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BACKGROUND: The efficacy of symmetrical-waveform high-frequency oscillating (HFO) air flow for airway secretion clearance is controversial and debated in the literature. METHODS: We conducted in vitro experiments with ovine tracheae to investigate the effects of symmetrical-waveform HFO on tracheal transport of artificial mucus. We mounted each trachea as an intact tube, with a 15o head-down tilt, infused artificial mucus (10 mL over one hour) at the caudal end of the trachea, and measured mucus-transport velocity as the time between the beginning of infusion and the first appearance of artificial mucus over 2 near-infrared sensors at the rostral end of the trachea and by measuring the amount of mucus emerging. In a second series of experiments we opened each trachea flat and with video microscopy we measured the transport velocity of plaques over the endogenous mucus sheet. RESULTS: In the intact-trachea preparation, HFO at 20 Hz and 50 cm H2O increased mucus-transport velocity from 5.8 mm/min to 7.8 mm/min. HFO led to nearly half the artificial mucus being cleared during the infusion period. In the opened-trachea experiments the mean control transport velocity was 8.7 mm/min, and HFO, at 14 Hz or 20 Hz (and 50 cm H2O), did not significantly alter that velocity. CONCLUSIONS: Symmetrical-waveform HFO increases mucus-transport velocity and mucus clearance when a thick layer of mucus is present. This may be important when considering the mechanisms of mucus clearance and using HFO for secretion clearance.

SUMMARY 1. Sheep hearts have been used to study the effects of P-adrenoceptor (P-AR) agonists in order to better understand the effects of common asthma treatment drugs on heart rate, cardiac power output and cardiac pathology. Hearts have been examined both in vivo and in vim. 2. In whole anaesthetized sheep, isoprenaline, fenoterol and salbutamol induced dose-dependent increases in heart rate. Hypokalaemia in response to salbutamol was accentuated in hypoxia. Many of these hearts showed significant myocardial lesions. Hypoxia alone caused no significant cardiac response. 3. As expected, the β1-AR agonist dobutamine caused dose-dependent increases in heart performance (heart rate and cardiac power output). Both responses were blocked by metoprolol and propranolol. The β2-AR agonist salbutamol caused dose-dependent increases in heart rate and although cardiac output increased, cardiac power output remained unchanged as a consequence of the fall in peripheral resistance. The heart rate changes were blocked by metoprolol. Importantly, propranolol blocked both the heart rate response and the fall in peripheral resistance. 4. Isolated atrial strips showed a right shift of their dose-response curve to isoprenaline in the presence of the highly selective β2-AR antagonist ICI 118 551 at concentrations above 1 × 10−-8 mol/L. 5. We conclude that the sheep heart shows many pharmacological characteristics of the human heart which makes it a good pharmacological model in addition to its being amenable to many common techniques available for humans.

We describe a new approach to attacking the problem of robust computer vision for mobile robots. The overall strategy is to mimic the biological evolution of animal vision systems. Our basic imaging sensor is based upon the eye of the common house fly, Musca domestica. The computational algorithms are a mix of traditional image processing, subspace techniques, and multilayer neural networks.

To test whether a reduction in air temperature within the clinical range [37 degrees C to 30, 100% relative humidity (RH)] altered mucus transport velocity (MTV) and ciliary beat frequency (CBF) in an in vitro ovine tracheal model.Controlled laboratory study.University research laboratory.Farm-reared sheep.Tracheae were mounted flat in an organ bath. Krebs Henseleit bathed the serosal surface and air at 100% (RH) was passed over the mucosal surface at 4 l/min. Cilial beat frequency (CBF) was measured photo-electrically and mucus transport velocity (MTV) by timing movement. After 2 h at 37 degrees C (100% RH) the tissue was either maintained with those settings (controls), or the air temperature reduced to 34 degrees C or 30 degrees C. Tissue was taken for histology before and after each experiment.CBF was 19.8+/-2.7 beats/s and MTV 5.7+/-2.6 mm/min in tissue exposed to air at 37 degrees C. Cilial activity continued for up to 6 h in the controls but mucus transport was more fragile. Reduction of the air temperature to either 34 degrees C or 30 degrees C led to a decrease in both CBF and MTV and, frequently, total mucociliary failure. There was a reduction in epithelial mucous cell numbers in all preparations. Tissues exposed to low temperature had additional abnormal histology.Delivery of inspired gas at 30 degrees C, or even 34 degrees C, with 100% RH may not be sufficient to prevent epithelial damage occurring during 6 h exposure.

CLA has a range of biological properties, including effects on lipid metabolism and body composition in experimental animals. The prevalent isomer of CLA found in the human diet is 9c,11 t-CLA, and it is predominantly found in products containing fat from ruminant animals. This study investigated the effect of dietary CLA on energy balance in mice. Synthetic CLA reduced body fat in growing male BALB/c mice in a dose-dependent manner over the range 0.25-1.0% w/w CLA in the diet. Weight gain was also reduced at the highest levels of dietary CLA, being only 5.88 +/- 2.68 g/4 mice (mean +/- 1 SD) after 4 wk of 2.0% CLA in the diet, compared with weight gains of 7.51 +/- 2.22 to 8.17 +/- 2.34 g/4 mice in the 0-0.5% CLA groups. There was no significant effect on weight gain if diets contained 0.5% synthetic CLA or less. These results suggest that high levels of a synthetic mixture of CLA isomers modify energy metabolism and body composition and that high levels of synthetic CLA impair weight gain and reduce body fat pad mass in growing mice.

At RMBS 2001 Olson presented a novel approach to image edge detection based on the vision system of the common house fly, Musca domestica [1]. Biologically based vision systems are inherently parallel and the vision related cells form a self-contained cartridge, ommatidium, which is duplicated across the surface of the fly's eye. Histological evidence provides the interconnection both within the vision cartridge and the connections to adjacent cartridges. Due to the parallel nature of biologically inspired vision systems, they outperform computer based digital vision systems in speed performance and memory requirements. Olson provided a model of the cartridge with its intra- and inter-connections. This model, rendered in MATLAB and Excel, demonstrated the feasibility of edge detection in the first several synaptic cellular connections within the cartridge. His results demonstrated how edge detection and object movements are easily obtained using a biologically based vision model. He demonstrated the model using simple rectangular and circular objects. We term this work Olson's Algorithm. We have extended Olson's Algorithm into a high-resolution model using a standard off-the-shelf frame grabber. Although, the frame grabber is a digitally based instrument, its image planes are used to model the photoreceptor layer (R1-R6), the L1, L2 monopolar cell layer, and also the monopolar L4 cell layer. The connections between these cells are programmed in "C". The high-resolution model demonstrates the feasibility of using a biologically based vision system in a real world application. Furthermore, it allows object segmentation, movement, and tracking to be modeled prior to implementation in parallel analog hardware.

Paclitaxel (taxol) phosphate derivatives BMY46366, BMY-46489, BMS180661 and BMS180820 were used to determine the ability of alkaline phosphatase to convert these water-soluble potential prodrugs to tubulin-polymerizing metabolites (i.e., paclitaxel). Compounds were treated up to 180 min with an in vitro metabolic activation system composed of 10% bovine alkaline phosphatase in 0.2 M tris, pH 7.4, or in 0.2 M glycine, pH 8.8, plus 0.05 M MgCl2. Samples were tested (either by direct addition or after methylene chloride extraction/dimethyl-sulfoxide resuspension) in spectrophotometric tubulin polymerization assays utilizing bovine-derived microtubule protein. Pretreatment of 2'- and 7-phosphonoxyphenylpropionate prodrugs BMS180661 and BMS180820 with alkaline phosphatase for 30 to 120 min yielded relative initial slopes of about 20 to 100% at test concentrations equimolar to paclitaxel. High-performance liquid chromatography/mass spectrometry of BMS180661 treated with alkaline phosphatase confirmed the production of paclitaxel from the prodrug. In contrast, 2'- and 7-phosphate analogs BMY46366 and BMY46489 treated with alkaline phosphatase were not active in tubulin assays. None of the paclitaxel phosphate prodrugs polymerized tubulin in the absence of metabolic activation. The differences in tubulin polymerization with metabolic activation may be related both to accessibility of the phosphate group to the enzyme and to anionic charge effects. These results demonstrate that certain paclitaxel phosphate prodrugs can be metabolized by alkaline phosphatase to yield effective tubulin polymerization.

The epithelial folding that occurs during bronchoconstriction requires that the pressure on the muscle side of the folding membrane be greater than that on the lumen side. The pressure required for a given level of folding depends on the elastic properties of the tissue and on the geometry of the folding. To quantify the elastic properties, uniaxial tensile stiffness of the tracheal inner wall of nine sheep was measured in two directions: parallel to the tracheal axis and circumferentially. The tissue showed anisotropic behavior, being approximately three times stiffer longitudinally than circumferentially. Histological examination showed that collagen in the lamina propria was randomly arranged, whereas there were straight elastin fibers aligned with the tracheal axis. This observation could explain the observed elastic anisotropy. Mechanical removal of the epithelium had no effect on tensile stiffness. It was also found that the tissue was under tension in situ. When a strip was excised, its length decreased by > or = 30%. After allowing for the systematic errors inherent in this experiment, the in situ circumferential tensile stiffness is estimated to be > or = 20 kPa. If the equivalent tissue in the bronchioles has the same tensile stiffness as that in the trachea, the forces required to fold the membrane are significant at small transbronchial pressure differences and increase in the presence of membrane thickening such as that seen in asthma.

Our objective was to see if activity of individual slowly and rapidly adapting pulmonary receptors was changed by pulmonary fibrosis. Diffuse interstitial lung fibrosis of several weeks' standing was induced in 8 rabbits. They displayed changes in lung mechanics and patterns of breathing, when compared to control rabbits, similar to those seen in patients who develop pulmonary fibrosis. Lung reflexes in the fibrotic rabbits were more profoundly changed than eupneic breathing in a way that could be interpreted as slowly adapting receptor activity, which was increased, being overpowered by a prepotent input from pulmonary rapidly adapting receptors. An increase in number of active rapidly adapting receptors was found in the fibrotic rabbits during direct vagal recording. We have demonstrated that pulmonary receptor activity is changed by lung fibrosis. It may be that these changes in receptor activity produce conflicting respiratory drives that could result in the sensation of dyspnea.

Adult rats of Wistar and Sprague Dawley strains were exposed to a 21-day period of hypoxia (10% O2). At the end of this period, the hypoxic animals and paired controls were anaesthetised, dissected and tissues were taken for light microscopy. All the hypoxic animals had an increased haematocrit, right ventricle weight and carotid body size when compared with controls. The Grimelius method was used to demonstrate argyrophil structures in the lung. This method stained the amine-containing cells of the epithelium, mast cells and nerves. Mast cells associated with the pulmonary vasculature were increased in number in the hypoxic animals. Single epithelial argyrophil cells were more frequent than those in groups. In control animals the groups of cells only rarely contained more than 5 cells. In the Wistar strain there was no significant difference in the number of argyrophil cells between the control animals and those exposed to chronic hypoxia. However, in the Sprague Dawley rats, the numbers of cells, both single and in groups, were significantly increased following 3 weeks chronic hypoxia. The cell groups were also larger in the hypoxic animals, with up to 12 cells per section.

The abdominal vagal paraganglia of the rat consist of small groups of cells, interspersed by blood vessels and nerve bundles and lying close to, or within, the vagus nerve or its branches. Each cell group consists of 2-10 Type I cells incompletely invested by 1-3 satellite cells. Type I cells are characterised by the presence of numerous dense-cored vesicles in their cytoplasm and may exhibit 'synaptic'-like contact with each other. Small efferent nerve endings make synaptic contacts with Type I cells. Larger cup-shaped afferent nerve endings also make synaptic contacts of two kinds with Type I cells. Nerve-nerve synapses are often seen within or close to paraganglia. Attention is drawn to the close similarity of fine structure of abdominal vagal paraganglia, carotid body and small intensely fluorescent cells of the superior cervical ganglion in rats. Possible functional implications of this morphological similarity are discussed.

In many vertebrates, including mammals, there are amine-containing cells in the walls of the airways and the lungs. Despite a plethora of names for these cells, there is a general agreement about their structure. They occur singly or in groups (NEBs), but the functional distinction between the two types of distribution is uncertain. In spite of ultrastructural similarities, the cells may be physiologically heterogenous. The cells are characterised by their staining characteristics and content of electron-dense-core vesicles, which are believed to contain a biogenic amine. They also have additional cytoplasmic features common to other sensory paraganglia. They may be more numerous in certain species and also in the neonate. The NEBs may be innervated with afferent and/or efferent nerves, though physiological evidence of their innervation is scanty. The most popular hypothesis is that they can be stimulated by hypoxia to release mediators or to induce reflex activity. In the healthy animal, the amine-cells may control local ventilation/perfusion (V/Q) ratios via an action on the pulmonary vasculature. In disease, they may cause pulmonary hypertension. They can also give rise to three forms of tumour. Their full significance has yet to be established.

The epithelium of the conducting airways of the mouse consists of a single layer of cells. The number, type and form of these cells have been investigated at five airway levels from the trachea to the distal conducting bronchi with both light and electron microscopes. Contrary to what is found in other species, the majority (50-60%) of cells in the murine airway epithelium are Clara cells. Mucus-producing tissue was infrequent throughout the airways, though epithelial mucous cells occurred in increased numbers at the carina and in the primary bronchus. No mucous or serous cells or submucosal glands were seen in intralobular airways. On a morphological basis, three distinct forms of Clara cell were recognized. On occasion, cells were observed which were apparently transitional types between these and also between Clara cells and mucous or ciliated cells. It is suggested that the 'transforming' cells may indicate a role for the Clara cell as a developmental cell involved in the epithelial cell turnover. Evidence is also provided that Clara cells may undergo both apocrine and merocrine secretion and, it is argued that the latter may be of a PAS + ve material. Free nerve endings were not seen in the epithelium. This may be related to athe restricted ability of mice to cough. It is suggested that the lack of mucus-producing tissue and of cough reflex may be due to the small diameter of the mouse airways.

A communication box paradigm which can eliminate the influence of the physical noxious stimuli such as electrical foot-shock from the conditioned emotional stimuli has recently been developed for producing gastric mucosal lesions (GML) in mice. In this situation, the unshocked animals (NE group) were exposed to affective stimuli such as visual, auditory and olfactory sensations from the shocked conspecifics (E group). The present study was conducted to investigate an experimental procedure that can be applied to rats. When the communication box paradigm was applied to rats, the incidence of GML was very low: E group (38%) and NE group (13%). Marked augmentation of the incidence of GML was obtained in both E and NE groups by reserpine pretreatment at the dose of 1 mg/kg which did not produce GML. Various kinds of GML were defined endoscopically using a narrow fibre scope. The manifestation of the GML in both E and NE groups was completely suppressed by vagotomy, whereas pyloroplasty was ineffective. The procedure for eliciting GML in rats was established by a combination of the communication box paradigm with reserpine pretreatment. The endoscopic technique may provide a clue for investigating the time-dependent healing process of GML, especially for evaluating the therapeutic effect of a drug.

The Clara cells are a group of cells, sometimes called "nonciliated bronchiolar secretory cells", found in the bronchiolar epithelium of mammals including man, and in the upper airways of some species such as mice. Their secretory function is assumed from their ultrastructural appearance, that usually includes copious smooth endoplasmic reticulum, many apical mitochondria and scanty secretory-like dense vesicles near the luminal membrane. An apical cap of the cell usually bulges into the airway lumen, and secretion may be by shedding this cap, or by diffusion secretion or by merocrine secretion in individual granules. The chemical nature of the secretion probably includes protein, glycoprotein and lipids. The secretion may contain enzymes. Its function is presumably to determine the chemical and physical properties of the lining of small airways, and it could behave as a kind of bronchiolar surfactant, limiting lung collapse. The Clara cells also contain much cytochrome P450 dependent mixed-function oxidases, which presumably play a detoxifying role. It is not known whether these oxidases can be secreted or whether they have a lipid-synthesizing function. Clara cells may be important in human disease, both by giving rise to tumours and by taking part in metaplastic changes in bronchiolar disease.

In the mouse, nerves were located throughout the trachea and extrapulmonary bronchi in both the smooth muscle and the connective tissue. However, no nerves were found within the epithelium. In the smooth muscle there were large numbers of nonmyelinated nerves. These were usually 'en passant' elements but varicosities containing small mitochondria and vesicles were also seen; these axons sometimes appeared to be efferent to the muscle. Unilateral cervical vagotomy reduced the numbers of nerves in the muscle of the trachea and ipsilateral primary bronchus, suggesting that they were afferent. The intramuscular nerves were characterized in terms of their complement of cytoplasmic organelles; in particular nerves containing many mitochondria disappeared following vagotomy. Pretreatment of mice with 5-hydroxydopamine to accentuate the electron-opacity of catecholamine-containing granules resulted in 3.5% of the nerves within tracheal muscle showing such granules. The afferent nerves of the smooth muscle may be complex branching structures with many varicosities. The absence of epithelial nerves may be related to the absence of the cough reflex in the mouse.

The tracheal epithelium of the mouse is a single layer of columnar cells resting on a basement membrane. Many of the cell types resemble those of other species. However, goblet cells are rare and ciliated cells occur only in scattered patches. Submucosal glands are absent from all but the highest reaches of the airway. The major proportion of the epithelial cells are non-ciliated. These usually project into the lumen of the trachea. Large amounts of smooth endoplasmic reticulum and many secretory vesicles occur within the cytoplasm. Secretory activity of these cells may be either apocrine or merocrine and these cells may transform into other cell types. It is suggested that these non-ciliated cells are Clara cells and that the mouse tracheal epithelium may make a useful model for the study of this type of cell.