The expression and impact of antifungal grooming in ants.

Parasites can cause extensive damage to animal societies in which many related individuals frequently interact. In response, social animals have evolved diverse individual and collective defences. Here, we measured the expression and efficiency of self-grooming and allo-grooming when workers of the ant Formica selysi were contaminated with spores of the fungal entomopathogen Metarhizium anisopliae. The amount of self-grooming increased in the presence of fungal spores, which shows that the ants are able to detect the risk of infection. In contrast, the amount of allo-grooming did not depend on fungal contamination. Workers groomed all nestmate workers that were re-introduced into their groups. The amount of allo-grooming towards noncontaminated individuals was higher when the group had been previously exposed to the pathogen. Allo-grooming decreased the number of fungal spores on the surface of contaminated workers, but did not prevent infection in the conditions tested (high dose of spores and late allo-grooming). The rate of disease transmission to groomers and other nestmates was extremely low. The systematic allo-grooming of all individuals returning to the colony, be they contaminated or not, is probably a simple but robust prophylactic defence preventing the spread of fungal diseases in insect societies.

Interannual Dynamics of Ice Cliff Populations on Debris-Covered Glaciers From Remote Sensing Observations and Stochastic Modeling.

Ice cliffs are common on debris-covered glaciers and have relatively high melt rates due to their direct exposure to incoming radiation. Previous studies have shown that their number and relative area can change considerably from year to year, but this variability has not been explored, in part because available cliff observations are irregular. Here, we systematically mapped and tracked ice cliffs across four debris-covered glaciers in High Mountain Asia for every late ablation season from 2009 to 2019 using high-resolution multi-spectral satellite imagery. We then quantified the processes occurring at the feature scale to train a stochastic birth-death model to represent the cliff population dynamics. Our results show that while the cliff relative area can change by up to 20% from year to year, the natural long-term variability is constrained, thus defining a glacier-specific cliff carrying capacity. In a subsequent step, the inclusion of external drivers related to climate, glacier dynamics, and hydrology highlights the influence of these variables on the cliff population dynamics, which is usually not a direct one due to the complexity and interdependence of the processes taking place at the glacier surface. In some extreme cases (here, a glacier surge), these external drivers may lead to a reorganization of the cliffs at the glacier surface and a change in the natural variability. These results have implications for the melt of debris-covered glaciers, in addition to showing the high rate of changes at their surface and highlighting some of the links between cliff population and glacier state.

Failure of a 1-day high-dose quadruple therapy for cure of Helicobacter pylori infection.

BACKGROUND: The optimal duration of treatment for eradication of Helicobacter pylori has still to be defined. A 1-day high-dose quadruple therapy with a combination of amoxycillin (or tetracycline), metronidazole, a bismuth salt and a proton pump inhibitor has led to eradication rates of 57-77%. In view of the high frequency of metronidazole-resistant strains of H. pylori in Europe, we hypothesized that by using clarithromycin in place of metronidazole and by increasing the dose of proton pump inhibitor, the efficacy of a 1-day high-dose quadruple therapy could be improved. METHODS: Patients were randomized to receive either amoxycillin 1000 mg b.d., clarithromycin 500 mg b.d. and lansoprazole 30 mg b.d. for 7 days, or amoxycillin 2000 mg q.d.s., clarithromycin 500 mg q.d.s., lansoprazole 30 mg t.d.s. and bismuth subcitrate 240 mg q.d.s. for 1 day. RESULTS: It was originally intended to include 100 patients. The first planned interim analysis performed after follow-up was completed for 30 patients revealed H. pylori eradication rates of 80% (12/15) in the 7-day triple therapy group and 20% (3/15) in the 1-day quadruple therapy group, the difference being highly significant (P = 0.003). Because the efficacy of the 1-day treatment was so low, the study was stopped for ethical reasons. Eleven patients who failed with the 1-day treatment were re-treated with the 7-day triple therapy: the eradication rate was 91% (10/11). CONCLUSIONS: One-day high-dose quadruple therapy with amoxycillin, clarithromycin, lansoprazole and bismuth subcitrate is dramatically less effective than the classic 7-day triple therapy with the same antibiotics.

Synthesis and characterization of an acylated di-peptide (Myr-Trp-Leu) with modified transmucosal transport properties.

In order to improve the buccal absorption of a dipeptide model compound, Tryptophan-Leucine (Trp-Leu), we have synthesised a lipophilic derivative by myristoylation of the N- terminal amino group of Trp-Leu. The acylated peptide (Myr-Trp-Leu) was characterized by HPTLC, purified and isolated by chromatography on a silica gel column. Its structure was confirmed by (13)C and (1)H NMR and mass spectroscopy. The increased lipophilicity of the Myr-Trp-Leu was compared to that of the native peptide by chromatography and by its partition coefficient between n-octanol and saline phosphate buffer. In addition, the sensitivity towards hydrolytic enzymes was studied. The interaction of Trp-Leu with liposomes as model membranes was also studied. The phase transition temperature of dipalmitoylphosphatidylcholine (DPPC) was lowered in the presence of Myr-Trp-Leu, while it was increased in the presence of native parent peptide. Permeation experiments performed in vitro with pig buccal mucosa showed that the Myr-Trp-Leu accumulated in the tissue at the various concentrations tested. In contrast, the native peptide was able to pass through the membrane at all concentrations used. Lipophilic modification of the peptide by acylation drastically changes its behaviour towards tissue systems.

Factors and strategies for improving buccal absorption of peptides.

Peptides and polypeptides have important pharmacological properties but only a limited number (e.g. insulin, oxytocin, vasopressin) have been exploited as therapeutics because of problems related to their delivery. The buccal mucosa offers an alternative route to conventional, parenteral administration. Peptides are generally not well absorbed through mucosae because of their molecular size, hydrophilicity and the low permeability of the membrane. Peptide transport across buccal mucosa occurs via passive diffusion and is often accompanied by varying degrees of metabolism. This review describes various approaches to improve the buccal absorption of peptides including the use of penetration enhancers to increase membrane permeability and/or the addition of enzyme inhibitors to increase their stability. Other strategies including molecular modification with bioreversible chemical groups or specific formulations such as bioadhesive delivery systems are also discussed.

In vivo evaluation of dosage forms: application of gamma scintigraphy to non-enteral routes of administration.

The trend to deliver drugs to defined areas of the body involves sophisticated carriers systems. In addition to the in vitro drug release profile one must be aware of the in vivo behaviour of the dosage form and the drug. Gamma scintigraphy is an elegant way to gain insights of the actual in vivo distribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables the in vivo determination of the targeting of the formulation administered through a large number of routes. The present paper reviews applications of gamma scintigraphy for the evaluation of dosage forms administered by the parenteral, rectal, buccal, nasal, pulmonary, and ophthalmic routes.

Mechanisms of potassium chloride release from compressed, hydrophilic, polymeric matrices: effect of entrapped air.

The release of potassium chloride from hydroxypropyl methylcellulose matrices was investigated for tablets prepared with several different compression forces. It was determined that the release kinetics for these systems deviates significantly from the classical t1/2 dependence. This behavior was attributed to air entrapped in the matrix during preparation. Removal of the air prior to release restored the traditional t1/2 behavior.

Permeation of a myristoylated dipeptide across the buccal mucosa: topological distribution and evaluation of tissue integrity.

The ex vivo permeation of an acylated model dipeptide, Myristoyl-Tryptophan-Leucine (Myr-Trp-Leu) was studied using pig buccal mucosa. Myr-Trp-Leu, being lipophilic, did not readily penetrate across the membrane. Rather, it accumulated in the epithelial and connective tissue of the mucosal barrier. The topological distribution of Myr-Trp-Leu across the mucosa, following its application in ethanol/phosphate buffer (30/70 pH 7.4), was determinated by thin-sectioning of the tissue, extraction of the peptide, and high performance thin layer chromatography (HPTLC). The concentration profile depended, of course, on the duration of the experiment and appeared to be dependent upon the presence of sufficient ethanol in order that the peptide could be solubilized. This important role for ethanol then raised the question of the solvent's effect on tissue integrity. Light microscopic examination of the mucosa was, therefore, undertaken, under identical conditions to those used in the permeation experiments, to evaluate any perturbation induced by the ethanolic vehicle. No obvious effects were observed.

Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention.

The mucoadhesive polysaccharide chitosan was evaluated as a potential component in ophthalmic gels for enabling increased precorneal drug residence times. This cationic vehicle was expected to slow down drug elimination by the lacrymal flow both by increasing solution viscosity and by interacting with the negative charges of the mucus. The molecular weight (Mw) and concentration of polysaccharide were studied in four types of chitosan as parameters that might influence ocular tolerability and precorneal residence time of formulations containing tobramycin as therapeutic agent. An ocular irritation test, using confocal laser scanning ophthalmoscopy (CLSO) combined with corneal fluorescein staining, clearly demonstrated the excellent tolerance of chitosan after topical administration onto the corneal surface. Gamma scintigraphic data showed that the clearance of the formulations labelled with 99mTc-DTPA was significantly delayed in the presence of chitosan with respect to the commercial collyrium (Tobrex(R)), regardless of the concentration and of the molecular weight of chitosan in solution. At least a 3-fold increase of the corneal residence time was achieved in the presence of chitosan when compared to Tobrex(R).

[The reliability of scintigraphic criteria of the lungs concerning the estimation of mediastinal involvement in case of bronchial carcinoma (prospective study) (author's transl)]. / Die Zuverlässigkeit lungenszintigraphischer Kriterien für die Beurteilung des Mediastinalbefalls beim Bronchialkarzinom (prospektive Studie)

The goal of this prospective study is to determine the reliability of the scintigraphic diagnosis of mediastinal involvement in patients with bronchial carcinoma, as well as to establish the value of each individual scintigraphic criterion. Ninety-four patients, all of whom were hospitalized because of suspicion of bronchial carcinoma were examined using 133-Xenon i.v., 133-Xenon gas inhalation, and 99m-Tc-MAA i.v. (macroaggregated albumin or microspheres of human albumin). The suspicion was confirmed in 77 patients. -The most reliable scintigraphic criteria are: 1. a localized delayed appearance of the activity in the afflicted lung area during the first 20 sec of the 133-Xenon i.v. series, and 2. the presence of a "dead-space" ventilation. Activity remaining in the area of the subclavian vein or the superior vena cava up to 10 min after the injection of 133-Xenon i.v. must be very carefully interpreted. Sixty-five patients underwent both mediastinoscopy and scintigraphy: in 44 patients (= 68%) the findings in both examinations were the same. Compared to the final diagnosis (mediastinoscopy, operation) there were 20 (= 30%) false negative but only one (= 2%) false positive scintigraphic diagnoses made. -When the scintigraphic criteria of hilar or mediastinal involvement are fulfilled, then the patient is practically certain to be no longer radically operable. This assertion is valid even when the mediastinoscopy is normal.

[Not Available]. / Mesure de la vitesse de dissolution pour l'amélioration et le contrôle de la qualité des médicaments.

The main purpose of this presentation is to define the different situations in which dissolution tests are used. The criteria for choosing a method and the establishment of the experimental procedure depend on the research goal. Information concerning the dissolution medium (surfactants, enzymes, volume, de-aeration) confirms, disproves, or completes the classical recommendations.

Determination of pilocarpine by HPLC in presence of isopilocarpine a pH-sensitive polymer in ophthalmic dispersions.

Quantification of pilocarpine in the presence of the epimer isopilocarpine in polymeric dispersions is reported. The method describes a technique using reversed-phase HPLC and UV detection of pilocarpine in the presence of a pH-sensitive polymer. As this method does not require prior sample preparation it will be of special interest for process control and development.

Cornea preparation for in vitro bio-pharmaceutical evaluation of ophthalmic dosage forms.

A system has been developed for a specific biopharmaceutical purpose: testing for ophthalmic preparations, the influence of formulation on drug transport through the cornea. The apparatus is a lucite cell, divided in two compartments by a clamped rabbit cornea. Physiological conditions are ensured by a supply of oxygenated perfusion medium. They are monitored by electrical conductivity and corneal thickness measurements. Reliability of the system was tested in a set of experiments.

Delivery of antibiotics to the eye using a positively charged polysaccharide as vehicle.

The positively charged polysaccharide chitosan is able to increase precorneal residence time of ophthalmic formulations containing active compounds when compared with simple aqueous solutions. The purpose of the study was to evaluate tear concentration of tobramycin and ofloxacin after topical application of chitosan-based formulations containing 0.3% wt/vol of antibiotic and to compare them with 2 commercial solutions: Tobrex and Floxal, respectively. The influence of the molecular weight, deacetylation degree, and concentration of 4 different samples of chitosan on pharmacokinetic parameters (area under the curve values [AUC(eff)] and time of efficacy [t(eff)]) of tobramycin and ofloxacin in tears was investigated over time. It was demonstrated that the 2 chitosan products of high molecular weight (1350 and 1930 kd) and low deacetylation degree (50%) significantly increased antibiotic availability when compared to the controls, with AUC(eff) showing a 2- to 3-fold improvement. The time of efficacy of ofloxacin was significantly increased from about 25 minutes to 46 minutes by the chitosan of higher Mw (1930 kd) at a concentration of 0.5% wt/vol, whereas a similar performance was achieved by a chitosan of low Mw (580 kd) at a concentration of 1.5% wt/vol in the case of tobramycin.

Gamma scintigraphic comparison of eyedrops containing pilocarpine in healthy volunteers.

The aim of the present study was to compare, in healthy human volunteers (male and female), the corneal contact time of various formulations, each containing one viscosity enhancer from the following list: a phase-transition system (gellan gum, Gelrite), a heteropolysaccharide (xanthan gum) and currently used polymers hydroxyethylcellulose, hydroxypropylmethylcellulose, or poly(vinyl alcohol). These different solutions were compared to a reference solution containing no viscosity enhancers. The corneal contact time of the formulations was evaluated over more than 20 minutes by gamma scintigraphy using Technetium-99m (Tc-99m DTPA) as a radioactive label. An eyedrop containing pilocarpine salts (25 microliters) was instilled in one eye only. Each volunteer received 4 formulations, the interval between the instillations being one week. The protocol has been approved by the relevant institutional human experimentation committee. One minute after instillation, only 23% of the reference solution remained on the ocular surface, whereas the novel formulations maintained, respectively, 77% (xanthan gum) or 82% (Gelrite) of the tracer on the ocular surface. Twenty-one min after instillation, 12% (reference solution), 25% (xanthan gum solution), and 39% (gelrite solution) of the tracer remained on the ocular surface. The results confirm that an increase in viscosity of the formulation (xanthan) delays the clearance of the instilled solution by the tear flow. The effect of the gelation mechanism is superior, especially at the later time points. In this respect, xanthan gum and, particularly, Gelrite are suitable vehicles for ophthalmic drugs.

Chitosan as tear substitute: a wetting agent endowed with antimicrobial efficacy.

A cationic biopolymer, chitosan, is proposed for use in artificial tear formulations. It is endowed with good wetting properties as well as an antibacterial effect that are desirable in cases of dry eye, which is often complicated by secondary infections. Solutions containing 0.5% w/v of a low molecular weight (M(w)) chitosan (160 kDa) were assessed for antibacterial efficacy against E. coli and S. aureus by using the usual broth-dilution technique. The in vitro evaluation showed that concentrations of chitosan as low as 0.0375% still exert a bacteriostatic effect against E. coli. Minimal inhibitory concentration (MIC) values of chitosan were calculated to be as low as 0.375 mg/ml for E. coli and 0.15 mg/ml for S. aureus. Gamma scintigraphic studies demonstrated that chitosan formulations remain on the precorneal surface as long as commonly used commercial artificial tears (Protagent collyrium and Protagent-SE unit-dose) having a 5-fold higher viscosity.

Prodrugs for the improvement of drug absorption via different routes of administration.

The authors critically review recent knowledge on the use of prodrugs to improve drug absorption. Main emphasis is placed on the parenteral, oral, transdermal and ocular routes. Mechanisms for drug absorption enhancement and bioavailability assessment are discussed. Some other applications of prodrugs are also examined. Finally, some comments are made regarding the present situation and future trends in prodrug design and their implications in biopharmaceutics and pharmacokinetics.

Role of the natural immunity to diphtheria in preventing an outbreak of the disease in the community.

PIP: The presence of immunity to diphtheria in children with no history of diphtheria vaccination from Tambon Chiang Rak Noi, Bang-Pa-In District, central Thailand was determined by Schick tests and throat and skin cultures. 69 or 36.3% of 190 children aged 1-9 had negative, or immune, Schick tests. 39 children showed Corynebacterium organisms, 6 of which were positive for C. diphtheriae. 37 of the positive isolates were from throat swabs, 3 of them were from skin lesions, and 1 child had positive cultures of both throat and skin. Diphtheria organisms are known to persist in the mucous membrane of the nose and throat for years in about 1% of convalescents of the disease.^ieng