The effect of inertial loading on wrist kinetic tremor and rhythmic muscle activity in individuals with essential tremor.

OBJECTIVES: Determine the effect of concentric and eccentric movement and contraction intensity on the strength of rhythmic muscle activity in individuals with essential tremor (ET). METHODS: 21 ET subjects and 22 healthy controls produced wrist flexion-extension movements while supporting sub-maximal loads (no-load, 5%, 15% and 25% 1-repetition maximum). Kinetic tremor and wrist extensor neuromuscular activity were recorded using an angular displacement sensor and electromyography (EMG). RESULTS: Rhythmic muscle activity was twice as big during movement compared to previous results involving postural or isometric tasks. ET subjects with greater rhythmic muscle activity had (1) larger overall kinetic tremor amplitude, (2) greater tremor spectral power during eccentric compared to concentric movement and (3) a reduction in overall kinetic tremor amplitude and the percentage of EMG spectral power accounted for by the tremor spectral peak in the presence of inertial loading. CONCLUSIONS: Greater than normal kinetic tremor amplitude appears to be limited to ET subjects with higher levels of rhythmic muscle activity. Furthermore, rhythmic muscle activity is much greater during movement compared to during postural or closed-kinetic tasks. SIGNIFICANCE: The strength of rhythmic muscle activity in ET is influenced by the type of contraction (i.e., static vs. dynamic) being performed. Clinicians and researchers should include measures of simple kinetic tremor as part of their assessments.

The effect of contraction intensity on force fluctuations and motor unit entrainment in individuals with essential tremor.

OBJECTIVES: Quantify the effect of increasing contraction intensity on the amplitude of force fluctuations and neuromuscular and force tremor spectral power. METHODS: Twenty-one subjects with essential tremor (ET) and 22 healthy controls applied isometric wrist extension contractions. Various sub-maximal contraction intensities were evaluated (5%-, 10%-, 20%- and 30%-MVC). Force fluctuations and wrist extensor neuromuscular activity were recorded using a load cell and electromyography (EMG). RESULTS: Higher contraction intensities were associated with larger amplitude force fluctuations and greater neuromuscular activation. However, spectral power associated with tremor peaks remained relatively constant (EMG) or decreased (force) with increasing contraction intensity. CONCLUSIONS: Motor unit entrainment associated with centrally generated oscillatory inputs does not increase with greater levels of muscle activation. SIGNIFICANCE: Rather than influencing a constant proportion of active motor units, abnormal oscillatory drive influences a relative constant number of total motor units. When combined with the findings from our previous study on postural tremor, the present results provide preliminary evidence that abnormal stretch reflex activity may contribute to this motor unit entrainment.

The effect of inertial loading on wrist postural tremor in essential tremor.

OBJECTIVES: Determine the effect of inertial loading on the strength of motor unit entrainment and the synergistic/competitive interaction between central and mechanical reflex tremor components in subjects with essential tremor (ET). METHODS: Twenty-three subjects with ET and 22 controls held their hand in an outstretched position while supporting sub-maximal loads (no-load, 5%, 15% and 25% 1-repetition maximum). Hand postural tremor and wrist extensor neuromuscular activity were recorded. RESULTS: Inertial loading resulted in a reduction in postural tremor in all ET subjects. The largest reduction in tremor amplitude occurred between 5% and 15% loads, which was associated with spectral separation of the mechanical reflex and central tremor components in a large number of ET subjects. Despite an increase in overall neuromuscular activity with inertial loading, EMG tremor spectral power did not increase with loading. CONCLUSIONS: The effect of inertial loading on postural tremor amplitude appears to be mediated in large part by its effect on the interaction between mechanical reflex and central tremor components. Also, ET is associated with a constant absolute level of motor unit entrainment. SIGNIFICANCE: The amplitude of postural tremor is dependent on both central and peripheral factors, with proportionally greater motor unit entrainment occurring at low contraction intensities.

Platelet P2Y(12) receptor influences the vessel wall response to arterial injury and thrombosis.

BACKGROUND: Platelets are believed to play an important role in atherogenesis and the vessel response to vascular injury. The P2Y(12) receptor (P2Y(12)) plays a central role in amplifying platelet aggregation, dense granule and alpha-granule secretion, P-selectin expression, microparticle formation, and procoagulant membrane changes, regardless of the activating stimulus. We hypothesized that P2Y(12) deficiency might reduce the vessel wall response to vascular injury as well as thrombosis in murine vascular injury models. METHODS AND RESULTS: P2Y(12)-deficient (-/-) mice and littermate controls (+/+) were bred on a C57 BL/6 background. In vivo murine models of arterial injury were employed alone and in combination with bone marrow transplantation to investigate the role of P2Y(12) in the vessel wall response to arterial injury and thrombosis. At 21 days after ferric chloride injury, neointima formation in P2Y(12)(-/-) arteries was significantly less than that observed in control strain arteries (P<0.025). In agreement with this, the intima-media ratio was significantly greater in femoral wire-injured arteries from P2Y(12)(+/+) compared with P2Y(12)(-/-) animals (P<0.05). Bone marrow transplantation was used to examine the importance of vessel wall P2Y(12) versus platelet P2Y(12). Analysis of arterial sections from chimeric animals at 21 days after injury revealed a smaller intima-media ratio in -/- to +/+ animals than in the positive (+/+ to +/+) control group (P<0.01). CONCLUSIONS: These data demonstrate a role for platelet P2Y(12) in the vessel wall response to arterial injury and thrombosis. This illustrates the manner in which platelets may contribute to atherogenesis and restenosis.

Treadmill walking in incomplete spinal-cord-injured subjects: 1. Adaptation to changes in speed.

UNLABELLED: Walking in spinal-cord-injured (SCI) subjects is usually achieved at a lower speed than in normal subjects. STUDY DESIGN/METHODS: Time and distance parameters, angular displacements of lower limbs and electromyographic (EMG) activity were measured for seven normal and seven SCI subjects at several walking speeds. Analyses of variance were used for comparing groups and speeds. OBJECTIVES: First, to measure the adaptability of SCI subjects' walking pattern to different speeds (0.1-1.0 m/s), and to compare it to that of normal subjects. Second, to characterize SCI subjects' walking pattern as compared to that of normal subjects at a matched treadmill speed (0.3 m/s). SETTING: University-Based Human Gait Laboratory, Montreal, Canada. RESULTS: SCI subjects' pattern adapted to a limited range of speeds. Longer cycle duration, flexed knee at foot contact, increased hip joint flexion at foot contact and during swing, and altered coordination of hip and knee joints were found for the SCI group. At all speeds, duration of muscle activity was longer in the SCI group and the increase in amplitude of soleus EMG activity at higher speeds was not specific to push-off. The importance of matching the walking speed of SCI and normal subjects in order to differentiate the features that are a consequence of SCI subjects' reduced walking speed rather than a direct consequence of the injury is demonstrated. CONCLUSIONS: All SCI subjects could adapt to a narrow range of speeds and only three could reach the maximal tested speed. This limited maximal speed seems to be a consequence of SCI subjects having reached their limit in increasing stride length and not being able to increase stride frequency further. This limitation in increasing stride frequency is likely because of the altered neural drive. SPONSORSHIP: Neuroscience Network of the Canadian Centre of Excellence.

The effect of noradrenergic drugs on the recovery of walking after spinal cord injury.

UNLABELLED: Clonidine, a noradrenergic agonist has been associated with improved walking in both spinal cat and spinal cord injured (SCI) subjects. OBJECTIVES: The objective of this brief review is to compare the effects of clonidine on walking capabilities in SCI subjects with functionally complete and incomplete spinal cord injuries. STUDY DESIGN/METHODS: Both oral administration and intrathecal injection of clonidine were investigated. A motorized treadmill was used and harness support provided in most of the SCI subjects as no walking capabilities could be observed overground. A single subject design was used in these chronic SCI subjects. SETTING: Canada and France. RESULTS: In complete SCI subjects while receiving clonidine, none of the subjects was able to initiate independent stepping. In contrast, the greatest effects were found in SCI subjects with injuries that are incomplete but still severely disabling while minimal effects could be observed in the more functional SCI subjects. These effects on walking are observed in measures of walking speed, and electromyographic and kinematic patterns. Regardless of effects on walking, however, a consistent decrease of the flexor reflex amplitude could be observed in all SCI subjects independent of the severity of the lesion. CONCLUSION: This review demonstrated that clonidine could be a powerful anti-spasmodic drug in addition to improving locomotion in a limited number of SCI subjects. The mechanism, significance and implications of these results will be discussed.

An effective and economical solution for digitizing and analyzing video recordings of the microcirculation.

OBJECTIVE: To assemble an economical system for analysis of microcirculation movies. METHODS: Images of cremaster microvessels were recorded onto sVHS video cassettes. These recordings were digitized onto a Macintosh computer using a MiroMotion DC30 plus video compression card and Adobe Premiere software, which permits video rate (25-30 fps) capture of full-sized (768 x 576 PAL, 640 x 480 NTSC) frames. Once captured, images were analyzed using NIH Image software. RESULTS: Combination of the Macintosh computer, the MiroMotion card, and Adobe Premiere allowed capture of high-resolution images at video rate, with the only limitation to sequence length being available hard-drive space. Captured movies could be directly accessed using the freely available NIH Image software. Use of built-in analysis tools and custom-written macros greatly facilitated rapid, accurate, and reproducible analysis of parameters such as blood flow velocity, leukocyte rolling velocity, and firm adhesion. CONCLUSIONS: Low-priced hardware and software aimed at the home-video enthusiast can be combined with free image-analysis software to provide a powerful image-analysis solution for study of the microcirculation.

A novel method for isolation of neutrophils from murine blood using negative immunomagnetic separation.

Inappropriate neutrophil activation has been implicated in the pathology of several clinically important inflammatory conditions. Although murine models are extensively used in the investigation of such pathological processes, a reliable method by which viable, quiescent neutrophils can be isolated from murine blood has not been developed. Here we describe a novel method based on negative immunomagnetic separation, which yields highly pure populations of murine neutrophils. Blood is incubated with a cocktail of antibodies against specific cell markers on unwanted cells, and then with secondary antibody-coated magnetic beads. After running the preparation through a column within a magnetic field, labeled cells are retained, and a neutrophil-rich effluent is collected. This method yields a >95% pure suspension of >97% viable neutrophils, recovering approximately 70% of neutrophils from whole blood. Flow cytometric analysis shows little difference in surface L-selectin and CD18 expression on isolated neutrophils compared with neutrophils in whole blood, indicating that neutrophils are minimally activated bythe isolation process. Stimulation with phorbol 12-myristate 13-acetate (PMA) reduced L-selectin andincreased CD18 expression. Isolated neutrophilsmigrate under agarose in response to fMLP, and fluorescently labeled neutrophils transfused into recipient mice interact with postcapillary venules in a manner comparable to endogenous leukocytes. These findings show that neutrophils isolated using this method can be used for inflammatory studies in vitro and in vivo.

P-selectin glycoprotein ligand-1 supports rolling on E- and P-selectin in vivo.

Selectin-dependent rolling is the earliest observable event in the recruitment of leukocytes to inflamed tissues. Several glycoproteins decorated with sialic acid, fucose, and/or sulfate have been shown to bind the selectins. The best-characterized selectin ligand is P-selectin glycoprotein-1 (PSGL-1) that supports P-selectin- dependent rolling in vitro and in vivo. In vitro studies have suggested that PSGL-1 may also be a ligand for E- and L-selectins. To study the in vivo function of PSGL-1, without the influence of other leukocyte proteins, the authors observed the interaction of PSGL-1-coated microspheres in mouse venules stimulated to express P- and/or E-selectin. Microspheres coated with functional recombinant PSGL-1 rolled in surgically stimulated and tumor necrosis factor alpha (TNFalpha)-stimulated mouse venules. P-selectin deficiency or inhibition abolished microsphere rolling in surgically and TNFalpha-stimulated venules, whereas E-selectin deficiency or inhibition increased microsphere rolling velocity in TNFalpha-stimulated venules. The results suggest that P-selectin-PSGL-1 interaction alone is sufficient to mediate rolling in vivo and that E-selectin-PSGL-1 interaction supports slow rolling.

The measurement of tremor using a velocity transducer: comparison to simultaneous recordings using transducers of displacement, acceleration and muscle activity.

Precise kinematic measurements of tremor have historically been obtained using accelerometers. However, current technology permits precise measurements in velocity and displacement. The primary advantage of velocity recording is that only one step of integration or differentiation is required for either displacement or acceleration. A method is presented of measuring finger tremor using a laser system that transduces velocity precisely. Measurements of postural finger tremor thus obtained were compared to those simultaneously obtained from a laser system that transduces displacement, from an accelerometer and from surface electromyography (EMG) of the extensor digitorum communis. A range of amplitude and frequency content was obtained by testing control subjects and subjects with Parkinson's disease. The velocity transducer showed excellent correspondence of amplitude and frequency measurement with the displacement transducer. Measures of absolute and relative amplitude correlated well (r > or = 0.96 in amplitude measures in displacement, velocity and acceleration), and high coherence was found throughout the frequency range of interest. Measurements by the accelerometer generally showed poorer correspondence with those of the other instruments. EMG measurements showed good correspondence in some trials but poorer correspondence in others, attributed to the low level of muscle activity required in the task. Precise kinematic measurements appear to be highly sensitive to neuromotor impairment.

Walking after spinal cord injury: evaluation, treatment, and functional recovery.

OBJECTIVE: To present some recent developments and concepts emerging from both animal and human studies aimed at enhancing recovery of walking after spinal cord injury (SCI). DATA SOURCES: Researchers in the field of restoration of walking after SCI, as well as references extracted from searches in the Medline computerized database. STUDY SELECTION: Studies that reported outcome measures of walking for spinal cord injured persons with an incomplete motor function loss or cats with either a complete or incomplete spinal section. DATA EXTRACTION: Data were extracted and validity was assessed by the authors. DATA SYNTHESIS: This review shows that a multitude of interventions--mechanical, electrical, or pharmacologic--can increase the walking abilities of persons with SCI who have incomplete motor function loss. CONCLUSIONS: A comprehensive evaluation of walking behavior requires tasks involving the different control variables. This comprehensive evaluation can be used to characterize the process of recovery of walking as well as the effectiveness of various treatments.

Effects of drugs on walking after spinal cord injury.

Clonidine, a noradrenergic agonist, and cyproheptadine, a serotonergic antagonist, have each been associated with improved walking in SCI subjects. Baclofen, a GABA agonist, is frequently prescribed for spasticity but its effects on walking have not been well quantified. The objective of this study was to compare the effects of clonidine, cyproheptadine and baclofen on walking in SCI subjects with incomplete injuries. A motorized treadmill was used and harness support provided when necessary. A repeated single-subject design was employed for the twelve subjects. The greatest effects were found in more severely disabled subjects. Cyproheptadine was associated with greatly reduced need for assistance, increases in maximum treadmill speed (MTS) and reduced clonus. Clonidine was associated with increases in MTS and a generally more upright posture. Baclofen was associated with minor changes in walking. In many cases of drug effects, MTS increases and other changes were retained following washout of drugs. The significance and implications of the drug effects and the retention of effects during washout periods are discussed. It is concluded that clonidine and cyproheptadine have different effects but both appear useful for severely disabled SCI subjects. The effects of baclofen on walking after spinal cord injury remains unclear.

Transit time of leukocytes rolling through venules controls cytokine-induced inflammatory cell recruitment in vivo.

Leukocyte recruitment requires leukocyte rolling, activation, firm adhesion, and transmigration. Injection of the proinflammatory cytokine TNF-alpha induces expression of E-selectin, interleukin-8, and other adhesion molecules and chemoattractants on the endothelial surface. TNF-alpha- treated CD18 null mouse cremaster muscle venules show increased leukocyte rolling velocity and reduced leukocyte recruitment efficiency. Leukocyte recruitment in CD18 null but not wild-type mice is significantly blocked by an mAb to E-selectin. To understand this overlap between adhesion events previously considered separate, we introduce a quantitative analysis of the efficiency of induction of rolling, conversion of rolling to adhesion, and of adhesion to transmigration. We find that CD18 and E-selectin cooperate to control the time a leukocyte needs to roll through an inflamed area and to convert rolling to firm adhesion. Leukocyte rolling time, defined as the time it takes for a rolling leukocyte to pass through a defined length of a vessel segment, emerges as a unifying parameter determining the efficiency of inducing firm adhesion, which is a rate-limiting step controlling leukocyte recruitment in inflammation. We conclude that leukocytes integrate chemoattractant signals while rolling along the endothelial surface until they reach a critical level of activation and become firmly adherent.

Sialyl Lewis(x) (sLe(x)) and an sLe(x) mimetic, CGP69669A, disrupt E-selectin-dependent leukocyte rolling in vivo.

Leukocyte rolling is the earliest observable even in their recruitment from the circulation to inflamed tissue. This rolling is mediated largely by interaction between the selectin family of adhesion molecules and their glycosylated ligands. Although the nature of these ligands and their interaction with the selectins is not fully understood, it is accepted that expression of fucosylated sialylated glycans such as sialyl Lewis(x) (sLe(x)) is required for function. Despite findings that sLe(x) inhibits binding of leukocytes to E-selectin in vitro, and has beneficial effects in inflammatory disease models, inhibition of E-selectin-dependent leukocyte rolling in vivo has not been described. Functional overlap between the selectins has been noted and reduction of rolling by E-selectin antibodies only occurs if P-selectin is absent or blocked. We demonstrate that leukocyte rolling velocity in tumor necrosis factor alpha (TNF alpha)-stimulated mouse cremaster is increased following treatment with either sLe(x) or the sLe(x)-mimetic CGP69669A and that rolling is dramatically reduced if CGP69669A is applied in the presence of anti-P-selectin antibody. These effects are characteristic of E-selectin antagonism. In contrast, surgically stimulated (L- or P-selectin-dependent) rolling is unaffected by either sLe(x) or CGP69669A. Our data demonstrate that CGP69669A is an effective and selective antagonist of E-selectin in vivo.

Comparison of the reversed passive Arthus and local Shwartzman reactions of rabbit skin: effects of the long-acting PAF antagonist UK-74,505.

1. By using the selective, potent and long acting platelet-activating factor (PAF) antagonist, UK-74,505, we investigated the role of PAF in a local Shwartzman reaction (LSR) and a reversed passive Arthus (RPA) reaction in rabbit skin. For comparison, we also studied the effect of the PAF antagonist on neutrophil aggregation in vitro and on acute inflammatory responses induced by intradermally (i.d.) injected lipopolysaccharide (LPS), PAF, bradykinin and zymosan-activated plasma. 2. Neutrophil aggregation was assessed photometrically. Haemorrhage, oedema formation, platelet deposition and neutrophil accumulation were quantified in rabbit skin by measuring the accumulation of i.v. injected 51Cr-labelled red blood cells (RBC), 125I-labelled human serum albumin, 111In-labelled platelets and 111In-labelled neutrophils respectively. 3. UK-74,505 inhibited in vitro neutrophil aggregation induced by PAF but not by leukotriene B4. When injected i.v. into rabbits UK-74,505 suppressed oedema formation in response to i.d. PAF for up to 4 h but had no effect on oedema induced by bradykinin or zymosan-activated plasma. 4. Oedema formation, but not neutrophil accumulation, produced during the RPA reaction was significantly inhibited by i.v. UK-74,505. The PAF antagonist also suppressed 111In-platelet but not 111In-neutrophil accumulation in response to i.d. LPS. UK-74,505 did not affect haemorrhage or oedema formation produced during the LPS-mediated LSR. 5. The results demonstrate that PAF is an important mediator of oedema formation, but not neutrophil accumulation, in the immune-complex mediated RPA reaction in rabbit skin. PAF also appears to be required for platelet, but not neutrophil, accumulation in response to locally injected LPS. Our studies do not suggest a role for PAF in the LPS-mediated LSR.

Functional assessment of balance and gait.

Individuals must be able to maintain an upright posture under a variety of conditions and to move independently. These constructs of balance and gait are fundamental components of physical functioning and should be incorporated into clinical assessment of older adults. The primary objective, therefore, is to review existing measures of functional balance and gait, concentrating on those which are quantitative, practical for use in clinical settings, and have demonstrated acceptable measurement properties. In addition, we discuss the rationale for the functional assessment of balance and gait, review essential measurement criteria, and discuss the utility of valid standardized measurement in clinical practice.

Peptides derived from the lectin domain of selectin adhesion molecules inhibit leukocyte rolling in vivo.

OBJECTIVE: The selectins are a family of adhesion molecules that mediate leukocyte rolling, a prerequisite for their later firm adhesion and migration to sites of inflammation. The N-terminal lectin domain of selectins is important for Ca(2+)-dependent binding to oligosaccharide ligands. We set out to study the effect of peptides corresponding to residues 11-20, 23-30, 36-50, 54-63, 70-79 and 109-118 (counting from the N-terminus of the mature proteins) of the lectin domain of human L-, P- and E-selectins on leukocyte rolling in vivo. METHODS: Peptides were applied by local intravascular microinfusion via a glass micropipette into rat mesenteric venules. Visibly rolling cells were counted off-line and compared with rolling cells counted during control periods. RESULTS: Peptides corresponding to residues 70-79 of P-selectin and 11-20 of L-selectin reduced leukocyte rolling flux in rat mesenteric venules to less than 30% of that measured during control infusion. Peptides corresponding to residues 109-118 of P-selectin, 54-63 of L-selectin and 23-30 of E-selectin also reduced leukocyte rolling flux, although to a lesser degree. CONCLUSIONS: We have shown that small peptides based on the lectin domain of all three selectins can be effective inhibitors of leukocyte rolling in vivo.

Effect of soluble P55 tumour-necrosis factor binding fusion protein on the local Shwartzman and Arthus reactions.

1. In this study, the effects of a protein synthesis inhibitor, cycloheximide, and a soluble tumour necrosis factor (TNF) binding/IgG fusion protein, p55-sf2, on the priming and challenge stages of the local Shwartzman reaction (LSR) were assessed and compared with their effects on the acute inflammatory response induced by recombinant human tumour necrosis factor-alpha (rhTNF), lipopolysaccharide (LPS) and a reversed passive Arthus (RPA) reaction in rabbit skin. 2. The LSR was induced in skin by giving an intradermal (i.d.) priming injection of LPS followed by two i.v. challenge injections 20 h and 22 h later. Accumulation of 51-Cr-labelled red blood cells and [125I]-albumin were measured at 24 h as markers of haemorrhage and oedema formation, respectively. 3. The RPA reaction was induced in the rabbit by giving i.d. injections of Arthus anti-serum (anti-bovine-gamma-globulin, BGG) followed 5 min later by an i.v. injection of the antigen (BGG). Oedema formation and the accumulation of 111In-labelled neutrophils produced in the RPA reaction and in response to i.d. injection of rhTNF and LPS were measured over the 4 h period after inducing the responses. 4. A single local injection of cycloheximide (10 micrograms/site) did not inhibit neutrophil accumulation or oedema formation produced by 100% Arthus anti-sera. Although LPS injected i.d. induced a marked dose-dependent neutrophil accumulation, there was little associated plasma leakage. Cycloheximide (10 micrograms/site) did not significantly inhibit the neutrophil accumulation induced by LPS (0.1 microgram/site). In the LSR, priming i.d. injections of LPS caused a dose-dependent increase in haemorrhage and plasma leakage at skin sites after challenge with LPS (two injections of 100 micrograms, i.v.). Co-injection of a single dose of cycloheximide (10 micrograms/site) with LPS (30 micrograms/site) caused a marked reduction in the amount of haemorrhage. Local cycloheximide (10 micrograms/site) administered immediately before LSR challenge did not affect the responses produced in the LSR. 5. Neutrophil accumulation induced by TNF (0.17 micrograms/site) was abolished by co-administration of p55-sf2 (3 micrograms/site) whereas neutrophil accumulation induced by i.d. LPS and produced in the RPA reaction was not affected. In the LSR, haemorrhage and oedema formation were inhibited by p55-sf2 (3 micrograms/site) when it was administered i.d. with the LPS priming injection, but not when given i.d. immediately before LSR challenge. 6. These data suggest that the acute neutrophil accumulation produced in the RPA reaction and in response to i.d. LPS may not be dependent on local protein synthesis or TNF production. On the other hand, haemorrhage appears to be dependent on local protein synthesis during the priming phase but not during the challenge stage of the LSR. Importantly, haemorrhage and plasma leakage appear to be dependent on local TNF generation during the priming phase but not during the challenge stage of the LSR. Thus TNF appears to play a key role in the LSR in rabbit skin.

Absence of trauma-induced leukocyte rolling in mice deficient in both P-selectin and intercellular adhesion molecule 1.

Leukocyte recruitment during inflammation is achieved through a multistep paradigm that includes margination, selectin-mediated rolling, beta 2 integrin-mediated firm adhesion, emigration, and migration into the site of inflammation. We have used the mouse cremaster muscle as a model of trauma- and cytokine-induced inflammation to study the possible role of intercellular adhesion molecule (ICAM) 1 in leukocyte rolling using gene-targeted mice deficient in ICAM-1, P-selectin, and a combination of P-selectin and ICAM-1. Rolling flux and average leukocyte rolling velocity in ICAM-1-deficient mice was not different from wild-type mice, but P-selectin/ICAM-1-deficient mice showed a total absence of rolling for at least 2 h after surgical trauma. Rolling in both wild-type and ICAM-1-deficient mice 60-120 min after trauma was significantly inhibited by a P-selectin monoclonal antibody (mAb) (RB40.34). In contrast, an mAb (KAT-1) blocking ICAM-1 binding to leukocyte function-associated antigen 1 did not block residual rolling in P-selectin-deficient mice. TNF-alpha induced leukocyte rolling in P-selectin/ICAM-1-deficient mice, but the rolling flux fraction was significantly lower than in TNF-alpha-treated ICAM-1-deficient mice. Leukocyte rolling in P-selectin/ICAM-1-deficient mice treated with TNF-alpha for 3 h was completely blocked by an E-selectin mAb (9A9E3), and partially by an L-selectin mAb (MEL-14). This clearly demonstrates E-selectin-dependent rolling in vivo. Leukocyte rolling velocities were significantly reduced after TNF-alpha treatment and were similar in wild-type and gene-targeted strains. We conclude that the residual trauma-induced leukocyte rolling seen in P-selectin-deficient mice is completely abolished by concomitant ICAM-1 deficiency. This severe defect in leukocyte rolling may explain the absence of leukocyte recruitment into the inflamed peritoneal cavity of P-selectin/ICAM-1-deficient mice at early time points (< or = 4 h).