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A transition between polymorphic phenotypes was observed within a single male Sternarchogiton nattereri. This individual was initially toothless, but developed into a toothed phenotype characterized by a swollen distal upper jaw and distinctive external dentition. Changes in morphological features were accompanied by shifts in electrocommunication (chirping) behaviour.

In this study we examined electrocommunication behavior in Sternarchogiton nattereri (Apteronotidae), a weakly electric fish from South America. We focused on variation between females and males lacking external dentition and used playbacks of simulated conspecifics to elicit chirps (modulations of their electric organ discharge, EOD). Chirp responses were not affected by the frequency of the playback stimulus. EOD frequency, chirp rate, and chirp duration were not sexually dimorphic; however, the amount of chirp frequency modulation was significantly greater in toothless males than in females. These results reinforce that sex differences in chirp structure are highly diverse and widespread in the Apteronotidae.

Supplementary methods and results

Nicotinamide (2) is a potent and selective inhibitor of the PDE4D isozyme and as a chemical tool selectively blocks eosinophil mediator release and chemotaxis thus linking the role of PDE4D to eosinophil function.

It is known that the only topological invariants P for which anti(P) = anti2 (P), anti( ) denoting Bankston's total negation operator, are those which are determined purely by the cardinality of the underlying point-set. We examine equations of the form antin (P) = antin (not P), reaching similar conclusions for n ≤ 2 but weaker ones for n > 3. A corresponding investigation for total negation within a constraint is initiated.

CP-80,633, un inhibiteur selectif de la phosphodiesterase (PDE) 4, neutralise fortement la bronchoconstriction induite par l'histamine chez des cobayes anesthesies (ED 5 0 10 μg/kg), mais ne decontracte que legerement la trachee de cobaye contractee par l'histamine (EC 5 0 137 μM). Utilisant CP-80,633 comme un inhibiteur prototypique de PDE4, nous avons verifie l'hypothese que la bronchodilatation induite par les inhibiteurs de PDE4 n'est pas vehiculee par une relaxation directe du muscle lisse des voies aeriennes. Chez les cobayes anesthesies, une dose bronchodilatatrice de CP-80,633 n'a pas augmente les catecholamines plasmatiques; de plus, la capacite de CP-80,633 de neutraliser la bronchoconstriction induite par l'histamine n'a pas ete modifiee de maniere significative par un pretraitement au propranolol. Dans une preparation d'organes isoles, l'activite des bronchodilatateurs pourrait etre attenuee par l'absence d'activateurs endogenes de l'adenylyl cyclase ou par la diminution des taux de nucleotides cycliques intracellulaires. Un pretraitement avec l'agoniste des adrenorecepteurs β, salbutamol, ou avec l'inhibiteur de PDE3, imazodan, n'a pas potentialise la capacite de bronchodilatation de CP-80,633. Un pretraitement au milrinone a augmente la puissance de CP-80,633 a decontracter les anneaux tracheaux contractes par le carbachol, mais seulement aux concentrations ou aucun effet specifique n'a ete signale. En comparant les capacites bronchodilatatrices des inhibiteurs de PDE dans les anneaux de trachee pourvus ou non d'endothelium, nous avons determine que l'epithelium n'a pas constitue une barriere a la penetration medicamenteuse. Ainsi, CP-80,633 est un puissant bronchodilatateur in vivo dont l'activite n'est ni vehiculee par la relaxation directe du muscle lisse des voies aeriennes ni dependante des catecholamines endogenes.

Perhaps the best indicators of the diverse mechanisms that contribute to the pathology of asthma are the number and variety of targets that have been identified, largely through advances in immunology and molecular biology. Here, the authors summarize the rationale and preliminary outcomes for novel therapeutic approaches that have developed as a result of such advances. The review is focused primarily on novel small-molecule approaches rather than the improvements that have been made in existing asthma therapies or the development of biological agents.

TheBAallele of theDrosophilacytochrome P450 geneCyp6g1confers resistance to a range of insecticides. It is also subject to intralocus sexual conflict when introgressed into theCanton-Sbackground, whose collection predates the widespread use of insecticides. In this genetic background, the allele confers a pleiotropic fitness benefit to females but a cost to males, and exhibits little sexual dimorphism in conferred insecticide resistance. It is unclear whether these sexually antagonistic effects also exist in current populations that have naturally evolved with insecticides, where genetic modifiers that offset male costs might be expected to evolve. Here, we explore these issues usingDrosophila melanogastercaught recently from an Australian population in which theBAallele naturally segregates. While we find increased fecundity in insecticide-resistantBAfemales and no consistent evidence of fitness costs in males, experimental evolution indicates balancing selection at the locus. We suggest that this apparent discrepancy may be due to reduced investment in reproduction in resistant males. Our results at the population level are consistent with previous work, and suggest that individual-level fitness assays do not always capture sexually antagonistic fitness effects that emerge in a population context.

A transition between polymorphic phenotypes was observed within a single male Sternarchogiton nattereri. This individual was initially toothless, but developed into a toothed phenotype characterized by a swollen distal upper jaw and distinctive external dentition. Changes in morphological features were accompanied by shifts in electrocommunication (chirping) behaviour.

The following study was performed to test the hypothesis that treatment with rolipram, a specific inhibitor of phosphodiesterase (PDE) IV, should inhibit many pulmonary responses to acute and chronic antigen challenge in atopic monkeys by elevating intracellular cAMP and subsequently inhibiting leukocyte function. Monkeys received subcutaneous injections of either vehicle (2% DMSO) or 10 mg/kg of rolipram 1 h before exposure to Ascaris suum antigen (Ag). Acute responses to Ag, including bronchoconstriction, pulmonary leukocyte infiltration, and cytokine production, were monitored before and 4 h after single Ag aerosol administration. To monitor the effects of rolipram on chronic Ag exposure, a 10-d, multiple-Ag protocol, previously demonstrated to induce airway hyperresponsiveness (AHR) to methacholine (MCh), was performed. Ag exposure increased respiratory system resistance (Rrs) 221.7 +/- 31.88% (n = 5). This increase in Rrs was not significantly altered by rolipram. Rolipram significantly (p0.002) increased cAMP levels in bronchoalveolar lavage (BAL) leukocytes 1 h after administration (n = 5). Ag-induced increases in BAL IL-8 and TNF were significantly reduced by rolipram, but IL-1 beta and IL-6 increases were unaffected (n = 9). Ag-induced increases in BAL eosinophils and neutrophils were significantly reduced by rolipram (n = 9). In the multiple-Ag protocol (n = 7), rolipram significantly reduced both the number of BAL eosinophils (p0.02) and the development of AHR (p0.002). Despite its inability to inhibit acute Ag-induced bronchoconstriction, rolipram was protective against acute and chronic inflammatory responses to Ag and prevented the development of AHR, suggesting that selective PDE-IV inhibition is a relevant target for asthma therapy.

Airway hyperresponsiveness (AHR) and pulmonary inflammation are observations that are consistently associated with asthma and also occur in a well-characterized monkey model of asthma. The following study was performed to determine whether treatment with an LTD4 receptor antagonist, ICI 198,615, could attenuate antigen-induced pulmonary inflammation and AHR in monkeys using the following protocol. On day 0, the PC200 (the concentration of methacholine (MCh) that doubled respiratory system resistance, Rrs) was determined in 6 male, atopic, cynomolgus monkeys, previously characterized in historical control trials (Control #1) as airway hyperresponsive. Bronchoalveolar lavage (BAL) was then performed to determine total and differential leukocyte counts. On days 3, 5 and 7, each monkey received 10 mg/kg ICI 198,615 (im) 30 min prior to Ascaris suum (Ag) aerosol exposures which doubled Rrs. On day 10, the post-Ag PC200 to MCh was determined and BAL was repeated. Five weeks after this trial was complete, a bracketing control trial (Control #2) was performed in which the monkeys were administered vehicle prior to each Ag exposure. In comparison to the response in both control trials, treatment with the LTD4 antagonist significantly (P < 0.05) inhibited the development of AHR and also significantly reduced (P < 0.05) peripheral blood lymphocyte counts after Ag challenge. Treatment with ICI 198,615 reduced the Ag-induced increase in BAL eosinophils, but statistical significance was obtained only when treated animals were compared to Control #1, not Control #2.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the potential role of neuropeptides in acrolein-induced airway responses, capsaicin-treated guinea pigs were exposed to acrolein aerosol in a regimen causing increased airway sensitivity to substance P. Acrolein exposure resulted in 100% mortality after capsaicin pretreatment compared with only 14% mortality in guinea pigs not pretreated with capsaicin. Acrolein exposure by itself caused marked pulmonary inflammation and large airway epithelial necrosis and denudation. Pretreatment with capsaicin exacerbated these responses throughout the lung. Intravenous acrolein caused an acute dose-related bronchoconstriction in naive guinea pigs that was diminished by capsaicin treatment and potentiated by thiorphan pretreatment, which suggests that arolein exposure causes an acute release of capsaicin-sensitive C-fiber neuropeptides. To determine whether acrolein-induced C-fiber release altered neuronal viability, either rhodamine or Fast Blue dye was instilled intratracheally into vehicle- or acrolein-exposed guinea pigs. Acrolein exposure did not reduce the neuronal uptake or retrograde transport of these dyes, as indicated by the number of fluorescent cell bodies in the nodose ganglia. To determine the functional state of airway neurons, the dose response to intravenous capsaicin was measured in vehicle-exposed and acrolein-exposed guinea pigs; no differences were observed. Thus, acrolein appears to activate airway C-fibers, which release neuropeptides that are protective against this insult, with no suggestion of an accompanying reduction in C-fiber function.

The effects of acrolein exposure on airway responses to intravenous substance P were determined in guinea pigs exposed to vehicle or 1.6 ppm acrolein for 7.5 h on 2 consecutive days and examined 1, 4, 8, 15, and 28 days after exposure by use of pulmonary mechanics and bronchoalveolar lavage (BAL). Lung, trachea, liver, and BAL fluid were also assayed for neutral endopeptidase (NEP) activity 1, 7, and 28 days after exposure. Pulmonary inflammation and epithelial damage were prominent 1 day after acrolein exposure. NEP activity was decreased in the lungs, trachea, and liver 1 and 7 days after acrolein. Twenty-eight days after exposure, NEP activity in the lungs and liver was not significantly different in vehicle- and acrolein-exposed guinea pigs but was still reduced in tracheal tissue. The BAL NEP activity in acrolein-exposed guinea pigs was approximately twice that of vehicle control guinea pigs at all three time points. Acrolein caused a prolonged increase in airway sensitivity to substance P. Experiments performed in the presence of thiorphan suggested that the acrolein-induced reduction in NEP may contribute to increased airway sensitivity to aerosolized substance P, but the increase in airway sensitivity to intravenous substance P may occur by additional mechanisms.

A technique for applying mature drops of insecticide aerosols, the Mature Aerosol Placement (MAP) technique, has been used in laboratory bioassays with tsetse flies (Glossina morsitans morsitans Westw.) to study a number of variables which could affect the efficacy of aerial applications in the field. Deltamethrin was more toxic to tsetse flies than endosulfan and this superiority was greater at a lower temperature, with factors of x 26 at 25°C and x 64 at 10°C. Toxicities of endosulfan‐deltamethrin and endosulfan‐alphacypermethrin mixtures were not affected by the different temperatures. The endosulfan‐deltamethrin mixture was superior to the endosulfan‐alphacypermethrin mixture by factors of x 1.4 at 10°C and x 2.0 at 25°C. The conventional EC formulation of endosulfan was less effective than the special T formulation, but the presence of emulsifiers in the T formulation did not affect its toxicity. No clear differences in LD50s (expressed as active ingredient) could be demonstrated between 15μ...

Experimental data on the precipitation chemistry in the semi-arid savanna of South Africa is presented in this paper. A total of 901 rainwater samples were collected with automatic wet-only samplers at a rural site, Louis Trichardt, and at an industrial site, Amersfoort, from July 1986 to June 1999. The chemical composition of precipitation was analysed for seven inorganic and two organic ions, using ion chromatography. The most abundant ion was SO4 2 − and a large proportion of theprecipitation is acidic, with 98% of samples at Amersfoort and 94% at LouisTrichardt having a pH below 5.6 (average pH of 4.4 and 4.9, respectively). This acidity results from a mixture of mineral and organic acids, with mineral acids being the primary contributors to the precipitation acidity in Amersfoort, while at Louis Trichardt, organic and mineral acids contribute equal amounts of acidity. It was found that the composition of rainwater is controlled by five sources: marine, terrigenous, nitrogenous, biomass burning and anthropogenic sources. The relative contributions of these sources at the two sites were calculated. Anthropogenic sources dominate at Amersfoort and biomass burning at Louis Trichardt. Most ions exhibit a seasonal pattern at Louis Trichardt, with the highest concentrations occurring during the austral spring as a result of agricultural activities and biomass combustion, while at Amersfoort it is less pronounced due to the dominance of relatively constant industrial emissions. The results are compared to observations from other African regions.

The notion of feature is widely used to denote the functional structure and visible properties of a software system. More specifically, features are meant to represent a user centric organization of a software system's functionality. Yet, other than during requirements analysis, features are seldom treated explicitly by most existing tools and methods. The paper argues that a feature orientation can provide benefits to software developers throughout the software life cycle. We envisage specific applications of the notion of feature that provide a powerful and unifying structure for software life cycle artifacts and activities. We discuss the problems and issues to be addressed, a brief summary of our current research work, and suggestions and directions for future research in a new area we call "feature engineering".

CP-80,633, a selective phosphodiesterase (PDE) 4 inhibitor, potently reverses histamine bronchoconstriction in anesthetized guinea pigs (ED50 10 micrograms/kg) but only weakly relaxes histamine-constricted guinea pig trachea (EC50 137 microM). Using CP-80,633 as a prototype PDE4 inhibitor, we evaluated the hypothesis that bronchodilation induced by PDE4 inhibitors is not mediated by direct relaxation of airway smooth muscle. In anesthetized guinea pigs, a bronchodilatory dose of CP-80,633 did not increase plasma catecholamines, nor did propranolol pretreatment significantly alter the ability of CP-80,633 to reverse histamine bronchoconstriction. In an isolated organ system, the activity of bronchorelaxants may be attenuated by the lack of endogenous activators of adenylyl cyclase or by decreased levels of intracellular cyclic nucleotides. Pretreatment with the beta-adrenoceptor agonist, salbutamol, or the PDE3 inhibitor imazodan did not potentiate the bronchorelaxant ability of CP-80,633. Milrinone pretreatment increased the potency of CP-80,633 to relax carbachol-constricted tracheal rings, but only at concentrations where nonspecific effects have been reported. By comparing the bronchorelaxant abilities of PDE inhibitors in tracheal rings with or without epithelium, we determined that the epithelium did not serve as a barrier to drug penetration. In conclusion, CP-80,633 is a potent bronchodilator in vivo, whose activity is neither mediated by direct airway smooth muscle relaxation nor dependent upon endogenous catecholamines.

Rolipram was previously reported to elevate plasma cyclic adenosine 3',5'-monophosphate (cAMP) and inhibit serum tumor necrosis factor-alpha (TNF-alpha) production in mice. CP-80,633, a new cyclic nucleotide phosphodiesterase (PDE4) inhibitor, has been shown to augment intracellular cAMP levels and to inhibit TNFalpha release from human monocytes in vitro. This study was undertaken to determine the effect of p.o. CP-80,633 on plasma cAMP levels and lipopolysaccharide-induced TNFalpha production in mice with and without adrenal glands. CP-80,633 dose-dependently (3-32 mg/kg p.o.) elevated plasma cAMP levels and decreased systemic TNFalpha production in response to i.p. injection of lipopolysaccharide. Elevated plasma cAMP levels can be detected for up to 4 hr. CP-80,633 (10 mg/kg p.o.) caused a 6-fold increase in the plasma cAMP level, a 2-fold increase in the plasma epinephrine level and a greater than 95% reduction in TNFalpha production. Unlike CP-80,633, neither vinpocetine, dipyridamole, SKB-94,120 nor zaprinast, at 100 mg/kg p.o., modified the cAMP response, which suggests that this response is mediated by inhibition of PDE4. Adrenalectomy reduced the cAMP response and completely blocked the epinephrine response; however, the levels of plasma cAMP in the CP-80,633-treated mice (10 mg/kg p.o.) remained elevated (vehicle: 47.3 +/- 6.8 vs. CP-80,633: 98.4 +/- 10.3 pmol/ml, n = 7, P.05). This effect is mimicked by treatment of control mice with propranolol, which demonstrates that beta adrenoreceptors contribute to the cAMP response. Removal of adrenal glands significantly increased the LPS-induced elevation of serum TNFalpha. The ability of CP-80,633 to block the TNFalpha response was only slightly affected by adrenalectomy (ED50 = 1.2 mg/kg in controls vs. 3.9 mg/kg in adrenalectomized mice). Taken together, these results show that CP-80,633, when given p.o. to mice, is capable of elevating plasma cAMP and inhibiting TNFalpha production and that adrenal catecholamines contribute significantly to the effect of CP-80,633 on the cAMP response but only slightly to its effect on the systemic TNFalpha response.

The following studies were conducted to characterize the bron-chodilatory and antiinflammatory activity of the novel, selective phosphodiesterase-IV inhibitor, CP-80,633 (2'S)5-[3-(2'-exobicyclo[2.2.1]heptyloxy-4-methoxy-phenyl]te trahydro- 2(1H)-pyrimidone, a compound in clinical development for atopic disease. In IgG1 passively sensitized guinea pigs, aerosolized ovalbumin challenge increases both pulmonary eosinophil peroxidase levels and airway obstruction. CP-80,633, administered before ovalbumin challenge, significantly attenuated both the increase in tissue eosinophil peroxidase levels (ED50 = 1.4 mg/kg, p.o.) and airway obstruction (ED50 = 0.93 +/- 0.14 mg/kg,p.o.) 10 to 30 times more potently than theophyl-line. Intraarterially administered CP-80,633 also reversed an established bronchoconstriction initiated by continuous infusion of histamine to guinea pigs (ED50 of 8.2 micrograms/kg vs. 5.6 mg/kg for theophylline). The antiinflammatory effect of CP-80,633 was also examined in atopic monkeys challenged with Ascaris suum (Ag) aerosol. CP-80,633 (1 mg/kg, qid, s.c., 1 hr before antigen challenge) significantly reduced antigen-induced increases in bronchoalveolar lavage neutrophils (72.8 +/- 15.8% inhibition) and eosinophils (61.1 +/- 5.7% inhibition) 4 hr postchallenge, but did not reduce leukocytes 24 hr postchallenge. CP-80,633 did not inhibit antigen-induced increases in BAL levels of interleukin-1 beta, -6 or -8 as measured by enzyme-linked immunosorbant assay. These results indicate that CP-80,633 possesses bronchodilatory activity in guinea pigs and some antiinflammatory effects in both guinea pigs and monkeys.

We present the in vitro pharmacology of a novel adenosine 3'-5' -cyclic monophosphate-specific phosphodiesterase (PDE) type 4 inhibitor, CP-80633 ((2'S)5-[3-(2' -exobicyclo[2.2.1]-heptyloxy)4-methoxyphenyl] tetrahydro-2(1H)-primidone), which has shown efficacy in phase II clinical trials for atopic dermatitis. CP-80633 inhibits PDE4 isozymes (human lung IC50 = 1.27 microM) in the absence of effects on PDE1, PDE2, PDE3 and PDE5 isozymes (IC50100 microM). It exhibits no significant selectivity for any single cloned PDE4A, B, C or D isoform. CP-80633 inhibits adenosine 3'-5'-cyclic monophosphate hydrolysis in partially purified human peripheral blood monocyte cytosol (IC50 = 3.52 microM), eosinophil membrane (IC50 = 1.10 microM) and T cell membrane (IC50 = 2.28 microM) preparations. Inhibition of eosinophil PDE4 adenosine 3'-5'-cyclic mono-phosphate hydrolysis by CP-80,633 occurs in a noncompetitive manner. Unlike theophylline, CP-80,633 is inactive against ratrain adenosine (A1,A2) receptors. Consistent with its action as a PDE4 inhibitor in whole cells, CP-80633 potentiates PGE1 dependent increases in adenosine 3'-5'-cyclic monophosphate levels in human U937 cells, and in human eosinophils, monocytes and T cells (EC200 approximately 1.0 microM). Consequently, CP-80633 inhibits many inflammatory cell functions including 1) human eosinophil superoxide anion production (IC500.6 microM), 2 C5a-(IC50 = 0.40 microM) and LTB4-(IC50 = 0.20 microM) mediated guinea pig peritoneal eosinophil chemotaxis and 3) lipopolysac-charide-induced tumor necrosis factor-alpha release from human monocytes (IC50 = 0.219 microM). These data clearly demonstrate that CP-80633 is a selective inhibitor of PDE4 isozymes, and support its potential use as a therapeutic agent for a number of inflammatory and immune disorders.

The following study was performed to further characterize a primate model of asthma using classes of drugs that target allergy (pyrilamine, cetirizine), are bronchodilators for the treatment of asthma (salbutamol, salmeterol) or are anti-inflammatory (dexamethasone). These drugs were examined for their ability to inhibit acute, antigen-induced bronchoconstriction, the development of airway hyperresponsiveness (AHR) and the infiltration of leukocytes into the lungs of atopic cynomolgus monkeys (Macaca facsicularis) using a 10-day, multiple antigen (Ag) challenge protocol. All compounds except dexamethasone and cetirizine significantly (p0.05) reduced acute, Ag-induced bronchoconstriction (salbutamol: 74.2%, salmeterol: 52.6%%, pyrilamine: 62.4% inhibition) compared to vehicle control trials. Only dexamethasone and salmeterol prevented the development of AHR to methacholine challenge by 90.4 +/- 6.81% and 85.7 +/- 5.61% respectively. Dexamethasone significantly reduced the Ag-induced increase in BAL eosinophils by 85.9 +/- 8.53%. Cetirizine reduced the eosinophil response in 5 of 6 monkeys and salmeterol demonstrated a trend towards reduced eosinophil increases after multiple Ag challenge, but neither of these were statistically significant. These results further illustrate the utility of this model in predicting compound effects against several relevant functional endpoints that are consistent with the effects of similar classes of compounds in humans.

To test the hypothesis that leukotriene (LT) B4 antagonists may be clinically useful in the treatment of asthma, CP-105,696 was evaluated in vitro, using chemotaxis and flow cytometry assays, and in vivo, using a primate asthma model. CP-105,696 inhibited LTB4-mediated monkey neutrophil chemotaxis (isolated cells, LTB4 = 5 nM) and CD11b upregulation (whole blood, LTB4 = 100 nM) with IC50 values of 20 nM and 16.5 microM, respectively. Using a modification of a previously described in vivo protocol (Turner et al. Am. J. Respir. Crit. Care Med. 1994. 149: 1153-1159), we observed that treatment with CP-105,696 inhibited the acute increase in bronchoalveolar lavage (BAL) levels of IL-6 and IL-8 by 56.9 +/- 13.2% and 46.9 +/- 14.5%, respectively, 4 h after challenge with Ascaris suum antigen (Ag). CP-105,696 tended to reduce the increase in BAL protein levels 0.5 h after Ag challenge by 47.5 +/- 18.3%, but this was not statistically significant. In addition, CP-105,696 prevented the significant 11-fold increase in airway responsiveness to methacholine after multiple Ag challenge. These results suggest that LTB4 partially mediates acute and chronic responses to antigen in an experimental primate asthma model and support the clinical evaluation of LTB4 antagonists in human asthma.

The effects of two 5-lipoxygenase (5LO) inhibitors, ZD2138 or Zileuton, on acute, inflammatory responses to aerosolized Ascaris suum (Ag) were determined in atopic Macaca fascicularis monkeys. Monkeys (n = 6 each group) were dosed with vehicle, 3 or 10 mg/kg ZD2138, or 30 mg/kg Zileuton (p.o.). Both ZD2138 or Zileuton significantly inhibited ex vivo LTB4 production in Ca2+ ionophore-stimulated whole blood from these same monkeys (n = 6 each group) by 45.5% (3 mg/kg ZD2138), 82.5% (10 mg/kg ZD2138) and 84.3% (30 mg/kg Zileuton). ZD2138 (10 mg/kg) reduced bronchoalveolar lavage (BAL) LTE4 levels (65.1% inhibition), BAL neutrophils (88.9% inhibition), and IL-6 (54.0% inhibition) 4h post Ag. Zileuton inhibited these responses and also reduced BAL levels of IL-8 (73.4% inhibition). A second study was performed to evaluate the effects of ZD2138 on chronic Ag-induced responses. Treatment with ZD2138 did not prevent pulmonary inflammation or the development of airway hyperresponsiveness (AHR). Based upon these results, 5LO inhibition significantly reduced ex vivo LTB4 and in vivo LTE4 production as well as several acute inflammatory responses to Ag in the lung. However, ZD2138 did not inhibit more chronic responses following multiple Ag exposure.

The use of animal models to mimic certain aspect of human disease has proven to be invaluable to biomedical research. Animal models allow experimentation that would be hazardous in humans [1, 2], provide tissue for study in vitro, enable validation of data in a variety of systems, allow genetic and environmental influences to be manipulated or controlled, and facilitate the preclinical assessment of drug efficacy [2].

The following study was performed to determine the effects of phosphodiesterase IV (PDE-IV) inhibition and its attenuation of tumor necrosis factor (TNF alpha) production in a rat model of the Adult Respiratory Distress Syndrome (ARDS). Rats were either unexposed (n = 8), pretreated orally with vehicle prior to intratracheal saline exposure (n = 11), pretreated with vehicle prior to 7 mg/kg intratracheal endotoxin (LPS) administration (n = 22), or pretreated with 5 or 50 mg/kg rolipram prior to LPS exposure (n = 6 and 7, respectively). Blood was sampled 1 and 3 hr post LPS exposure and assayed for plasma TNF alpha concentrations. Twenty-four hours after LPS exposure, blood was sampled again for hematologic measurements. The rats were then anesthetized and exsanguinated. Bronchoalveolar lavage (BAL) was performed after the lung of each rat was removed and weighed. Rolipram pretreatment was protective against LPS-induced mortality and also resulted in reduced plasma TNF alpha concentrations. LPS induced pulmonary edema, as indicated by wet/dry lung weight ratio (W/D) and total BAL protein content (TP) was attenuated by rolipram pretreatment. LPS-induced alveolar hemorrhage was reduced by rolipram pretreatment, but LPS-induced pulmonary neutrophilia was not. The hemoconcentration induced by LPS was reduced by rolipram, as was the LPS-induced thrombocytopenia. However, LPS-induced changes in circulating leukocyte populations were actually exacerbated by rolipram. LPS-induced alterations in renal and hepatic function, indicated by increased blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were inhibited by rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)

A technique is described for the intratracheal aerosolization of endotoxin into the rat. Using a miniaturized nozzle within the tracheal lumen to optimize uniform distribution 0·5 ml of an endotoxin solution (7 mg/kg) was aerosolized and dispersed throughout the lung. Time course studies of pulmonary function and histological changes revealed marked functional and morphological changes by 24 h. Histopathologic changes consisted of widespread pulmonary oedema and a diffuse neutrophilic alveolitis. At the same time, there were significant decreases in tidal volume, minute ventilation and lung compliance. Haematologic changes were also seen, including profound chrombocytopaenia and leukopaenia together with an increased haematocrit, indicating systemic effects in this model. Bronchoalveolar lavage (BAL) at 24 h revealed significant increases in BAL protein, erythrocytes and neutrophils. The functional, cytological and histological changes observed after endotoxin challenge mimic those seen in the Adult Respiratory Distress Syndrome in humans and can thus be used as a model to compare the efficacy of a variety of therapeutic interventions for this syndrome.

Current strategies for the treatment of ARDS have been unsuccessful in reducing mortality. In the present study, we have evaluated the role of cyclooxygenase (CO) products in a rat model of ARDS by testing naproxen, indomethacin, ibuprofen, and a thromboxane A2 (TXA2) receptor antagonist (SKF 96148). Rats were treated 1 hr prior to endotoxin (LPS) exposure and 24 hr later, survival, body weight changes, wet/dry lung weight (W/D), total protein content (TP) of the bronchoalveolar lavage (BAL) fluid, and total erythrocyte and differential leukocyte counts of the BAL fluid were measured. In addition, the following hematologic measurements were taken: hemoglobin (Hb), hematocrit (Hct), circulating erythrocyte, differential leukocyte, and platelet counts. Treatment with the TXA2 receptor antagonist reduced mortality to zero after 24 hr after LPS administration. Other compounds had no significant effect on LPS-induced mortality. Pretreatment with CO inhibitors or the TXA2 receptor antagonist attenuated the LPS-induced increase in TP and W/D. Although all compounds tended to reduce the LPS-induced increase in BAL erythrocytes, only the TXA2 receptor antagonist did so significantly. The LPS-induced increase in BAL neutrophil counts was significantly reduced by 30 mg/kg ibuprofen, but not by the other compounds. In fact, the TXA2 receptor antagonist actually exacerbated BAL neutrophil counts, but diminished the peripheral neutrophilia and lymphopenia induced by LPS. None of the CO inhibitors tested significantly affected LPS-induced hematologic responses. We conclude that by virtue of its protection against LPS-induced mortality, the TXA2 receptor antagonist was the most effective compound in this model. However, it did cause certain negative side effects such as increased pulmonary inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to investigate the role of 5-lipoxygenase (5LO) metabolites in an endotoxin (LPS)-induced model of the adult respiratory distress syndrome (ARDS) in the rat. The therapeutic value of two 5LO inhibitors and a specific LTB4 and a LTD4 receptor antagonist were examined. Rats were treated 1 hr prior to administration of aerosolized LPS. Rats were either unexposed (n = 11), or pretreated with vehicle sham (n = 63), 50 mg/kg phenidone t.i.d. (n = 7, n = 10 for assessment of mortality), 30 mg/kg SKF 103842 b.i.d. (n = 6), 50 mg/kg SKF 106203 t.i.d. (n = 11), or 5 mg/kg SKF 107324 b.i.d. (n = 6) 1 hr prior to the administration of aerosolized endotoxin (LPS, 7 mg/kg) or phosphate-buffered saline (PBS, n = 22). Twenty-four hours later, blood samples were collected for hematologic evaluation and after wet lung weight was determined, broncho-alveolar lavage (BAL) was performed to measure cells counts and total protein (TP). 5LO inhibition and LTD4 receptor antagonism reduced LPS-induced mortality to zero compared to 35% in rats pretreated with vehicle sham. Pretreatment with the LTD4 receptor antagonist attenuated the LPS-induced increased in wet/dry lung weight (W/D) whereas 5LO inhibition reduced TP increases. Both 5LO inhibition and LTD4 receptor antagonism attenuated the LPS-induced BAL erythrocyte increase. The LPS-induced thrombocytopenia was attenuated by phenidone, the 5LO receptor antagonist. We conclude that the increased microvascular permeability was associated with the formation of 5LO products since 5LO inhibition lessened the severity of the LPS-induced increase in W/D and TP.(ABSTRACT TRUNCATED AT 250 WORDS)

The protective effects of altered arachidonic acid metabolism, using either methylprednisolone or a dual cyclooxygenase and 5-lipoxygenase inhibitor (SKF 86002), were compared in a rat model of adult respiratory distress syndrome (ARDS). Rats were either unexposed (n = 9) or pretreated with vehicle (n = 25), 100 mg/kg SKF 86002 (n = 8) or 30 mg/kg methylprednisolone (MP, n = 7) 1 h prior to the intratracheal administration of 7 mg/kg aerosolized endotoxin (LPS) or phosphate buffered saline (PBS). Twenty-four hours later, blood samples were collected and the rats were anesthetized and exsanguinated. The lungs were surgically removed, weighed and bronchoalveolar lavage (BAL) was performed. LPS caused 30-35% mortality and induced significant differences in body weight, BAL erythrocyte and neutrophil counts, lung wet/dry weight ratio (W/D), total BAL protein (TP), hemoglobin (Hb), hematocrit (HCT), and circulating leukocyte and platelet counts as compared with controls. Pretreatment with MP reduced mortality to zero and also attenuated the LPS-induced alterations in body weight, W/D, TP, BAL erythrocyte count, and circulating platelet count. However, MP exacerbated LPS-induced increases in Hb, HCT and circulating neutrophil counts while enhancing lymphopenia. Pretreatment with SKF 86002 also reduced mortality to zero and attenuated LPS-induced alterations in W/D, TP, HCT and circulating platelet count. Like MP, SKF 86002 exacerbated the LPS-induced lymphopenia, and increased circulating neutrophils above baseline values. We conclude that both MP and SKF 86002 provided protection against LPS-induced responses in this model of ARDS. Mechanistically, this indicates the critical role of eicosanoid mediators in this model. Therapeutically, SKF 86002, or a similar compound, may be beneficial in preventing the acute phase responses so harmful to ARDS patients.

Cypermethrin, fenvalerate, permethrin, (S)-α-cyano-3-phenoxybenzyl (1R,cis)-3-(2, 2-dibromovinyl)-2, 2-dimethylcyclopropanecarboxylate (NRDC 161) and (R,S)-α-cyano-3-phenoxybenzyl 2, 2,3, 3-tetramethylcyclopropanecarboxylate (S-3206; WL 41706) have been tested against adult mosquitoes (Anopheles stephensi) and tsetse flies (Glossina austeni). They possess many of the necessary characteristics such as high intrinsic toxicity, low volatility, and high stability but vary considerably in the contact action of their spray residues.

Tests to evaluate candidate insecticides and formulations for tsetse control are described, and some data are presented to indicate that some new synthetic pyrethroids (e.g. permethrin and NRDC 161) are effective for a long period at such extremely low doses that they could have a pronounced influence on future tsetse control operations.

A semi-automated procedure for the calculation of point doses and isodose distributions for a curved multi-wire implant is described. A dose optimisation method has been developed for producing acceptable dose distributions from non-ideal implants and the dosimetry of such implants is discussed. Source preparation, handling and stock control methods are described which facilitate the re-use of the encapsulated wire with consequent benefits in the reduction of staff radiation exposure and the costs of treatment.

Tsetse control in the Okavango Delta of Botswana is being conducted using a night‐time drift spraying technique, the effectiveness of which is dependent on the production of the correct droplet size spectrum and on suitable meteorological conditions. A 35 e.c. formulation of endosulfan was sprayed at 5 l/min with an atomiser rotation speed of 10,000–12,000 rev/min and flying speed of approximately 70 m/s. Droplet size measurements were made by sampling on to magnesium oxide coated glass slides, and chemical assessments were made by collecting droplets on filter papers or strands of synthetic angora wool for analysis. The results showed that the method was effective, producing an aerosol cloud of 20–30 μm diam. droplets, but that airborne spray concentrations varied considerably with meteorological parameters. Insecticide drift decayed exponentially with distance downwind from the nearest spray point, but amounts recovered up to 12.5 km downwind were sufficient to kill tsetse. The wool sampler was...

Insecticidal aerosols dispersed from aircraft are used in control measures against Glossina spp., and the interpretation of spray monitoring data in terms of the likely effect on the flies requires some knowledge of variation of the collection efficiency of the flies under a range of appropriate conditions. A low speed wind tunnel was used to measure the collection efficiencies of the various component parts of an adult of G. morsitans Westwood when at rest on cylinders simulating the branches and twigs of the natural habitat. The wind speed range was from 0·25 to 1·5 m/s and monodisperse droplets 10, 15, 20 and 25 μm in diameter were used. Although certain body zones exhibited very high apparent collection efficiencies (primarily due to interception), the average overall efficiencies varied from as low as 0·8% for 10-μm droplets at 0·25 m/s up to 22% for 25-μm droplets at 1·5 m/s.

SUMMARY The joint action of insecticides on adult female mosquitoes, Aedes aegypti and Anopheles stephensi, has been studied by topical applications of known dosages separately and in mixtures. Results indicated that the two organophosphorus compounds, malathion and diazinon, have a similar action on the mosquitoes. Responses to mixtures of an organophosphate (malathion) and a carbamate (Sevin), an organo-phosphate (malathion) or a carbamate (Sevin) and a chlorinated hydrocarbon (DDT or dieldrin), and of two chlorinated hydrocarbons (DDT and dieldrin) were less than expected for similar action. In other experiments in which two insecticides were applied separately with an interval of 48 hr. between treatments, the order of application was of importance. Mosquitoes receiving a sublethal dose of malathion were more susceptible to Sevin, DDT and dieldrin than untreated mosquitoes from the same population, whereas pre-treatment with Sevin did not influence susceptibility to malathion, DDT and dieldrin.

A conductimetric method for following the small concentration changes that occur when a temperature gradient is maintained in an aqueous electrolyte is described. The solution is contained in a Perspex cell between silver end-plates which are faced with platinized platinum and kept at temperatures differing by about 10°C. A further connexion to the cell (a ‘centretap’) is made through a small lateral hole equidistant from the ends. The cell is incorporated in an audio-frequency Wheatstone bridge and movement of solute from one half of the cell to the other is followed by measuring the ratio of their resistances. For a convection-free system, the Soret coefficient (σ) may be derived either from the initial rate of change of the ratio or from its value in the steady state. It is found experimentally that there are discrepancies between the two estimates of σ, and also related anomalies in the rate of change of concentration, which can be ascribed to convection. It can be shown that the initial rate observations should be free from convection errors, and the effect of convection on the steady state can be analysed by dimensional methods. The observed discrepancies are correlated with the relevant properties of the solutions in the manner suggested by this analysis. The Soret coefficients of eighteen 1:1 salts in 0⋅01 m aqueous solution and at mean temperature 25⋅0°C have been determined by this method. Some additional measurements have been made at 34⋅7°C and at other concentrations in the range 0⋅002 to 0⋅02m. Three salts of other valency types (potassium, thallous and cadmium sulphates) have also been studied. The molar heats of transport of the salts ( Q *) have been calculated from the Soret coefficients. The results show that Q * (i) is an additive function of contributions characteristic of the constituent ions in dilute (0⋅01 M) solutions of 1:1 electrolytes, (ii) increases markedly on raising the mean temperatures from 25⋅0 to 34⋅7°C, in agreement with the results of Alexander (1954) and Longsworth (1957) (iii) increases appreciably on dilution below 0⋅01 M, indicating that heats of transport are influenced by long-range inter-ionic forces.

Equations are developed describing the attainment of Soret equilibrium in two-component liquid systems flowing in a laminar fashion through a rectangular duct. The resulting diffusion equation is solved in a simplified form, valid for small temperature intervals, by a suitable finite difference approximation. A complementary solution yielding an explicit expression for the separation and valid for large times is derived from the calculus of variations. Use of this expression for interpreting practical results, as in the calibration experiments, is shown in part 1. Consideration of the errors involved in the simplified diffusion equation leads to an upper limit on the temperature interval for the validity of the solution. Errors arising from finite thermal and velocity entry lengths are shown to be negligible.

The Soret effect was investigated in aqueous solutions at 25 deg C. The salts studted were CaCl/sub 2/ and SrCl/sub 2/ at 0.005 m, and MgCl/sub 2/, BaCl/ sub 2/, and MgSO/sub 4/ from about 0.0005 to 0.0l m or higher. Results are compared with those for other salts obtained using the same apparatus. (auth)

Experimental measurements of thermal diffusion at 25°C are reported for the liquid systems CCl4+ CH3OH, benzene + CH3OH, and cyclohexane + CH3OH. The Soret coefficients for these mixtures are large and extremely composition-dependent. The results are discussed in terms of the marked non-ideality, or even immiscibility, shown by these systems.

The optimum size range of particles of two carbamates and two organophosphorus compounds in deposits on plywood and plaster for contact toxicity to blood-fed females of Anopheles stephensi List, was 5–30 µm. The effect of particle size on the contact toxicity of these compounds of high intrinsic toxicity was not great and in this respect resembled that found previously for dieldrin and γBHC. In the few tests done, the concentration of active ingredient in wettable powder formulations was not an important factor in determining the contact toxicity of deposits of such toxic materials.

The laminar-flow technique,1, 2 has been applied to measure the Soret coefficient of mixtures of CCl4 and cyclohexane. Measurements were made at 25°C over the full range of compositions, and at 35°C at one composition. The apparatus, though requiring a careful calibration, proved precise and easy to use. The results are in good agreement with those of Horne and Bearman,4 if their correction for the “forgotten effect” is considered to be inapplicable13 and is neglected.

Experimental measurements of thermal diffusion at 25°C in the liquid systems CCl4+ benzene, and cyclohexane + benzene are reported. The results for these systems and for CCl4+ cyclohexane3 are compared with three theoretical calculations. It is deduced that these theories cannot be used to calculate Soret coefficients; even the sign of the effect may be wrongly predicted.