Muscle-driven simulations and experimental data of cycling.

Muscle-driven simulations have provided valuable insights in studies of walking and running, but a set of freely available simulations and corresponding experimental data for cycling do not exist. The aim of this work was to develop a set of muscle-driven simulations of cycling and to validate them by comparison with experimental data. We used direct collocation to generate simulations of 16 participants cycling over a range of powers (40-216 W) and cadences (75-99 RPM) using two optimization objectives: a baseline objective that minimized muscle effort and a second objective that additionally minimized tibiofemoral joint forces. We tested the accuracy of the simulations by comparing the timing of active muscle forces in our baseline simulation to timing in experimental electromyography data. Adding a term in the objective function to minimize tibiofemoral forces preserved cycling power and kinematics, improved similarity between active muscle force timing and experimental electromyography, and decreased tibiofemoral joint reaction forces, which better matched previously reported in vivo measurements. The musculoskeletal models, muscle-driven simulations, simulation software, and experimental data are freely shared at https://simtk.org/projects/cycling_sim for others to reproduce these results and build upon this research.

Emissivity evaluation of human enamel and dentin.

Background: Human enamel and dentin temperatures have been assessed with non-contact infrared imaging devices for safety and diagnostic capacity and require an emissivity parameter to enable absolute temperature measurements. Emissivity is a ratio of thermal energy emitted from an object of interest, compared to a perfect emitter at a given temperature and wavelength, being dependent on tissue composition, structure, and surface texture. Evaluating the emissivity of human enamel and dentin is varied in the literature and warrants review. The primary aim of this study was to evaluate the emissivity of the external and internal surface of human enamel and dentin, free from acquired or developmental defects, against a known reference point. The secondary aim was to assess the emissivity value of natural caries in enamel and dentin. Method: Fourteen whole human molar teeth were paired within a thermally stable chamber at 30°C. Two additional teeth (one sound and one with natural occlusal caries-ICDAS caries score 4 and radiographic score RB4) were sliced and prepared as 1-mm-thick slices and placed on a hot plate at 30°C within the chamber. A 3M Scotch Super 33 + Black Vinyl Electrical Tape was used for the known emissivity reference-point of 0.96. All samples were allowed to reach thermal equilibrium, and a FLIR SC305 infrared camera recorded the warming sequence. Emissivity values were calculated using the Tape reference point and thermal camera software. Results: The external enamel surface mean emissivity value was 0.96 (SD 0.01, 95% CI 0.96-0.97), whereas the internal enamel surface value was 0.97 (SD 0.01, 95% CI 0.96-0.98). The internal crown-dentin mean emissivity value was 0.94 (SD 0.02, 95% CI 0.92-0.95), whereas the internal root-dentin value was 0.93 (SD 0.02, 95% CI 0.91-0.94) and the surface root-dentin had a value of 0.84 (SD 0.04, 95% CI 0.77-0.91). The mean emissivity value of the internal enamel surface with caries was 0.82 (SD 0.05, 95% CI 0.38-1.25), and the value of the internal crown-dentin with caries was 0.73 (SD 0.08, 95% CI 0.54-0.92). Conclusion: The emissivity values of sound enamel, both internal and external, were similar and higher than those of all sound dentin types in this study. Sound dentin emissivity values diminished from the crown to the root and root surface. The lowest emissivity values were recorded in caries lesions of both tissues. This methodology can improve emissivity acquisition for comparison of absolute temperatures between studies which evaluate thermal safety concerns during dental procedures and may offer a caries diagnostic aid.

Predicting gait adaptations due to ankle plantarflexor muscle weakness and contracture using physics-based musculoskeletal simulations.

Deficits in the ankle plantarflexor muscles, such as weakness and contracture, occur commonly in conditions such as cerebral palsy, stroke, muscular dystrophy, Charcot-Marie-Tooth disease, and sarcopenia. While these deficits likely contribute to observed gait pathologies, determining cause-effect relationships is difficult due to the often co-occurring biomechanical and neural deficits. To elucidate the effects of weakness and contracture, we systematically introduced isolated deficits into a musculoskeletal model and generated simulations of walking to predict gait adaptations due to these deficits. We trained a planar model containing 9 degrees of freedom and 18 musculotendon actuators to walk using a custom optimization framework through which we imposed simple objectives, such as minimizing cost of transport while avoiding falling and injury, and maintaining head stability. We first generated gaits at prescribed speeds between 0.50 m/s and 2.00 m/s that reproduced experimentally observed kinematic, kinetic, and metabolic trends for walking. We then generated a gait at self-selected walking speed; quantitative comparisons between our simulation and experimental data for joint angles, joint moments, and ground reaction forces showed root-mean-squared errors of less than 1.6 standard deviations and normalized cross-correlations above 0.8 except for knee joint moment trajectories. Finally, we applied mild, moderate, and severe levels of muscle weakness or contracture to either the soleus (SOL) or gastrocnemius (GAS) or both of these major plantarflexors (PF) and retrained the model to walk at a self-selected speed. The model was robust to all deficits, finding a stable gait in all cases. Severe PF weakness caused the model to adopt a slower, "heel-walking" gait. Severe contracture of only SOL or both PF yielded similar results: the model adopted a "toe-walking" gait with excessive hip and knee flexion during stance. These results highlight how plantarflexor weakness and contracture may contribute to observed gait patterns.

OpenSim: Simulating musculoskeletal dynamics and neuromuscular control to study human and animal movement.

Movement is fundamental to human and animal life, emerging through interaction of complex neural, muscular, and skeletal systems. Study of movement draws from and contributes to diverse fields, including biology, neuroscience, mechanics, and robotics. OpenSim unites methods from these fields to create fast and accurate simulations of movement, enabling two fundamental tasks. First, the software can calculate variables that are difficult to measure experimentally, such as the forces generated by muscles and the stretch and recoil of tendons during movement. Second, OpenSim can predict novel movements from models of motor control, such as kinematic adaptations of human gait during loaded or inclined walking. Changes in musculoskeletal dynamics following surgery or due to human-device interaction can also be simulated; these simulations have played a vital role in several applications, including the design of implantable mechanical devices to improve human grasping in individuals with paralysis. OpenSim is an extensible and user-friendly software package built on decades of knowledge about computational modeling and simulation of biomechanical systems. OpenSim's design enables computational scientists to create new state-of-the-art software tools and empowers others to use these tools in research and clinical applications. OpenSim supports a large and growing community of biomechanics and rehabilitation researchers, facilitating exchange of models and simulations for reproducing and extending discoveries. Examples, tutorials, documentation, and an active user forum support this community. The OpenSim software is covered by the Apache License 2.0, which permits its use for any purpose including both nonprofit and commercial applications. The source code is freely and anonymously accessible on GitHub, where the community is welcomed to make contributions. Platform-specific installers of OpenSim include a GUI and are available on simtk.org.

Simulation-Based Design for Wearable Robotic Systems: An Optimization Framework for Enhancing a Standing Long Jump.

GOAL: Technologies that augment human performance are the focus of intensive research and development, driven by advances in wearable robotic systems. Success has been limited by the challenge of understanding human-robot interaction. To address this challenge, we developed an optimization framework to synthesize a realistic human standing long jump and used the framework to explore how simulated wearable robotic devices might enhance jump performance. METHODS: A planar, five-segment, seven-degree-of-freedom model with physiological torque actuators, which have variable torque capacity depending on joint position and velocity, was used to represent human musculoskeletal dynamics. An active augmentation device was modeled as a torque actuator that could apply a single pulse of up to 100 Nm of extension torque. A passive design was modeled as rotational springs about each lower limb joint. Dynamic optimization searched for physiological and device actuation patterns to maximize jump distance. RESULTS: Optimization of the nominal case yielded a 2.27 m jump that captured salient kinematic and kinetic features of human jumps. When the active device was added to the ankle, knee, or hip, jump distance increased to between 2.49 and 2.52 m. Active augmentation of all three joints increased the jump distance to 3.10 m. The passive design increased jump distance to 3.32 m by adding torques of 135, 365, and 297 Nm to the ankle, knee, and hip, respectively. CONCLUSION: Dynamic optimization can be used to simulate a standing long jump and investigate human-robot interaction. SIGNIFICANCE: Simulation can aid in the design of performance-enhancing technologies.

Surfing the spectrum - what is on the horizon?

Diagnostic imaging techniques have evolved with technological advancements - but how far? The objective of this article was to explore the electromagnetic spectrum to find imaging techniques which may deliver diagnostic information of equal, or improved, standing to conventional radiographs and to explore any developments within radiography which may yield improved diagnostic data. A comprehensive literature search was performed using Medline, Web of Knowledge, Science Direct and PubMed Databases. Boolean Operators were used and key-terms included (not exclusively): terahertz, X-ray, ultraviolet, visible, infra-red, magnetic resonance, dental, diagnostic, caries and periodontal. Radiographic techniques are primarily used for diagnostic imaging in dentistry, and continued developments in X-ray imaging include: phase contrast, darkfield and spectral imaging. Other modalities have potential application, for example, terahertz, laser doppler and optical techniques, but require further development. In particular, infra-red imaging has regenerated interest with caries detection in vitro, due to improved quality and accessibility of cameras. Non-ionising imaging techniques, for example, infra-red, are becoming more commensurate with traditional radiographic techniques for caries detection. Nevertheless, X-rays continue to be the leading diagnostic image for dentists, with improved diagnostic potential for lower radiation dose becoming a reality.

Estimation of remaining dentine thickness below deep lesions of caries.

OBJECTIVE: The objective of this study was to investigate agreement between the estimated remaining dentine thickness (RDT) under lesions of caries, measured from a conventional in vivo periapical radiograph, compared directly to the measured RDT of the tooth. Additional investigation was to be made for agreement between in vitro digital radiographs and conventional radiographs. DESIGN AND SETTING: This was a cross-sectional, single centre study at Leeds Dental Institute, United Kingdom, in 2009.Subjects, materials and methods Twenty-five carious teeth with occlusal or proximal lesions were collected from patients aged 19 to 82 years attending the Oral Surgery Department. Each patient had a pre-extraction in vivo periapical radiograph of the tooth demonstrating an intact layer of dentine below the lesions of caries. Post-extraction in vitro digital and conventional radiographs were taken. MAIN OUTCOME MEASURES: Agreement of the RDT was analysed using Bland-Altman plots.Results A trend for the radiographic images to over-estimate the RDT compared to the tooth was found. Greater over-estimation of the RDT by conventional radiographs both in vivo and in vitro was shown compared to the in vitro digital images in the majority of cases. CONCLUSION: This analysis has demonstrated it is not possible to estimate the dimension of the RDT from a periapical radiograph.

The impact of digital image processing artefacts mimicking pathological features associated with restorations.

BACKGROUND: Image processing of digital X-ray images is known to have the potential to produce artefacts that may mimic pathology. A study was conducted at a UK dental radiology conference to demonstrate this effect in dentistry. METHOD: Sixteen digital X-rays of single teeth containing restorations were randomly presented in both unprocessed and processed formats to an auditorium of 42 participants. Participants interactively scored each image on a scale from 1-5 where 1 was definitely no pathology and 5 was definitely pathology. The display conditions were confirmed for each participant using a validated threshold contrast test. RESULTS: The results show that 52% (81/157) of responses at level 1 for the unprocessed images changed to levels 4 or 5 after image processing. CONCLUSION: This study illustrates the potential for image processing artefacts to mimic pathology particularly at high contrast boundaries and introduces the risk of unnecessary interventions. In order to minimise this risk, it is recommended that for digital radiographs containing pathology relating to high contrast boundaries, non-related high contrast features such as unrelated restorations or tooth/bone margins are also considered to exclude the possibility of artefact. If there is doubt, reference should be made to the unprocessed data.

Who will care? Employment participation and willingness to supply informal care.

The impact of informal care responsibilities on the willingness and ability of caregivers to undertake paid employment has been the subject of a number of studies. In contrast, the effect of employment status on willingness to undertake informal care has been less well explored. This paper concentrates on this less-studied direction of causality using the data provided by 15 waves of the British Household Panel Survey. We find that employment participation and earnings both impact negatively on willingness to supply informal care. This evidence has implications for health and social care policy since informal care has been shown to be a significant substitute for formal long-term care.

The novel hemoglobin-based oxygen carrier HRC 101 improves survival in murine sickle cell disease.

BACKGROUND: Erythrocyte transfusion decreases morbidity in sickle cell disease, but is not without risk. Use of a hemoglobin-based oxygen carrier could offer the benefits of erythrocyte transfusion while reducing related complications. The authors tested the hypothesis that the novel hemoglobin-based oxygen carrier, HRC 101, would improve survival during exposure to acute hypoxia in a murine model of sickle cell disease, the transgenic mouse expressing hemoglobin SAD (alpha2beta2). METHODS: Wild-type (n = 30) and transgenic SAD (n = 36) mice received 0.02 ml/g HRC 101 (hemoglobin concentration, 10 g/dl) or an equal volume of 5% albumin. Thirty percent or 6% oxygen was administered to spontaneously breathing mice during halothane anesthesia (inspired concentration, 0.5%). The time to cessation of cardiac electrical activity was recorded. Survival was compared using Kaplan-Meier analysis. RESULTS: Control mice survived the 60-min study period, whether breathing 30% or 6% oxygen. In contrast, all SAD mice given albumin and 6% oxygen died, with a median survival time of 9.0 min (interquartile range, 6.9-11.6 min; P < 0.0001). HRC 101 significantly increased survival in SAD mice breathing 6% oxygen. Of 12 SAD mice given HRC 101 and 6% oxygen, 4 survived the entire study period and 8 died, with a median survival time of 48 min (19-60 min; P < 0.0001 vs. albumin). CONCLUSION: HRC 101 significantly decreased sickle-related mortality during exposure to acute hypoxic stress in transgenic mice expressing hemoglobin SAD. HRC 101 warrants further evaluation as a therapeutic modality in sickle cell disease.

The effect of magnesium deficiency on volatile anaesthetic requirement in the rat: the role of central noradrenergic neuronal activity.

Volatile anaesthetic minimum alveolar concentration (MAC, a measure of anaesthetic requirement) increased in a time-dependent manner in rats fed a Mg2+-deficient diet. MAC values in hypomagnesemic rats were 22-30 per cent greater than those in age-matched controls at 12 and 17 days after starting the diet (p < 0.01). Noradrenergic neuronal activity, as assessed from the ratio of the concentration of 3,4-dihydroxyphenylethylene-glycol (DHPG) to that of norepinephrine (NE), decreased in the brain stem and cerebrum-cerebellum in hypomagnesemic rats owing to an increase in NE concentration in both regions of the brain (p < 0.025). We conclude that prolonged hypomagnesemia (> or = 12 days) increases volatile anaesthetic MAC in the rat. The concomitant decrease in the ratio of DHPG/NE suggests that this increase in MAC cannot be attributed to an increase in noradrenergic neuronal activity in brain.

Effects of hypoxia and isoflurane on liver blood flow: the role of adenosine.

We investigated the role of endogenous adenosine in mediating the effects of hypoxia and isoflurane on portal tributary blood flow (PTBF) and hepatic arterial blood flow (HABF) in rats. Liver blood flows were determined using radiolabelled microspheres. Hypoxia resulting from the exposure of rats to an atmosphere containing 15% oxygen for 30 min decreased PTBF (23%) (P<0.05) and cardiac index (15%) (P<0.05), and increased HABF (78%) (P<0.05). Isoflurane (1.4 vol%) increased HABF in both normoxic and hypoxic conditions but did not affect PTBF. The adenosine receptor antagonist 8-phenyltheophylline attenuated the hypoxia-induced increase in HABF but did not affect that resulting from the administration of isoflurane. In conclusion, in contrast to the increase in HABF induced by hypoxia, that induced by isoflurane appears to be independent of endogenous adenosine.

Recent developments in hemoglobin-based oxygen carriers--an update on clinical trials.

Considerable progress has been made in the development of the hemoglobin based oxygen carriers (HBOCs), with a number of products in the final stages of clinical development prior to licensing application. This follows many years of concentrated study. Although there are limitations to the clinical use of the currently studied HBOCs, there are a number of advantages that suggest that these products will have an important role in future clinical practice. It is anticipated that these products will be commercially available within two years.

A phase I study of oxidized raffinose cross-linked human hemoglobin.

OBJECTIVE: To evaluate the safety of oxidized-raffinose cross-linked human hemoglobin, Hemolink, in normal healthy volunteers. DESIGN: Randomized, placebo-controlled, double-blind study. SETTING: Clinical research facility of a contract research organization. PATIENTS: Forty-two healthy adult male volunteers of which 33 received Hemolink. INTERVENTIONS: Oxidized-raffinose cross-linked and polymerized hemoglobin as a 10% (w/v) solution, in doses of 0.025-0.6 g/kg or an equivalent volume of lactated Ringer's solution, was infused intravenously on day 1, and subjects were monitored for 3 days in the clinical facility with < or =6 wks follow-up. Major organ function was assessed pre- and postinfusion, by hemodynamic, electrocardiographic, pulmonary function, and clinical chemistry measurements. MEASUREMENTS AND MAIN RESULTS: Doses of 1.7-42 g of hemoglobin were administered with no serious adverse events noted. Abdominal pain of moderate to severe intensity was seen in some subjects at doses >0.4 g/kg and was alleviated with smooth muscle relaxants. There was a dose-dependent increase in mean arterial pressure with a plateau of approximately 14% above baseline at 0.1 g/kg. There was a concomitant reduction in heart rate, with no electrocardiographic abnormalities found. Respiratory function was not affected. There was a dose-dependent increase in serum bilirubin with values above the upper limit of normal at doses of > or =0.4 g/kg. Small increases in aspartate aminotransferase and alanine aminotransferase were noted in some patients, whereas alkaline phosphatase and gamma-glutamyltransferase remained in the normal range. Serum amylase concentrations were normal in 31 of 33 patients receiving Hemolink, whereas lipase was within the normal range in 21 of 33 patients. LDH was increased in a dose-dependent fashion. Two patients had increased creatine kinase concentrations, with a normal creatine kinase-MB mass fraction. All hematologic variables were within the normal range. The half-life of the oligomeric (>64 kDa) fraction of Hemolink was 18-20 hrs. CONCLUSION: Oxidized-raffinose cross-linked hemoglobin, Hemolink, at doses < or =0.6 g/kg were well tolerated in healthy volunteers with no evidence of organ dysfunction. Further investigation of its potential use in surgical and trauma settings appears warranted.

Haemodynamic response following a 10% topload infusion of HemolinkTM in conscious, anaesthetized and treated spontaneously hypertensive rats.

HemolinkTM (HLK), a haemoglobin-based oxygen carrier (HBOC), is currently undergoing Phase II/III clinical trials in surgical patients. It causes some blood pressure rise in animal and human tests. This study was designed to investigate the systemic haemodynamic response to HemolinkTM in spontaneously hypertensive rats (SHR rats). Conscious or anaesthetized SHR rats and control Wistar Kyoto rats (WKY rats) received either HemolinkTM or homologous plasma as a 10% topload infusion. Some awake animals were pretreated with nifedipine and followed by HLK infusion. In the conscious animal study, HLK induced a greater pressure rise and less bradycardia in SHR rats than in WKY rats. In the anaesthetized animal experiment, HLK-induced pressure rise and bradycardia were similar in both strains and less pronounced than in the conscious animals. In the nifedipine pretreated SHR rats, HLK-induced pressure rise was significantly smaller than that observed in nontreated SHR rats and was not different from that of nontreated WKY rats. The HLK-induced bradycardia was significantly smaller in nifedipine-treated animals than in the nontreated SHR or WKY rats. This study suggests that the pressor effect of HemolinkTM can be attenuated in hypertensive animals with general anaesthesia or treatment with antihypertensive agents.

A comparison of the diagnostic utility of two image receptors for panoramic radiography.

OBJECTIVE: To compare the diagnostic utility of two screen-film systems for panoramic radiography, one based on green and the other on ultraviolet light. MATERIALS AND METHODS: Two hundred consecutive adult patients with teeth in all four quadrants requiring panoramic radiographs were randomly allocated to one of two groups. One group was imaged with OGA L (CEA AB, Strängnäs, Sweden) film using Lanex Regular (Eastman Kodak, Rochester, NY, USA) screens (the Lanex group). The other group was imaged using Ultra-Vision (Dupont UK Limited, Hertfordshire, UK) film and screens (the Ultra-vision group). Two different panoramic machines were used, a Planmeca (Planmeca OY, Helsinki, Finland) and Cranex (Soredex Orion Corporation, Helsinki, Finland). The radiographs were evaluated by two radiographers for overall quality and any faults recorded. Two dental radiologists evaluated the crestal and apical areas of every standing tooth on a 4-point scale. The likelihood of getting a high-quality image with the different films was modelled using logistic regression, adjusting for the radiologist and the area of the tooth being examined. Inter- and intra-examiner agreement was calculated using Kappa and weighted Kappa where appropriate. RESULTS: The radiographers recorded no significant differences in positioning errors between the two groups of film. However, the films produced on the Cranex were less likely to be recorded as excellent. The radiologists' interexaminer agreement for the lower molars and upper incisors was only moderate at best (kappa = 0.56). No significant differences were found between the likelihood of the two types of film providing a high-quality image. Crestal areas were more likely to be scored well than apical areas. CONCLUSION: There were no differences in ease of discerning apical and crestal areas between the two screen-film systems. There was only poor to moderate agreement between the two radiologists. Ultra-Vision can be recommended as an alternative to existing rare earth systems for panoramic radiography.

Neuroprotective effects of acetylsalicylic acid in an animal model of focal brain ischemia.

Recent studies have shown neuroprotective effects of acetylsalicylic acid (ASA) in cell cultures and hippocampal slices. The present study demonstrates similar effects in a whole-animal modal of focal ischemic stroke. Focal cortical ischemia was produced in Wistar rats by ligation of the common carotid and middle cerebral arteries. Subjects were sacrificed 8 days after ligation, and infarct volume was assessed via automated densitometry. Significant reductions in infarct volume were seen with i.p. ASA doses of 15 mg/kg and above. Reductions occurred when ASA was injected 2 h or 30 min before ligation, but not when it was injected 8 or 24 h before, or 30 min after ligation.

Hemolink-induced effects on intestinal motor function and attenuation of these effects by selected agents.

Hemolink, an oxidized, ring-opened raffinose-crosslinked hemoglobin-based oxygen carrier produced by Hemosol Inc., stimulates esophageal peristalsis, possibly by interference with neural NO-mediated effects. The effects of Hemolink on jejunal tone and contractions, arterial pressure and heart rate were measured in anesthetized rats, and the effect of selected agents in attenuating or reversing these effects was studied. Infusion of L-NAME was used to validate the study model; it caused an immediate increase in tone and initiated phasic contractions indicating that the model was responsive to NO-mediated effects. Hemolink administration caused effects on intestinal motor function similar to those caused by L-NAME, including increases in basal tone and contraction amplitude. Rat whole blood caused none of these changes. The Hemolink-induced effects were less immediate in some animals compared to those observed after L-NAME. As well there was greater inter-animal variability on the effects. Hemolink administration also caused a mild increase in arterial blood pressure and a reciprocal decrease in heart rate in some animals. Co-administration of morphine, a common analgesic that has been reported to influence the motility of the GI tract; L-arginine, a substrate for NO synthesis; and glycopyrrolate, an anti-cholinergic agent, did not significantly modulate the Hemolink effects, whereas nitroglycerin, an NO donor; and nifedipine, a slow calcium-channel blocker, attenuated or reversed these effects.

Applications of Scanora multimodal maxillofacial imaging in orthodontics.

The principles of the Scanora multimodal radiography system are described. This self-contained unit of X-ray generator, patient chair, and imaging elements incorporates the two basic principles of narrow beam radiography and spiral tomography. Conventional panoramic images or magnified images of the dentition can be produced. In orthodontics, the application of spiral tomography in order to obtain cross sectional images has proved helpful in the assessment of a number of patients. Four cases are reported in which the images obtained using this system has substantially contributed to their management.

Circulating neutrophils and liver injury in rat models of experimental alcoholic liver disease.

The present study examined the relationship between circulating neutrophils and liver injury in two widely used rat models of chronic ethanol administration. Hematological alterations, liver histopathology, and biochemical indices of liver injury were assessed in rats receiving chronic ethanol by oral liquid diet feeding (Lieber-DeCarli method) or by continuous intragastric infusion (Tsukamoto-French method). Oral administration of ethanol did not affect circulating neutrophil counts, but resulted in minimal liver injury characterized by elevated serum alanine aminotransferase (79%), increased liver mass (15%), and moderate steatosis. In contrast, rats receiving ethanol by continuous intragastric infusion showed an approximately 2-fold increase in circulating neutrophils, and a moderate degree of liver injury, indicated by a 169% elevation of serum alanine aminotransferase and a 2-fold increase in liver mass. Liver biopsies from these rats showed severe steatosis and scattered necrotic hepatocytes, and some neutrophil infiltrates. To determine whether an increase in the number of circulating neutrophils could potentiate liver injury induced by oral ethanol feeding, rats were treated with human recombinant granulocyte colony-stimulating factor at a dose of 100 microg/kg/day (s.c.) for 4 days. Treatment with granulocyte colony-stimulating factor resulted in a 6- to 9-fold increase in circulating neutrophil counts. Nevertheless, this change did not enhance the minor degree of ethanol-induced liver injury in this model. Our results indicate that, whereas neutrophil leukocytosis accompanies more severe manifestations of ethanol hepatotoxicity in rats, this condition per se does not directly induce or exacerbate ethanol-induced liver injury.