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The Total Solar Irradiance (TSI) is an important input for the Earth’s climate. To describe the competing contributions of sunspots and faculae on irradiance variability, the San Fernando Observatory (SFO) irradiance model has two components: One component is an index derived from a continuum image that provides a sunspot signal. The other component is an index determined from a Ca II K-line image that provides a facular signal. These components are determined using two different methods, one based on feature identification and one based on photometric sum. Feature identification determines whether an active region feature is darker or brighter than the surrounding quiet Sun and by how much. Photometric sum simply adds up all the image pixels to determine a single value for that image. In this paper, we investigate the use of space-based UV images from the Solar Dynamics Observatory (SDO) as a substitute for ground-based Ca II K-line images from the San Fernando Observatory in modeling TSI variability. SDO indices are obtained by processing SDO/Atmospheric Imaging Assembly (AIA) 160 nm and 170 nm images with SFO algorithms, then SFO models are modified by substituting either a 160 nm or a 170 nm UV index from SDO in place of the Ca II K image. The different models are regressed against TSI measurements from the Total Irradiance Monitor (TIM) on the Solar Radiation and Climate Experiment (SORCE) spacecraft. The sunspot signal for all models used here is determined from SFO red continuum images at 672.3 nm. The facular signal is determined from either Ca II K-line images at 393.4 nm or space-based UV images from the SDO/AIA experiment. Images at both AIA wavelengths are processed with the standard San Fernando Observatory (SFO) algorithms. The SFO data is obtained from two photometric telescopes, which differ in spatial resolution by a factor of 2. The results of the linear regressions show good agreement between the fits that use SFO Ca II K-line data and the fits that use SDO UV data. However, facular indices obtained from SDO/AIA 170 nm images give significantly better fits than SDO/AIA 160 nm. We compare the goodness of the correlation using R2, that is, the multiple regression coefficient R, squared. The best two-component fit using ground-based Ca II K-line data was R2 = 0.873; using AIA 170 nm produced R2 = 0.896. Correlations using the AIA 160 nm data were consistently lower with values of R2 as low as 0.793, where R2 is the coefficient of multiple correlation.

The Australian and New Zealand College of Anaesthetists (ANZCA) recently reviewed and updated the guideline on equipment to manage a difficult airway. An ANZCA-established document development group, which included representatives from the Australasian College for Emergency Medicine and the College of Intensive Care Medicine of Australia and New Zealand, performed the review, which is based on expert consensus, an extensive literature review, and bi-nationwide consultation. The guideline (PG56(A) 2021, https://www.anzca.edu.au/getattachment/02fe1a4c-14f0-4ad1-8337-c281d26bfa17/PS56-Guideline-on-equipment-to-manage-difficult-airways) is accompanied by a detailed background paper (PG56(A)BP 2021, https://www.anzca.edu.au/getattachment/9ef4cd97-2f02-47fe-a63a-9f74fa7c68ac/PG56(A)BP-Guideline-on-equipment-to-manage-difficult-airways-Background-Paper), from which the current recommendations are reproduced on behalf of, and with the permission of, ANZCA. The updated 2021 guideline replaces the 2012 version and aims to provide an updated, objective, informed, transparent, and evidence-based review of equipment to manage difficult airways.

Airway Management is the key for anaesthetists dealing with patients undergoing diagnostic procedures and surgical interventions. The present coronavirus pandemic underpins even more how important safe airway management is. It also highlights the need to apply stringent precautions to avoid infection and ongoing transmission to patients, anaesthetists and other healthcare workers (HCWs). In light of this extraordinary global situation the aim of this article is to update the reader on the varied aspects of the ever-changing tasks anaesthetists are involved in and highlight the equipment, devices and techniques that have evolved in response to changing technology and unique patient and surgical requirements.

Tannins are natural and nutritionally significant components of the diets of browsing ungulates. In trials on supplemented pastures and in drylots, we estimated dry matter intake (DMI), weight gain, and urea N, potassium, cortisol and creatinine in urine of captive white-tailed deer fed pelleted diets that differed only in the respective quebracho tannin (QT) content. The low control, medium and high QT rations were 3.6, 63 and 152 g/kg DM respectively. There was no tannin-free pellet option. Trials were divided into winter pasture, restricted choice and spring growth. In winter pasture trial on pasture using QT, deer reduced QT intake relative to that expected under random foraging. This aversion was also apparent during the spring growth trial. While DMI in the winter pasture trial remained similar among treatments (p > 0.05), averaging 130 g/kg(0.75)/day, deer gained more weight (p < 0.05) when given a choice that included the high QT ration. During subsequent spring growth, DMI and weight gains generally exceeded those of the winter period. Unlike the winter pasture trial, weight gains in spring growth trial were higher (p < 0.05) in the low-control QT treatment. In the restricted choice trial, weight gain was again higher (p < 0.05) for deer fed a low-control QT diet. The urea N/creatinine ratio of deer fed the low-control QT diet (0.0357) was over three times that of deer fed the high QT diet (0.0107). Neither potassium/creatinine nor cortisol/creatinine ratios were affected by diet (p > 0.05). Collectively, these results suggest that although deer do not avoid tannins, and even ingested up to 5% under the choice options in these trials, the effect of tannins on deer performance may vary by season as well as by foraging opportunities.

Little information exists on the performance of deer on alternative forage species in northern temperate environments during summer and fall, the period of inherent maximum growth in deer. In performance and choice experiments, we compared live weight gain (g/kg(0.75)/day), absolute [kg/ha dry matter (DM)] and relative (% DM) herbage utilization, relative preference index (RPI) as well as plant community visitation of white-tailed deer grazing alfalfa (Medicago sativa), birdsfoot trefoil (Lotus corniculatus) or chicory (Cichorium intybus) in north central Alberta, Canada. Herbage phytomass and quality was also measured on the grazed pastures. Alfalfa had higher dry matter yields and crude protein concentrations than chicory and trefoil. Chicory had lower neutral detergent fiber concentrations than the other forages. Tannin concentrations were greatest in birds foot trefoil (nearly 55 g/kg DM), well above those in the other forages (<5 g/kg DM). Live weight gain was similar among deer feeding within the paddocks seeded to birds foot trefoil and chicory, and more than two times higher (p < 0.05) than deer feeding in paddocks seeded to alfalfa. Deer spent more grazing time (about 40%) on chicory pastures than on alfalfa and birds foot trefoil pastures. RPI values were greatest for birds foot trefoil at 2.11, intermediate for chicory at 1.40, and lowest for alfalfa at <0.60. Absolute herbage utilization remained similar (p > 0.05) among the three forage species. In contrast, relative herbage utilization was greater from birds foot trefoil (52% DM) than chicory (40% DM) or alfalfa (25% DM). These results suggest that the use of alfalfa with other alternative forages may prove beneficial to deer production, rather than using alfalfa pasture alone.

Objective: The chemokine receptor CXCR3 is implicated in migration of leukocytes to sites of inflammation. Antagonizing CXCR3 may be a strategy to inhibit inflammation-induced leukocyte migration and subsequently reduce atherosclerosis. We used the CXCR3 specific antagonist NBI-74330 to block CXCR3-mediated signaling in peritonitis and diet-induced atherosclerosis., Methods and Results: Antagonizing CXCR3 with NBI-74330 resulted in a significant reduction in CD4+ T cell and macrophage migration to the peritoneal cavity, which was as shown in ex vivo migration studies totally CXCR3 dependent. Atherosclerotic lesion formation in the aortic valve leaflet area and the entire aorta was significantly inhibited in NBI-74330 treated mice. Lymph nodes draining from the aortic arch were significantly smaller in treated mice and were enriched in regulatory T cells and contained fewer activated T cells, whereas the markers for regulatory T cells within the lesion were enhanced after NBI-74330 treatment., Conclusions: This study shows for the first time that treatment with a CXCR3 antagonist results in attenuating atherosclerotic lesion formation by blocking direct migration of CXCR3+ effector cells from the circulation into the atherosclerotic plaque and by beneficially modulating the inflammatory response in the lesion and the lymph nodes draining from the atherosclerotic lesion.

The synthesis and biological evaluation of a novel series of 2-aminoquinoline substituted piperidines and tropanes incorporating a homotropene moiety is herein described. The series exhibits potent antagonism of the CXCR3 receptor and superior physicochemical properties. Compound 24d was found to be orally bioavailable, and PK/PD studies suggested it as a suitable tool for studying the role of CXCR3 in models of disease.

The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine with an exo-tropanyl unit led to the identification of compound 15 which provides a combination of excellent potency against human and murine receptors, drug-like properties and pharmacokinetics, thus providing a valuable tool for the evaluation of CXCR3 antagonists in models of human disease.

Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4h.

The synthesis and biological evaluation of a series of 1-aryl-3-piperidin-4-yl-urea derivatives as small-molecule CXCR3 antagonists is described. SAR studies resulted in significant improvement of potency and physicochemical properties and established the key pharmacophore of the series, and led to the identification of 9t, which exhibits an IC50 of 16 nM in the GTPgammaS35 functional assay.

Anaesthetists and intensivists spend a considerable proportion of their working time inserting needles and catheters into patients. In order to access deeper structures like central veins and nerves, they have traditionally relied on surface markings to guide the needle into the correct position. However, patients may present challenges due to anatomical abnormalities and size. Irrespective of the skill of the operator, there is the ever-present risk of needle misplacement with the potential of damage to structures like arteries, nerve bundles and pleura. Repeated attempts, even if ultimately successful, cause patient suffering and probably increase the risk of infection and other long term complications. Portable and affordable, high-resolution ultrasound scanners, has accelerated the interest in the use of ultrasound guidance for interventional procedures. Ultrasound guidance offers several advantages including a greater likelihood of success, fewer complications and less time spent on the procedure. Even if the target structure is identified correctly there is still the challenge to place the needle or other devices in the optimum site. The smaller and deeper the target, the greater the challenge and potential usefulness of ultrasound guidance. As a result of limited training in the use of ultrasound we believe that many clinicians fail to use it to its full potential. A lack of understanding, with regard to imaging the location of the needle tip remains a major obstacle. Needle visualisation and related topics form the basis for this review.

Serum total cortisol has traditionally been used for the interpretation of tests of the hypothalamic-pituitary-adrenal axis. Approximately 80% of total cortisol is bound to cortisol-binding globulin (CBG), and variation in CBG significantly affects serum total cortisol levels. Reliable assessment of hypothalamic-pituitary-adrenal axis reserve is difficult in severely ill patients, because CBG falls substantially during the acute phase response. The free cortisol index (FCI), defined as the ratio of total cortisol/CBG, correlates well with serum free cortisol. We evaluated the FCI in the context of severe stress and the acute phase response by measuring total cortisol and CBG pre- and postoperatively in 31 patients undergoing major elective surgery. Serum total cortisol increased by 55% from 453 +/- 35.2 (mean +/- SEM) nmol/liter (range, 88-882) to 700 +/- 47.2 (range, 294-1631) nmol/liter. Serum CBG decreased by 30% from 45 +/- 1.7 (range, 26.6-64.1) to 31.4 +/- 1.62 (range, 16.1-51.9) mg/liter, but FCI increased by 130% from 10 +/- 0.8 (range, 2-18) to 23 +/- 1.7 (range, 13-58) nmol/mg. In seven patients (23%), postoperative serum total cortisol was less than 500 nmol/liter, but their postoperative CBG levels were significantly lower than levels in the rest of the group (P < 0.01). However, there was no difference in the FCI between this subgroup and the rest of the group. This study demonstrates the importance of CBG measurement and the calculation of FCI for the interpretation of serum total cortisol in situations where CBG changes significantly.

Sequential proteolytic processing of the Amyloid Precursor Protein (APP) by beta- and gamma-secretases generates the 4-kDa amyloid (A beta) peptide, a key component of the amyloid plaques seen in Alzheimer's disease (AD). We and others have recently reported the identification and characterisation of an aspartic proteinase, Asp2 (BACE), as beta-secretase. Here we describe the characterization of a second highly related aspartic proteinase, Asp1 as a second beta-secretase candidate. Asp1 is expressed in brain as detected at the mRNA level and at the protein level. Transient expression of Asp1 in APP-expressing cells results in an increase in the level of beta-secretase-derived soluble APP and the corresponding carboxy-terminal fragment. Paradoxically there is a decrease in the level of soluble A beta secreted from the cells. Asp1 colocalizes with APP in the Golgi/endoplasmic reticulum compartments of cultured cells. Asp1, when expressed as an Fc fusion protein (Asp1-Fc), has the N-terminal sequence ALEP..., indicating that it has lost the prodomain. Asp1-Fc exhibits beta-secretase activity by cleaving both wild-type and Swedish variant (KM/NL) APP peptides at the beta-secretase site., (Copyright 2000 Academic Press.)

Fractalkine is a recently identified chemokine that exhibits cell adhesion and chemoattractive properties. It represents a unique member of the chemokine superfamily because it is located predominantly in the brain in which it is expressed constitutively on specific subsets of neurons. To elucidate the possible role of neuronally expressed fractalkine in the inflammatory response to neuronal injury, we have analyzed the regulation of fractalkine mRNA expression and protein cleavage under conditions of neurotoxicity. We observed that mRNA encoding fractalkine is unaffected by experimental ischemic stroke (permanent middle cerebral artery occlusion) in the rat. Similarly, in vitro, levels of fractalkine mRNA were unaffected by ensuing excitotoxicity. However, when analyzed at the protein level, we found that fractalkine is rapidly cleaved from cultured neurons in response to an excitotoxic stimulus. More specifically, fractalkine cleavage preceded actual neuronal death by 2-3 hr, and, when evaluated functionally, fractalkine represented the principal chemokine released from the neurons into the culture medium upon an excitotoxic stimulus to promote chemotaxis of primary microglial and monocytic cells. We further demonstrate that cleavage of neuron-derived, chemoattractive fractalkine can be prevented by inhibition of matrix metalloproteases. These data strongly suggest that dynamic proteolytic cleavage of fractalkine from neuronal membranes in response to a neurotoxic insult, and subsequent chemoattraction of reactive immune cells, may represent an early event in the inflammatory response to neuronal injury.

Recombinant fractalkine possesses both chemoattractive and adhesive properties in vitro. Previous studies have demonstrated an upregulation of this molecule on the membranes of activated human endothelial cells and hypothesised that fractalkine plays a role in the recruitment and adherence of monocytes to the activated endothelium. Here we present data analysing both the adhesive and chemoattractive properties of this chemokine expressed by activated human umbilical vein endothelial cells. We demonstrate that both recombinant fractalkine and endogenously produced fractalkine function as adhesion molecules, tethering monocytes to the endothelium. However, our data demonstrate that although recombinant fractalkine has the potential to function as a potent monocyte chemoattractant, the endogenous fractalkine cleaved from activated human umbilical vein endothelial cells is not responsible for the observed chemotaxis in this model. Instead, we show that monocyte chemoattractant protein-1 (MCP-1), secreted from the activated human umbilical vein endothelial cells, is responsible for the chemotaxis of these monocytes.

Metallothionein III (MT III) has been reported to suppress neuronal growth in a rat in vitro model system. The protein and its specific mRNA are detected predominantly in the brain, differentiating MT III from the well-characterised archetypal metallothioneins. Isolation, sequencing and functional analysis of the rat MT III genomic locus indicated that, although the organisation of the gene was conserved between MT III and the more conventional metallothioneins, the 5' flanking region of the MT III gene was distinct. Within this region, a number of putative regulatory elements were identified, including the metal regulatory elements (MREs) characteristic of metallothionein promoters. However, despite their conservation in sequence with active elements, the MREs of MT III were unresponsive to zinc. A 'silencing element' was revealed within a 250 bp section of the MT III promoter which suppressed gene expression in two brain cell lines. The operation of this silencing region in conjunction with the inactive MREs may explain the distinct expression profile observed for MT III within the central nervous system and during neuronal development.

Embryos, larval stages (instars I-V), pupal stages, and pharate adults of the caddisfly Clistoronia magnifica (Limnephilidae) were exposed to a range of dissolved oxygen (DO) concentrations (0.9-8.3 mg/L) for 4-88 days in the laboratory. Some embryos suspended growth at low DO, resuming growth and hatch when DO was increased. Embryos and larvae all had 96-h EC50 values (50% mortality at 96 h) of about 2.0 mg/L DO. The statistical Effect and No-Effect Thresholds for larvae exposed through two molts from instars I-III were 1.6 and 2.4 mg/L, respectively. At DO concentrations below 4.6 mg/L, egg hatch, larval development, molting success, time of molting, pupation, and adult emergence were delayed.

We compared the inhibitory effects of calcium channel blockers, gallopamil and verapamil on acetylcholine (Ach)-induced contractions of ovine tracheal muscle in vitro. Adult sheep were sacrificed and tracheal strips were obtained by cutting the single tracheal rings from the mid-trachea. Tracheal strips were suspended in Krebs-Henseleit solution and isometric tension measured upon stimulation with cumulative doses of Ach (10(-7) to 10(-4) M) without and after pretreatment with gallopamil (10(-7) to 10(-6) M) or verapamil (10(-6) to 10(-5) M). In untreated tissues, the mean concentration of Ach required to produce 50% of maximal response (EC50) was 4.3 x 10(-6) M Ach. Both gallopamil and verapamil inhibited the Ach-induced contractions of ovine tracheal smooth muscle, by shifting the dose-response curves to Ach to the right. EC50 Ach for gallopamil (10(-6) M) and verapamil (10(-6) M) was 2.6 x 10(-5) and 5.2 x 10(-6) M, respectively. Dose ratio defined as postantagonist EC50 Ach/control EC50 Ach, was 7.7 for gallopamil and 2.0 for verapamil. Thus, the inhibitory effect of gallopamil was approximately 4-fold more potent than that of verapamil. Gallopamil was 17-fold more potent than verapamil in relaxing precontracted tracheal strips. The dose of calcium antagonists required to produce 25% relaxation (EC25) of tracheal strips precontracted with 10(-4) Ach was 3.7 x 10(-5) M for verapamil and 2.2 x 10(-6) M for gallopamil. These results indicate that gallopamil is effective against Ach-induced contractions of ovine trachealis muscles, and is more potent than verapamil.

We tested the hypothesis that allergic sheep that develop both early and late airway responses to inhaled Ascaris suum antigen (late responders) have an increased capacity to generate leukotrienes (LTs) compared with allergic sheep that show only early responses to inhaled antigen (acute responders). To test this hypothesis, we measured LTB4 production, in vitro, by granulocytes isolated from peripheral blood and by macrophages isolated from bronchoalveolar lavage (BAL) from both groups of sheep greater than or equal to 2 wk after the animal's last antigen challenge; LTB4 production by granulocytes isolated from BAL from both groups of sheep 6 and 48 h after local airway challenge with A. suum antigen was also measured. LTB4 production was induced by incubating cells (i.e., either granulocytes or macrophages) with calcium ionophore (A23187, 2 microM) and arachidonic acid (30 microM). LTB4 production was quantitated by high-performance liquid chromatography and verified by radioimmunoassay (RIA). On stimulation peripheral blood granulocytes from late responders (n = 7) produced (means +/- SD/10(6) cells) 13.3 +/- 5.2 ng LTB4 compared with 5.3 +/- 1.5 ng LTB4 (P less than 0.05) for acute responders (n = 7). This increased LTB4 production did not result from variations in granulocyte differential or cyclooxygenase activity (as indicated by RIA measurements of prostaglandin E2 production).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of a four-hour exposure (via a Plexiglas hood) to sulfur dioxide (SO2) on airway reactivity was studied in both normal and allergic conscious sheep. Allergic sheep were defined as animals in whom inhalation of Ascaris suum extract resulted in an increase in mean pulmonary flow resistance (RL). Airway reactivity (delta RL) was assessed by measuring the increase in RL after 18 breaths of 0.25% carbachol, from an initial value obtained after 18 breaths of buffered saline. RL and delta RL were determined prior to, immediately after and 24 hours following SO2 exposure in three groups of sheep: six normal sheep exposed to 5 ppm SO2 (group A); six normal sheep exposed to 10 ppm SO2 (group B) and seven allergic sheep exposed to 5 ppm SO2 (group C). RL was not affected by SO2 exposure in any group but both groups B and C showed increases in delta RL 24 hours after exposure. Since the increase in delta RL was greater in group C than in either groups A or B, we conclude that allergic sheep have enhanced susceptibility to the injurious airway effects of SO2.

Pulmonary mechanics of anesthetized dogs were not changed or were minimally altered by breathing the following compounds as submicron aerosols in concentrations up to 17.3 mg/m3 for 7.5 min: (1) sodium chloride (as a control), (2) sodium sulfate, (3) ammonium sulfate, (4) zinc sulfate, (5) zinc ammonium sulfate, (6) ammonium bisulfate, (7) aluminum sulfate, (8) manganese sulfate, (9) nickel sulfate, (10) copper sulfate, (11) ferrous sulfate, and (12) ferric sulfate. Submicron aerosols of these compounds in concentrations of 4.1-8.8 mg/m3, administered for 4 h to anesthetized dogs, did not affect mechanics of breathing, hemodynamics, and arterial blood gases. In conscious sheep, tracheal mucous velocity was not altered by exposure to the submicron aerosols of the sulfate compounds. None of these compounds, injected iv in a dose of 1 mg, had adverse effects on mechanics of breathing, pulmonary and systemic hemodynamics, or arterial blood gases. In 100-mg injections, zinc sulfate and zinc ammonium sulfate produced a fall in cardiac output, systemic hypotension, hypoxemia, and metabolic acidosis. Copper sulfate at this dose produced pulmonary hypertension, a fall in cardiac output, hypoxemia, respiratory acidosis, and a decrease of specific total respiratory conductance. It is concluded that submicron aerosols of sulfate salts do not have adverse cardiopulmonary effects when administered in high concentrations for up to 4 h. However, prolonged exposure to high concentrations of zinc sulfate, zinc ammonium sulfate, and copper sulfate aerosols should be carefully monitored because of the possibility that lower levels of these compounds in the bloodstream for long time period might have adverse cardiopulmonary effects.

The effects of local isotope radiation and x-ray radiation on mucociliary transport of sheep were investigated. X-ray radiation from fluoroscopy equivalent to that used to determine tracheal mucous velocity in intact animals (approximately 3 min) did not alter transport of teflon discs in an isolated sheep trachael preparation. In conscious sheep, 2 ml of a solution containing 8 mCi of macroaggregates of albumin labeled with technetium-99m (99mTc) and 99mTc-pyrophosphate were instilled under direct vision into the trachea via a fiberoptic bronchoscope, providing an actual deposition on the tracheal epithelium of 1.8 to 2 mCi. Physiologic saline and unlabeled macroaggregates of albumin were instilled as control solutions. Tracheal mucous velocity measured by movement of teflon discs increased by 93.2 per cent with 99mTc-labeled macroaggregated albumin and 86.7 per cent with 99mTc-pyrophosphate (P less than 0.01), but no significant increase occurred after saline or unlabeled macroaggregates of albumin. Discrepancies in the values of trachael mucous velocity determined using inert particles and radioactive tracer solution or aerosols might be related in part to the local effects of the tracer radiation.

Environmental toxicant exposure commonly vary in terms of duration and concentration. However, laboratory toxicity tests usually entail continuous exposures to constant concentrations. We compared survival, growth, and toxicant accumulation in early life-stage steelhead trout intermittently or continuously exposed to fenvalerate (FV) for 70 d after fertilization. Acute lethality was assessed in ancillary 96-h LC50 determinations with juvenile fish. Intermittent exposures were daily 4.5-h introductions of toxicant, and continuous exposures were to constant concentrations. All tests were conducted in a flow-through dilution apparatus, and mean concentrations for the entire exposure period were calculated for comparisons between regimens. The respective 96-h LC50 values for intermittently and continuously exposed were 88 and 172 ng/l. In the subchronic study, marked lethality (32%) and reduced terminal weight (50%) were found following exposures to cyclic FV concentrations that yielded an average of 80 ng/l (peak of 461). Continuous exposure to 80 ng FV/l did not affect these parameters. At mean FV concentrations above 20 ng/l, bioaccumulation was greater following intermittent than continuous exposure. Interaction of partitioning and elimination processes may partially explain differences in FV accumulation and subsequent toxicity.

High-precision measurements of total solar irradiance, made by the active cavity radiometer irradiance monitor on the Solar Maximum Mission satellite, show the irradiance to have been variable throughout the first 153 days of observations. The corrected data resolve orbit-to-orbit variations with uncertainties as small as 0.001 percent. Irradiance fluctuations are typical of a band-limited noise spectrum with high-frequency cutoff near 0.15 day(-1) their amplitudes about the mean value of 1368.31 watts per square meter approach +/- 0.05 percent. Two large decreases in irrradiance of up to 0.2 percent lasting about 1 week are highly correlated with the development of sunspot groups. The magnitude and time scale of the irradiance variability suggest that considerable energy storage occurs within the convection zone in solar active regions.

The response of specific lung resistance (SRL) to inhalation of 5 and 10 mg/ml carbachol was compared with the response of SRL to intravenous infusion of 2 and 5 micrograms/kg carbachol before and after a 2-day exposure to 0.5 ppm ozone (O3) in eight conscious sheep. Airway reactivity was defined as the slope of the dose-response curve and airway sensitivity as the largest increase in SRL after carbachol challenge. O3 exposure did not alter mean airway reactivity or mean airway sensitivity as determined by inhalation challenge. In contrast, O3 exposure significantly increased mean airway reactivity by 34% (P less than 0.01) and mean airway sensitivity by 31% (P less than 0.01) as assessed by intravenous challenge. The failure of O3 exposure to enhance responsiveness to inhaled carbachol may have been related to decreased airway penetration of the aerosol, possibly due to mucus hypersecretion. However, O3 exposure may have had a direct effect on the airway smooth muscle, thereby explaining the increased response to infused carbachol.

Some allergic sheep respond to inhalation of Ascaris suum antigen with both immediate and late increases in airflow resistance (late response). The mechanism of the late response is unknown but recent evidence suggests that the initial generation of slow-reacting substance of anaphylaxis (SRS-A) immediately after antigen challenge is a necessary pre-requisite for the physiologic expression of this late response. Based on this evidence we hypothesized that airway challenge with leukotriene D4 (LTD4), an active component of SRS-A would produce acute and late airway responses in allergic sheep similar to those observed with antigen. In five allergic sheep with documented early and late pulmonary responses to Ascaris suum antigen, inhalation of leukotriene D4 aerosol (delivered dose (mean +/- SE) 0.55 +/- 0.08 ug) resulted in significant early and late increases in specific lung resistance (SRL). In three allergic sheep which only demonstrated acute responses to antigen, LTD4 aerosol (delivered dose 0.59 +/- 0.09 ug) only produced an acute increase in SRL. In the late responders pretreatment with aerosol cromolyn sodium (1 mg/kg) did not affect the acute response but blunted the late increase in SRL. Pretreatment with aerosol FPL-57231 (1% w/v solution) completely blocked both the acute and late responses. These data support the hypothesis that initial release of LTD4 in the airways of sensitive animals is important for the physiologic expression of the late response.

Many patients with chronic simple bronchitis, viz., chronic productive cough without major airway obstruction, frequently show enhanced aerosol deposition in the airways. We hypothesized that this phenomenon might relate in part to wave motion of an accumulated layer of mucus caused by dynamic, two-phase gas-liquid interactions. In the present investigation, two-phase gas-liquid interaction was demonstrated in vivo by observing wave motion during tidal breathing of radiopaque-labeled viscous and viscoelastic fluids that had been added to distal tracheas of conscious sheep. Total aerosol deposition in the lung and mean pulmonary resistance (RL) were measured after addition of 4 to 10 ml of viscoelastic or viscous fluids to the distal main bronchi of conscious sheep. Change in aerosol deposition over baseline after fluid addition was compared with change in RL. In 21 experiments, 5 for each of 3 viscoelastic fluids with varying characteristics and 6 for a viscous fluid, aerosol deposition was significantly enhanced in every experiment, irrespective of the type of fluid added. This increase in aerosol deposition ranged from 13 to 66% above baseline. The RL increased in 5 of the 6 experiments with viscous fluid and in 4 of the 15 experiments with viscoelastic fluids. There was less wavelike motion with viscous than with viscoelastic fluids. These results suggest that two-phase gas-liquid interaction in the airways can account for increased aerosol deposition with little alteration in airway resistance.

A new roentgenographic method is described for the estimation of mucous velocity in airways. Radiopaque discs of teflon mixed with bismuth trioxide were deposited in the trachea, and their motion was observed by a fluoroscopic image intensifier. Simultaneous measurements of disc movement were obtained by a previously reported cinebronchofiberscopic method and by the roentgenographic method in 6 anesthetized dogs. Mean +/- SD tracheal mucous velocity was 8.5 +/- 7.3 mm per min by the roentgenographic method, and 7.6 +/- 7.1 mm per min by the cinebronchofiberscopic method. Discrepancies between the 2 methods for individual disc velocities could be accounted for by the cumulative errors of both methods. The roentgenographic method was also used in 7 normal volunteers who did not have topical anesthesia of the tracheobronchial tree. The discs were blown through the inner channel of a bronchofiberscope, the tip of which was located just above the vocal cords. Placement of the discs on the tracheal mucosa generally did not produce coughing. Tracheal mucous velocity ranged from 7.4 to 19.4 mm per min as estimated from videotape recordings of the image intensifier images. There was no consistent difference in velocity between the erect or supine position, or after topical anesthesia with lidocaine.

We determined the effect of aerosol challenge with leukotriene D4 (LTD4) on specific lung resistance (sRL) and tracheal mucous velocity (TMV) in conscious sheep with (allergic) and without (nonallergic) Ascaris suum hypersensitivity. In allergic sheep LTD4 in concentrations of 50, 100, and 150 micrograms/ml produced dose-dependent increases in mean sRL by 44 (P = NS), 154 (P less than 0.05), and 233% (P less than 0.05), respectively. The increase in sRL produced by 150 micrograms/ml LTD4 was prevented by FPL 55712, an antagonist of slow-reacting substance of anaphylaxis. In nonallergic sheep 150 micrograms/ml LTD4 failed to elicit a significant change in sRL. In contrast to the changes in airway mechanics, concentrations of LTD4 as low as 25 micrograms/ml produced significant decreases in TMV in allergic sheep. The maximum decrease in TMV at this dose occurred 2 h after challenge; with larger doses of LTD4 (100 and 150 micrograms/ml) the maximum effect was observed 3 h after challenge. Furthermore, 150 micrograms/ml LTD4 reduced TMV in nonallergic sheep (mean decrease 43%, P less than 0.05). FPL 55712 only had a minor effect on the LTD4-induced decreases in TMV. We conclude that allergic sheep exhibit greater airway responsiveness to inhaled LTD4 than nonallergic sheep but that this difference is not evident for the concomitant changes in mucociliary transport. This suggests that the allergic state is associated with an increased responsiveness to LTD4 in tissues controlling airway caliber but not in those contributing to mucociliary function.

The photoresection of endobronchial tumors produces smoke which is partly inhaled by the patient as well as the surgical staff. In an animal study we investigated whether a single exposure or repetitive exposures to smoke might have harmful side effects on the airways. Eleven sheep were exposed to smoke produced by laser-vaporizing (6,500 J) sections of bronchial tissue (1 cm3) in a Plexiglas chamber. The smoke analysis revealed 0.92 mg/liter particles with a mean particle size of 0.54 micron. Carbon monoxide content was estimated as 0.04%. We measured the effects of one or three separate ten-minute exposures on airway resistance, gas exchange, and mucociliary clearance rate in the trachea. We found that the smoke inhalation resulted in a decrease of arterial PO2 with relatively little change in airway mechanics. Tracheal mucus velocity, a marker of lung mucociliary clearance, was significantly depressed in a dose-dependent manner with increasing smoke exposures. Results of bronchoalveolar lavages performed before and one day after the exposure showed that the smoke inhalation induced a severe inflammation with dramatic increases of inflammatory cells. The total number of cells per milliliter lavage return increased from 3.2 million to 25 million; percent neutrophils increased from 2.3 to 45.6% and percent macrophages decreased from 86 to 41%. These findings indicate that the side effects of smoke inhalation during intrabronchial laser surgery should not be neglected. The impairment of the defense mechanism of the lung combined with the inflammation as well as hypoxia might be fatal in compromised patients. Effective smoke removal devices should be developed to protect the patient as well as the surgeon.

Leukotriene (LT) D4 is a putative mediator of allergic asthma: inhaled LTD4 produces early and late increases in specific lung resistance (SRL) and slows tracheal mucus velocity (TMV) similar to inhaled antigen. In this study we examined the effects of an orally active LTD4/LTE4 antagonist, LY171883 [1-less than 2-Hydroxy-3-propyl-4-less than 4-(1H-Tetrazol-5-yl) Butoxy greater than Phenyl greater than Ethanone], on early and late changes in SRL and TMV following airway challenge with Ascaris suum antigen in conscious allergic sheep. SRL and TMV were measured before and up to 8 h and 24 h after antigen challenge after either LY171883 (30 mg/kg, p.o. 2 h before challenge) or placebo pretreatment. After placebo pretreatment antigen challenge resulted in significant early (483% over baseline) and late (221% over baseline) increases in SRL (n = 9). LY171883 pretreatment, however, significantly reduced the early increase in SRL (163% over baseline) and blocked the late response. LY171883 did not prevent the antigen-induced fall in TMV from 5-8 h post challenge (n = 6), but TMV recovered more rapidly in the drug trial returning to baseline values by 24 h. These results suggest that the generation of LTD4, and its metabolite LTE4, during airway anaphylaxis contributes to the early increase in SRL and is important for eliciting the late increase in SRL as well as contributing to the fall in TMV.

This study was designed to investigate the effect of an experimental low-energy chest wall oscillator and of a commercial chest percussor on central airway mucociliary clearance. Five normal dogs were anesthetized, intubated, and placed supine in a trough to which the oscillator or percussor was mounted. Tracheal mucus velocity (TMV) was measured by radiopaque particle or charcoal spot movement. The commercial percussor (a fixed sinusoidal device) used at its minimum frequency of 40 Hz, produced a mean (+/- SE) maximum expiratory flow rate of 0.25 +/- 0.04 L/sec at the airway opening, and had no measurable effect on TMV. The experimental oscillator, when operated at a level sufficient to generate flows of 2-3 L/sec, and with an unbiased 13-Hz sine wave (estimated energy, 150 W), increased mean TMV to 204 +/- 13% of control (P less than 0.003); the percent increase was independent of baseline TMV. We conclude that moderate oscillatory power applied to the chest wall can enhance mucus clearance in central airways, but that currently available commercial percussors may not meet the mechanical requirements for this effect.

Antigen-induced bronchospasm is associated with an impairment of airway mucociliary clearance, but the duration of this defect has not been examined. In the present study, we determined the time course of mucociliary dysfunction following inhalation challenge with Ascaris suum extract in conscious sheep with hypersensitivity to this antigen. Tracheal mucous velocity (TMV) as an index of mucociliary function, pulmonary resistance (RL), and arterial oxygen tension (Pao2) were measured prior to, immediately after, and serially for 8 h after inhalation challenge. TMV and Pao2 were then measured periodically for at least 2 wk. Immediately after A. suum challenge, mean RL increased to 264% of base line (P less than 0.05), and mean Pao2 decreased to 61% of base line (P less than 0.05). By 2 h postchallenge, mean RL and Pao2 had returned to base line but mean TMV had fallen to 61% of base line (P less than 0.05). Mean TMV reached a minimum of 35% of base line after 5 h (P less than 0.05) and remained significantly depressed between 37% and 54% of base line for 7 days; by day 9, mean TMV had returned to base line. Inhalation challenge with a control antigen (ragweed) failed to alter mean TMV, RL, and Pao2 during the first 8 h and TMV and Pao2 at any time throughout the 2-wk observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effects of nedocromil sodium and cromolyn sodium on early and late bronchial responses to inhaled Ascaris suum antigen in allergic sheep in vivo, and the antigen-induced contractile responses of sheep tracheal smooth muscle in vitro. For the in vivo studies the sheep were pretreated with aerosols of placebo (buffered saline solution), 20 mg of nedocromil sodium, or 20 mg of cromolyn sodium (both dissolved in 3 ml of buffered saline solution) and then challenged with aerosol antigen. Specific pulmonary resistance (SRL) was measured before and after challenge to document the responses of the airways. In the trial with placebo, challenge with antigen resulted in significant early and late increases in SRL. Treatment with nedocromil sodium significantly reduced the early response to antigen and blocked the late response. Cromolyn sodium gave the same results; there were no statistical differences between the responses of the airways for the two dogs. In vitro nedocromil sodium at doses of 10(-6)M and 10(-5)M inhibited significantly the contractile responses of sheep tracheal smooth muscle to A suum. Cromolyn sodium only showed efficacy at 10(-5)M. These results suggest that nedocromil sodium may be potentially useful in the treatment of reversible allergic disease of the airways.

In order to mimic the delivery of CO2 into the pelvic circulation during sustained hysteroscopic surgery, direct insufflation of CO2 was done into the femoral vein of six anesthetized ewes. Following the establishment of baseline values in each animal, cardiac output, pulmonary arterial pressure (Ppa), pulmonary arterial wedge pressure (Ppw), arterial pH and gas levels, and ECG changes were recorded at ten-minute intervals. CO2 was delivered into the femoral circulation for 30 minutes. Following the experiment, measurements were repeated during a 20-minute recovery period. Ppa and Ppw increased significantly during the experiment but returned to baseline values after 70 minutes. Cardiac output, which increased significantly, remained high after the same period and was paralleled by cardiac rate. There was no significant change in systemic blood pressure or arterial oxygenation. Only at the highest flow rate were there observable changes in PCO2, accompanied by mild acidosis. One of the six animals displayed premature ventricular contractions at the inception of the highest flow rate. Since the delivery rate of CO2 per kilogram of body weight clearly exceeded that generally used in human hysteroscopic surgery (35-100 mL/min), these experimental results suggest that CO2, when employed as a distension modality in hysteroscopic surgery, displays a wide margin of safety.

The purpose of this study was to determine if atropine, which has been shown to alter mucosal function, prolongs the persistence of inhaled bacteria in the trachea. In conscious sheep, bacterial counts in the trachea were determined by quantitative sterile brush cultures obtained before and serially after a controlled inhalation challenge with an aerosolized solution containing P. hemolytica (10(8) CFU X ml-1). The same animals were studied on two days, once without (control day) and once before and during intramuscular administration of 0.2 mg X kg-1 atropine sulfate at hourly intervals for up to 10 h (atropine day). On the control and atropine days, bacterial counts were zero before, and between 5 X 10(5) and 1.6 X 10(7) CFU X ml-1 immediately after inhalation of P. hemolytica. During the first 2 h after challenge, there was a similar semilogarithmic decline in bacterial counts on the control and atropine days despite the fact that mean tracheal mucociliary transport velocity remained unchanged on the control day, and ranged between 32% and 62% of baseline (p less than 0.05) during the 6-10 h post-drug observation period on the atropine day. However, the time to achieve sterility on the control day was less than or equal to 8 h in all animals, and greater than or equal to 8 h on the atropine day. We conclude that atropine prolongs the persistence of viable bacteria in the trachea. This effect of atropine may be related to an impairment of mucociliary clearance or to other alterations in mucosal function.

Net outward wave motion of secretions from airways by two-phase gas-liquid transport is favored by higher airflow during expiration than inspiration. This can be accomplished by IRV in which the controlled mode of mechanical ventilation is adjusted such that the inspiratory cycle is prolonged and the expiratory phase is shortened. Studies were done on six anesthetized, nasally intubated sheep. Simulated mucus was instilled into the bronchi at 15-min intervals during I-E ratio of 1:2.7, 1.9:1, and 3:1. The IRV modes of 1.9:1 and 3:1 promoted transport of simulated mucus outward. Neither systemic blood pressure nor cardiac output were altered by IRV. Thus, IRV might be useful in the management of excessive bronchial secretions in mechanically ventilated patients. However, clinical trials of IRV should take into account its potential for producing adverse hemodynamic effects and barotrauma in patients with compromised cardiac function due to auto-PEEP attendant with its usage.