Quantifying the External and Internal Loads of Professional Rugby League Training Modes: Consideration for Concurrent Field-Based Training Prescription.

Weaving, D, Jones, B, Till, K, Marshall, P, Earle, K, and Abt, G. Quantifying the external and internal loads of professional rugby league training modes: consideration for concurrent field-based training prescription. J Strength Cond Res 34(12): 3514-3522, 2020-Practitioners prescribe numerous training modes to develop the varied physical qualities that professional rugby league players must express during competition. The aim of this study was to determine how the magnitude of external and internal training load per minute of time differs between modes in professional rugby league players. These data were collected from 17 players across 716 individual sessions (mean [SD] sessions: 42 [13] per player) which were categorized by mode (conditioning [CON], small-sided games, skills, and sprint training). Derived from global positioning systems (5 Hz with 15 Hz interpolation), the distances covered within arbitrary speed and metabolic power thresholds were determined to represent the external load. Session rating of perceived exertion and individualized training impulse represented the internal load. All data were made relative to the session duration. The differences in time-relative load methods between each mode were assessed using magnitude-based inferences. Small-sided games and CON very likely to almost certainly produced the greatest relative internal and external loads. Sprint training provided players with the greatest sprinting and maximal-power distances without a concomitant increase in the internal load. The metabolic power method complements speed-based quantification of the external load, particularly during small-sided games and skills training. In practice, establishing normative loads per minute of time for each mode can be useful to plan future training by multiplying this value by the planned session duration.

Exercise tolerance during VO2max testing is a multifactorial psychobiological phenomenon.

Fifty-nine men completed a VO2max test and a questionnaire to establish reasons for test termination, perceived exercise reserve (difference between actual test duration and the duration the individual perceived could have been achieved if continued until physical limitation), and perception of verbal encouragement. Participants gave between 1 and 11 factors as reasons for test termination, including leg fatigue, various perceptions of physical discomfort, safety concerns, and achievement of spontaneously set goals. The two most common main reasons were leg fatigue and breathing discomfort, which were predicted by pre-to-post test changes in pulmonary function (p = 0.038) and explosive leg strength (p = 0.042; R2 = 0.40). Median (interquartile range) perceived exercise reserve, was 45 (50) s. Two-thirds of participants viewed verbal encouragement positively, whereas one-third had a neutral or negative perception. This study highlights the complexity of exercise tolerance during VO2max testing and more research should explore these novel findings.

The internal dynamics of mini c TAR DNA probed by electron paramagnetic resonance of nitroxide spin-labels at the lower stem, the loop, and the bulge.

Electron paramagnetic resonance (EPR) at 236.6 and 9.5 GHz probed the tumbling of nitroxide spin probes in the lower stem, in the upper loop, and near the bulge of mini c TAR DNA. High-frequency 236.6 GHz EPR, not previously applied to spin-labeled oligonucleotides, was notably sensitive to fast, anisotropic, hindered local rotational motion of the spin probe, occurring approximately about the NO nitroxide axis. Labels attached to the 2'-aminocytidine sugar in the mini c TAR DNA showed such anisotropic motion, which was faster in the lower stem, a region previously thought to be partially melted. More flexible labels attached to phosphorothioates at the end of the lower stem tumbled isotropically in mini c TAR DNA, mini TAR RNA, and ψ(3) RNA, but at 5 °C, the motion became more anisotropic for the labeled RNAs, implying more order within the RNA lower stems. As observed by 9.5 GHz EPR, the slowing of nanosecond motions of large segments of the oligonucleotide was enhanced by increasing the ratio of the nucleocapsid protein NCp7 to mini c TAR DNA from 0 to 2. The slowing was most significant at labels in the loop and near the bulge. At a 4:1 ratio of NCp7 to mini c TAR DNA, all labels reported tumbling times of >5 ns, indicating a condensation of NCp7 and TAR DNA. At the 4:1 ratio, pulse dipolar EPR spectroscopy of bilabels attached near the 3' and 5' termini showed evidence of an NCp7-induced increase in the 3'-5' end-to-end distance distribution and a partially melted stem.

Multi-wave analyses of coping, athlete burnout, and well-being among F. A. Premier League academy players.

Being a player with an F. A. Premier football academy is very prestigious for young players, but it can also be very stressful too. Coping with stress is particularly important given that one of the undesirable consequences linked to chronic stress is athlete burnout, which may also negatively impact psychological well-being. Understanding the most effective ways to cope with stress, therefore, is important for optimizing academy athlete education. Consequently, the aim of the present study was to examine whether coping predicted changes in athlete burnout, and whether athlete burnout predicted changes in well-being across 14 weeks of the competitive season. A sample of 26, under-18 and under-23, male F.A. Premier academy athletes completed weekly assessments of coping (task-, distraction-, and disengagement-oriented), athlete burnout, and psychological well-being on 14 separate occasions. The results of within-person analyses revealed that task-oriented coping predicted decreases in athlete burnout, which in turn predicted decreased well-being. Teaching high-level academy athletes task-oriented coping strategies may be useful in reducing athlete burnout, which may additionally protect athletes' well-being.

Magnetic Resonance Spectra and Statistical Geometry.

Methods of statistical geometry are introduced which allow one to estimate, on the basis of computable criteria, the conditions under which maximally informative data may be collected. We note the important role of constraints which introduce curvature into parameter space and discuss the appropriate mathematical tools for treating curvature effects. Channel capacity, a term from communication theory, is suggested as a useful figure of merit for estimating the information content of spectra in the presence of noise. The tools introduced here are applied to the case of a model nitroxide system as a concrete example, but we stress that the methods described here are of general utility.

Perceptions of the Coach-Athlete Relationship Predict the Attainment of Mastery Achievement Goals Six Months Later: A Two-Wave Longitudinal Study among F. A. Premier League Academy Soccer Players.

All football teams that compete within the F. A. Premier League possess an academy, whose objective is to produce more and better home-grown players that are capable of playing professionally. These young players spend a large amount of time with their coach, but little is known about player's perception of the coach-athlete relationship within F. A. Premier League Academies. The objectives of this study were to examine whether perceptions of the coach-athlete relationship changed over six months and if the coach-athlete relationship predicted self-reported goal achievement among F. A. Premier League academy players. This study included cross-sectional (n = 104) and longitudinal (n = 52) assessments, in which academy soccer players completed a measure of the coach-athlete relationship and goal achievement across either one or two time periods. The cross-sectional data were subjected to bivariate correlations, whereas the longitudinal data were analyzed using multiple regressions. Perceptions of the coach-athlete relationship remained stable over time. The coach-athlete relationship predicted the achievement of mastery goals six months later. Enhancing the quality of the coach-athlete relationship among elite adolescent athletes appears to be a suitable way of maximizing mastery achievement goals, particularly among developmental athletes who participate in team sports.

High-field ESR on aligned membranes: a simple method to record spectra from different membrane orientations in the magnetic field.

A combination of isopotential spin-dry ultracentrifugation (ISDU) and microtome techniques was used to facilitate the collection of high field/high frequency (170 GHz) ESR spectra corresponding to different orientations of the membrane normal relative to the magnetic field. This technique is particularly valuable for aligned biological samples in vitro. At 170 GHz, conventional sample preparation techniques based solely on ISDU constrained the sample to be oriented so that the membrane normal was parallel to the applied magnetic field due to the geometry and the millimeter wave field distribution of the Fabry-Pérot resonator used in these experiments. This orientational constraint limited the information that could be obtained from aligned membranes at high field. The combined ISDU/microtome technique overcame this limitation. Spectra from spin-labeled Gramicidin A and the spin label cholestane in aligned DPPC membranes provide a demonstration of the technique. We also discuss some virtues of high field/high frequency ESR on aligned membranes compared to X-band.

A variable temperature EPR study of Mn(2+)-doped NH(4)Cl(0.9)I(0.1) single crystal at 170 GHz: zero-field splitting parameter and its absolute sign.

EPR measurements have been carried out on a single crystal of Mn(2+)-doped NH(4)Cl(0.9)I(0.1) at 170-GHz in the temperature range of 312-4.2K. The spectra have been analyzed (i) to estimate the spin-Hamiltonian parameters; (ii) to study the temperature variation of the zero-field splitting (ZFS) parameter; (iii) to confirm the negative absolute sign of the ZFS parameter unequivocally from the temperature-dependent relative intensities of hyperfine sextets at temperatures below 10K; and (iv) to detect the occurrence of a structural phase transition at 4.35K from the change in the structure of the EPR lines with temperature below 10K.

Exisulind in combination with docetaxel inhibits growth and metastasis of human lung cancer and prolongs survival in athymic nude rats with orthotopic lung tumors.

Docetaxel, a semisynthetic taxane, improves the survival of stage IIIB and IV non-small cell lung cancer patients. However, the 5-year survival remains poor, and few patients experience a complete remission. In this report, we evaluated the effects of exisulind, a novel proapoptotic agent that is a sulfone metabolite of sulindac, in combination with docetaxel on the growth of the human non-small cell lung cancer cell line A549 in vitro and in vivo. Exisulind is a novel sulindac metabolite in that it does not inhibit cyclooxygenase enzymes and has been shown to induce apoptosis in a variety of human cancers by inhibiting cyclic GMP-dependent phosphodiesterase. Exisulind alone increased the fraction of cells in the G(1) phase of the cell cycle from 46% to 65%, whereas it decreased the fraction of cells in the S phase from 38% to 14%. Docetaxel increased the fraction of cells in the S phase from 17% to 19%, and 10 nM docetaxel increased the G2-M phase by 23%. Docetaxel alone induced apoptosis from 11% to 64% at 12-24 h after incubation. The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution) reduced the G(1) accumulation induced by exisulind, increased the fraction of cells in G(2)-M (9-17%), and increased apoptosis (5-62%). The IC(50) for in vitro growth inhibition by exisulind alone was approximately 200 microM and 2.5 nM for docetaxel. The in vitro combination of exisulind and docetaxel produced an additive to synergistic growth inhibition. In athymic nude rats with A549 orthotopic lung cancers, both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases, and increased apoptosis compared with control animals treated with a carrier. However, the combination of exisulind with docetaxel significantly prolonged survival (P = < 0.0004), inhibited tumor growth and metastases (P = < 0.0001), and increased apoptosis (P = < 0.001) when compared with control animals. These results provide rationale for conducting clinical trials using the combination of exisulind and docetaxel in patients with advanced lung cancer.

Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival.

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.

Preclinical and clinical studies of docetaxel and exisulind in the treatment of human lung cancer.

Lung cancer is the leading cause of cancer death in the United States. The majority of patients with non-small cell lung cancers present with inoperable disease because of the presence of metastases to regional lymph nodes or other metastatic sites. About one third of patients have stage IV disease with metastases to distant organs at the time of diagnosis. The prognosis for these patients is very poor. With best supportive care the median survival is only 4 months and the 1-year survival rate is 10% to 15%. Current chemotherapy combinations improve the survival and quality of life for patients with advanced non-small cell lung cancer. With two-drug combinations, median survival is increased to 8 months or more and 1-year survival is increased to 35% to 40%. Still, complete response rates are low and more than 80% of patients die within 1 year of diagnosis. The improvements created by current therapies led to studies of chemotherapy in the second-line setting. Docetaxel has been shown to improve survival of patients who failed platinum-based chemotherapy and was approved by the U.S. Food and Drug Administration for therapy in this setting. However, response rates were very low and survival very short. Therefore, new therapies are urgently needed. Exisulind is a novel oral anticancer agent that holds promise for the treatment of patients with advanced non-small cell lung cancer. Exisulind was originally developed as a chemoprevention agent for colorectal cancer. Preclinical studies showed that exisulind could prevent polyp formation and inhibit the growth of colorectal cancers. Subsequent preclinical studies showed that exisulind also inhibited the growth of human breast, prostate, and lung cancers. Phase I clinical studies showed that twice-daily oral doses could be given safely and would provide peak concentrations that were equivalent to those required for in vitro effects. These observations lead to the studies of the combination of exisulind and docetaxel in preclinical and clinical studies in human lung cancer described in this article.

Variable-frequency EPR study of Mn(2+)-doped NH(4)Cl(0.9)I(0.1) single crystal at 9.6, 36, and 249.9 GHz: structural phase transition.

Multifrequency electron paramagnetic resonance studies on the Mn(2+) impurity ion in a mixed single crystal NH(4)Cl(0.9)I(0.1) were carried out at 9.62 (X-band) in the range 120-295 K, at 35.87 (Q-band) at 77 and 295 K, and at 249.9 GHz (far-infrared band) at 253 K. The high-field EPR spectra at 249.9 GHz are well into the high-field limit leading to a considerable simplification of the spectra and their interpretation. Three magnetically inequivalent, but physically equivalent, Mn(2+) ions with their respective magnetic Z-axes oriented along the crystallographic [100], [010], [001] axes were observed. Simultaneous fitting of EPR line positions observed at X-, Q-, and far infra-red bands was performed using a least-squares procedure and matrix diagonalization to estimate accurately the Mn(2+) spin-Hamiltonian parameters. The temperature variation of the linewidth and peak-to-peak intensities of the EPR lines indicate the presence of lambda-transitions in the mixed NH(4)Cl(0.9)I(0.1) crystal at 242 and 228 K consistent with those observed in the pure NH(4)Cl and NH(4)I crystals, respectively. A superposition-model analysis of the spin-Hamiltonian parameters reveals that the local environment of the Mn(2+) ion is considerably reorganized to produce axially symmetric crystal fields about the respective Z-axes of the three magnetically inequivalent ions as a consequence of the vacancy created due to charge-compensation when the divalent Mn(2+) ion substitutes for a monovalent NH(4)(+) ion in the NH(4)Cl(0.9)I(0.1) crystal. This reorganization is almost the same as that observed in NH(4)Cl and NH(4)I single crystals, although the latter two are characterized by different, simple cubic and face-centered cubic, structures.

Combining internal- and external-training-load measures in professional rugby league.

PURPOSE: This study investigated the effect of training mode on the relationships between measures of training load in professional rugby league players. METHODS: Five measures of training load (internal: individualized training impulse, session rating of perceived exertion; external-body load, high-speed distance, total impacts) were collected from 17 professional male rugby league players over the course of two 12-wk preseason periods. Training was categorized by mode (small-sided games, conditioning, skills, speed, strongman, and wrestle) and subsequently subjected to a principal-component analysis. Extraction criteria were set at an eigenvalue of greater than 1. Modes that extracted more than 1 principal component were subjected to a varimax rotation. RESULTS: Small-sided games and conditioning extracted 1 principal component, explaining 68% and 52% of the variance, respectively. Skills, wrestle, strongman, and speed extracted 2 principal components each explaining 68%, 71%, 72%, and 67% of the variance, respectively. CONCLUSIONS: In certain training modes the inclusion of both internal and external training-load measures explained a greater proportion of the variance than any 1 individual measure. This would suggest that in training modes where 2 principal components were identified, the use of only a single internal or external training-load measure could potentially lead to an underestimation of the training dose. Consequently, a combination of internal- and external-load measures is required during certain training modes.

Effect of freezing conditions on distances and their distributions derived from Double Electron Electron Resonance (DEER): a study of doubly-spin-labeled T4 lysozyme.

Pulsed dipolar ESR spectroscopy, DEER and DQC, require frozen samples. An important issue in the biological application of this technique is how the freezing rate and concentration of cryoprotectant could possibly affect the conformation of biomacromolecule and/or spin-label. We studied in detail the effect of these experimental variables on the distance distributions obtained by DEER from a series of doubly spin-labeled T4 lysozyme mutants. We found that the rate of sample freezing affects mainly the ensemble of spin-label rotamers, but the distance maxima remain essentially unchanged. This suggests that proteins frozen in a regular manner in liquid nitrogen faithfully maintain the distance-dependent structural properties in solution. We compared the results from rapidly freeze-quenched (≤100 µs) samples to those from commonly shock-frozen (slow freeze, 1 s or longer) samples. For all the mutants studied we obtained inter-spin distance distributions, which were broader for rapidly frozen samples than for slowly frozen ones. We infer that rapid freezing trapped a larger ensemble of spin label rotamers; whereas, on the time-scale of slower freezing the protein and spin-label achieve a population showing fewer low-energy conformers. We used glycerol as a cryoprotectant in concentrations of 10% and 30% by weight. With 10% glycerol and slow freezing, we observed an increased slope of background signals, which in DEER is related to increased local spin concentration, in this case due to insufficient solvent vitrification, and therefore protein aggregation. This effect was considerably suppressed in slowly frozen samples containing 30% glycerol and rapidly frozen samples containing 10% glycerol. The assignment of bimodal distributions to tether rotamers as opposed to protein conformations is aided by comparing results using MTSL and 4-Bromo MTSL spin-labels. The latter usually produce narrower distance distributions.

Parameter Estimation as a Problem in Statistical Thermodynamics.

In this work, we explore the connections between parameter fitting and statistical thermodynamics using the maxent principle of Jaynes as a starting point. In particular, we show how signal averaging may be described by a suitable one particle partition function, modified for the case of a variable number of particles. These modifications lead to an entropy that is extensive in the number of measurements in the average. Systematic error may be interpreted as a departure from ideal gas behavior. In addition, we show how to combine measurements from different experiments in an unbiased way in order to maximize the entropy of simultaneous parameter fitting. We suggest that fit parameters may be interpreted as generalized coordinates and the forces conjugate to them may be derived from the system partition function. From this perspective, the parameter fitting problem may be interpreted as a process where the system (spectrum) does work against internal stresses (non-optimum model parameters) to achieve a state of minimum free energy/maximum entropy. Finally, we show how the distribution function allows us to define a geometry on parameter space, building on previous work[1, 2]. This geometry has implications for error estimation and we outline a program for incorporating these geometrical insights into an automated parameter fitting algorithm.

Multifrequency electron spin resonance study of the dynamics of spin labeled T4 lysozyme.

An extensive set of electron spin resonance spectra was obtained over a wide range of frequencies (9, 95, 170, and 240 GHz) and temperatures (2 to 32 degrees C) to explore the dynamic modes of nitroxide-labeled T4 lysozyme in solution. A commonly used nitroxide side chain (R1), or a methylated analogue with hindered internal motion (R2), was substituted for the native side chain at solvent-exposed helical sites, 72 or 131. The spectra at all four frequencies were simultaneously fit with the slowly relaxing local structure (SRLS) model. Good fits were achieved at all the temperatures. Two principle dynamic modes are included in the SRLS model, the global tumbling of the protein and the internal motion consisting of backbone fluctuations and side chain isomerizations. Three distinct spectral components were required for R1 and two for R2 to account for the spectra at all temperatures. One is a highly ordered and slow motional component, which is observed in the spectra of both R1 and R2; it may correspond to conformers stabilized by interaction with the protein surface. The fraction of this component decreases with increasing temperature and is more populated in the R2 spectra, possibly arising from stronger interaction of the nitroxide ring with the protein surface due to the additional methyl group. The other two components of R1 and the second component of R2 are characterized by fast anisotropic diffusion and relatively low ordering, most likely corresponding to conformers having little or no interactions with nearby residues. Ficoll of different concentrations was added to increase the solution viscosity, thereby slowing down the global tumbling of the protein. A significant effect of Ficoll on the internal motion of an immobilized component was apparent in R2 but not in R1. The ability of such multifrequency studies to separate the effects of faster internal modes of motion from slower overall motions is clearly demonstrated, and its utility in future studies is considered.

Multifrequency ESR study of spin-labeled molecules in inclusion compounds with cyclodextrins.

The molecular dynamics of spin-labeled compounds included into the solid phase of cyclodextrins (CDs) has been studied using conventional (X-band) ESR at 9 GHz and high-field high-frequency (HFHF) ESR at 240 and 170 GHz. The patterns of axial rotation at these higher frequencies are clear just by inspection of the spectrum, unlike the case for 9 GHz spectra. That is HFHF ESR is sensitive to molecular motion about the diffusion axis collinear with the X, Y or Z-direction of the magnetic g- and A-tensors of the nitroxide moiety (referred to, respectively, as X, Y or Z-rotation). For doxyl stearic acids (Z-rotation) and TEMPOyl caprylate (X-rotation) included in beta- and gamma-CDs we were able to determine the rate of molecular motion and the corresponding potential barriers. We emphasize that determining the rate of Z-rotation by ESR is feasible only using HFHF ESR. For the X-rotation case we suggest that the motion of the nitroxide moiety consists of fast small-angle librations about the magnetic X-axis superimposed by rotational diffusion about the same axis. The potential barrier of 1.7 Kcal mol(-1) for this rotational diffusion is unusually low. A fascinating feature of TEMPO derivatives included in beta-CD is the detectable molecular motion at temperatures below 77 K. For the other CD-spin probe systems, we used multifrequency analysis to assign the conformations of spin-labeled molecules. A dramatic spectral change for 16-sasl in beta- and gamma-CDs at approximately 260 K corresponds to a tilting of the position of the nitroxide moiety on the rotating molecule relative to the long diffusion axis, while for TEMPO derivatives in gamma-cyclodextrin below 200 K, we observe a rapid transition from fast to very slow rotational motion. More complex features are best studied by means of multifrequency ESR experiments. The visual clarity and the simplicity of analysis of the ESR spectra shown in this work should provide a benchmark for future studies of molecular motion by HFHF ESR.

High-frequency ESR at ACERT.

High-field ESR offers many advantages in exploring fundamental questions of structure and dynamics in chemical, biological and physical samples. We provide a review of recent work performed at ACERT demonstrating the utility and flexibility of our methods for extracting both qualitative and quantitative information from a variety of systems. In particular, we emphasize the utility of multi-frequency ESR techniques for unraveling the details of the complex dynamical modes of proteins in solution and in heterogeneous systems such as lipid bilayers. We also include indications of directions for future work where appropriate.

Rapid development of colitis in NSAID-treated IL-10-deficient mice.

BACKGROUND & AIMS: Interleukin (IL)-10 is an anti-inflammatory and immune regulatory cytokine. IL-10-deficient mice (IL-10(-/-)) develop chronic inflammatory bowel disease (IBD), indicating that endogenous IL-10 is a central regulator of the mucosal immune response. Prostaglandins are lipid mediators that may be important mediators of intestinal inflammation. In this study we assessed the role of prostaglandins in the regulation of mucosal inflammation in the IL-10(-/-) mouse model of IBD. METHODS: Prostaglandin (PG) synthesis was inhibited with nonselective or cyclooxygenase (COX)-isoform selective inhibitors. Severity of inflammation was assessed histologically. Cytokine production was assessed by ribonuclease protection analysis and enzyme-linked immunosorbent assay. PGE(2) levels were assessed by enzyme immunoassay. COX-1 and COX-2 expression was assessed by Western blot analysis. RESULTS: Nonsteroidal anti-inflammatory drug (NSAID) treatment of wild-type mice had minimal effect on the colon. In contrast, NSAID treatment of 4-week-old IL-10(-/-) mice resulted in rapid development of colitis characterized by infiltration of the lamina propria with macrophages and interferon gamma-producing CD4(+) T cells. Colitis persisted after withdrawal of the NSAID. NSAID treatment decreased colonic PGE(2) levels by 75%. Treatment of IL-10(-/-) mice with sulindac sulfone (which does not inhibit PG production) did not induce colitis whereas the NSAID sulindac induced severe colitis. COX-1- or COX-2-selective inhibitors used alone did not induce IBD in IL-10(-/-) mice. However, the combination of COX-1- and COX-2-selective inhibitors did induce colitis. CONCLUSIONS: NSAID treatment of IL-10(-/-) mice results in the rapid development of severe, chronic IBD. Endogenous PGs are important inhibitors of the development of intestinal inflammation in IL-10(-/-) mice.