The first suggestion that physical exercise results in free radical-mediated damage to tissues appeared in 1978, and the past three decades have resulted in a large growth of knowledge regarding exercise and oxidative stress. Although the sources of oxidant production during exercise continue to be debated, it is now well established that both resting and contracting skeletal muscles produce reactive oxygen species and reactive nitrogen species. Importantly, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Furthermore, oxidants can modulate a number of cell signaling pathways and regulate the expression of multiple genes in eukaryotic cells. This oxidant-mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant-modulated genes have been identified and include antioxidant enzymes, stress proteins, DNA repair proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species promote contractile dysfunction resulting in muscle weakness and fatigue. Ongoing research continues to probe the mechanisms by which oxidants influence skeletal muscle contractile properties and to explore interventions capable of protecting muscle from oxidant-mediated dysfunction.

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Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production

Biomedical applications of polymer-composite materials: a review

The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer.

Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

In the past five years, skeletal muscle has emerged as a paradigm of “nitric oxide” (NO) function and redox-related signaling in biology. All major nitric oxide synthase (NOS) isoforms, including a muscle-specific splice variant of neuronal-type (n) NOS, are expressed in skeletal muscles of all mammals. Expression and localization of NOS isoforms are dependent on age and developmental stage, innervation and activity, history of exposure to cytokines and growth factors, and muscle fiber type and species. nNOS in particular may show a fast-twitch muscle predominance. Muscle NOS localization and activity are regulated by a number of protein-protein interactions and co- and/or posttranslational modifications. Subcellular compartmentalization of the NOSs enables distinct functions that are mediated by increases in cGMP and byS-nitrosylation of proteins such as the ryanodine receptor-calcium release channel. Skeletal muscle functions regulated by NO or related molecules include force production (excitation-cont...

Physiology of Nitric Oxide in Skeletal Muscle

Reperfusion injury, the paradoxical tissue response that is manifested by blood flow-deprived and oxygen-starved organs following the restoration of blood flow and tissue oxygenation, has been a focus of basic and clinical research for over 4-decades. While a variety of molecular mechanisms have been proposed to explain this phenomenon, excess production of reactive oxygen species (ROS) continues to receive much attention as a critical factor in the genesis of reperfusion injury. As a consequence, considerable effort has been devoted to identifying the dominant cellular and enzymatic sources of excess ROS production following ischemia-reperfusion (I/R). Of the potential ROS sources described to date, xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase have gained a status as the most likely contributors to reperfusion-induced oxidative stress and represent priority targets for therapeutic intervention against reperfusion-induced organ dysfunction and tissue damage. Although all four enzymatic sources are present in most tissues and are likely to play some role in reperfusion injury, priority and emphasis has been given to specific ROS sources that are enriched in certain tissues, such as xanthine oxidase in the gastrointestinal tract and mitochondria in the metabolically active heart and brain. The possibility that multiple ROS sources contribute to reperfusion injury in most tissues is supported by evidence demonstrating that redox-signaling enables ROS produced by one enzymatic source (e.g., Nox) to activate and enhance ROS production by a second source (e.g., mitochondria). This review provides a synopsis of the evidence implicating ROS in reperfusion injury, the clinical implications of this phenomenon, and summarizes current understanding of the four most frequently invoked enzymatic sources of ROS production in post-ischemic tissue.

Reperfusion injury and reactive oxygen species: The evolution of a concept.

To define the role of two-portal endoscopic carpal-tunnel release as a method for the treatment of compression of the median nerve at the wrist, a prospective, randomized, multicenter study was performed on 169 hands in 145 patients. Either open or endoscopic carpal-tunnel release was performed in all of the patients who had clinical signs and symptoms consistent with carpal tunnel syndrome, had not responded to or had refused non-operative management, and had had electrodiagnostic studies consistent with carpal tunnel syndrome. Follow-up evaluations were performed at twenty-one, forty-two, and eighty-four days. At the end of the follow-up period, both the open and endoscopic methods had resulted in high levels of achievement of the primary outcomes (relief of pain and paresthesias). The numbness and paresthesias were relieved in eighty (98 per cent) of eighty-two hands in the open-release group compared with seventy-seven (99 per cent) of seventy-eight hands in the endoscopic-release group. This parameter was not recorded for three hands in the open-release group or six hands in the endoscopic-release group. The satisfaction of the patients with the procedure, graded on a scale of 0 to 100 per cent, averaged 84 per cent in the open-release group compared with 89 per cent in the group that had had endoscopic release. We found no significant differences between the two groups with regard to the secondary quantitative-outcome measurements, including two-point discrimination, postoperative interstitial-pressure data for the carpal canal, Semmes-Weinstein monofilament testing, and motor strength. The open technique resulted in more tenderness of the scar than did the endoscopic method. Thirty-two (39 per cent) of eighty-two hands in the open-release group and fifty (64 per cent) of seventy-eight hands in the endoscopic-release group were not tender at eighty-four days. This parameter was not recorded for three hands in the open-release group and six hands in the endoscopic-release group. The open method also resulted in a longer interval until the patient could return to work (median, twenty-eight days, compared with fourteen days for the open-release and endoscopic-release groups). Four complications occurred in the endoscopic carpal-tunnel release group: one partial transection of the superficial palmar arch, one digital-nerve contusion, one ulnar-nerve neuropraxia, and one wound hematoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Carpal tunnel release : a prospective, randomized assessment of open and endoscopic methods

The results for 103 consecutive hips (eighty-nine patients) that had been treated with free vascularized fibular grafting because of symptomatic osteonecrosis of the femoral head were reviewed in a prospective study. The disease was associated with consumption of alcohol in 30 percent of the hips, use of steroids in 17 percent, trauma in 13 percent, and Perthes disease in 3 percent; in the remaining 38 percent, the condition was idiopathic. All patients, except for one who died of unrelated causes 4.5 years after the operation, were followed for at least five years. By the time of the most recent follow-up evaluation, a total arthroplasty had been performed in thirty-one hips: two of the nineteen that were in stage II, according to the criteria of Marcus et al., at the time of the operation; five (23 percent) of the twenty-two that were in stage III; seventeen (43 percent) of the forty that were in stage IV; and seven (32 percent) of the twenty-two that were in stage V. Kaplan-Meier survivorship analyses demonstrated that the probability of conversion to a total hip arthroplasty within five years after free vascularized fibular grafting was 11 percent for the stage-II hips, 23 percent for the stage-III hips, 29 percent for the stage-IV hips, and 27 percent for the stage-V hips. There was a trend toward a lower rate of conversion to a total hip arthroplasty in patients who were less than thirty years old, but this difference did not reach significance (p = 0.06). No association was found between a causative factor and the probability of conversion to a total hip arthroplasty. The average Harris hip scores had improved at the latest follow-up evaluation, compared with the preoperative values (p < 0.001). For the stage-II hips, the average score improved from 56 to 80 points; for the stage-III hips, from 52 to 85 points; for the stage-IV hips, from 41 to 76 points; and for the stage-V hips, from 36 to 75 points. An outcome questionnaire, completed for 73 percent of the hips, revealed that 59 per cent of the hips that had not been subsequently treated with an arthroplasty did not limit or only slightly limited the patient's ability to carry out daily activities, and 62 percent did not limit or only slightly limited the patient's ability to work.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of osteonecrosis of the femoral head with free vascularized fibular grafting

Treatment of osteonecrosis of the femoral head with free vascularized fibular grafting. A long-term follow-up study of one hundred and three hips.

One hundred and ninety-eight consecutive patients (247 vascularized fibular grafts) were studied to determine the prevalence of morbidity at the donor site after the grafts had been obtained. Objective motor weakness, subjective discomfort in the ankle and other sites in the leg, and sensory abnormalities in the lower limb (or limbs) from which the graft had been obtained were recorded. The average duration of follow-up was forty-seven months (range, twenty-four to 144 months). Kaplan-Meier analysis was used to estimate the prevalence of each finding for the entire cohort over time. Forty-seven (19.0 per cent) of the 247 lower limbs had at least one of the findings, and eighteen(24.3 percent) of the seventy-four limbs for which data were available at five years or more had findings at that time. Twenty-five (10.1 per cent) of the 247 limbs had evidence of motor weakness at three months postoperatively, although no limb had this finding subsequently. At five years or more postoperatively, the prevalence had decreased to two (2.7 per cent) of the seventy-four limbs. Twelve (4.9 per cent) of the 247 limbs had sensory deficits at three months; this increased to 11.8 per cent (95 per cent confidence interval, 7.7 to 17.7 per cent), according to the Kaplan-Meier analysis, at five years. Pain at sites other than the ankle was noted in nine (3.6 per cent) of the 247 limbs at three months and in 8.9 per cent (95 per cent confidence interval, 5.5 to 14.1 per cent), according to the Kaplan-Meier analysis, at five years. The prevalence of pain in the ankle also increased with time, from four (1.6 per cent) of the 247 limbs at three months to 11.5 per cent (95 per cent confidence interval, 7.4 to 17.6 per cent), according to the Kaplan-Meier analysis, at five years. Removal of a vascularized portion of the fibula is associated with a low prevalence of motor weakness and sensory deficits in the foot. The prevalence of pain in the ankle and lower limb increases with time, with some patients having a late onset of the symptoms. While free vascularized fibular grafts remain ideal for many applications, the morbidity must be weighed against the benefits.

Donor-site morbidity with use of vascularized autogenous fibular grafts

Avascular necrosis of the femoral head is a multifaceted process that leads to articular incongruity and subsequent osteoarthrosis of the joint. Clinicians concur that primary treatment should focus on preservation of the natural surface of the joint; however, there has not been a consensus on how best to accomplish this. While a number of therapeutic interventions have been reported, the efficacy has varied markedly and there have been few statistical comparisons. The purpose of the current study was to use statistical analysis to compare the results of two widely used procedures, vascularized fibular grafting (614 hips; 480 patients) and core decompression (ninety-eight hips; seventy-two patients), for the treatment of avascular necrosis. The patients were stratified according to age and the stage of disease, and a survival analysis was performed with total hip arthroplasty as the end point for failure. None of the eleven hips that had Ficat stage-I disease needed a total joint replacement after being treated with either regimen. Analysis of the hips that had stage-II disease revealed rates of survival, at fifty months, of 65 per cent (twenty-eight of forty-three hips) after core decompression and 89 per cent (ninety-nine of 111 hips) after vascularized fibular grafting. For the hips that had Ficat stage-III disease, the rates of survival at fifty months were 21 per cent (ten of forty-seven hips) after core decompression and 81 per cent (405 of 500 hips) after vascularized fibular grafting. Among the hips that had Ficat stage-II or III disease, the rate of eventual total joint arthroplasty after vascularized fibular grafting was significantly lower than that after core decompression (p < 0.0001). The results indicate that the increased morbidity associated with vascularized fibular grafting is justified by the associated delay in or prevention of articular collapse in hips that have stage-II or III disease.

James R. Urbaniak

Papers

Carpal tunnel release : a prospective, randomized assessment of open and endoscopic methods

Treatment of osteonecrosis of the femoral head with free vascularized fibular grafting

Treatment of osteonecrosis of the femoral head with free vascularized fibular grafting. A long-term follow-up study of one hundred and three hips.

Donor-site morbidity with use of vascularized autogenous fibular grafts

Survival analysis of hips treated with core decompression or vascularized fibular grafting because of Avascular necrosis