Does anesthesia duration or number of cases per patient predict safety events?

BACKGROUND: The need for dental rehabilitation under general anesthesia is increasing, with varying needs between patients. Mortality has been found to be a rare event in these patients; however other perioperative events can and do occur. Previous studies have established increased incidence of perioperative events with younger, sicker children, and longer anesthetics, however, no studies to date have evaluated if the incidence of perioperative events is more closely associated with one long anesthetic or multiple anesthetics per patient. AIMS: To evaluate the association of perioperative events related to single anesthetic duration or number of anesthetics per patient for dental rehabilitation. METHODS: After Children's Wisconsin Human Research Protection Program determined this quality activity did not meet the definition of human subjects research, we performed an epidemiologic observational evaluation by extracting all dental related cases (dental alone or with oral surgeon vs. dental with other specialties) with an associated general anesthesia encounter from Children's Wisconsin electronic data warehouse from June 1, 2015 to December 31, 2021. These cases occurred at a free-standing children's hospital or associated pediatric-only ambulatory surgery center. The risk of perioperative safety events was analyzed for previously identified risk groups such as American Society of Anesthesiologists Physical Status (ASA-PS), patient age, anesthesia case time with the addition of number of dental cases per patient. RESULTS: In this study, 8468 procedures were performed on 8082 patients. Of this cohort, 7765 patients underwent one procedure for dental care while 317 patients underwent a total of 703 dental-related procedures, ranging from two to five procedures per patient. Multivariable logistic regression identified increased risk of perioperative events in patients with ASA-PS 3 (n = 1459, rate 1.78%, p value .001, OR 5.7, CI 2.1-15.5) and ASA-PS 4 (n = 86, rate 5.8%, p < .001, OR 17.2, CI 4.4-67.3), anesthesia duration (p < .001, OR 1.46, CI 1.21-1.76), but no increased risk with number of anesthetics per patient (p value .54, OR 0.81, CI 0.4-1.61). CONCLUSIONS: Limiting dental care under general anesthesia to multiple short cases may decrease the risk of perioperative events when compared to completing all treatment in one long operative session.

Alterations of Circulating Biomarkers During Late Term Pregnancy Complications in the Horse Part I: Cytokines.

Equine abortions are attributed to both infectious and noninfectious causes. Clinical extrapolations are often made from the experimental model for ascending placentitis towards other causes of fetal compromise, including various markers of inflammation, including the cytokines IL-2, 5, IL-6, IL-10, IFNγ, and TNF. It is unknown if these cytokine changes are noted under field conditions, or if they increase preceding other pregnancy related complications. To assess this, Thoroughbred mares (n = 702) had weekly blood obtained beginning in December 2013 and continuing until parturition. Fetal membranes were submitted to the UKVDL for complete gross and pathologic assessment and classified as either ascending placentitis (n = 6), focal mucoid placentitis (n = 6), idiopathic abortion (n = 6) or control (n = 20). Weekly serum samples were analyzed via immunoassay for concentrations of IL-2, IL-5, IL-6, IL-10, IFNγ, and TNF. For both focal mucoid placentitis and ascending placentitis, an increase (P < .05) in the concentrations of IL-2, IL-5, IL-6, IL-10, IFNγ, and TNF was noted preceding parturition in comparison to controls. Cytokine profiles preceding idiopathic abortion did not differ from controls. In conclusion, serum cytokines may be considered potential biomarkers for the prediction of placental infection, while no changes in cytokine profiles were noted when noninfectious causes of abortion occurred. Additionally, this is the first study to report an increase in cytokines during the disease process of focal mucoid placentitis, the etiology of which includes Nocardioform placentitis.

Short communication: Substituting dry distillers grains with solubles and rumen-protected amino acids for soybean meal in late-lactation cows' diets based on corn silage or ryegrass silage.

Excess protein in dairy cattle diets increases production costs and contributes to environmental pollution. The objective of the present study was to evaluate the effect of feeding dry distillers grains with solubles (DDGS) supplemented with rumen-protected Lys and Met in place of solvent-extracted soybean meal on the performance of late-lactation cows. Two experiments were carried out, with each using 24 late-lactating dairy cows distributed among 4 pens. In trial 1, corn silage was the main forage source. Control (HP1) total mixed ration (TMR) contained 16.3% crude protein (CP) with soybean meal as the main protein source. Treatment TMR (LP1) had 13.7% CP when soybean meal was replaced with DDGS and rumen-protected Lys and Met. Forage in trial 2 was ryegrass silage; control TMR (HP2; 15.4% CP) contained soybean meal and rumen-protected Met, whereas treatment TMR (LP2; 13.8% CP) contained DDGS and rumen-protected Lys and Met. Trials were analyzed as crossover design using the MIXED procedure of SAS (SAS Institute Inc., Cary NC) with cow as sampling unit and pen as the experimental unit. Treatments were similar in dry matter intake (21.0 and 20.4 kg/cow per day for HP1 and LP1, respectively) and milk yield (20.7 and 20.5 kg/cow per day for HP1 and LP1, respectively) during trial 1. Milk composition was similar between treatments, averaging 4.22, 3.73, 4.54, and 9.15, respectively, for fat, protein, lactose, and solids nonfat. Milk urea nitrogen decreased from 17.2 mg/dL for HP1 to 9.93 mg/dL for LP1. In trial 2, no significant differences were observed for dry matter intake (21.4 and 20.9 kg/cow per day for HP2 and LP2, respectively), milk yield (28.1 and 26.6 kg/d for HP2 and LP2, respectively), fat yield (0.99 vs. 0.92 kg/d for HP2 and LP2, respectively), protein yield (0.94 vs. 0.86 kg/d for HP2 and LP2, respectively) and lactose yield (1.37 vs. 1.28 for HP2 and LP2, respectively). Milk urea nitrogen decreased from 9.88 mg/dL with HP2 to 6.39 mg/dL with the LP2 treatment. Milk N efficiency tended to be higher for LP treatments in trial 1, but not in trial 2. Low milk urea N suggested nitrogen losses to the environment may be lower when cows were fed diets based on DDGS in both trials. The studies indicated that DDGS with rumen-protected Lys and Met could substitute solvent-extracted soybean meal in low-protein corn silage- and ryegrass silage-based diets for late-lactation dairy cows averaging 20.6 or 27.4 kg of milk/d, respectively.

Effect of condensed corn distillers solubles concentration on lactation performance of Holstein cows.

Forty-eight Holstein cows (32 multiparous and 16 primiparous) in mid to late lactation averaging 219±71 days in milk and 30.5±6.6 kg/d of 3.5% fat-corrected milk were used in a 56-d completely randomized design experiment to evaluate condensed corn distillers solubles (CCDS) inclusion in high-fiber total mixed rations (TMR). Inclusion rates evaluated were 0, 6.6, 13.2, and 19.8% CCDS as a percentage of dry matter (DM). Distiller solubles substituted for soybean meal, corn grain, and whole cottonseed such that diets were similar in protein (16.6%) and fat (4.50%). Water was added to 0, 6.6, and 13.2% CCDS treatments so that final TMR DM concentrations (47.8%) were similar across diets. The forage portion of the diet was kept constant at 19.6% annual ryegrass hay and 26.0% sorghum baleage. Diet in vitro true digestibility tended to increase as CCDS addition increased, but neutral detergent fiber digestibility trended lower in CCDS diets. Percent P (0.39, 0.55, 0.69, and 0.73%) and S (0.32, 0.35, 0.39, and 0.42%) in TMR increased as CCDS concentration increased. Milk yield (23.5, 24.7, 25.5, and 24.8 kg/d of 3.5% fat-corrected milk) was similar for control and CCDS diets. Milk fat (3.88, 3.73, 3.78, and 3.68%), protein (3.28, 3.27, 3.31, and 3.31%), and lactose (4.61, 4.66, 4.69, and 4.77) percentages were similar across diets. Milk urea nitrogen (16.60, 15.58, 15.43, and 14.75 mg/dL) declined with increasing CCDS addition. Animal activity, body weight, body condition scores, and locomotion scores were not influenced by CCDS. Day 28 poststudy locomotion scores were similar across diets. Ruminal acetate concentrations did not differ among diets, but propionate and butyrate concentrations were elevated in rumen fluid of cows receiving 19.6% CCDS. Although rumen fluid pH values were similar (6.5, 6.4, 6.3, and 6.2), the two highest CCDS diets exhibited depressed acetate:propionate ratios relative to controls. The results from this study indicate that CCDS may be included in high-fiber TMR for lactating dairy cows at up to nearly 20% of diet DM; however, caution is recommended because high CCDS P concentrations may create Ca:P imbalances and excess P may be introduced into the environment.

Bale Location Effects on Nutritive Value and Fermentation Characteristics of Annual Ryegrass Bale Stored in In-line Wrapping Silage.

In southeastern regions of the US, herbage systems are primarily based on grazing or hay feeding with low nutritive value warm-season perennial grasses. Nutritious herbage such as annual ryegrass (Lolium multiflorum Lam.) may be more suitable for preserving as baleage for winter feeding even with more intensive production inputs. Emerging in-line wrapped baleage storage systems featuring rapid wrapping and low polyethylene film requirements need to be tested for consistency of storing nutritive value of a range of annual ryegrass herbage. A ryegrass storage trial was conducted with 24-h wilted 'Marshall' annual ryegrass harvested at booting, heading and anthesis stages using three replicated in-line wrapped tubes containing ten round bales per tube. After a six-month storage period, nutritive value changes and fermentation end products differed significantly by harvest stage but not by bale location. Although wilted annual ryegrass exhibited a restricted fermentation across harvest stages characterized by high pH and low fermentation end product concentrations, butyric acid concentrations were less than 1 g/kg dry matter, and lactic acid was the major organic acid in the bales. Mold coverage and bale aroma did not differ substantially with harvest stage or bale location. Booting and heading stage-harvested ryegrass baleage were superior in nutritive value to anthesis stage-harvested herbage. Based on the investigated nutritive value and fermentation characteristics, individual bale location within in-line tubes did not significantly affect preservation quality of ryegrass round bale silages.

Forage conservation efficiency and lactation response to bahiagrass conserved as barn-stored hay, outdoor-stored hay, or baleage.

A study was conducted to determine the effect of conserving bahiagrass as outdoor-stored hay (OSH), barn-stored hay (BSH), or baleage (BAL) on storage losses and lactation performance by Holstein cows. For baleage production, bahiagrass forage was cut and allowed to dry for 20 h in windrows, baled (1.2 × 1.4 m), and individually wrapped with white stretch film. Forage cut on the same day was dried to hay stage, baled (1.2 × 1.6 m round bales), and stored either outdoors (OSH) or in an enclosed hay barn (BSH). Bales were core sampled and weighed at harvest and again following a 6-mo storage period. At the end of the storage period, 30 multiparous mid-lactation Holstein cows [39.2 ± 5.6 kg of 3.5% fat-corrected milk and 142 ± 27 d in milk (DIM)] were stratified according to milk yield and DIM and randomly assigned to 1 of the 3 forage conservation treatments. Cows were trained to Calan feeding gates and were offered a common partial mixed ration in a 10-d covariate period followed by a 42-d treatment feeding period. Forage dry matter losses were highest for OSH, but were similar between BSH and baleage. Conservation method had little effect on poststorage crude protein levels, but acid detergent fiber and neutral detergent fiber concentrations were higher in OSH than in either BSH or BAL, which resulted in a 12.8% depression in net energy for OSH compared with the other treatments. Dry matter intake (20.5 vs. 22.1 kg/d) and milk yield (28.2 vs. 30.2 kg/d) tended to be lower for OSH than for BSH. Lactation performance was similar between BSH and BAL: 29.6 versus 28.7 kg/d of fat-corrected milk, respectively. No differences in milk composition, feed efficiency, body weight, or body condition score change related to conservation system were observed. In this study, dry matter losses and lactation performance from bahiagrass conserved as baleage were similar to that of similar forage stored indoors as hay, whereas hay stored outside resulted in less satisfactory forage quality.

Influence of calcium and phosphorus feeding on markers of bone metabolism in transition cows.

A study was carried out to verify the effect of Ca and P levels on production, digestibility, and serum bone metabolism biomarkers in dairy cows. Fifty-two nonlactating multiparous cows (>or=3 lactations) were confined in a free-stall barn approximately 20 d before calving. A standard close-up diet was fed to cows once daily until d 2 postpartum. Cows were randomly assigned to 1 of 4 dietary treatments arranged in a 2 x 2 factorial approach averaging 0.64% Ca for high Ca (HCa), 0.46% Ca for low Ca (LCa), 0.47% P for high P (HP), and 0.38% P for low P (LP) on a dry matter basis. Experimental diets were fed twice daily from 3 d in milk (DIM) until 31 DIM. Intake and milk yield were recorded daily. Milk samples were collected on d 28, 29, and 30 postpartum for components analyses. Blood samples were drawn 10 d before expected calving, at calving, and at 15 and 30 DIM for serum analyses of osteocalcin, a biomarker of bone accretion, and pyridinoline, a biomarker of bone resorption. Total fecal collection was conducted when cows in a block averaged 20 DIM. Intake and production traits were not significantly affected by any of the dietary treatments. Cows averaged nearly 21 kg/d dry matter intake and 44 kg/d milk yield from 6 to 31 DIM. There were no significant differences across treatments in body weight or body condition score loss. Phosphorus intake, P fecal output, P digestibility, and P apparent absorption were affected by dietary P content. Calcium intake was higher with HCa, but Ca fecal output, digestibility, and apparent absorption showed an interaction between dietary Ca and dietary P. Calcium fecal output was 100.6 g/d for cows fed HCaHP, intermediate for cows on the HCaLP diet (89 g/d), and similar among cows fed the 2 LCa diets (70 g/d with LCaHP and 75 with LCaLP). There was no significant effect of Ca or P on osteocalcin measurements. Pyridinoline concentrations were affected by dietary Ca levels and tended to have a significant dietary Ca x dietary P interaction. Phosphorus apparent digestibility occurred independently of dietary Ca levels. Results of this study suggest that more bone was mobilized in cows fed LCa diets, but excess dietary P caused greater and prolonged bone mobilization regardless of dietary Ca content.

Effect of protein source and soluble carbohydrate addition on rumen fermentation and lactation performance of Holstein cows.

Rumen in vitro and in vivo experiments were conducted to evaluate the effect of rumen undegradable protein and soluble carbohydrates on rumen ammonia N release and lactation performance of Holstein cows. In the in vitro experiment, freeze-dried annual ryegrass (Lolium multiflorum, LAM) pasture was supplemented 1:1 with ground corn-based grain supplements containing expeller or solvent soybean meal with sucrose or lactose supplements at 0, 2.5, or 5% of dry matter (DM). The ammonia release rate was slower with expeller compared with solvent soybean meal-supplemented diets. Sucrose supplementation at the 5% level lowered rumen ammonia concentrations, but lactose-fortification of grain supplements was without effect. In the in vivo study, 32 multiparous Holstein cows were blocked according to milk yield and randomly assigned to corn-based grain supplements containing 1) solvent soybean meal, 2) solvent soybean meal + 5% sucrose supplement, 3) expeller soybean meal, or 4) expeller soybean meal + 5% sucrose supplement. Grain supplements and fresh annual ryegrass were component fed at approximately a 1:1 grain to forage ratio (DM basis). Forage DM intake was higher for cows receiving solvent soybean meal supplemented grain supplements than those receiving expeller soybean meal (12.2 +/- 2.1 vs. 11.4 +/- 2.2 kg/d), but total DM intake was similar for all diets (22.8 +/- 2.9 kg/d). Fat-corrected milk yield was similar for all diets averaging 37.5, 38.2, 39.1, and 37.6 kg/d for diets 1 to 4, respectively. Rumen fermentation, milk urea nitrogen, and body condition were unaffected by supplements; however, cows fed grain supplement 1 utilized dietary energy more efficiently than cows offered the other dietary treatments. High dietary crude protein concentrations may have limited lactation response to rumen undegradable protein and sugar.

Supplemental dietary protein for grazing dairy cows: effect on pasture intake and lactation performance.

One hundred twenty-four cows (92 multiparous and 32 primiparous) were used to evaluate the effect of grain supplements containing high crude protein [(22.8% CP, 5.3% rumen undegradable protein (RUP), dry matter basis], moderate CP (16.6% CP, 6.1% RUP), and moderate CP with supplemental RUP (16.2% CP, 10.8% RUP) on lactation performance of Holstein cows rotationally grazing annual ryegrass-oat pastures. Supplemental protein was provided by solvent extracted soybean meal in the high CP and moderate CP supplements and as a corn gluten meal-blood meal mixture (2.8:1) in the moderate CP, high RUP supplement. Cows were blocked according to previous mature milk equivalent production and calving date (partum group; 0 d in milk or postpartum group; 21 to 65 d in milk) and randomly assigned to dietary treatments. Grain was individually fed, at approximately a 1:3 grain to milk ratio, before a.m. and p.m milkings. The study was replicated during two grazing seasons that averaged 199 d. Cows had ad libitum access to bermudagrass hay while on pasture (dry matter intake = 1.3 kg/d). Protein supplementation had no effect on study long pasture dry matter (12.7 +/- 1.0 kg/d) or total dry matter (23.9 +/- 1.2 kg/d) consumption. Protein concentration did not affect actual milk yield of either calving group (high CP vs. moderate CP); however, postpartum group cows receiving high CP grain supplements maintained greater milk fat concentrations (3.34 vs. 3.11%), which led to higher fat-corrected milk (FCM) yields than control cows receiving moderate CP grain diets (30.3 vs. 28.9 kg/d). Crude protein concentration in milk of high CP-supplemented, postpartum group cows was also higher than moderate CP cows (3.42 vs. 3.27%). Additional RUP did not increase FCM yield above that generated by moderate CP grain diets for partum (34.3 vs. 32.9 kg/d) or postpartum-group cows (28.9 vs. 28.2 kg/d). Increasing CP concentration of grain supplement did not affect milk yield of Holstein cows grazing immature winter annual pastures. Supplementing additional RUP was without benefit, indicating that in this study energy deprivation may have been the major nutritional constraint for high-producing dairy cows grazing lush pastures.

Supplemental dietary protein for grazing dairy cows: reproduction, condition loss, plasma metabolites, and insulin.

An experiment was conducted over a 2-yr period to investigate the influence of grain crude protein (CP) and rumen undegradable protein (RUP) concentration on reproduction and energy status of dairy cows grazing annual ryegrass (Lolium multiflorum) and oats (Avena sativa). Holstein cows (n = 122) were blocked by calving group [partum (0 d postpartum) vs. postpartum (41 +/- 19 d postpartum at study initiation)] and assigned to grain supplements containing high CP [22.8% of dry matter (DM)], moderate CP (16.6%), or moderate CP (16.2%)] supplemented with RUP from blood meal and corn gluten meal. Postpartum condition loss was greater and first-service pregnancy rate was lower for partum-group cows receiving high CP grain supplements compared with control cows receiving moderate CP supplements. The RUP supplements reduced grain consumption, increased days to first estrus, and reduced first-service pregnancy rate of partum-group cows. The reproduction of postpartum group cows was unaffected by protein supplements. Plasma urea nitrogen was higher for cows fed high CP diets, but plasma ammonia nitrogen, glycated hemoglobin, nonesterified fatty acids, beta-hydoxybutyrate, glucose, and insulin concentrations were similar to cows fed moderate CP. Excess postpartum condition loss, coupled with inconsistent protein supplement effects on days to first service and first-service pregnancy rate, suggest that energy deprivation may have contributed to the low fertility experienced by grazing cows in this study.

Chemical composition, ensiling characteristics, and apparent digestibility of summer annual forages in a subtropical double-cropping system with annual ryegrass.

A 2-yr study was conducted to determine the chemical composition and digestibility of silages made from forage sorghum, pearl millet, and tropical corn managed to optimize forage quality. Silages were ensiled in upright concrete silos lined with plastic and fed to heifers to determine in vivo apparent digestibility. Samples were collected before and after ensiling to determine ensiling characteristics and forage quality. After ensiling, tropical corn had the greatest dry matter (DM), the lowest crude protein, and the greatest water-soluble concentrations. Tropical corn silage had a pH of 3.96. The pH of forage sorghum silage was 4.09, and pearl millet had a pH of 4.50. Pearl millet had the lowest concentration of preensiled water-soluble carbohydrate, which likely caused the high pH in the silage. There were no differences among the forages in DM loss during ensiling in yr 2. Heifers fed pearl millet silage consumed more DM, but digestible DM intake was not different among the three groups of heifers. The results of this experiment indicate that pearl millet would be less desirable as a crop intended solely for silage production. Both forage sorghum and tropical corn could be grown specifically for ensiling based on DM digestibility. The decision on which crop to use should be based on factors such as production costs, forage yields, and local growing conditions rather than silage quality.

Crude protein and rumen undergradable protein effects on reproduction and lactation performance of Holstein cows.

We conducted a study to determine the effects of excess dietary crude protein (CP) and rumen undegradable protein (RUP) on reproduction and lactation performance of Holstein cows. During each of three yearly replicates, cows were blocked by previous mature equivalent milk production and randomly assigned at calving (n = 47; partum group) or at 42 +/- 21 d postpartum (n = 134; postpartum group) to the following dietary treatments: 1) ryegrass pasture supplemented with a corn and soybean meal grain mix (high CP, moderate RUP); 2) ryegrass pasture mornings and corn silage evenings, supplemented with grain as in diet 1 (moderate CP, moderate RUP control diet), and 3) ryegrass pasture mornings and corn silage evenings, supplemented with a grain mix containing corn, soybean meal, corn gluten meal, and blood meal (moderate CP, high RUP). Dietary CP and RUP concentrations were approximately 23.1, 5.8; 17.7, 5.0; and 17.2, 6.8% of dry matter for diets 1 to 3, respectively. Plasma urea N concentrations were highest in cows fed diet 1 (25.0 mg/dl), intermediate in cows on diet 2 (20.1 mg/dl), and lowest in cows on diet 3 (18.5 mg/dl). Cows fed excess dietary protein (diet 1) exhibited lower first breeding pregnancy rates (24.1 vs. 41.0%) and lower overall pregnancy rates (53.4 vs. 75.4%) than did cows fed diet 2, increasing time nonpregnant by an average of 15.1 d per cow. Reproductive performance was similar between cows fed diets 2 and 3. Mean fat-corrected milk (FCM) yield was not affected by protein concentration (diet 1 vs. 2); however, partum group cows that received supplemental RUP (diet 3) produced more 3.5% FCM than controls in early lactation. Feeding grain diets that contained excess dietary protein impaired the reproductive performance of dairy cows grazing ryegrass.

Leukotrienes do not regulate interleukin 1 production by activated macrophages.

The objective of this work was to investigate the role of leukotrienes in the production of IL-1 by activated human peripheral blood monocytes and mouse peritoneal macrophages. Using overnight adherent macrophages, stimulation with lipopolysaccharide or zymosan caused a time-dependent increase in IL-1 production. LTC4 was detected and preceded IL-1 production only in zymosan-treated macrophages. Lipopolysaccharide did not stimulate macrophages to produce LTC4. Zymosan-stimulated LTC4 production was inhibited by the lipoxygenase inhibitors, ICI207968 (3.20 microM), nordihydroguaiaretic acid (0.22 microM), phenidone (4.60 microM), REV5901 (0.20 microM), and the Merck 5-lipoxygenase "translocation inhibitor" MK886 (0.02 microM) with IC50 values as shown in parenthesis. However, none of these inhibitors reduced IL-1 production at concentrations which completely inhibited leukotriene synthesis. Taken together, these results do not support a role for leukotrienes in the production of IL-1 by zymosan-activated macrophages.

Serum proteins as carriers of amino acids to and from the hindlimbs of fed and fasted calves.

Venoarterial differences in the amino acid composition of serum proteins were measured across the hindlimbs of growing Holstein steer calves (147 kg) surgically fitted with abdominal aorta and caudal vena cava cannulae. Steers were maintained in near steady-state metabolism by feeding at hourly intervals in a continuously lighted environment. The steady-state blood samples were obtained 10 d post-surgery; then the steers were fasted and resampled. Arterial and venous serum proteins were chromatographically separated into four fractions and the amino acid composition of each was determined. Under steady-state conditions, there appeared to be a tendency for serum protein amino acids to appear on the venous side of the tissue in either greater or lesser concentrations than on the arterial side, depending upon the protein fraction. However, after the steers had fasted for 72 h, virtually all amino acids from all protein fractions were present in greater concentrations in venous serum than in arterial serum. Furthermore, the quantitative differences were several-fold larger than during steady-state sampling. It appears that serum proteins may contribute to the transport of amino acids to and from peripheral tissues. Data further suggest that all serum proteins do not appear to function in the same manner, and physiological state influences this process.

The inflammatory response of rabbit skin to topical arachidonic acid and its pharmacological modulation.

The inflammatory reaction induced by the intradermal injection of arachidonic acid into the rabbit dermis has been investigated. Plasma extravasation was measured by the leakage of 125I-albumin into the tissues and polymorphonuclear leukocyte (PMNL) accumulation was assessed histologically. Arachidonic, 5,8,11,14,17-eicosapentaenoic and 8,11,14-eicosatrienoic acids, but not oleic, linoleic or linolenic acids, caused a concentration-related plasma extravasation following their intra-dermal injection. The plasma extravasation induced by arachidonic acid was dependent on PMNLs. PMNL infiltration and plasma extravasation into arachidonic acid-injected skin sites was inhibited by the mixed cyclo-oxygenase-lipoxygenase inhibitor, BW755C. Arachidonic acid-induced plasma extravasation was inhibited by cyclo-oxygenase and 5-lipoxygenase inhibitors but not by the Paf antagonist, kadsurenone. The inflammation induced by arachidonic acid in the rabbit dermis may be a useful model for evaluating 5-lipoxygenase inhibitors which could be potentially useful anti-inflammatory agents for the treatment of psoriasis and other inflammatory diseases.

Leukocyte recruitment in the subcutaneous sponge implant model of acute inflammation in the rat is not mediated by leukotriene B1.

The subcutaneous sponge implant model of acute inflammation in the rat has been evaluated as a suitable test system for evaluating the potential anti-inflammatory efficacy of 5-lipoxygenase inhibitors. The inflammatory parameters measured were exudate volume and leukocyte recruitment. Specific radioimmunoassays were used to measure (1) 5-lipoxygenase (LPO) and cyclo-oxygenase (CO) activity in exudate leukocytes stimulated ex vivo with A23187, and (2) the LTB4 and PGE2 content of inflammatory exudate. The NSAIDs flurbiprofen and indomethacin inhibited cell recruitment, exudate volume and CO activity with ED50S of approximately 1 mg per kg p.o. but failed to inhibit LPO activity at 10 mg per kg p.o. Nafazatrom (Bayer 6575), quercetin and NDGA, which inhibit LPO activity in vitro, were inactive against all parameters when dosed at 100 mg per kg p.o. The "mixed inhibitors" BW755C and phenidone were approximately equipotent inhibitors of LPO activity but BW755C was 10 times more potent than phenidone against CO activity. BW755C was also greater than 10 times more potent at inhibiting cell recruitment and exudate volume than phenidone suggesting that the anti-inflammatory efficacy of the mixed inhibitors reflect their potency against CO rather than LPO activity. Time course studies demonstrated that the inhibitor effects of BW755C and phenidone on leukocyte recruitment reflected a reduction in the PGE2 but not the LTB4 content of the inflammatory exudate. Polyester sponges soaked in high concentrations of LTB4 caused only a modest (2-fold) increase in leukocyte recruitment whilst physiological levels were inactive. The results taken together suggest that CO products make a major contribution to leukocyte recruitment in this model whilst the LPO product LTB4 has little role. This model therefore is of little value for evaluating the anti-inflammatory efficacy of 5-lipoxygenase inhibitors. Moreover, the rat would appear to be unsuitable for evaluating the role of LTB4 in acute inflammation.