which control important biological processes including embryonic development and wound healing. These processes are associated with changes in actin assembly, which is regulated by controlling the balance between polymerized and non-polymerized actin. To maintain a significant pool of non-polymerized actin, mechanism(s) linking actin synthesis to its state of polymerization were proposed. We have studied this relationship between actin synthesis and organization by modulating actin assembly using different drugs. Unassembled actin was increased in 3T3 cells using either the Clostridium botulinum C2 toxin, which ADP-ribosylates actin, or by latrunculin A, a Red Sea sponge product, which binds monomeric actin. The synthesis of actin was dramatically reduced in these cells owing to a concomitant decrease in actin RNA level. Similar results were obtained with HeLa cells grown in both monolayer and in suspension, suggesting that cell shape changes associated with drug treatment are not the primary cause for the effect on actin synthesis. In contrast, the scrape-loading of 3T3 cells with phalloidin, a stabilizer of polymerized actin that increased the level of assembled actin, resulted in elevated actin synthesis and RNA content. The expression of vinculin, a major component of adhesion plaques and cell-cell junctions, which is involved in actin-membrane associations, was altered in parallel with that of actin in cells treated with these drugs. The decrease in actin RNA resulted from destabilization of actin mRNA in cells where unassembled actin level was elevated. This is suggested by the unchanged transcription of actin in isolated nuclei from drug-treated cells, and by demonstrating that actin mRNA was degraded faster in cells after C2 toxin treatment than in control cells. This feedback control mechanism is mainly confined to the cytoplasm, as it remained active in enucleated cells. The results suggest the existence of an autoregulatory pathway for the expression of actin and other microfilament-associated proteins which is linked to the state of actin polymerization in the cell.

[Clinical experiences with local capsaicin treatment of chronic rhinopathy]. / Klinische Erfahrungen mit lokaler Capsaicinbehandlung bei chronischer Rhinopathie.

Eighty-four patients with clinical findings of hyperactive rhinopathy and no significant septal deviations were treated for 4 weeks with topical applications of capsaicin, which is the pungent substance in hot peppers. A neutral solution of low-dose capsaicin allowed patients to administer self-therapy without the need for local anesthesia. The majority of the patients showed a marked reduction in symptoms without significant side effects. Patients with (additional) allergic or medication-related rhinopathy seemed to show fewer therapeutic effects when compared to patients with only hyperactive rhinopathy.

Modulation of alpha-actinin levels affects cell motility and confers tumorigenicity on 3T3 cells.

alpha-Actinin is an abundant actin crosslinking protein, also localized at adherens type junctions. In adhesion plaques, alpha-actinin can link the actin filaments to integrin via vinculin and talin, or directly by binding to the cytoplasmic domain of beta 1-integrin. The expression of alpha-actinin is rapidly elevated in growth-activated quiescent cells, and is reduced in SV40-transformed 3T3 cells and various differentiating cell types (reviewed by Glück, U., Kwiatkowski, D. J. and Ben-Ze'ev, A. Proc. Nat. Acad. Sci. USA 90, 383-387, 1993). To study the effect of changes in alpha-actinin levels on cell behavior, alpha-actinin expression was elevated in 3T3 cells by transfection with a full-length human nonmuscle alpha-actinin cDNA. To suppress alpha-actinin levels, 3T3 cells were transfected with an antisense alpha-actinin cDNA construct. Cells overexpressing alpha-actinin by 40-60% displayed a significant reduction in cell motility, as demonstrated by their slower locomotion into an artificial wound, and by forming shorter phagokinetic tracks on colloidal gold-coated substrata. 3T3 cells in which the expression of alpha-actinin was reduced to 25-60% of control levels, after antisense alpha-actinin transfection, had an increased cell motility. Moreover, such alpha-actinin-deficient 3T3 cells formed tumors upon injection into nude mice. The results demonstrate that modulations in alpha-actinin expression can affect, in a major way, the motile and tumorigenic properties of cells, and support the view that decreased alpha-actinin expression could be a common regulatory pathway to malignant transformation of 3T3 cells.

Suppression of tumorigenicity in simian virus 40-transformed 3T3 cells transfected with alpha-actinin cDNA.

Human cytoskeletal alpha-actinin cDNA was transfected into highly malignant simian virus 40-transformed BALB/c 3T3 (SVT2) cells that express 6-fold lower levels of alpha-actinin than nontransformed BALB/c 3T3 cells. SVT2 clones expressing various levels of alpha-actinin were isolated and their structure and tumorigenic properties were determined. Transfected SVT2 clones expressing alpha-actinin at levels found in nontumorigenic 3T3 cells displayed a flatter phenotype, a decreased ability to grow in suspension culture in soft agar, and a marked reduction in their ability to form tumors in syngeneic BALB/c mice and in athymic nude mice. Clones overexpressing alpha-actinin at the highest level (about 2-fold higher than 3T3 cells) were completely suppressed in their ability to form tumors in syngeneic BALB/c mice. The results suggest that alpha-actinin, an actin-crosslinking protein that is also localized in cell junctions, may have an effective suppressive ability on the transformed phenotype.

[The history of bronchial asthma]. / Die Geschichte des Asthma bronchiale.

'Panta rhei': everything flows. The significance of bronchial asthma is currently changing to no less a degree than medicine itself. In order to know where we are, we must know where we have come from. The historical course of bronchial asthma to some extent reflects the history of medicine itself: the Hellenic systems were followed by Byzantine, Galenic teaching methods, while Humanism and the Renaissance were followed by the considerable fireworks of early modern medicine. This continued with Magendie's experimental revolution in the 19th century and, finally, analytic medical research up to today.