The surgical treatment of brachial plexus injuries in adults

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Evaluate clinically a patient with brachial plexus paralysis and define the appropriate electrophysiologic and radiographic studies. 2. Differentiate between preganglionic (root) avulsion and postganglionic lesions and identify appropriate motor donors and nerve grafts. 3. Describe various nerve reconstructive strategies and make appropriate selection of secondary procedures for shoulder stability, elbow flexion, and hand reanimation. 4. Anticipate the possible functional outcome.     

cAMP regulates respiration and oxidative stress during rehydration in Anabaena sp. PCC 7120

Cellular cAMP level increased dramatically upon rehydration following dehydration for 24h in Anabaena sp. PCC 7120, but not in disruptant of an adenylate cyclase gene, cyaC. Oxygen consumption in the cyaC disruptant upon rehydration was higher than that in wild-type strain. Determination of lipid peroxidation and protein carbonylation of the cells revealed greater oxidative stress in the cyaC disruptant than in the wild-type strain during rehydration. Addition of cAMP or KCN to the cyaC disruptant decreased cellular oxygen consumption upon rehydration and oxidative damage. These results suggest that respiration upon rehydration is regulated by cAMP and that the higher respiration activity results in more oxidative damage in cyaC disruptant.     

Effects of soccer matches on neutrophil and lymphocyte functions in female university soccer players

In this study, changes in physical fatigue and biological functions of Japanese female soccer players were investigated by determining changes in neutrophil and lymphocyte functions. Study subjects included 18 female soccer players. Body composition, serum myogenic enzymes, neutrophil function, including reactive oxygen species (ROS) production capability, phagocytic activity (PA) and serum opsonic activity, as well as lymphocyte subpopulation were measured before and after a soccer match. Levels of myogenic enzymes (AST, ALT, CK and LDH) and immunoglobulins (IgG and IgA) and complements (C3) increased significantly after the match. In addition, leukocyte, neutrophils and lymphocyte counts increased whereas total PA decreased significantly. The number of T and Th1 cells (subsets of T helper cells) decreased whereas Th2 increased significantly. In addition, the number of B cells increased and NK cells decreased significantly after the match. The match was found to result in degenerative changes in and damage to athlete muscle tissues together with damage‐ and change‐mediated stress. These data also suggest a post‐match accelerated inflammatory reaction and potential immunosuppression as indicated by reductions in neutrophil PA and lymphocyte functions. Copyright © 2012 John Wiley & Sons, Ltd.     

Neutrophils from Brazilian patients with Graves' disease: some biochemical and functional aspects

Graves' disease shows important systemic inflammatory complications and has been considered to be systemic autoimmune thyroid, skeletal muscle and connective tissue syndrome. Neutrophils participate in the pathophysiology of the two major immune and inflammatory manifestations of the disease, ophthalmopathy and myxedema, and may worsen the inflammatory picture. In this study we analysed some biochemical and functional aspects of neutrophils in Graves' disease patients to assess their participation in these processes. The results show that the complement and/or Fcgamma receptor-mediated oxygen radical production by neutrophils was increased when patient cells were compared with controls. However the percentage of cells expressing complement and IgG receptors and the per-cell fluorescence, were similar, indicating that the increased oxidative burst was not due to an abnormal expression of mediating receptors. The production of hydrogen peroxide was also increased in hyperthyroid patient neutrophils as compared to controls. Conversely, antioxidant defences (superoxide dismutase activity and reduced glutathione content) in neutrophils from patients were not significantly different from healthy controls. The liberation of potent oxidative compounds together with the absence of adequate quenching of them by antioxidant mechanisms could be responsible for greater tissue damage in inflammatory conditions, as is the case in ophthalmopathy and myxedema patients. Considering our results and those of other workers, we encourage and suggest an associated antioxidant therapy to complement the conventional anti-thyroid therapy, especially in obvious inflammatory cases and in individuals who smoke.     

Reactive Oxygen Species and Human Inflammatory Periodontal Diseases

Reactive oxygen species (ROS) have emerged as important signaling molecules in the regulation of various cellular processes. They can be generated by the mitochondrial electron transport chain in mitochondria and activation of polymorphonuclear leukocytes (PMN) during inflammatory conditions. Excessive generation of ROS may result in attack of and damage to most intracellular and extracellular components in a living organism. Moreover, ROS can directly induce and/or regulate apoptotic and necrotic cell death. Periodontal pathologies are inflammatory and degenerative diseases. Several forms of periodontal diseases are associated with activated PMN. Damage of tissues in inflammatory periodontal pathologies can be mediated by ROS resulting from the physiological activity of PMN during the phagocytosis of periodontopathic bacteria.__________Translated from Biokhimiya, Vol. 70, No. 6, 2005, pp. 751–761.Original Russian Text Copyright © 2005 by Canakci, Cicek, Canakci.     

Taxifolin ameliorates cerebral ischemia-reperfusion injury in rats through its anti-oxidative effect and modulation of NF-kappa B activation

Summary Infarction in adult rat brain was induced by middle cerebral arterial occlusion (MCAO) followed by reperfusion to examine whether taxifolin could reduce cerebral ischemic reperfusion (CI/R) injury. Taxifolin administration (0.1 and 1.0 μg/kg, i.v.) 60 min after MCAO ameliorated infarction (by 42%±7% and 62%±6%, respectively), which was accompanied by a dramatic reduction in malondialdehyde and nitrotyrosine adduct formation, two markers for oxidative tissue damage. Overproduction of reactive oxygen species (ROS) and nitric oxide (NO) via oxidative enzymes (e.g., COX-2 and iNOS) was responsible for this oxidative damage. Taxifolin inhibited leukocyte infiltration, and COX-2 and iNOS expressions in CI/R-injured brain. Taxifolin also prevented Mac-1 and ICAM-1 expression, two key counter-receptors involved in firm adhesion/transmigration of leukocytes to the endothelium, which partially accounted for the limited leukocyte infiltration. ROS, generated by leukocytes and microglial cells, activated nuclear factor-kappa B (NF-κB) that in turn signaled up-regulation of inflammatory proteins. NF-κB activity in CI/R was enhanced 2.5-fold over that of sham group and was inhibited by taxifolin. Production of both ROS and NO by leukocytes and microglial cells was significantly antagonized by taxifolin. These data suggest that amelioration of CI/R injury by taxifolin may be attributed to its anti-oxidative effect, which in turn modulates NF-κB activation that mediates CI/R injury. Yea-Hwey Wang, Wen-Yen Wang, Chia-Che Chang, and Kuo-Tong Liou contributed equally to this work.     

Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons

Generation of reactive oxygen species (ROS) with the accumulation of oxidative damage has been implicated in neurodegenerative disease and in the degradation of nervous system function with age. Here we report that ROS inhibit the activity of ciliary neurotrophic factor (CNTF) in nerve cells. Treatment with hydrogen peroxide (H(2)O(2)) as a generator of ROS inhibited CNTF-mediated Jak/STAT signaling in all cultured nerve cells tested, including chick ciliary ganglion neurons, chick neural retina, HMN-1 motor neuron hybrid cells, and SH-SY5Y and BE(2)-C human neuroblastoma cells. H(2)O(2) treatment of non-neuronal cells, chick skeletal muscle and HepG2 hepatoma cells, did not inhibit Jak/STAT signaling. The H(2)O(2) block of CNTF activity was seen at concentrations as low as 0.1 mm and within 15 min, and was reversible upon removal of H(2)O(2) from the medium. Also, two other mediators of oxidative stress, nitric oxide and rotenone, inhibited CNTF signaling. Treatment of neurons with H(2)O(2) and rotenone also inhibited interferon-gamma-mediated activation of Jak/STAT1. Depleting the intracellular stores of reduced glutathione by treatment of BE(2)-C cells with nitrofurantoin inhibited CNTF activity, whereas addition of reduced glutathione protected cells from the effects of H(2)O(2). These results suggest that disruption of neurotrophic factor signaling by mediators of oxidative stress may contribute to the neuronal damage observed in neurodegenerative diseases and significantly affect the utility of CNTF-like factors as therapeutic agents in preventing nerve cell death.     

Diagnostic accuracy of the neurological upper limb examination I: Inter-rater reproducibility of selected findings and patterns

Background

Recent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for production of prostanoids, which may sensitise sensory neurones via the EP1 receptor. We have recently reported that while macrophages infiltrate injured nerves within days of injury, they express increased Cox-2-immunoreactivity (Cox-2-IR) from 2 to 3 weeks after injury. We have now investigated the time course of EP1 and Cox-2 changes in injured human nerves and dorsal root ganglia (DRG), and the chronic constriction nerve injury (CCI) model in the rat.

Methods

Tissue sections were immunostained with specific antibodies to EP1, Cox-2, CD68 (human macrophage marker) or OX42 (rat microglial marker), and neurofilaments (NF), prior to image analysis, from the following: human brachial plexus nerves (21 to 196 days post-injury), painful neuromas (9 days to 12 years post-injury), avulsion injured DRG, control nerves and DRG, and rat CCI model tissues. EP1 and NF-immunoreactive nerve fibres were quantified by image analysis.

Results

EP1:NF ratio was significantly increased in human brachial plexus nerve fibres, both proximal and distal to injury, in comparison with uninjured nerves. Sensory neurones in injured human DRG showed a significant acute increase of EP1-IR intensity. While there was a rapid increase in EP1-fibres and CD-68 positive macrophages, Cox-2 increase was apparent later, but was persistent in human painful neuromas for years. A similar time-course of changes was found in the rat CCI model with the above markers, both in the injured nerves and ipsilateral dorsal spinal cord.

Conclusion

Different stages of infiltration and activation of macrophages may be observed in the peripheral and central nervous system following peripheral nerve injury. EP1 receptor level increase in sensory neurones, and macrophage infiltration, appears to precede increased Cox-2 expression by macrophages. However, other methods for detecting Cox-2 levels and activity are required. EP1 antagonists may show therapeutic effects in acute and chronic neuropathic pain, in addition to inflammatory pain.     

Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis

The mechanisms for motor neuron degeneration and regeneration in adult spinal cord following axotomy and target deprivation are not fully understood. We used a unilateral sciatic nerve avulsion model in adult rats to test the hypothesis that retrograde degeneration of motor neurons resembles apoptosis. By 21 days postlesion, the number of large motor neurons in lumbar spinal cord was reduced by ∼30%. The death of motor neurons was confirmed using the terminal transferase‐mediated deoxyuridine triphosphate‐biotin nick‐end labeling method for detecting fragmentation of nuclear DNA. Motor neuron degeneration was characterized by aberrant accumulation of perikaryal phosphorylated neurofilaments. Structurally, motor neuron death was apoptosis. Apoptotic motor neurons undergo chromatolysis followed by progressive cytoplasmic and nuclear condensation with chromatin compaction into uniformly large round clumps. Prior to apoptosis, functionally active mitochondria accumulate within chromatolytic motor neurons, as determined by cytochrome c oxidase activity. These dying motor neurons sustain oxidative damage to proteins and nucleic acids within the first 7 days after injury during the progression of apoptosis, as identified by immunodetection of nitrotyrosine and hydroxyl‐modified deoxyguanosine and guanosine. We conclude that the retrograde death of motor neurons in the adult spinal cord after sciatic nerve avulsion is apoptosis. Accumulation of active mitochondria within the perikaryon and oxidative damage to nucleic acids and proteins may contribute to the mechanisms for apoptosis of motor neurons in the adult spinal cord. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 185–201, 1999     

Platelet-activating factor receptor knockout mice are protected from MPTP-induced dopaminergic degeneration

Platelet-activating factor (PAF), a potent mediator of inflammatory and immune responses, plays various roles in neuronal functions. However, little is known about the role of PAF/platelet-activating factor receptor (PAF-R) in Parkinson’s disease. Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in significant increases in PAF species in the striatum of wild-type mice. These increases paralleled PAF-R gene expression in wild-type mice. Although nuclear factor kappa B (NF-κB) DNA-binding activity was increased significantly in MPTP-treated wild-type mice, this increase was not significant in PAF-R antagonist ginkgolide B (GB)-treated mice or PAF-R knockout (PAF-R^−/−) mice. Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, significantly ameliorated the dopaminergic deficits induced by MPTP in wild-type mice. MPTP treatment significantly increased oxidative damage, the immunoreactivity of ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglial cells, and microglial differentiation of the M1 type in the striatum of wild-type mice. Consistently, PDTC significantly attenuated MPTP-induced behavioral impairments in wild-type mice. However, dopaminergic deficits, oxidative damage, reactive microglial cells, and behavioral impairments induced by MPTP were not significantly observed in GB-treated mice or PAF-R^−/− mice. PDTC did not significantly alter the attenuations evident in MPTP-treated PAF-R^−/− mice, indicating that NF-κB is a critical target for neurotoxic modulation of PAF-R. We propose for the first time that PAF/PAF-R can mediate dopaminergic degeneration via an NF-κB-dependent signaling process.     

Effect of Semecarpus anacardium Linn. nut milk extract on rat neutrophil functions in adjuvant arthritis

Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA) and various inflammatory conditions, by accumulation and liberation of active proteolytic enzymes. The effect of milk extract of Semecarpus anacardium Linn. nuts (SA) at a dosage of 150 mg kg(-1) body weight day(-1) for 14 days on adjuvant arthritis was studied to gain some insight into this intriguing disease in relation to neutrophil functions. The decreased phagocytic function of neutrophils (phagocytic index and avidity index) found in adjuvant arthritis was significantly increased by the administration of the drug SA. Increased levels of reactive oxygen species (superoxide radical, hydroxyl radical, H2O2 and myeloperoxidase), lysosomal enzymes (acid phosphatase and cathepsin D) and increased accumulation of neutrophils in the joints observed in adjuvant arthritic animals were reverted back to near normal levels by treatment with SA. The results of this study indicate that SA can be considered to be a good therapeutic agent for inflammation and arthritis.     

Oxidative stress in cerebral small vessel disease. Role of reactive species

Cerebral small vessel disease (CSVD) is a wide term describing the condition affecting perforating arterial branches as well as arterioles, venules, and capillaries. Cerebral vascular net is one of the main targets of localised oxidative stress processes causing damage to vasculature, changes in the blood flow and blood–brain barrier and, in consequence, promoting neurodegenerative alterations in the brain tissue. Numerous studies report the fact of oxidation to proteins, sugars, lipids and nucleic acids, occurring in most neurodegenerative diseases mainly in the earliest stages and correlations with the development of cognitive and motor disturbances. The dysfunction of endothelium can be caused by oxidative stress and inflammatory mechanisms as a result of reactions and processes generating extensive reactive oxygen species (ROS) production such as high blood pressure, oxidised low density lipoproteins (oxLDL), very low density lipoproteins (vLDL), diabetes, homocysteinaemia, smoking, and infections. Several animal studies show positive aspects of ROS, especially within cerebral vasculature.     

Down-regulation of aldose reductase renders J774A.1 cells more susceptible to acrolein- or hydrogen peroxide-induced cell death

Aldose reductase (AR) is abundantly expressed in a variety of cell lineages and has been implicated in the cellular response against oxidative stress. However, the exact functional role of AR against oxidative stress remains relatively unclear. This study investigated the role of AR in acrolein- or hydrogen peroxide-induced apoptosis using the J774.A.1 macrophage cell line. Ablation of AR with a small interference RNA or inhibition of AR activity significantly enhanced the acrolein- or hydrogen peroxide-induced generation of reactive oxygen species and aldehydes, leading to increased apoptotic cell death. Blockade of AR activity in J774A.1 cells markedly augmented the acrolein- or hydrogen peroxide-induced translocation of Bax to mitochondria along with reduced Bcl-2 and increased release of cytochrome c from the mitochodria. Taken together, these findings indicate that AR plays an important role in the cellular response against oxidative stress, by sequestering the reactive molecules generated in cells exposed to toxic substances.     

Soluble Nogo Receptor Down-regulates Expression of Neuronal Nogo-A to Enhance Axonal Regeneration

Nogo-A, a member of the reticulon family, is present in neurons and oligodendrocytes. Nogo-A in central nervous system (CNS) myelin prevents axonal regeneration through interaction with Nogo receptor 1, but the function of Nogo-A in neurons is less known. We found that after axonal injury, Nogo-A is increased in dorsal root ganglion (DRG) neurons unable to regenerate following a dorsal root injury or a sciatic nerve ligation-cut injury and that exposure in vitro to CNS myelin dramatically enhanced neuronal Nogo-A mRNA and protein through activation of RhoA while inhibiting neurite growth. Knocking down neuronal Nogo-A by small interfering RNA results in a marked increase of neurite outgrowth. We constructed a nonreplicating herpes simplex virus vector (QHNgSR) to express a truncated soluble fragment of Nogo receptor 1 (NgSR). NgSR released from QHNgSR prevented myelin inhibition of neurite extension by hippocampal and DRG neurons in vitro. NgSR prevents RhoA activation by myelin and decreases neuronal Nogo-A. Subcutaneous inoculation of QHNgSR to transduce DRG neurons resulted in improved regeneration of myelinated fibers in both the dorsal root and the spinal dorsal root entry zone, with concomitant improvement in sensory behavior. The results indicate that neuronal Nogo-A is an important intermediate in neurite growth dynamics and its expression is regulated by signals related to axonal injury and regeneration, that CNS myelin appears to activate signaling events that mimic axonal injury, and that NgSR released from QHNgSR may be used to improve recovery after injury.     

Pro-inflammatory and pro-oxidant properties of the HIV protein Tat in a microglial cell line: attenuation by 17 beta-estradiol

Microglia are activated in humans following infection with human immunodeficiency virus (HIV), and brain inflammation is thought to be involved in neuronal injury and dysfunction during HIV infection. Numerous studies indicate a role for the HIV regulatory protein Tat in HIV-related inflammatory and neurodegenerative processes, although the specific effects of Tat on microglial activation, and the signal transduction mechanisms thereof, have not been elucidated. In the present study, we document the effects of Tat on microglial activation and characterize the signal transduction pathways responsible for Tat's pro-inflammatory effects. Application of Tat to N9 microglial cells increased multiple parameters of microglial activation, including superoxide production, phagocytosis, nitric oxide release and TNF alpha release. Tat also caused activation of both p42/p44 mitogen activated protein kinase (MAPK) and NF kappa B pathways. Inhibitor studies revealed that Tat-induced NF kappa B activation was responsible for increased nitrite release, while MAPK activation mediated superoxide release, TNF alpha release, and phagocytosis. Lastly, pre-treatment of microglial cells with physiological concentrations of 17 beta-estradiol suppressed Tat-mediated microglial activation by interfering with Tat-induced MAPK activation. Together, these data elucidate specific components of the microglial response to Tat and suggest that Tat could contribute to the neuropathology associated with HIV infection through microglial promulgation of oxidative stress.     

Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression

Reactive oxygen species (ROS) and subsequent oxidative damage may contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. ROS initiate lesion formation by inducing blood–brain barrier disruption, enhance leukocyte migration and myelin phagocytosis, and contribute to lesion persistence by mediating cellular damage to essential biological macromolecules of vulnerable CNS cells. Relatively little is known about which CNS cell types are affected by oxidative injury in MS lesions. Here, we show the presence of extensive oxidative damage to proteins, lipids, and nucleotides occurring in active demyelinating MS lesions, predominantly in reactive astrocytes and myelin-laden macrophages. Oxidative stress can be counteracted by endogenous antioxidant enzymes that confer protection against oxidative damage. Here, we show that antioxidant enzymes, including superoxide dismutase 1 and 2, catalase, and heme oxygenase 1, are markedly upregulated in active demyelinating MS lesions compared to normal-appearing white matter and white matter tissue from nonneurological control brains. Particularly, hypertrophic astrocytes and myelin-laden macrophages expressed an array of antioxidant enzymes. Enhanced antioxidant enzyme production in inflammatory MS lesions may reflect an adaptive defense mechanism to reduce ROS-induced cellular damage.     

Insulin resistance and diabetes in hyperthyroidism: a possible role for oxygen and nitrogen reactive species

In addition to insulin, glycemic control involves thyroid hormones. However, an excess of thyroid hormone can disturb the blood glucose equilibrium, leading to alterations of carbohydrate metabolism and, eventually, diabetes. Indeed, experimental and clinical hyperthyroidism is often accompanied by abnormal glucose tolerance. A common characteristic of hyperthyroidism and type 2 diabetes is the altered mitochondrial efficiency caused by the enhanced production of reactive oxygen and nitrogen species. It is known that an excess of thyroid hormone leads to increased oxidant production and mitochondrial oxidative damage. It can be hypothesised that these species represent the link between hyperthyroidism and development of insulin resistance and diabetes, even though direct evidence of this relationship is lacking. In this review, we examine the literature concerning the effects of insulin and thyroid hormones on glucose metabolism and discuss alterations of glucose metabolism in hyperthyroid conditions and the cellular and molecular mechanisms that may underline them.     

Levels of oxidative damage and proinflammatory cytokines are enhanced in patients with active vitiligo

Vitiligo is an autoimmune depigmenting skin disease characterised by loss of melanocytes wherein oxidative stress is proposed to be the initial triggering factor with subsequent immune dysregulation. This study aimed to evaluate the relationship, if any, between the generation of reactive oxygen species (ROS), markers of oxidative damage and circulating cytokines in patients with active vitiligo. The generation of ROS in erythrocytes and neutrophils was significantly higher in patients with active vitiligo than healthy controls. Alongside, markers of oxidative stress-mediated damage namely lipid peroxidation, DNA damage and protein carbonylation were evaluated. Patients with active vitiligo demonstrated increased lipid and DNA damage but minimal protein damage. There was a significant decline in the free radical scavenging capacity of active vitiligo cases. A positive correlation existed between baseline levels of ROS and lipid peroxidation as also DNA damage. Patients with active vitiligo demonstrated an increase in several proinflammatory (IL-6, TNF-α, IL-1β, IFN-γ and IL-8) and some anti-inflammatory/immunoregulatory (IL-5 and IL-10) cytokines. Importantly, the levels of IFN-γ and IL-10 consistently correlated with the generation of ROS, markers of damage and their free radical scavenging capacity. Taken together, patients with active vitiligo demonstrated an enhanced generation of ROS in erythrocytes and neutrophils which mediated lipid peroxidation, DNA damage and coupled with a decline in their antioxidant capacity created a pro-oxidant milieu that favoured tissue damage and potential generation of neoantigens, accounting for disease progression.     

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis

Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor β-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)α pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-α treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBα signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBα pathway exhibited increased ROS production and TNF-α- or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.