Targeting Inflammation and Oxidative Stress to Improve Outcomes in a TNBS Murine Crohn's Colitis Model.

Inflammation and oxidative stress are implicated in the pathogenesis of Crohn's disease. Cerium oxide nanoparticle (CNP) conjugated to microRNA 146a (miR146a) (CNP-miR146a) is a novel compound with anti-inflammatory and antioxidative properties. We hypothesized that local administration of CNP-miR146a would improve colitis in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS) mouse model for Crohn's disease by decreasing colonic inflammation. Balb/c mice were instilled with TNBS enemas to induce colitis. Two days later, the mice received cellulose gel enema, cellulose gel with CNP-miR146a enema, or no treatment. Control mice received initial enemas of 50% ethanol and PBS enemas on day two. The mice were monitored daily for weight loss and clinical disease activity. The mice were euthanized on days two or five to evaluate their miR146a expression, inflammation on histology, and colonic IL-6 and TNF gene expressions and protein concentrations. CNP-miR146a enema successfully increased colonic miR146a expression at 12 h following delivery. At the end of five days from TNBS instillation, the mice treated with CNP-miR146a demonstrated reduced weight loss, improved inflammation scores on histology, and reduced gene expressions and protein concentrations of IL-6 and TNF. The local delivery of CNP-miR146a in a TNBS mouse model of acute Crohn's colitis dramatically decreased inflammatory signaling, resulting in improved clinical disease.

Polyethylene glycol (PEG) and other bioactive solutions with neurorrhaphy for rapid and dramatic repair of peripheral nerve lesions by PEG-fusion.

BACKGROUND: Nervous system injuries in mammals often involve transection or segmental loss of peripheral nerves. Such injuries result in functional (behavioral) deficits poorly restored by naturally occurring 1-2 mm/d axonal outgrowths aided by primary repair or reconstruction. "Neurorrhaphy" or nerve repair joins severed connective tissues, but not severed cytoplasmic/plasmalemmal extensions (axons) within the tissue. NEW METHOD: PEG-fusion consists of neurorrhaphy combined with a well-defined sequence of four pharmaceutical agents in solution, one containing polyethylene glycol (PEG), applied directly to closely apposed viable ends of severed axons. RESULTS: PEG-fusion of rat sciatic nerves: (1) restores axonal continuity across coaptation site(s) within minutes, (2) prevents Wallerian degeneration of many distal severed axons, (3) preserves neuromuscular junctions, (4) prevents target muscle atrophy, (5) produces rapid and improved recovery of voluntary behaviors compared with neurorrhaphy alone, and (6) PEG-fused allografts are not rejected, despite no tissue-matching nor immunosuppression. COMPARISON WITH EXISTING METHODS: If PEG-fusion protocols are not correctly executed, the results are similar to that of neurorrhaphy alone: (1) axonal continuity across coaptation site(s) is not re-established, (2) Wallerian degeneration of all distal severed axons rapidly occurs, (3) neuromuscular junctions are non-functional, (4) target muscle atrophy begins within weeks, (5) recovery of voluntary behavior occurs, if ever, after months to levels well-below that observed in unoperated animals, and (6) allografts are either rejected or not well-accepted. CONCLUSION: PEG-fusion produces rapid and dramatic recovery of function following rat peripheral nerve injuries.

Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers.

INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.

Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats.

Many publications report that ablations of segments of peripheral nerves produce the following unfortunate results: (1) Immediate loss of sensory signaling and motor control; (2) rapid Wallerian degeneration of severed distal axons within days; (3) muscle atrophy within weeks; (4) poor behavioral (functional) recovery after many months, if ever, by slowly-regenerating (∼1mm/d) axon outgrowths from surviving proximal nerve stumps; and (5) Nerve allografts to repair gap injuries are rejected, often even if tissue matched and immunosuppressed. In contrast, using a female rat sciatic nerve model system, we report that neurorrhaphy of allografts plus a well-specified-sequence of solutions (one containing polyethylene glycol: PEG) successfully addresses each of these problems by: (a) Reestablishing axonal continuity/signaling within minutes by nonspecific ally PEG-fusing (connecting) severed motor and sensory axons across each anastomosis; (b) preventing Wallerian degeneration by maintaining many distal segments of inappropriately-reconnected, PEG-fused axons that continuously activate nerve-muscle junctions; (c) maintaining innervation of muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; (d) inducing remarkable behavioral recovery to near-unoperated levels within days to weeks, almost certainly by CNS and PNS plasticities well-beyond what most neuroscientists currently imagine; and (e) preventing rejection of PEG-fused donor nerve allografts with no tissue matching or immunosuppression. Similar behavioral results are produced by PEG-fused autografts. All results for Negative Control allografts agree with current neuroscience data 1-5 given above. Hence, PEG-fusion of allografts for repair of ablated peripheral nerve segments expand on previous observations in single-cut injuries, provoke reconsideration of some current neuroscience dogma, and further extend the potential of PEG-fusion in clinical practice.

Polyethylene glycol solutions rapidly restore and maintain axonal continuity, neuromuscular structures, and behaviors lost after sciatic nerve transections in female rats.

Complete severance of major peripheral mixed sensory-motor nerve proximally in a mammalian limb produces immediate loss of action potential conduction and voluntary behaviors mediated by the severed distal axonal segments. These severed distal segments undergo Wallerian degeneration within days. Denervated muscles atrophy within weeks. Slowly regenerating (∼1 mm/day) outgrowths from surviving proximal stumps that often nonspecifically reinnervate denervated targets produce poor, if any, restoration of lost voluntary behaviors. In contrast, in this study using completely transected female rat sciatic axons as a model system, we provide extensive morphometric, immunohistochemical, electrophysiological, and behavioral data to show that these adverse outcomes are avoided by microsuturing closely apposed axonal cut ends (neurorrhaphy) and applying a sequence of well-specified solutions, one of which contains polyethylene glycol (PEG). This "PEG-fusion" procedure within minutes reestablishes axoplasmic and axolemmal continuity and signaling by nonspecifically fusing (connecting) closely apposed open ends of severed motor and/or sensory axons at the lesion site. These PEG-fused axons continue to conduct action potentials and generate muscle action potentials and muscle twitches for months and do not undergo Wallerian degeneration. Continuously innervated muscle fibers undergo much less atrophy compared with denervated muscle fibers. Dramatic behavioral recovery to near-unoperated levels occurs within days to weeks, almost certainly by activating many central nervous system and peripheral nervous system synaptic and other plasticities, some perhaps to a greater extent than most neuroscientists would expect. Negative control transections in which neurorrhaphy and all solutions except the PEG-containing solution are applied produce none of these remarkably fortuitous outcomes observed for PEG-fusion.

Beliefs about medicines among Hong Kong hospital outpatients.

OBJECTIVES: (1) To identify demographic characteristics associated with different patients' belief attitudes among older Hong Kong hospital outpatients. (2) To identify important implementation criteria for developing a more effective adherence-improving intervention. METHODS: Six hundred and ninety-eight patients completed a questionnaire consisting of demographic information and Belief about Medicines Questionnaire. Findings were statistically analysed. KEY FINDINGS: Among respondents, 56.9% were either in the hesitant (Mixed-feelings and Indifferent) or negative (Distrustful) medication belief constructs. The majority of these patients were younger females, with better education, taking fewer regular medications and for shorter duration. Rheumatoid and gout accounted for 46.1% of cases in the Distrustful construct, while cardiovascular and diabetic conditions accounted for 63.8% of cases in the positive (In-favour) construct. Patients' concerns about medications were reaffirmed to be a predominant factor affecting medication beliefs. The mean Necessity-Concern Differential scores in the two hesitant constructs illustrated that patients within these two constructs were more pliant towards medicines and, therefore, were predicted to be more subject to modification. CONCLUSIONS: Our results identified the demographic characteristics of patients with negative or hesitant belief attitudes about medicines. In order to effectively achieve improvement in long-term beliefs about medications, the design of interventions should target positively modifying belief attitudes in these two patient groups. Furthermore, addressing patients' concern about their medicines was reaffirmed to be an important criterion for researchers to focus on when designing effective interventions in the future.

A novel radiographic targeting guide for percutaneous placement of transfacet screws in the cervical spine with limited fluoroscopy: A cadaveric feasibility study.

BACKGROUND: We describe a technique for percutaneous transfacet screw placement in the cervical spine without the need for lateral-view fluoroscopy. METHODS: Previously established articular pillar morphometry was used to define the ideal trajectory for transfacet screw placement in the subaxial cervical spine. A unique targeting guide was developed to allow placement of Kirschner wires across the facet joint at 90° without the guidance of lateral-view fluoroscopy. Kirschner wires and cannulated screws were placed percutaneously in 7 cadaveric specimens. Placement of instrumentation was performed entirely under modified anteroposterior-view fluoroscopy. All specimens were assessed for acceptable screw placement by 2 fellowship-trained orthopaedic spine surgeons using computed tomography. Open dissection was used to confirm radiographic interpretation. Acceptable placement was defined as a screw crossing the facet joint, achieving purchase in the inferior and superior articular processes, and not violating critical structures. Malposition was defined as a violation of the transverse foramen, spinal canal, or nerve root or inadequate fixation. RESULTS: A total of 48 screws were placed. Placement of 45 screws was acceptable. The 3 instances of screw malposition included a facet fracture, a facet distraction, and a C6-7 screw contacting the C7 nerve root in a specimen with a small C7 superior articular process. CONCLUSIONS: Our data show that with the appropriate radiographic technique and a targeting guide, percutaneous transfacet screws can be safely placed at C3-7 without the need for lateral-view fluoroscopy during the targeting phase. Because of the variable morphometry of the C7 lateral mass, however, care must be taken when placing a transfacet screw at C6-7. CLINICAL RELEVANCE: This study describes a technique that has the potential to provide a less invasive strategy for posterior instrumentation of the cervical spine. Further investigation is needed before this technique can be applied clinically.

Interference screw fixation versus Pulvertaft weave in a simulated early-motion suspensionplasty protocol.

PURPOSE: To compare interference screw fixation to Pulvertaft weave fixation in a cadaveric basal joint abductor pollicis longus (APL) suspensionplasty model with an early range of motion protocol. We asked whether the interference screw fixation would provide comparable initial stability while minimizing the dorsal incision and eliminating the prominent dorsal mass associated with the traditional Pulvertaft weave. METHODS: Six matched cadaveric forearms underwent suspensionplasty with tendon fixation via an interference screw or a Pulvertaft weave. We then loaded the specimens to 10,000 cycles and used a modification of a previously validated cyclic pinch model. One third of the load required for maximal pinch strength was used. The APL was not loaded because we used the tendon for ligament reconstruction. We obtained measurements of residual trapezial space with feeler gauges after trapeziectomy, after suspensionplasty, and at 1,000-cycle intervals. RESULTS: Suspensionplasty with interference screw fixation maintained statistically significantly larger trapezial space heights compared with the Pulvertaft weave. Moreover, after the first 1,000 cycles, none of the specimens fixed with the interference screw lost further height up to the 10,000th cycle. All of the specimens fixed with the Pulvertaft weave continued to lose height with cycling, and 1 specimen showed contact of the first metacarpal with the scaphoid after only 1,000 cycles. With interference screw fixation, the height achieved initially and maintained through 10,000 cycles was an average of 5.5 mm. When the Pulvertaft weave was used, the height achieved was 3.0 mm initially, declining to 2.3 mm after 10,000 cycles. The polylactic acid interference screw was placed through a 5-mm dorsal stab incision and the extra tendon graft was cut flush as it exited the bone tunnel, eliminating the dorsal prominence associated with the Pulvertaft weave. CONCLUSIONS: Although traditional APL suspensionplasty with a Pulvertaft weave provides good initial stability, it requires a large dorsal incision and leaves a prominent dorsal mass that may be bothersome to some patients.

Out-of-hospital cardiac arrest in denver, colorado: epidemiology and outcomes.

OBJECTIVES: The annual incidence of out-of-hospital cardiac arrest (OOHCA) in the United States is approximately 6 per 10,000 population and survival remains low. Relatively little is known about the performance characteristics of a two-tiered emergency medical services (EMS) system split between fire-based basic life support (BLS) dispersed from fixed locations and hospital-based advanced life support (ALS) dispersed from nonfixed locations. The objectives of this study were to describe the incidence of OOHCA in Denver, Colorado, and to define the prevalence of survival with good neurologic function in the context of this particular EMS system. METHODS: This was a retrospective cohort study using standardized abstraction methodology. A two-tiered hospital-based EMS system for the County of Denver and 10 receiving hospitals were studied. Consecutive adult patients who experienced nontraumatic OOHCA from January 1, 2003, through December 31, 2004, were enrolled. Demographic, prehospital arrest characteristics, treatment data, and survival data using the Utstein template were collected. Good neurologic survival was defined by a Cerebral Performance Categories (CPC) score of 1 or 2. RESULTS: During the study period, 1,985 arrests occurred. Of these, 715 (36%) had attempted resuscitation by paramedics and constitute our study sample. The median age was 65 years (interquartile range = 52-78 years), 69% were male, 41% had witnessed arrest, 25% had bystander cardiopulmonary resuscitation (CPR) performed, and 30% had ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) as their initial rhythm. Of the 715 patients, 545 (76%) were transported to a hospital, 223 (31%) had return of spontaneous circulation (ROSC), 175 (25%) survived to hospital admission, 58 (8%) survived to hospital discharge, and 42 (6%, 95% confidence interval [CI] = 4% to 8%) had a good neurologic outcome. CONCLUSIONS: Out-of-hospital cardiac arrest survival in Denver, Colorado, is similar to that of other United States communities. This finding provides the basis for future epidemiologic and health services research in the out-of-hospital and ED settings in our community.

Angiogenesis as a predictive marker of neurological outcome following hypoxia-ischemia.

Cerebral ischemia induces angiogenesis within and around infarcted tissue. The protection of existing and growth of new blood vessels may contribute to a more favorable outcome. The present study assessed whether angiogenesis can be used as a marker for neurodegeneration/neuroprotection in a model of hypoxia-ischemia (HI). Increased CD31 immunoreactivity 7 days post-HI indicated increased angiogenesis compared to controls (P<0.001). Treatment with the GABA(A) receptor modulator, clomethiazole (CMZ; 414 mg/kg/day), normalized the level of angiogenesis compared to HI + saline (P<0.001). Conversely, the non-selective nitric oxide synthase (NOS) inhibitor, L-NAME (5 mg/kg/day), markedly decreased angiogenesis compared to controls (P<0.001). Circulating plasma levels of IL-1alpha, IL-1beta and GM-CSF were significantly elevated post-HI. CMZ treatment attenuated these increases while also stimulating IL-10 levels. L-NAME treatment did not alter IL-1alpha or IL-1beta levels, but decreased endogenous IL-10 levels and exacerbated the ischemic lesion (P<0.001). CMZ treatment has been shown to increase NOS levels, while L-NAME halted the HI-induced increase in NOS activity (P<0.001). We conclude that angiogenesis can be used as a marker of neurodegeneration/neuroprotection for cerebral HI and is correlated to NOS activity and circulating inflammatory mediators.

Creating a successful school-based mobile dental program.

BACKGROUND: Dental disease is one of the leading causes of school absenteeism for children. This article describes the creation and evolution of the St. David's Dental Program, a mobile school-based dental program for children. METHODS: The dental program is a collaboration of community partners in Central Texas that provides free dental care to low-income children in schools without relying on reimbursements or government funding. RESULTS: Since 1998, the program has provided 132,791 screenings for oral health treatment needs and 38,634 encounters for sealants or treatment. In 2005, the program provided $2.1 million worth of services at a cost of $1.2 million (not including donated services). Factors important to the program's success included sustained funding for general operating costs; well-compensated clinicians to deliver care and experienced human service workers to manage program operations; the devotion of resources to maximize consent form return rates; and the development of strong relationships with school district and individual school staff. CONCLUSIONS: By removing cost, time, transportation, and bureaucratic barriers, the program was able to reach more children than fixed-site clinics. The program was a merging of private and public health dentistries. This model can be useful to other communities in light of the unmet need for dental care and tighter federal, state, and local government budgets.

Back pain in whitewater rafting guides.

OBJECTIVE: The purpose of this study was to quantify rates of back pain among whitewater rafting guides and to look for correlations between the presence of back pain and specific activities associated with guiding. The secondary objective was to provide suggestions for outfitters according to the results of this study, which may be of assistance to their guide staff. METHODS: A mail-out-mail-back survey was sent to 2510 rafting guides working in Washington, Oregon, Idaho, Utah, Colorado, and the Grand Canyon during the summer of 2004 to quantify whitewater raft guiding characteristics and incidence of back pain. RESULTS: Of the 390 surveys returned, 77.4% of guides reported back pain while guiding and 20.8% had back pain lasting longer than 1 week at the time of the survey. Stacking 5 or more inflated boats for transport was correlated with the presence of pain (chi(2) = 8.4, v = 1, P < .01), and loading and unloading rafts while guests are waiting was correlated with back pain lasting longer than 1 week (chi(2) = 8.1, v = 1, P < .01). CONCLUSIONS: The rates of back pain among, and activities of, whitewater rafting guides were reported. Rates of back pain among whitewater rafting guides who returned our survey appear similar to the general population. Although determining a particular cause of pain is difficult, the typical injury seems to be relatively minor in scope.

Clomethiazole: mechanisms underlying lasting neuroprotection following hypoxia-ischemia.

Damage after hypoxia-ischemia (HI) is observed in both cortical and subcortical regions. In this study, we employed a "Levine" rat model of HI (left carotid ligation + 1 h global hypoxia on PND-26) and used histological and electrophysiological paradigms to assess the long-term neuroprotective properties of clomethiazole (CMZ; a GABA(A) receptor modulator). Key enzymes involved in inflammation, namely nitric oxide synthase (NOS) and arginase, were also examined to assess potential CMZ mechanisms not involving GABA-R activation. Assessments were carried out 3 and 90 days post-HI. Extensive CNS lesions were evident after HI ipsilaterally at both short- and long-term intervals. CMZ significantly decreased the lesion size at 3 and 90 days (P<0.01; P<0.05). Evoked field potential analyses were used to assess hippocampal CA1 neuronal activity ex vivo. Electrophysiological measurements contralateral to the occlusion revealed impaired neuronal function after HI relative to short- and long-term controls (P<0.001, 3 and 14 days; P<0.01, 90 days), with CMZ treatment providing near complete protection (P<0.001 at 3 and 14 days; P<0.01 at 90 days). Both NOS and arginase activities were significantly increased at 3 days (P<0.01), with arginase remaining elevated at 90 days post-HI (P<0.05) ipsilaterally. CMZ suppressed the HI-induced increase in iNOS and arginase activities (P<0.001; P<0.05). These data provide evidence of long-term functional neuroprotection by CMZ in a model of HI. We further conclude that under conditions of HI, functional deficits are not restricted to the ipsilateral hemisphere and are due, at least in part, to changes in the activity of NOS and arginase.

Neuroprotective effects of spermine following hypoxic-ischemic-induced brain damage: a mechanistic study.

The polyamines (spermine, putrescine, and spermidine) can have neurotoxic or neuroprotective properties in models of neurodegeneration. However, assessment in a model of hypoxia-ischemia (HI) has not been defined. Furthermore, the putative mechanisms of neuroprotection have not been elucidated. Therefore, the present study examined the effects of the polyamines in a rat pup model of HI and determined effects on key enzymes involved in inflammation, namely, nitric oxide synthase (NOS) and arginase. In addition, effects on mitochondrial function were investigated. The polyamines or saline were administered i.p. at 10mg/kg/day for 6 days post-HI. Histological assessment 7 days post-HI revealed that only spermine significantly (P<0.01) reduced infarct size from 46.14 +/- 10.4 mm3 (HI + saline) to 4.9 +/- 2.7 mm3. NOS activity was significantly increased following spermine treatment in the left (ligated) hemisphere compared with nonintervention controls (P<0.01) and HI + saline (P<0.05). In contrast, spermine decreased arginase activity compared with HI + saline but was still significantly elevated in comparison to nonintervention controls (P<0.01). Assessment of mitochondrial function in the HI + saline group, revealed significant and extensive damage to complex-I (P<0.01) and IV (P<0.001) and loss of citrate synthase activity (P<0.05). No effect on complex II-III was observed. Spermine treatment significantly prevented all these effects. This study has therefore confirmed the neuroprotective effects of spermine in vivo. However, for the first time, we have shown that this effect may, in part, be due to increased NOS activity and preservation of mitochondrial function.

Oxygen free radical traps for the treatment of ischemia-associated organ injury.

Ischemia and reperfusion can induce an excess of free radicals that cannot be mopped-up by the body's endogenous defense mechanisms. This can lead to a breakdown in protein, lipid and DNA molecules, resulting in potentially irreversible organ damage. Radical traps are currently under development for the prevention of major damage in tissues such as the brain (after a stroke-like episode) and heart (after ischemia and reperfusion). While clinical studies are scant, many compounds have been developed and tested in the laboratory. Most radical traps are effective in a variety of preclinical models and one particular class, the nitrones (which includes NXY-059), has been studied intensively as potential neuroprotectants in acute ischemic stroke. NXY-059 is currently undergoing phase III clinical trials and will be the first compound to test the concept that radical traps may be effective and safe neuroprotectants in acute ischemic stroke.

Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059.

Stroke is a major clinical problem, and acute pharmacological intervention with neuroprotective agents has so far been unsuccessful. Recently, there has been considerable interest in the potential therapeutic benefit of nitrone-derived free radical trapping agents as neuroprotective agents. Nitrone compounds have been shown to be beneficial in animal models of various diseases, and the prototypic compound alpha-phenyl-N-tert-butylnitrone (PBN) has been extensively demonstrated to be neuroprotective in rat models of transient and permanent focal ischemia. The nitrone radical trapping agent disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) has also been shown to be neuroprotective in these models. Furthermore, it has recently been shown to improve neurological function and reduce infarct volume in a primate model of permanent focal ischemia even when given 4 hr postocclusion. While radical trapping activity is demonstrable with NXY-059 and other nitrone compounds such as PBN, this activity is weak. Arguments for and against ascribing radical trapping as the therapeutic mechanism of action are discussed. This compound is well tolerated in human stroke patients and can be administered to produce plasma concentrations exceeding those effective in animal models; crucially, at the same time, it has also been shown to be effective in animal models. NXY-059 may thus be the first compound to be examined in stroke patients using drug exposure and time to treatment that have been shown to be effective in animal models of stroke.

Neuroprotective effects of nitrone radical scavenger S-PBN on reperfusion nerve injury in rats.

The nitrone-based free radical scavengers have potent neuroprotective activities in models of stroke in which oxidative stress plays a key role in its development. We examined the effects of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide), a spin trap nitrone, on reperfusion injury in rat peripheral nerves. Immediately after the onset of 4-h ischaemia in rat right hindlimb, S-PBN was administered via mini-osmotic pumps, containing 2 ml of S-PBN (1.2 M), inserted subcutaneously. S-PBN, in addition, was given by a single injection (50 mg/kg BW, i.p.). Mean plasma concentrations of S-PBN were significantly greater in S-PBN-treated rats than in controls after 24, 48 and 72 h of reperfusion. Pump and dosing solution analysis indicated that the rats received between 82 and 99% of the target S-PBN concentration. Morphology in sciatic, tibial and peroneal nerves was assessed after 4 h of ischaemia followed by 72 h and 7 days of reperfusion. After 72 h of reperfusion, saline-treated control rats showed endoneurial oedema at the thigh level and diffuse axonal degeneration of myelinated nerve fibres distally. S-PBN-treated nerves were normal or revealed less severe abnormalities in myelinated fibres after 72 h and 7 days of reperfusion, when compared with those in saline-treated control nerves. Morphometrically, the frequency of abnormal myelinated fibres at calf levels was significantly less in S-PBN-treated nerves than in controls. In conclusion, post-ischaemic administration of S-PBN exhibits substantial neuroprotective properties in ischemia/reperfusion nerve injury.