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Plates with leading-edge tubercles experience beneficially more gradual aerodynamics stalling when entering the post-stall regime. Little is known, however, about the corresponding aquatic flow responses when these tubercles-furnished plates are subjected to the maximal angle of attack, with the flow direction perpendicular to their planar area. Hence, this study presents numerically, by means of the flow behavior solver ANSYS, the flow responses alteration in terms of the geometrical effects of tubercles on plates through changes in amplitudes (5 mm, 10 mm, 15 mm) and wavelengths (50 mm, 100 mm, 150 mm) under the maximal angle of attack in comparison to a control case, i.e., without tubercles. Additional to the commonly examined flow velocity and pressure, characteristics such as wake (area, reattachment length, flow recirculation intensity) and newly defined downstream vortical parameters (area, perimeter, and Feret diameters) for the vortex region have been proposed and assessed. It is found that the drag increases with the tubercle wavelength but corresponds inversely with the tubercle amplitude. By correlating with the best beneficial velocity and pressure profiles, it has been characterized that the optimally performing plate is the one that generates the greatest flow recirculation intensity, wake area, and reattachment length, corresponding to the capability to produce also the highest vortical area, perimeter, and major Feret diameter. Compared to the control case, all plates with tubercles alter beneficially these flow behaviors. In conclusion, plates with tubercles contribute favorably to the flow behaviors under the maximal angle of attack compared to the control case while the newly proposed downstream parameters could serve capably as alternatives in corroborating the flow physics description in future studies. [ABSTRACT FROM AUTHOR]

We have recently designed a medicated bi-layer wound dressing to address the key requirements for treating external, contaminated war wounds. This study assessed the in vitro and in vivo bactericidal efficacies of the DRDC hydrogel/polyurethane wound dressing. Chloramphenicol- and chlorhexidine-loaded DRDC dressings produced significantly larger zones of inhibition against Pseudomonas aeruginosa than the other medicated dressings for 4 d. Chlorhexidine-loaded Allevyn and Hydrasorb remained bactericidal for 48 h only. Chloramphenicol-loaded Hydrasorb and Allevyn remained bactericidal for 1 and 3 d, respectively. Ps. aeruginosa and Staphylococcus epidermidis counts in wounds treated with chlorhexidine- and chloramphenicol-loaded DRDC dressings for 24 h were 1-3-log lower than those of control wounds. While Ps. aeruginosa counts in the wounds on day 4 were comparable following daily changes of either antiseptic-loaded dressings, chlorhexidine showed a 75% greater bactericidal efficacy against Staph. epidermidis than chloramphenicol. Though increasing the frequency of dressing changes led to a greater reduction in the wound bacterial load, the contamination levels of all antiseptic-treated wounds remained below 10(5) CFU/g of wound. Cerium nitrate-loaded dressings did not exert any bactericidal effect, irrespective of the experimental conditions. These data show that the DRDC dressing is effective in delivering medications, such as an antimicrobial agent, to the wound bed. [ABSTRACT FROM AUTHOR]

Severe burns remain a significant cause of morbidity and mortality despite the availability of numerous therapies. We assessed the wound healing and skin-cooling properties of a DRDC hydrogel/polyurethane wound dressing using different pre-clinical models. Our results show that 85% of partial-thickness, non-contaminated porcine wounds treated with our dressing healed within 6 days. In contrast, 85% of the wounds treated with commercial dressings healed within 8 days. Application of a moist DRDC dressing (to simulate a condition of exudate absorption) on a scald burn covering 25% of the dorsal area in rats reduced skin temperature by 1.70 +/- 0.14 degrees C for 5 min, the skin temperature being comparable to that of control burned rats after 20 min. The application of a moist DRDC dressing did not induce significant differences in body temperatures compared with that of burned animals without dressing coverage throughout the 90-min experiment. While no change in body temperatures were observed when standard dressings (i.e., not pre-moistened) were applied, skin temperature increased gradually. These data show that our dressing is effective in promoting faster healing of the treated wound; and providing a transient, but beneficial cooling effect to the skin contact-site, without the adverse effect of inducing whole-body hypothermia. [ABSTRACT FROM AUTHOR]

Regular, moderate exercise enhances immune function and attenuates immune disturbances associated with acute exercise (ie, a single bout of vigorous exercise). Epidemiologic data suggest that vigorous exercise may temporarily reduce resistance to viral infection. However, objective data do not clearly show a J-shaped dose-response relationship between exercise and immune function. Nutritional, hygienic, exercise, environmental, and pharmacologic strategies can minimize the risk of infection. Persons who have systemic symptoms should avoid competition and heavy training. [ABSTRACT FROM AUTHOR]

Objective. Health, nutritional status, aerobic power, mood state and immune function were studied over 112 days of aerobic activity (a 7250 km cross-Canada run). Type of study. Case report: a healthy nulliparous 43 yr old woman ran 65 km/day for 112 days at a 7.9 km/h pace. Measures. Food intake, Profile of Mood State and Beck Depression Inventory were monitored weekly. Resting lymphocyte subsets and cytokines were determined before the run, at 3324, 5700 and 7250 km, and after recovery. Clinical data, ventilatory threshold, maximal oxygen intake and immune responses to maximal exercise were obtained before and after the run. Results. Early muscle pain was treated with Ibuprofen. A mild paronychia responded to saline soaks, and exercise-induced asthma necessitated inhalation of fenoterol hydrobromide, beclomethasone diproprionate and ipatropium bromide. Food intake, (16.7 MJ/day), was 4.3 MJ/day less than expenditure, covered by metabolizing 16.7 kg of tissue (81.4% fat, 18.6% lean tissue). Ventilatory threshold and aerobic power showed little change. Initial psychological data showed tension and lack of confidence. Depression increased when crossing the Rockies, and there was anger and lack of vigor after the event. The CD8 count was low throughout; the CD25 count increased, but the CD16/56 count, IL-6 and TNF-alpha decreased over the run. Three weeks later, IL-6 had increased, but TNF-alpha remained low. Conclusions. Given substantial fat reserves, an exercise-induced energy deficit of 43 MJ/day can be sustained for 112 days without significant adverse consequences for immune function. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) initiates interrelated inflammatory and coagulation cascades characterized by wide-spread cellular activation, induction of leukocyte and endothelial cell adhesion molecules and release of soluble pro/antiinflammatory cytokines and thrombotic mediators. Resuscitative care is focused on optimizing cerebral perfusion and reducing secondary injury processes. Hypertonic saline is an effective osmotherapeutic agent for the treatment of intracranial hypertension and has immunomodulatory properties that may confer neuroprotection. This study examined the impact of hypertonic fluids on inflammatory/coagulation cascades in isolated head injury.Methods: Using a prospective, randomized controlled trial we investigated the impact of prehospital resuscitation of severe TBI (GCS < 8) patients using 7.5% hypertonic saline in combination with 6% dextran-70 (HSD) vs 0.9% normal saline (NS), on selected cellular and soluble inflammatory/coagulation markers. Serial blood samples were drawn from 65 patients (30 HSD, 35 NS) at the time of hospital admission and at 12, 24, and 48-h post-resuscitation. Flow cytometry was used to analyze leukocyte cell-surface adhesion (CD62L, CD11b) and degranulation (CD63, CD66b) molecules. Circulating concentrations of soluble (s)L- and sE-selectins (sL-, sE-selectins), vascular and intercellular adhesion molecules (sVCAM-1, sICAM-1), pro/antiinflammatory cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL-10)], tissue factor (sTF), thrombomodulin (sTM) and D-dimers (D-D) were assessed by enzyme immunoassay. Twenty-five healthy subjects were studied as a control group.Results: TBI provoked marked alterations in a majority of the inflammatory/coagulation markers assessed in all patients. Relative to control, NS patients showed up to a 2-fold higher surface expression of CD62L, CD11b and CD66b on polymorphonuclear neutrophils (PMNs) and monocytes that persisted for 48-h. HSD blunted the expression of these cell-surface activation/adhesion molecules at all time-points to levels approaching control values. Admission concentrations of endothelial-derived sVCAM-1 and sE-selectin were generally reduced in HSD patients. Circulating sL-selectin levels were significantly elevated at 12 and 48, but not 24 h post-resuscitation with HSD. TNF-alpha and IL-10 levels were elevated above control throughout the study period in all patients, but were reduced in HSD patients. Plasma sTF and D-D levels were also significantly lower in HSD patients, whereas sTM levels remained at control levels.Conclusions: These findings support an important modulatory role of HSD resuscitation in attenuating the upregulation of leukocyte/endothelial cell proinflammatory/prothrombotic mediators, which may help ameliorate secondary brain injury after TBI.Trial Registration: NCT00878631. [ABSTRACT FROM AUTHOR]

Rotational thromboelastometry (ROTEM) and thromboelastography (TEG) have been increasingly used to diagnose acute coagulopathy and guide blood transfusion. The tests are routinely performed using different triggering activators such as tissue factor and kaolin, which activate different pathways yielding different results. To optimize the global blood coagulation assays using ROTEM and TEG, we conducted a comparative study on the activation methods employing tissue factor and kaolin at different concentrations as well as standard reagents as recommended by the manufacturer of each device. Key parameter values were obtained at various assay conditions to evaluate and compare coagulation and fibrinolysis profiles of citrated whole blood collected from healthy volunteers. It was found that tissue factor reduced ROTEM clotting time and TEG R, and increased ROTEM clot formation time and TEG K in a concentration-dependent manner. In addition, tissue factor affected ROTEM alpha angle, and maximum clot firmness, especially in the absence of kaolin activation, whereas both ROTEM and TEG clot lysis (LI30, CL30, and LY30) remained unaffected. Moreover, kaolin reduced ROTEM clotting time and TEG R and K, but to a lesser extent than tissue factor, in-tem and ex-tem. Correlations in all corresponding parameters between ROTEM and TEG were observed, when the same activators were used in the assays compared with lesser correlations between standard kaolin TEG and ROTEM (INTEM/EXTEM). The two types of viscoelastic point-of-care devices provide different results, depending on the triggering reagent used to perform the assay. Optimal assay condition was obtained to reduce assay time and improve assay accuracy.

Background: Awareness to neurocognitive issues after mild traumatic brain injury (mTBI) is increasing, but currently no imaging markers are available for mTBI. Advanced structural imaging recently showed microstructural tissue changes and axonal injury, mild but likely sufficient to lead to functional deficits. Magnetoencephalography (MEG) has high temporal and spatial resolution, combining structural and electrophysiological information, and can be used to examine brain activation patterns of regions involved with specific tasks., Methods: 16 adults with mTBI and 16 matched controls were submitted to neuropsychological testing (Wechsler Abbreviated Scale of Intelligence (WASI); Conners; Alcohol Use Disorders Identification Test (AUDIT); Generalised Anxiety Disorder Seven-item Scale (GAD-7); Patient Health Questionnaire (PHQ-9); Symptom Checklist and Symptom Severity Score (SCAT2)) and MEG while tested for mental flexibility (Intra-Extra Dimensional set-shifting tasks). Three-dimensional maps were generated using synthetic aperture magnetometry beamforming analyses to identify differences in regional activation and activation times. Reaction times and accuracy between groups were compared using 2×2 mixed analysis of variance., Findings: While accuracy was similar, patients with mTBI reaction time was delayed and sequence of activation of brain regions disorganised, with involvement of extra regions such as the occipital lobes, not used by controls. Examination of activation time showed significant delays in the right insula and left posterior parietal cortex in patients with mTBI., Conclusions: Patients with mTBI showed significant delays in the activation of important areas involved in executive function. Also, more regions of the brain are involved in an apparent compensatory effort. Our study suggests that MEG can detect subtle neural changes associated with cognitive dysfunction and thus, may eventually be useful for capturing and tracking the onset and course of cognitive symptoms associated with mTBI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Post-traumatic stress disorder (PTSD) is a mental health injury characterised by re-experiencing, avoidance, numbing and hyperarousal. Whilst the aetiology of the disorder is relatively well understood, there is debate about the prevalence of cognitive sequelae that manifest in PTSD. In particular, there are conflicting reports about deficits in executive function and mental flexibility. Even less is known about the neural changes that underlie such deficits. Here, we used magnetoencephalography to study differences in functional connectivity during a mental flexibility task in combat-related PTSD (all males, mean age = 37.4, n = 18) versus a military control (all males, mean age = 33.05, n = 19) group. We observed large-scale increases in theta connectivity in the PTSD group compared to controls. The PTSD group performance was compromised in the more attentionally-demanding task and this was characterised by 'late-stage' theta hyperconnectivity, concentrated in network connections involving right parietal cortex. Furthermore, we observed significant correlations with the connectivity strength in this region with a number of cognitive-behavioural outcomes, including measures of attention, depression and anxiety. These findings suggest atypical coordination of neural synchronisation in large scale networks contributes to deficits in mental flexibility for PTSD populations in timed, attentionally-demanding tasks, and this propensity toward network hyperconnectivity may play a more general role in the cognitive sequelae evident in this disorder.

Posttraumatic stress disorder (PTSD) is a mental disorder that stems from exposure to one or more traumatic events. While PTSD is thought to result from a dysregulation of emotional neurocircuitry, neurocognitive difficulties are frequently reported. Mental flexibility is a core executive function that involves the ability to shift and adapt to new information. It is essential for appropriate social-cognitive behaviours. Magnetoencephalography (MEG), a neuroimaging modality with high spatial and temporal resolution, has been used to track the progression of brain activation during tasks of mental flexibility called set-shifting. We hypothesized that the sensitivity of MEG would be able to capture the abnormal neurocircuitry implicated in PTSD and this would negatively impact brain regions involved in set-shifting. Twenty-two soldiers with PTSD and 24 matched control soldiers completed a colour-shape set-shifting task. MEG data were recorded and source localized to identify significant brain regions involved in the task. Activation latencies were obtained by analysing the time course of activation in each region. The control group showed a sequence of activity that involved dorsolateral frontal cortex, insula and posterior parietal cortices. The soldiers with PTSD showed these activations but they were interrupted by activations in paralimbic regions. This is consistent with models of PTSD that suggest dysfunctional neurocircuitry is driven by hyper-reactive limbic areas that are not appropriately modulated by prefrontal cortical control regions. This is the first study identifying the timing and location of atypical neural responses in PTSD with set-shifting and supports the model that hyperactive limbic structures negatively impact cognitive function.

Post-traumatic stress disorder (PTSD) is a serious mental health injury which can manifest after experiencing a traumatic life event. The disorder is characterized by symptoms of re-experiencing, avoidance, emotional numbing and hyper-arousal. Whilst its aetiology and resultant symptomology are better understood, relatively little is known about the underlying cortical pathophysiology, and in particular whether changes in functional connectivity may be linked to the disorder. Here, we used non-invasive neuroimaging with magnetoencephalography to examine functional connectivity in a resting-state protocol in the combat-related PTSD group (n = 23), and a military control group (n = 21). We identify atypical long-range hyperconnectivity in the high-gamma-band resting-state networks in a combat-related PTSD population compared to soldiers who underwent comparable environmental exposure but did not develop PTSD. Using graph analysis, we demonstrate that apparent network connectivity of relevant brain regions is associated with cognitive-behavioural outcomes. We also show that left hippocampal connectivity in the PTSD group correlates with scores on the well-established PTSD Checklist (PCL). These findings indicate that atypical synchronous neural interactions may underlie the psychological symptoms of PTSD, whilst also having utility as a potential biomarker to aid in the diagnosis and monitoring of the disorder.

It is well known that we continuously filter incoming sensory information, selectively allocating attention to what is important while suppressing distracting or irrelevant information. Yet questions remain about spatiotemporal patterns of neural processes underlying attentional biases toward emotionally significant aspects of the world. One index of affectively biased attention is an emotional variant of an attentional blink (AB) paradigm, which reveals enhanced perceptual encoding for emotionally salient over neutral stimuli under conditions of limited executive attention. The present study took advantage of the high spatial and temporal resolution of magnetoencephalography (MEG) to investigate neural activation related to emotional and neutral targets in an AB task. MEG data were collected while participants performed a rapid stimulus visual presentation task in which two target stimuli were embedded in a stream of distractor words. The first target (T1) was a number and the second (T2) either an emotionally salient or neutral word. Behavioural results replicated previous findings of greater accuracy for emotionally salient than neutral T2 words. MEG source analyses showed that activation in orbitofrontal cortex, characterized by greater power in the theta and alpha bands, and dorsolateral prefrontal activation were associated with successful perceptual encoding of emotionally salient relative to neutral words. These effects were observed between 250 and 550 ms, latencies associated with discrimination of perceived from unperceived stimuli. These data suggest that important nodes of both emotional salience and frontoparietal executive systems are associated with the emotional modulation of the attentional blink.

The concept of cold-formed light steel framing construction has been widespread after understanding its structural characteristics with massive research works over the years. Connection serves as one of the important elements for light steel framing in order to achieve its structural stability. Compared to hot-rolled steel sections, cold-formed steel connections perform dissimilarity due to the thin-walled behaviour. This paper aims to review current researches on cold-formed steel connections, particularly for screw connections, storage rack connections, welded connections, and bolted connections. The performance of these connections in the design of cold-formed steel structures is discussed.

Background: Activation of polymorphonuclear neutrophils (PMNs) is thought to contribute to traumatic brain injury (TBI). Since hypertonic fluids can inhibit PMN activation, we studied whether hypertonic fluid resuscitation can reduce excessive PMN activation in TBI patients., Methods: Trauma patients with severe TBI were resuscitated with 250 mL of either 7.5% hypertonic saline (HS; n = 22), HS + 6% dextran-70 (HSD; n = 22), or 0.9% normal saline (NS; n = 39), and blood samples were collected on hospital admission and 12 and 24 h after resuscitation. Polymorphonuclear neutrophil activation (CD11b, CD62L, CD64) and degranulation (CD63, CD66b, CD35) markers and oxidative-burst activity, as well as spontaneous PMN apoptosis were measured by flow cytometry., Results: Relative to healthy controls, TBI patients showed increased PMN activation and decreased apoptosis of PMNs. In the HS group, but not in the HSD group, markers of PMN adhesion (CD11b, CD64) and degranulation (CD35, CD66b) were significantly lower than those in the NS group. These effects were particularly pronounced 12 h after resuscitation. Treatment with HS and HSD inhibited PMN oxidative burst responses compared with NS-treated patients. Hypertonic saline alone partially restored delayed PMN apoptosis. Despite these differences, the groups did not differ in clinical outcome parameters such as mortality and Extended Glasgow Outcome Scale., Conclusions: This study demonstrates that prehospital resuscitation with HS can partially restore normal PMN activity and the apoptotic behavior of PMNs, whereas resuscitation with HSD was largely ineffective. Although the results are intriguing, additional research will be required to translate these effects of HS into treatment strategies that improve clinical outcome in TBI patients.

Posttraumatic inflammation and excessive neutrophil activation cause multiple organ dysfunction syndrome (MODS), a major cause of death among hemorrhagic shock patients. Traditional resuscitation strategies may exacerbate inflammation; thus, novel fluid treatments are needed to reduce such posttraumatic complications. Hypertonic resuscitation fluids inhibit inflammation and reduce MODS in animal models. Here we studied the anti-inflammatory efficacy of hypertonic fluids in a controlled clinical trial. Trauma patients in hypovolemic shock were resuscitated in a prehospital setting with 250 mL of either 7.5% hypertonic saline (HS; n = 9), 7.5% hypertonic saline + 6% dextran 70 (HSD; n = 8), or 0.9% normal saline (NS; n = 17). Blood samples were collected on hospital admission and 12 and 24 h after resuscitation. Multicolor flow cytometry was used to quantify neutrophil expression of cell-surface activation/adhesion (CD11b, CD62L, CD64) and degranulation (CD63, CD66b, CD35) markers as well as oxidative burst activity. Circulating concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVACM-1), P- and E-selectins, myeloperoxidase (MPO), and matrix metalloproteinase 9 (MMP-9) were assessed by immunoassay. Multiple organ dysfunction syndrome, leukocytosis, and mortality were lower in the HS and HSD groups than in the NS group. However, these differences were not statistically significant. Hypertonic saline prevented priming and activation and neutrophil oxidative burst and CD11b and CD66b expression. Hypertonic saline also reduced circulating markers of neutrophil degranulation (MPO and MMP-9) and endothelial cell activation (sICAM-1, sVCAM-1, soluble E-selectin, and soluble P-selectin). Hypertonic saline + 6% dextran 70 was less capable than HS of suppressing the upregulation of most of these activation markers. This study demonstrates that initial resuscitation with HS, but neither NS nor HSD, can attenuate posttraumatic neutrophil and endothelial cell activation in hemorrhagic shock patients. These data suggest that hypertonic resuscitation without dextran may inhibit posttraumatic inflammation. However, despite this effect, neither HS nor HSD reduced MODS in trauma patients with hemorrhagic shock.

In this study, we validated a thromboelastography (TEG) method to evaluate the hemostatic effects of 3 peptides. The first peptide is an ideal amphipathic peptide composed of 22 leucine and lysine in a ratio of 2:1. At a very low concentration, the peptide had a procoagulant effect shown by decreases in reaction time (R) and coagulation time (K) but was impaired by a decrease in maximum amplitude (MA). At higher concentrations, the peptide had an anticoagulant effect. The α angle was minimally affected by the peptide. The second peptide is melittin derived from bee venom. Melittin showed procoagulant effects reflected by a decrease in clotting time but led to lower MA. The third peptide derived from fibrinogen γ chain promoted hemostasis only at an optimal concentration and became anticoagulant at a higher concentration. The hemostatic mechanisms of each peptide were discussed. Our study would facilitate further development of peptides for either hemorrhage control or thrombosis treatment.

Shock-wave exposure from improvised explosive devices (IEDs) has been implicated as a possible contributing factor to neurological impairment reported in combat veterans. However, evidence-based substantiation of this implication, particularly for low-level exposure in the absence of external signs of trauma, remain elusive. Accordingly, we constructed an open-ended shock tube producing a short-duration, low-amplitude shockwave. Low-level (11.5 kPa static overpressure) complex shock-wave exposure in rats resulted in no histological evidence of lung injury. By contrast, delayed cytoskeletal proteolysis of αII-spectrin was detected in the cortex and hippocampus by 12 h post-injury. Cell death was minimal and localized predominantly in the corpus callosum and periventricular regions. These regions, with presumably different density interfaces, exhibit biological responses to shockwaves consistent with interface turbulence described by Richtmyer-Meshkov instability. Evoked compound action potential (CAP) recordings from the corpus callosum showed a significant increase in the duration of CAP responses at 14 and 30 days post-injury, and a gradual depression in the unmyelinated fiber amplitude. Shielding the head attenuated αII-spectrin cytoskeletal breakdown, thus directly implicating low-level shock-wave exposure as a cause of brain injury in the rat. Despite anatomical and scaling differences in rats compared to humans, the results suggest the potential for undiagnosed traumatic brain pathologies occurring in combat veterans following shock-wave exposure.

Wound sealants provide an excellent alternative for closing surgical and non-surgical wounds, as well as stopping external bleeding for prehospital trauma injuries. Numerous biomaterials have been investigated to address specific requirements for their use as suitable wound sealants. This article focuses on the development of new wound sealant biomaterials and recent advances in the surgical applications of wound sealants. In the past 5 years, many new sealant materials had been reported, including keratin, mussel-adhesive proteins, dendrimers and in situ-forming hydrogels. Fibrin sealants remain the most clinically studied for a variety of surgical procedures, while clinical experience with wound sealants for orthopedic surgery is limited. Both liquid and solid wound sealants have been developed and found effective by possessing strong adhesive properties. Biocompatible and biodegradable wound sealants hold much promise in eventually replacing sutures in most surgical procedures.

An ideal amphipathic peptide (IAP), composed of simply lysine and leucine residues in a 1:2 ratio (K(7)L(15)), specifically prolongs in vitro coagulation assays that use phospholipids, such as the activated partial thromboplastin time (APTT). The main hypothesis of the present work is that IAP's anticoagulant effect occurs by competing with phospholipid membranes in in vitro coagulation reactions. We verified this hypothesis by employing different phospholipid-dependent coagulation assays, such as the APTT, the dilute prothrombin time (dPT) and the dilute Russell viper venom time (dRVVT) with both low and high amounts of phospholipids. We show that coagulation times are prolonged by IAP in a concentration-dependent manner, and that this prolongation is abrogated by adding excess phospholipid, demonstrating a phospholipid dependence for this inhibition. Using an ELISA-based binding assay, we show IAP inhibits the binding of one of the vitamin K-dependent coagulation factors, factor X, to phospholipid membranes. This is further confirmed with fluorescence spectroscopy, where the interaction of IAP and factor X is inhibited by phospholipid. In summary, this work demonstrates that IAP can act as an anticoagulant by impairing the interaction of coagulation factors with phospholipid membranes and provides a paradigm for the development of novel anticoagulants., (Copyright 2009 Elsevier Inc. All rights reserved.)

Thromboelastography (TEG) provides a functional evaluation of coagulation. It has characteristics of an ideal coagulation test for trauma, but is not frequently used, partially due to lack of both standardized techniques and normal values. We determined normal values for our population, compared them to those of the manufacturer and evaluated the effect of gender, age, blood type, and ethnicity. The technique was standardized using citrated blood, kaolin and was performed on a Haemoscope 5000 device. Volunteers were interviewed and excluded if pregnant, on anticoagulants or having a bleeding disorder. The TEG parameters analyzed were R, K, alpha, MA, LY30, and coagulation index. All volunteers outside the manufacturer's normal range underwent extensive coagulation investigations. Reference ranges for 95% for 118 healthy volunteers were R: 3.8-9.8 min, K: 0.7-3.4 min, alpha: 47.8-77.7 degrees, MA: 49.7-72.7 mm, LY30: -2.3-5.77%, coagulation index: -5.1-3.6. Most values were significantly different from those of the manufacturer, which would have diagnosed coagulopathy in 10 volunteers, for whom additional investigation revealed no disease (81% specificity). Healthy women were significantly more hypercoagulable than men. Aging was not associated with hypercoagulability and East Asian ethnicity was not with hypocoagulability. In our population, the manufacturer's normal values for citrated blood-kaolin had a specificity of 81% and would incorrectly identify 8.5% of the healthy volunteers as coagulopathic. This study supports the manufacturer's recommendation that each institution should determine its own normal values before adopting TEG, a procedure which may be impractical. Consideration should be given to a multi-institutional study to establish wide standard values for TEG.

We report the preparation of in situ-forming hydrogels, composed of oxidized dextran (Odex) and amine-containing polymers, for their potential use as a wound dressing to promote blood clotting. Dextran was oxidized by sodium periodate to introduce aldehyde groups to form hydrogels, upon mixing in solution with different polymers containing primary amine groups, including polyallylamine (PAA), oligochitosan and glycol chitosan. A series of experiments were conducted to identify the optimum gelation condition for the Odex-PAA system. The polymer concentration appeared to have a major effect on gelation time and the polymer weight ratio affected the resulting gel content and swelling. Other influencing factors included pH of the buffer used to dissolve each polymer, PAA molecular weight, and the type of individual material. The latter also contributed significantly to gel content and swelling. Thromboelastography was used to examine the effects of the in situ gelation on blood coagulation in vitro, where the Odex-PAA combination was found to be most pro-hemostatic, as indicated by a decrease in clotting time and an increase in clot strength. The results of this study demonstrated that in situ-forming hydrogels could promote clotting in vitro; however, further studies are required to determine if the same hydrogel formulations are effective in controlling hemorrhage in vivo.

This report describes the synthesis and characterization of hydrogel dispersions for the potential use as an in situ gel-forming wound sealant. A series of polyacrylamide (PAAm) particles (solid content 5-10 wt %) were prepared by dispersion polymerization of acrylamide (AAm) in a solvent mixture of ethanol/water (90/10 w/w). These particles are characterized by the presence of a "core" [ethylene glycol dimethacrylate (EGDMA) crosslinked PAAm] surrounded by a "shell" [acetoacetoxyethyl methacrylate (AAEMA) or 2-aminoethylmethacrylate-containing PAAm, named as AAEMA-xPAAm and NH(2)-xPAAm, respectively; x represents "crosslinked"]. Two "2-in-1" working systems were prepared: (1) AAEMA-xPAAm mixed with NH(2)-xPAAm and (2) AAEMA-xPAAm mixed with 1,6-diaminohexane [AAEMA:NH(2) (1:1 mol/mol in (1) and (2)]. These systems appeared to possess essential characteristics for their potential use as wound sealants. For example, at 37 degrees C (and/or room temperature), both systems (1) and (2) formed transparent films, within 2 min upon applying them to a substrate; a rapid, concomitant crosslinking reaction occurred between AAEMA and -NH(2) on their outer "shells," knitting the EGDMA-crosslinked PAAm micro-"gel" together into a macro one. In contrast to other reported wound sealants, which are in either solution form or powder form, the advantages of hydrogel dispersion-based sealant may include ease of application (sprayable due to its low viscosity), species encapsulation and protection, and so forth. To our best knowledge, this is the first report on designing a wound sealant based on micro-particle dispersions.

In the treatment of severe traumatic brain injury (TBI), the choice of fluid and osmotherapy is important. There are practical and theoretical advantages to the use of hypertonic saline. S100B, neuron-specific enolase (NSE), and myelin-basic protein (MBP) are commonly assessed biomarkers of brain injury with potential utility as diagnostic and prognostic indicators of outcome after TBI, but they have not previously been studied in the context of fluid resuscitation. This randomized controlled trial compared serum concentrations of S100B, NSE, and MBP in adult severe TBI patients resuscitated with 250 mL of 7.5% hypertonic saline plus 6% dextran70 (HSD; n = 31) versus 0.9% normal saline (NS; n = 33), and examined their relationship with neurological outcome at discharge. Blood samples drawn on admission (

The fabrication of a novel in situ forming hydrogel composed of a multifunctional poly(ethylene glycol) (PEG) N-hydroxysuccinimide ester (NHS) and poly(allylamine hydrochloride) (PAA) was investigated. FTIR confirmed that PAA formed the hydrogel matrix (i.e., the formation of a PAA-like hydrogel). A factorial experiment was conducted to identify the key parameters that controlled gelation time, gel content, and swelling properties. The type of PEG (e.g., 4- and 6-arm) appeared to play a major role in determining all three performance parameters, with the greatest effect on gelation time. Other influencing factors include (a) the PEG concentration, which contributes to the gelation time and gel content; (b) pH of the buffer used for dissolving each polymer, which can affect the gelation time; and (c) PAA molecular weights, which contribute to the gel content and swelling. The concentration of PAA solution had no significant effects on hydrogel formation and properties within the investigated range, presumably due to negligible changes in the crosslinking density of the hydrogels. The PAA buffer pH influenced the gel content as well. Finally, thromboelastography was used to examine the effects of each polymer and their in situ gelation on blood coagulation in vitro. All individual polymers tested reduced clot strength, while the gelation of the polymers enhanced overall procoagulant effects. These results suggest that the biomaterial can be optimized to provide a combination of rapid gelation and swelling properties suitable for hemorrhage control and thus warrant further studies in animal bleeding models.

On the basis of previous evidence that amphipathic helical peptides accelerate Factor IXa activation of Factor X [Blostein, Rigby, Furie, Furie and Gilbert (2000) Biochemistry 39, 12000-12006], the present study was designed to assess the procoagulant activity of an IAP (ideal amphipathic peptide) of Lys(7)Leu(15) composition. The results show that IAP accelerates Factor X activation by Factor IXa in a concentration-dependent manner and accelerates thrombin generation by Factor Xa with a comparable peptide- and substrate-concentration-dependence. A scrambled helical peptide with the same amino acid composition as IAP, but with its amphipathicity abolished, eliminated most of the aforementioned effects. The Gla (gamma-carboxyglutamic acid)-rich domain of Factor X is required for IAP activity, suggesting that this peptide behaves as a phospholipid membrane. This hypothesis was confirmed, using fluorescence spectroscopy, by demonstrating direct binding between IAP and the Gla-rich domain of Factor X. In addition, the catalytic efficiencies of the tenase and prothrombinase enzymatic complexes, containing cofactors Factor VIIIa and Factor Va respectively, are enhanced by IAP. Finally, we show that IAP delays clot lysis in vitro. In summary, these observations demonstrate that IAP not only enhances essential procoagulant reactions required for fibrin generation, but also inhibits fibrinolysis, suggesting a potential role for IAP as a haemostatic agent.

To optimize the preparation of a gelatin-HydroThane Interpenetrating Polymer Network (IPN) and obtain optimum physical properties for its use as a wound dressing, we studied IPN films prepared with two types of gelatin having different molecular weights. The effects of the gelatin molecular weight and type on the IPN film's structure, morphology, swelling and mechanical properties were determined. While FTIR did not reveal any noticeable differences between the IPNs prepared using different gelatin, light microscopy showed a lesser phase separation of the film prepared with a high-molecular-weight type A gelatin. Furthermore, these films displayed slightly less swelling, higher strength and lower strain, compared to the IPNs prepared with either low-molecular-weight type A or type B gelatin. The IPN prepared with type B gelatin showed higher swelling in serum-containing medium than those prepared with type A gelatin, because of its ionic charges under the condition. Increases in viscosity were observed with increasing molecular weight, type A being more viscous than type B gelatin despite having a lower bloom number. The viscosity of the high-molecular-weight gelatin was in the same magnitude as that of HydroThane, which might lead to less phase separation. A better understanding of the effects of alterations in the gelatin molecular weight and type on the formation and properties of the gelatin-HydroThane IPN should facilitate the development of promising composite biomaterials for wound dressing applications.

This study was conducted to understand the effects of aging methacrylated gelatin solutions on the properties of gelatin-HydroThane Interpenetrating Polymer Network (IPN) films. The latter were prepared from methacrylated gelatin solutions that were either freshly made or stored at different concentrations and temperatures for various periods. The morphology, swelling stability and mechanical properties of the IPNs were then accordingly characterized. The IPNs prepared with aged solutions showed a reduced phase separation; changed from a network-like structure to a continuous phase structure; and demonstrated higher swelling stabilities and higher elasticity under optimal aging conditions, compared to the IPN prepared with a fresh methacrylated gelatin solution. An increase in viscosity and a change in phase transition of aged methacrylated gelatin solutions were also observed, presumably due to the physical structuring of methacrylated gelatin chains (e.g., by the formation of a helix structure), thus altering the resulting IPN characteristics. A better understanding of the effects of aging methacrylated gelatin solution on the formation and properties of gelatin-HydroThane IPNs should enable us to further develop our composite biomaterials for different dressing applications.

We prepared interpenetrating polymer networks (IPNs) composed of a gelatin hydrogel and a HydroThane elastomer to combine the advantages of both polymers into one biomaterial. Fourier transform Infrared (FTIR) spectroscopy and Differential Scanning Calorimetry (DSC) confirmed the co-existence of the two polymers in the IPNs. Optical light microscopy confirmed hydrogel domains were interspaced into an elastomer network. Hydration and stability studies in aqueous solution showed that, although the IPN biomaterials exhibited stable swelling for more than 30 days, approximately 10% and 50% loss of the hydrogel component were confirmed at room temperature and 37 degrees C, respectively, using gel permeation chromatography (GPC). The swelling study in the serum-containing medium indicated the biomaterials maintained their swelling stability for different periods, depending on the extent of gelatin methacrylation, photoinitiator concentration and incubation temperature. Lastly, the biomaterials exhibited higher failure stress and lower failure strain in a dry state than in a swollen state, and showed limited changes in both stress and strain at room temperature and at 37 degrees C, in contrast with a decrease at 50 degrees C. No significant effects of gelatin methacrylation on mechanical properties were noticed. The preparation and characterization methods were well established and formed the basis of further developing the biomaterials.

This study investigated the effect of an intratracheal (i.t.) administration of a liposome-entrapped Delta9-tetrahydrocannabinol (LTHC) preparation on intraocular pressure (IOP) in nonanaesthetized Brown Norway rats. The ocular hypotensive effects of i.t. LTHC were compared to that of intraperitoneal (i.p.) LTHC administration. All i.t. LTHC doses >0.05 mg/kg significantly decreased IOP (P < 0.05) within 30 min of administration, and doses of i.t. LTHC >0.1 mg/kg decreased IOP within 15 min of administration. A maximal reduction in IOP of 2.32 +/- 0.27 mmHg (n = 4) was seen with 1.0 mg/kg of i.t. LTHC. In comparison, no significant IOP drop was apparent prior to 30 min with all doses (0.01-1.0 mg/kg) of i.p. LTHC tested, although a similar maximum drop in IOP (2.15 +/- 0.12 mmHg; n = 8) was obtained with 1.0 mg/kg of LTHC. The ED(50) for i.t. and i.p. LTHC was 0.08 mg/kg and 0.12 mg/kg, respectively. The IOP-lowering effects of i.p. LTHC (0.2 mg/kg) were reduced by 14% and 80% by 0.25 mg/kg (n = 6) and 2.5 mg/kg (n = 6), respectively, of the CB1R antagonist, SR141716A. In conclusion, i.t. LTHC was superior to i.p. LTHC in producing a more rapid and potent decrease in IOP. The IOP-lowering effect of LTHC was blocked by the CB1R-selective antagonist, SR141716A, suggesting that CB1Rs contribute to the ocular hypotensive effect of Delta9-tetrahydrocannabinol.

Objective: To investigate the potential immunologic and anti-inflammatory effects of hypertonic saline plus dextran (HSD) in hemorrhagic trauma patients., Background: Unbalanced inflammation triggered by shock has been linked to multiorgan dysfunction (MOD) and death. In animal and cellular models, HSD alters the inflammatory response to shock, attenuating MOD and improving outcome. It remains untested whether HSD has similar effects in humans., Methods: A single 250-mL dose of either HSD (7.5% NaCl, 6% dextran-70) or placebo (0.9% NaCl) was administered to adult blunt trauma patients in hemorrhagic shock. The primary outcome was to measure changes in immune/inflammatory markers, including neutrophil activation, monocyte subset redistribution, cytokine production, and neuroendocrine changes. Patient demographics, fluid requirements, organ dysfunction, infection, and death were recorded., Results: A total of 27 patients were enrolled (13 HSD) with no significant differences in clinical measurements. Hyperosmolarity was modest and transient, whereas the immunologic/anti-inflammatory effects persisted for 24 hours. HSD blunted neutrophil activation by abolishing shock-induced CD11b up-regulation and causing CD62L shedding. HSD altered the shock-induced monocyte redistribution pattern by reducing the drop in "classic" CD14 and the expansion of the "pro-inflammatory" CD14CD16 subsets. In parallel, HSD significantly reduced pro-inflammatory tumor necrosis factor (TNF)-alpha production while increasing anti-inflammatory IL-1ra and IL-10. HSD prevented shock-induced norepinephrine surge with no effect on adrenal steroids., Conclusions: This first human trial evaluating the immunologic/anti-inflammatory effects of hypertonic resuscitation in trauma patients demonstrates that HSD promotes a more balanced inflammatory response to hemorrhagic shock, raising the possibility that similar to experimental models, HSD might also attenuate post-trauma MOD.

The immunomodulatory effects of physiological temperature change remain poorly understood and inter-relationships between changes in core temperature, stress hormones and cytokines during exertional hyperthermia are not well established. This experimental study was designed to examine how cytokine (tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-12 and IL-1ra (receptor antagonist)) and hormone (epinephrine (Epi), norepinephrine (NE), growth hormone (GH) and cortisol (CORT)) responses are modified when the exercise-induced rise in core temperature is attenuated or exacerbated by immersion in a water bath. Ten men ((mean +/- SD) age: 26.9 +/- 5.7 years; height 1.75 +/- 0.07 m; body mass 76.0 +/- 10.9 kg; O(2 peak): 48.0 +/- 12.4 mL kg(-1) min(-1)) completed two 40-min cycle ergometer exercise trials at 65% O(2 peak) while immersed to mid-chest. Rectal temperature (T(re)) peaked at 39.1 +/- 0.03 and 37.5 +/- 0.13 degrees C during the hot (39 degrees C) and cold (18 degrees C) conditions, respectively. Blood samples were collected before, during (20- and 40-min) and after (30- and 120-min) exercise. Increases in circulating NE (>350%), Epi (>500%), GH (>900%), IL-12 (>150%) and TNF-alpha (>90%) were greatest after 40-min exercise in the heat. Substantial elevations of CORT (80%), IL-1ra (150%) and IL-6 (>400%) did not occur until after exercise was complete. Core temperature clamping decreased the rise in circulating stress hormone concentrations and abolished increases in plasma cytokine concentrations. These findings suggest that exercise-associated elevations of T(re) mediate increases of circulating stress hormones, which subsequently contribute to induction of circulating cytokine release.

The purpose of this study was to examine the impact of intensive training for competitive sports on natural killer (NK) cell lytic activity and subset distribution. Eight female college-level volleyball players undertook 1 mo of heavy preseason training. Volleyball drills were performed 5 h/day, 6 days/wk. Morning resting blood samples were collected before training (Pre), on the 10th day of training (During), 1 day before the end of training (End), and 1 wk after intensive training had ceased (Post). CD3(-)CD16(bright)CD56(dim) (CD56(dim) NK), CD3(-)CD16(dim/-)CD56(bright) NK (CD56(bright) NK), and CD3(+)CD16(-)CD56(dim) (CD56(dim) T) cells in peripheral blood were determined by flow cytometry. The circulating count of CD56(dim) NK cells (the predominant population, with a high cytotoxicity) did not change, nor did the counts for other leukocyte subsets. However, counts for CD56(bright) NK and CD56(dim) T cells (subsets with a lower cytotoxicity) increased significantly (P < 0.01) in response to the heavy training. Overall NK cell cytotoxicity decreased from Pre to End (P = 0.002), with a return to initial values at Post. Lytic units per NK cell followed a similar pattern (P = 0.008). Circulating levels of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha remained unchanged. These results suggest that heavy training can decrease total NK cell cytotoxicity as well as lytic units per NK cell. Such effects may reflect in part an increase in the proportion of circulating NK cells with a low cytotoxicity.

The bactericidal effectiveness of liposomal polymyxin B against Pseudomonas aeruginosa was investigated in an animal model of pulmonary infection. Polymyxin B was incorporated into liposomes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol (Chol) (2:1). Lung infection was induced in rats following intratracheal instillation of 10(7) colony-forming units (CFU) of P. aeruginosa (ATCC 27853) embedded in agar beads. Starting on day 3 post-infection, animals were treated daily, for 3 consecutive days, with saline, empty liposomes, free polymyxin B, or liposomal polymyxin B (2mg polymyxin B/kg body weight) by intratracheal instillation; animals were killed 24hr after the third drug instillation. Treatment of infected animals with liposomal polymyxin B significantly reduced the pulmonary bacterial counts (3.7+/-0.4log CFU/paired lungs) as compared with that of free polymyxin B (5.1+/-0.2log CFU/paired lungs). Treatment of infected animals with empty liposomes gave pulmonary bacterial counts similar to those obtained from the saline-treated group. Pulmonary infection with P. aeruginosa also resulted in lung injury as evidenced by increases in wet lung weight and decreases in angiotensin converting enzyme activity as well as increases in myeloperoxidase activity, an index of the inflammatory response. Treatment with free polymyxin B ameliorated the lung injuries induced by the microorganism, a protective effect that was more pronounced in the liposomal polymyxin B-treated group. The levels of polymyxin B in the lungs of the infected animals treated with the liposomal suspension were significantly higher (42.8+/-6.2 microg/paired lungs) compared with those treated with the free drug (8.2+/-0.4 microg/paired lungs). These data suggest that direct delivery of liposomal polymyxin B to the lung can be effective in the treatment of pulmonary infection with P. aeruginosa by enhancing retention of the antibiotic in the lung.

Physical stress is associated with circulating cytokinemia. However the mechanisms of cytokine regulation during such stress are not clearly defined. Non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, are widely used in countering the effects of excessive exercise, but their impact on circulating pro- and anti-inflammatory cytokine production in healthy humans also remains unclear. This study investigated the effect of five days of oral indomethacin treatment (75 mg per day) on the serum concentrations of IL-6, IL-10, IL-12, and TNF-alpha induced by exercising healthy volunteers. The results demonstrate that indomethacin does not alter resting serum cytokine concentrations. Increased circulating levels were noted, however, for all four cytokines with exercise, but with a different time-course. During and after strenuous physical exercise, indomethacin treatment blunted serum IL-6, and augmented TNF-alpha and IL-10. These findings may have important implications for both host defense and the injuries associated with excessively vigorous exercise., (Copyright 2002 Elsevier Science Ltd.)

This study examined the naive and memory phenotypic profiles of CD4+ and CD8hi T cells that were mobilized to the peripheral circulation during a combination of aerobic exercise and heat stress, determining expression of the adhesion molecules CD62L and CD11a on the recruited cells. Twelve recreationally active males (age 27.1 +/- 5.3 yr, height 1.77 +/- 0.08 m, mass 76.9 +/- 12.0 kg, VO2peak 43.9 +/- 6.7 mL x kg(-1) x min(-1)) completed a 40 min bout of cycle ergometry at 65 % of VO2peak while immersed to mid-chest in a water bath at 39 degrees C. Venous blood samples were collected before (T0), during (T40) and 30 min after (T70) exposure to combined exercise and heat stress. Specimens were analyzed by three-colour flow cytometry for CD4+ and CD8hi T cell expression of CD45RO, CD11a and CD62L. Some 80 % of the CD4+ T cells that were mobilized were of the CD45RO memory phenotype, with the numbers of CD11alo and CD62L+ cells increasing more than those of CD11ahi and CD62L- cells. For the CD8hi cells, there was a more equal recruitment of CD45RO- naive (43 %) and CD45RO+ memory (57 %) cells. The majority (84 %) of recruited CD8+ cells were CD11ahi; there was a trend to predominance of CD62L- cells (57 %) for the memory subset, but with almost equal recruitment of CD62L+/- for the naive subset. We conclude that the exercise + heat stress induced trend to an increase in CD4+ T cells is linked in some way to memory phenotype; it cannot be explained simply by a high density expression of CD11a and lack of the lymph node homing receptor (CD62L). Furthermore, although mobilization of CD8hi T cells is not linked to memory phenotype, a high density expression of CD11a and a lack of the lymph node homing receptor are important determinants of CD8hi T cell mobilization.

Pseudomonas aeruginosa is a Gram-negative pathogen that can cause lung injury in immunocompromised patients, primarily by inducing a release of host-derived mediators responsible for the influx of phagocytes to the lung. These phagocytes exert their antimicrobial actions by releasing toxic metabolites, including reactive oxygen species and proteases, which can also cause cell injury. This study was carried out to assess the pulmonary oxidant-antioxidant status of male adult Sprague-Dawley rats infected with different numbers of P. aeruginosa (10(4)-10(7)cfu/animal). Intratracheal instillation of P. aeruginosa resulted in lung injury, as evidenced by increases in wet lung weight and decreases in the lung activities of angiotensin converting enzyme and alkaline phosphatase, enzymes localized primarily in pulmonary endothelial and alveolar type II epithelial cells, respectively. The P. aeruginosa -induced lung injury was directly related to the infiltration of neutrophils, as indicated by increases in myeloperoxidase activity. The challenge of animals with P. aeruginosa resulted in increases in lipid peroxidation and decreases in glutathione content, which were associated with the indices of lung injury and neutrophil infiltration. Such a challenge also resulted in weakening the antioxidant defence system, as evidenced by decreases in superoxide dismutase, catalase and glutathione peroxidase activities. These data suggest that changes in the pulmonary oxidant-antioxidant status may play an important role in the P. aeruginosa -induced lung injury., (Copyright 2002 Academic Press.)

The present review examines the impact of basic recruit training on health and lifestyle. Many of those recruited begin training with a less than optimal lifestyle with respect to fitness, smoking habits, alcohol consumption, drug abuse, and exposure to sexually transmitted diseases. Thus, there is scope to enhance training programs that address fitness and lifestyle, minimizing potential losses in health and efficiency from upper respiratory infections, musculoskeletal injuries, cardiac catastrophes, mental disturbances, and adverse responses to extreme environments.

This study tested the hypothesis that exercise elicits monocytic cytokine expression and that prolonged cold exposure modulates such responses. Nine men (age, 24.6 +/- 3.8 y; VO(2 peak), 56.8 +/- 5.6 ml. kg(-1). min(-1)) completed 7 days of exhausting exercise (aerobic, anaerobic, resistive) and underwent three cold, wet exposures (CW). CW trials comprised

This study was undertaken to determine the cell adhesion molecule profile of CD4+, CD8hi and CD56+ lymphocytes, which are mobilised to and from the peripheral blood during and after prolonged aerobic exercise. Ten healthy males (21-35 years old) were tested on two occasions, separated by at least 14 days. On the first occasion, subjects were examined in a rested state but did not exercise. On the second occasion, the same subjects were examined at the same time of day before, during and after 2 h of exercise at 65% of peak oxygen consumption. Blood samples obtained at rest (t0), during (at 0.5, 1, 1.5 and 2 h, t0.5, t1, t1.5 and t2, respectively) and after (at 4 and 24 h, t4 and t24, respectively) exercise were analysed by two-colour flow cytometry for CD4+, CD8hi and CD56+ cell surface expression, and density of CD62L, CD49d and CD11a. At t2, circulating concentrations of CD56+, CD8hi and CD4+ lymphocytes had increased (P < 0.05) by 330%, 105% and 30%, respectively. The majority of CD4+, CD8hi and CD56+ lymphocytes mobilised to the blood at t2 were CD62L- and CD11ahi, although populations of CD4+ and CD56+ cells that expressed CD62L+ and CD11alo were also mobilised. Changes in subset concentrations at t0.5 were positively associated (r = 0.63; P < 0.01) with their corresponding mean surface density of CD11a at t0. Our findings suggest that the differential mobilisation of lymphocytes during prolonged aerobic exercise is linked to the surface expression of CD11a (i.e. lymphocyte-function-associated antigen-1). However, mechanisms unrelated to CD11a expression also appear to be involved.

This study examined the hypothesis that several days of exhaustive exercise would impair thermoregulatory effector responses to cold exposure, leading to an accentuated core temperature reduction compared with exposure of the same individual to cold in a rested condition. Thirteen men (10 experimental and 3 control) performed a cold-wet walk (CW) for up to 6 h (6 rest-work cycles, each 1 h in duration) in 5 degrees C air on three occasions. One cycle of CW consisted of 10 min of standing in the rain (5.4 cm/h) followed by 45 min of walking (1.34 m/s, 5.4 m/s wind). Clothing was water saturated at the start of each walking period (0.75 clo vs. 1.1 clo when dry). The initial CW trial (day 0) was performed (afternoon) with subjects rested before initiation of exercise-cold exposure. During the next 7 days, exhaustive exercise (aerobic, anaerobic, resistive) was performed for 4 h each morning. Two subsequent CW trials were performed on the afternoon of days 3 and 7, approximately 2.5 h after cessation of fatiguing exercise. For controls, no exhaustive exercise was performed on any day. Thermoregulatory responses and body temperature during CW were not different on days 0, 3, and 7 in the controls. In the experimental group, mean skin temperature was higher (P < 0.05) during CW on days 3 and 7 than on day 0. Rectal temperature was lower (P < 0.05) and the change in rectal temperature was greater (P < 0.05) during the 6th h of CW on day 3. Metabolic heat production during CW was similar among trials. Warmer skin temperatures during CW after days 3 and 7 indicate that vasoconstrictor responses to cold, but not shivering responses, are impaired after multiple days of severe physical exertion. These findings suggest that susceptibility to hypothermia is increased by exertional fatigue.

The lymphatic system has a critical role in the return of fluids, proteins, and cells to the circulatory system. However, the effects of stress, including exercise, on this system have not been adequately studied. We investigated the effect of a physiological dose (1 mg) of epinephrine (Epi) on lymph flow, cell concentration, and lymphocyte subsets in efferent subcutaneous lymph in sheep. Blood leukocyte numbers, differential, lymphocyte subsets, and blood and lymph pools of lymphocytes were determined simultaneously. A significant acute increase in lymph flow was followed by a post-injection decrease in flow and cellular output. No changes in lymphocyte subsets or pools of lymphocytes were seen in either blood or lymph. The timing of elevated plasma and lymph concentrations of Epi and norepinephrine (NE) corresponded with the increased lymph flow. In conclusion, Epi injection caused no change in lymphocyte subset distribution, leukocyte concentration, or pools of lymphocytes. A decrease in lymph flow and cellularity was documented post-injection, indicating that lymphatic tissue has no role in the leukocytosis seen after Epi injection. Lymphocyte retention by lymph nodes, however, may contribute to post-injection lymphopenia.

Cytokines are soluble glycoproteins that are produced by and mediate communication between and within immune and nonimmune cells, organs and organ systems throughout the body. Pro- and anti-inflammatory mediators constitute the inflammatory cytokines, which are modulated by various stimuli, including physical activity, trauma and infection. Physical activity affects local and systemic cytokine production at different levels, often exhibiting striking similarity to the cytokine response to trauma and infection. The present review examines the cytokine response to short term exercise stress, with an emphasis on the balance between pro- and anti-inflammatory mechanisms and modulation of both innate and specific immune parameters through cytokine regulation. The effects of long term exercise on cytokine responses and the possible impact on various facets of the immune system are also discussed, with reference to both cross-sectional and longitudinal studies of exercise training. Finally, the validity of using exercise as a model for trauma and sepsis is scruti- nised in the light of physiological changes, symptomatology and outcome, and limitations of the model are addressed. Further studies, examining the effect of exercise, trauma and infection on novel cytokines and cytokine systems are needed to elucidate the significance of cytokine regulation by physical activity and, more importantly, to clarify the health implications of short and long term physical activity with respect to overall immune function and resistance to infection.