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Spinal Cord Edema, 5-Hydroxytryptamine, Lipid Peroxidation, and Lysosomal Enzyme Release After Acute Contusion and Compression Injury in Primates
Abstract
Physical and biochemical changes in the spinal cord of monkeys at 1/2, 2, and 4 hours following 200 g cm contusion injury and 50 g of compression injury and 2 hours of decompression following 4 hours of compression were studied. The pathophysiologic changes were milder in compression compared to contusion injury. Following contusion injury, at 1/2 and 2 hours there was significant increase in % water content, lipid peroxidation, and alpha-L-fucosidase. alpha-D-Mannosidase was significantly increased at all time periods, and beta-D-hexosaminidase was increased at 1/2 and 4 hours. At 4 hours following injury, serotonin (5 HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) showed a significant increase. From 10 minutes to 2 hours there was increased platelet aggregation. In compression injury, a significant increase in water content and 5 HT was observed only at 1/2 hour. Lipid peroxidation had increased at all time periods, whereas B-D-hexosaminidase, beta-D-galactosidase, and 5-HIAA were increased at 2 hours. alpha-D-Mannosidase had increased at 1/2 and 2 hours, and alpha-L-fucosidase had increased at 4 hours. After 2 hours decompression following 4 hours compression, water content, beta-D-galactosidase, and alpha-D-Mannosidase were significantly increased. An attempt was made to correlate the findings and to understand the sequential pathophysiologic changes in the first 4 hours following spinal cord trauma, providing a baseline for evaluation of the efficacy of any therapeutic maneuvers.
... The autophagy-lysosome pathway may be a part of secondary injury processes of SCI [55]. Abraham et al. observed in an animal model an increase in NAGase upon contusion injury of spinal cord [56]. In addition, the values of contact angle observed for the films based on CSL AA and CSL GA with and without 10% LOADED nanofibers have been measured (Figure 12). ...
... The autophagy-lysosome pathway may be a part of secondary injury processes of SCI [55]. Abraham et al. observed in an animal model an increase in NAGase upon contusion injury of spinal cord [56]. In order to investigate whether the different salification of CS could affect the biodegradation of the formulation, both scaffolds, consisting of CSL AA and CSL GA films loaded with 10% LOADED nanofibers, have been placed in contact for 7 and 14 days with (i) PBS, (ii) H 2 O 2 1.25 mM in PBS, and (iii) β-N acetylglusosaminidase (NAGase) 5 U/L in PBS. ...
... The autophagy-lysosome pathway may be a part of secondary injury processes of SCI [55]. Abraham et al. observed in an animal model an increase in NAGase upon contusion injury of spinal cord [56]. Figure 13 reports weight loss % values (a) and SEM images (b) of CSL AA and CSL GA based scaffolds after soaking in PBS, H 2 O 2 1.25 mM in PBS and in β-N acetylglusosaminidase (NAGase) 5 U/L in PBS for 7 and 14 days at 37 • C. ...
The present work proposed a novel therapeutic platform with both neuroprotective and neuroregenerative potential to be used in the treatment of spinal cord injury (SCI). A dual-functioning scaffold for the delivery of the neuroprotective S1R agonist, RC-33, to be locally implanted at the site of SCI, was developed. RC-33-loaded fibers, containing alginate (ALG) and a mixture of two different grades of poly(ethylene oxide) (PEO), were prepared by electrospinning. After ionotropic cross-linking, fibers were incorporated in chitosan (CS) films to obtain a drug delivery system more flexible, easier to handle, and characterized by a controlled degradation rate. Dialysis equilibrium studies demonstrated that ALG was able to form an interaction product with the cationic RC-33 and to control RC-33 release in the physiological medium. Fibers loaded with RC-33 at the concentration corresponding to 10% of ALG maximum binding capacity were incorporated in films based on CS at two different molecular weights—low (CSL) and medium (CSM)—solubilized in acetic (AA) or glutamic (GA) acid. CSL- based scaffolds were subjected to a degradation test in order to investigate if the different CSL salification could affect the film behavior when in contact with media that mimic SCI environment. CSL AA exhibited a slower biodegradation and a good compatibility towards human neuroblastoma cell line.
... With respect to other subcortical substrates, there are few brainstem or spinal cord results on the acute effects of spinal cord injury in monkeys. Nonetheless, acute changes in neurochemistry and structure have been reported at the spinal and brainstem levels [21,54,55]. At the cellular level, acute SCI leads to immediate cell necrosis, lipid peroxidation, lysosomal enzyme release, and cell membrane damage [54]. ...
... Nonetheless, acute changes in neurochemistry and structure have been reported at the spinal and brainstem levels [21,54,55]. At the cellular level, acute SCI leads to immediate cell necrosis, lipid peroxidation, lysosomal enzyme release, and cell membrane damage [54]. ...
Spinal cord injury (SCI) has devastating physical and socioeconomical impact. However, some degree of functional recovery is frequently observed in patients after SCI. There is considerable evidence that functional plasticity occurs in cerebral cortical maps of the body, which may account for functional recovery after injury. Additionally, these plasticity changes also occur at multiple levels including the brainstem, spinal cord, and peripheral nervous system. Although the interaction of plasticity changes at each level has been less well studied, it is likely that changes in subcortical levels contribute to cortical reorganization. Since the permeability of the blood-brain barrier (BBB) is changed, SCI-induced factors, such as cytokines and growth factors, can be involved in the plasticity events, thus affecting the final functional recovery after SCI. The mechanism of plasticity probably differs depending on the time frame. The reorganization that is rapidly induced by acute injury is likely based on unmasking of latent synapses resulting from modulation of neurotransmitters, while the long-term changes after chronic injury involve changes of synaptic efficacy modulated by long-term potentiation and axonal regeneration and sprouting. The functional significance of neural plasticity after SCI remains unclear. It indicates that in some situations plasticity changes can result in functional improvement, while in other situations they may have harmful consequences. Thus, further understanding of the mechanisms of plasticity could lead to better ways of promoting useful reorganization and preventing undesirable consequences.
... Therefore it seems likely that the elevation of 5HT 7 receptor accumulation in the traumatized cord in treated animals with LP-211 may partly be responsible for some of the harmful effects of the drug. Furthermore, multiple studies have proposed that 5-HT contributes to the posttraumatic decline of blood flow and edema seen in injured spinal cords [80][81][82][83]. ...
The observed controversy that N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211), a selective serotonin (5-HT 7 ) receptor agonist, may either modify or exacerbate imbalances in serum electrolyte concentrations and renal tissue of spinal cord trauma cases has not been reported yet. The aim of this study was to better understand the effects of a new 5-HT 7 receptor agonist, LP-211, on serum electrolyte changes in spinal cord injured- (SCI) rats.
Methods
Sixty male rats were assigned to the following groups: A) Intact (saline as vehicle, 1 ml/kg, i.p.), B) Intact [LP-211, (0.003–0.3 mg/kg, i.p.)], C) Sham-operated [laminectomy + vehicle (1 ml/kg, i.p.)], D) Sham-operated [laminectomy + LP-211 (0.003–0.3 mg/kg, i.p.)], E) Treatment [laminectomy + spinal trauma (SCI) + vehicle (1 ml/kg, i.p.)], F) Treatment [laminectomy + spinal trauma + LP-211 (0.003–0.3 mg/kg, i.p.)]. SCI was performed by placing an aneurysm clip, extradurally at the level of T10. After two weeks, LP-211 was administered cumulatively and each dose was injected (i.p.) with 20 min interval. At the end of the experiment, blood samples were collected for biochemical evaluations of the electrolytes employing standard commercial kits.
Results
The present results indicate elevated serum levels of Na + , K + , and Mg 2+ in SCI rats and significant differences demonstrated between the groups [P < 0.001, F(5, 35) = 23.92], [P < 0.001, F(5, 35) = 67.63], [P < 0.001, F(5, 35) = 71.144], respectively. So that, in groups B, D and F, there was a significant increase in K + and Mg 2+ serum levels compared to the groups A, C, and E (P < 0.001). Furthermore, Na + serum levels in SCI (LP-211), laminectomy (LP-211), and intact (LP-211) groups tended to be statistically lower than SCI (saline), laminectomy (saline) and intact (saline) groups. Infact, hyponatremia, hyperkalemia and hypermagnesemia was obtained in group F. Nevertheless, in the remaining measured serum electrolytes such as calcium (Ca 2+ ), iron (Fe 2+ ) and phosphorus (P 3− ), chlorine (Cl − ), copper (Cu + ), and zinc (Zu + ), no significant changes were observed.
Conclusion
It was shown that acute additive LP-211 treatments in the SCI group led to hyponatremia, hyperkalemia and hypermagnesemia, it may be stated that LP-211 treatment as a promising candidate for treating SCI complications in some systems especially urinary tract might take into consideration and further studies would be needed to clarify its benefits or drawbacks. The observed discrepancies, nevertheless; will also pose new questions. Altogether, this will ultimately contribute to further understanding the pathophysiological role regarding 5-HT 7 receptor activation.
... 5-HT is released from neural elements at the injury site and is transiently taken up by platelets (48,49). It has been proposed that 5-HT contributes to post- traumatic decline of blood flow and edema in injured spinal cords (1,13,52). We recently found that spinal axons possess 5-HT receptors and suggested that 5-HT may have direct excitotoxic effect on spinal axons (50). ...
To determine the role of serotonin (5-HT) in recovery from spinal cord injury, we examined spinal cord 5-HT immunohistologically and assessed locomotor recovery after thoracic (T8) spinal cord hemisection in 68 rats. Forty eight rats had laminectomy and hemisection, while the remaining 20 rats received laminectomy only. All rats were evaluated every other day for 4 weeks, using a 0-14 point scale open field test. Hemisection markedly reduced mean hindlimbs scores from 14 to 1.5 +/- 0.32 and 5.6 +/- 0.31 (mean +/- standard error of mean) in the ipsilateral and contralateral side, respectively. The rats all recovered apparently normal walking by 4 weeks. The 5-HT immunohistological study revealed a marked reduction of 5-HT-containing terminals in the ipsilateral but not the contralateral lumbosacral cord by 1 week after hemisection. By 4 weeks after hemisection, 5-HT immunoreactive fibers and terminals returned to the ipsilateral lumbosacral cord, with many 5-HT fibers crossing over the central canal at thoracic level. We estimated the recovery of 5-HT neural elements in lumbosacral ventral horn by ranking 5-HT staining intensity and counting 5-HT terminals. The return of 5-HT immunoreactivity of the lumbosacral ventral horn correlated with locomotor recovery. Locomotory recovery invariably occurred when the density of 5-HT terminals approached 20% of control values. These results indicate that return of 5-HT fibers and terminals predict the time course and extent of locomotory recovery after thoracic spinal cord hemisection.
... On the other hand, 8-OH-DPAT increased refractory periods and should reduce ability of the axons to follow high frequency stimuli. Since high concentrations of 5-HT are released into the extracellular space of injured spinal cords 1,17,29,30,3132 and the 5-HT 1A depressive effects are more prominent than the 5-HT 2A excitatory effects, our results predict that injury-induced 5-HT release will depress axonal conduction in adult spinal cords but increase axonal excitability in neonatal cords. ...
We have recently shown both inhibitory and excitatory effects of serotonin on neonatal rat dorsal column axons. While neonatal rat dorsal column axons also respond to norepinephrine and GABA, adult rat dorsal columns are insensitive to the actions of both compounds. Therefore, we studied the effects of serotonin agonists on adult rat dorsal column axons using randomized double pulse stimuli at 0.2 Hz with random interpulse intervals of 3, 4, 5, 8, 10, 20, 30, 50 and 80 ms. The serotonin(1A) agonist, 8-hydroxy-dipropylaminotetralin-hydrobromide (8-OH-DPAT), significantly modulated test response amplitudes at 3, 4, 5 and 8 ms interpulse intervals by 29.6+/-4.0%, 17.4+/-2.1%, 9.6+/-2.3%, and 12.4+/-2.2% of conditioning pulse amplitudes, respectively. The mean latencies at 3, 4 and 5 ms interpulse intervals increased by 17.0+/-5.1%, 8.6+/-2.1%, and 5.1+/-1.4%, respectively (P<0.05). However, neither 10 microM 8-OH-DPAT nor 100 microM serotonin hydrochloride affected the compound action potentials evoked by conditioning or test pulses. In contrast, treatment with 100 microM quipazine dimaleate (a serotonin(2A) agonist) decreased the refractory period. While the response amplitudes to a 3-ms double pulse were reduced by 11.0+/-1.5% during the control period, the test response fell to only 2.4+/-1.8% of the conditioning response amplitudes after exposure to 100 microM quipazine. 8-OH-DPAT decreased the amplitude, prolonged the latency and increased the refractory periods of compound action potentials in the adult rat dorsal column, although a high concentration of the agonist (100 microM) was required for these effects. In contrast, the serotonin(2A) agonist, quipazine, decreased refractory periods. These results suggest that both serotonin(1A) and serotonin(2A) receptor subtypes are present on adult spinal dorsal column axons. Further, these receptors have opposing effects on axonal excitability, despite the fact that their sensitivities are relatively low.
Background:
Decompression of the injured spinal cord confers neuroprotection. Compared with timing of surgery, verification of surgical decompression is understudied.
Objective:
To compare the judgment of cervical spinal cord decompression using real-time intraoperative ultrasound (IOUS) following laminectomy with postoperative MRI and CT myelography.
Methods:
Fifty-one patients were retrospectively reviewed. Completeness of decompression was evaluated by real-time IOUS and compared with postoperative MRI (47 cases) and CT myelography (4 cases).
Results:
Five cases (9.8%) underwent additional laminectomy after initial IOUS evaluation to yield a final judgment of adequate decompression using IOUS in all 51 cases (100%). Postoperative MRI/CT myelography showed adequate decompression in 43 cases (84.31%). Six cases had insufficient bony decompression, of which 3 (50%) had cerebrospinal fluid effacement at >1 level. Two cases had severe circumferential intradural swelling despite adequate bony decompression. Between groups with and without adequate decompression on postoperative MRI/CT myelography, there were significant differences for American Spinal Injury Association motor score, American Spinal Injury Association Impairment Scale grade, AO Spine injury morphology, and intramedullary lesion length (IMLL). Multivariate analysis using stepwise variable selection and logistic regression showed that preoperative IMLL was the most significant predictor of inadequate decompression on postoperative imaging (P = .024).
Conclusion:
Patients with severe clinical injury and large IMLL were more likely to have inadequate decompression on postoperative MRI/CT myelography. IOUS can serve as a supplement to postoperative MRI/CT myelography for the assessment of spinal cord decompression. However, further investigation, additional surgeon experience, and anticipation of prolonged swelling after surgery are required.
Since the time of the Edwin Smith Papyrus (ca. 1700 B.C.), paraplegia has been considered one of the most depressing clinical states to manage and has consequently been a challenge to the basic research worker and the clinician (Collins 1983, Harris 1985).
The pathochemistry of acute spinal cord injury has been reviewed with special emphasis placed upon the inflammatory component of this response. The primary thesis of this review has been that vascular mediators of inflammation and hemostasis are activated by the injury and induce a number of pathophysiological responses in the circulation. The most notable of these responses include platelet activation, vasoconstriction, hypoperfusion, blood-brain barrier disruption, Chemotaxis and extravasation. This results in direct ischemic damage to neural tissue as well as a number of indirect effects in the CNS. These indirect effects develop as a result of an abnormal interaction between high levels of vascular-derived mediators with homologous CNS receptors subsequent to their leakage across a compromised blood-brain barrier. Evidence was presented for a role of platelet-derived serotonin in this process.
The axon, which is interposed between the cell body and the synaptic terminals in most neurons, plays a crucial role in connecting neurons and acting as a conduit for the transmission of information between them. Axons have always been a favorite site for investigation in neuroscience. Axonology has moved ahead rapidly more recently. Molecular biology has provided new tools for studying the molecules that make up the axon and their associated glial cells. Increasingly powerful physiological techniques, together with immunocytochemical and immuno-ultrastructural methods, have facilitated a molecular dissection of the channels, exchangers, and pumps that are responsible for the functional properties of axons. The role of calcium in axonal function is now better understood and the complex dialogue between axons and glial cells that are associated with them now yield scrutiny. Such advances have applied not only to normal axons but also to their abnormal counterparts. Thus, the molecular and cellular events triggered by trauma, demyelination, and axonal injury in axons are being delineated, as the response of axons—and the cell bodies from which they originate—to injuries is studied in many laboratories. This book discusses, in close juxtaposition, various aspects of both normal and diseased axons. The book takes a multiauthored approach to this task.
Experimental spinal cord injury.
To determine the role of serotonin (5-HT) and 5-HT transporter in recovery from spinal cord injury.
We examined 5-HT and 5-HT transporter of spinal cord immunohistologically and assessed locomotor recovery after extradural compression at the thoracic (T8) spinal cord in 21 rats. Eighteen rats had laminectomy and spinal cord injury, while the remaining three rats received laminectomy only. All rats were evaluated every other day for 4 weeks, using a 0-14 point scale open field test.
Extradural compression markedly reduced mean hindlimbs scores from 14 to 1.5 +/- 2.0 (mean +/- standard error of mean). The rats recovered apparently normal walking by 4 weeks. The animals were perfused with fixative 1-3 days, 1, 2 and 4 weeks (three rats in each) after a spinal cord injury. The 5-HT transporter immunohistological study revealed a marked reduction of 5-HT transporter-containing terminals by 1 day after injury. By 4 weeks after injury, 5-HT transporter immunoreactive terminals returned to the control level. The 5-HT immunohistological study revealed a reduction of 5-HT-containing terminals by 1 week after injury. By 4 weeks after injury, 5-HT immunoreactive fibers and terminals returned to the control level.
We estimated the recovery of 5-HT transporter and 5-HT neural elements in lumbosacral ventral horn by ranking 5-HT transporter and 5-HT staining intensity and counting 5-HT and 5-HT transporter terminals. The return of 5-HT transporter and 5-HT immunoreactivity of the lumbosacral ventral horn correlated with locomotor recovery, while 5-HT transporter showed closer relationship with locomotor recovery than 5-HT. The presence of 5-HT transporter indicates that the 5-HT fibers certainly function. This study shows that return of the function of 5-HT fibers predict the time course and extent of locomotory recovery after thoracic spinal cord injury.
The present study attempts to define the capacity of methylprednisolone sodium succinate (MP) to protect neuronal membranes against a free radical challenge in primary cultures of fetal mouse spinal cord. Incubation of these cultures with MP significantly increased the Na+,K(+)-ATPase activity, an effect that was blocked by the RNA synthesis inhibitor, actinomysin D and the protein synthesis inhibitor, cycloheximide, suggesting an induction of protein synthesis by MP. In contrast, incubation with FeCl2 for 1 or 2 h significantly inhibited Na+,K(+)-ATPase activity and elevated the levels of thiobarbituric acid-reactive substances (TBARS). Pretreatment with MP prevented the rise in TBARS and partially prevented the decrease in Na+,K(+)-ATPase activity for the first hour of FeCl2 incubation, an effect that was lost during the second hour. A second dose of MP after the first hour of incubation with FeCl2 partially restored Na+,K(+)-ATPase activity and reduced TBARS levels after the second hour of exposure to FeCl2. Co-incubation of MP with cycloheximide completely prevented the decrease in Na+,K(+)-ATPase activity seen after a 2-h incubation with FeCl2 and eliminated the need for a second dose of MP after the first hour of incubation with FeCl2. These findings suggest a capacity for rapid protein induction and antioxidant activity for MP in vitro.
The effect of the 21-aminosteroid U74006F and methylprednisolone (MP) on motor function and oedema were investigated after spinal cord compression in rats. Each compound was administered i.v. as a single dose 60 min after injury. The hind limb motor function was assessed using the inclined plane technique and expressed as the capacity angle. The water content was calculated as the percent wet weight of the total weight. Prior to compression the capacity angle was close to 62-64 degrees. One day after compression the motor function was reduced significantly in all rats. However, the capacity angle was significantly higher after treatment with U74006F or MP than with vehicle, i.e. 50 degrees +/- 4, 45 degrees +/- 5, and 32 degrees +/- 3, respectively. This improved functional recovery persisted during the initial nine days. After compression of the spinal cord the water content increased to a maximum on day 4 in all groups. The water content was not significantly different in any of the groups except on day one and nine when it was less in groups treated with U74006F. In conclusion, a single i. v. injection of U74006 or MP given 60 min after compression of the spinal cord improved motor function without effecting oedema expressed as water content.
The present study characterizes axonal pathology associated with traumatic compression injuries of the spinal cord and quantitatively assesses subtypes of axonal pathology in the acute, post-injury period. Eighteen adult female Wistar rats underwent spinal cord compression injury with a 53 g modified aneurysm clip at the C8-T1 segment. Six additional rats served as sham controls. Six experimental animals were sacrificed at each of the three post-injury time points: 15 min, 2 h and 24 h. From all animals, the C8-T1 spinal cord was dissected and processed for both light and electron microscopy. Axonal pathology included periaxonal swelling, organelle accumulation, vesicular myelin, myelin invagination, myelin rupture, and giant axons. Early myelin rupture and the ultrastructural features of giant axons are described here for the first time in the context of spinal cord compression injury. The quantitative analysis characterizes the prevalence of types of axonal pathology over the acute post-injury period and provides evidence for the secondary injury hypothesis regarding the evolution of axonal pathophysiology following trauma.
We evaluated the effects of serotonin (5-HT) agonists on in vitro models of spinal cord compressive injury. Evoked potentials in injured rat spinal cords (n=24) were recorded during perfusion with 5-HT agonists.
To evaluate the therapeutic effects of 5-HT agonists on the recovery of compound action potentials in injured spinal cords.
Rat dorsal columns were isolated, placed in a chamber, and injured by extradural compression with a clip. Conducting action potentials were activated by supramaximal constant current electrical stimuli and recorded during perfusion with 5-HT agonists and antagonists.
After inducing compression injuries, mean action potential amplitudes were reduced to 33.9+/-5.4% of the pre-injury level. After 120 min of perfusion with Ringer's solution, the mean amplitudes recovered to 62.8+/-8.4% of the pre-injury level. At a concentration of 100 micro M, perfusion with tandospirone (a 5-HT1A agonist) resulted in a significantly greater recovery of mean action potential amplitudes at 2 h after the injury (86.2+/-6.9% of pre-injury value) as compared with the control Ringer's solution (62.8+/-8.4% of pre-injury value, P<0.05). In contrast, quipazine (a 5-HT2A agonist) accelerated the decrease of amplitude (54.5+/-11.7% of pre-injury value). 5-HT1A and 5-HT2A agonist did not consistently alter latencies of the action potentials.
The 5-HT1A receptor agonist was effective for the recovery of spinal action potential amplitudes in a rat spinal cord injury model.
Injuries of peripheral inputs from the body cause sensory dysfunctions that are thought to be attributable to functional changes in cerebral cortical maps of the body. Prevalent theories propose that these cortical changes are explained by mechanisms that preeminently operate within cortex. This paper reviews findings from humans and other primates that point to a very different explanation, i.e. that injury triggers an immediately initiated, and subsequently continuing, progression of mechanisms that alter substrates at multiple subcortical as well as cortical locations. As part of this progression, peripheral injuries cause surprisingly rapid neurochemical/molecular, functional, and structural changes in peripheral, spinal, and brainstem substrates. Moreover, recent comparisons of extents of subcortical and cortical map changes indicate that initial subcortical changes can be more extensive than cortical changes, and that over time cortical and subcortical extents of change reach new balances. Mechanisms for these changes are ubiquitous in subcortical and cortical substrates and include neurochemical/molecular changes that cause functional alterations of normal excitation and inhibition, atrophy and degeneration of normal substrates, and sprouting of new connections. The result is that injuries that begin in the body become rapidly further embodied in reorganizational make-overs of the entire core of the somatosensory brain, from peripheral sensory neurons to cortex. We suggest that sensory dysfunctions after nerve, root, dorsal column (spinal), and amputation injuries can be viewed as diseases of reorganization in this core.
The rise of China in the era of globalization is significant due to its global implications and is attributed to various factors like rapid economic growth, strategic modernization, reconnecting with the Chinese Diaspora, particularly in the west, modernization of its military, and vibrant maritime trade strategy and so on. In the process of sustaining its rise, China has initiated several ambitious plans like the Asia Infrastructure Investment Bank (AIIB) and Belt and Road Initiative (BRI). The BRI is a combination of Silk Road Economic Belt targeting Central Asia and Europe and Maritime Silk Road (MSR) focussed on Southeast, South and North Asian regions. To make this a reality, the Chinese government has already made tremendous efforts to mobilize political, economic and diplomatic resources. However, BRI will not yield great results without the critical role of India. In this context, the paper attempts to identify the guiding factors for China to initiate BRI and its impact on its peaceful rise and the regions. India's response and strategies to BRI is critically analyzed. Finally, the paper also explores the mutual benefits and challenges for both India and China for successful implementation of BRI.
The current debate over China's rise and the future of international primacy is polarized between two prevalent views: one foresees China becoming the world's largest economy and taking over the position of international primacy from the United States, whereas the other believes that the Chinese economy will falter as a result of structural imbalances and China will not become a superpower. Both predictions miss the mark. This study argues that notwithstanding the political will to rebalance the economy, China will continue to follow an investment-intensive growth path, and despite the structural imbalances, this path will still be able to lead to Chinese economic primacy. But sheer economic size is not a good indicator of hard power. Using an organic combination of wealth and productivity as an indicator of hard power, the article shows how close the power competition between China and the United States will likely be and that Beijing may not be able to surpass Washington as a superpower.
The majority of existing research on the Indo-Pakistani conflict has shown that this conflict persists due to the confronting actors' long-term incompatibility in goals and their use of realpolitik conceptions to resolve their core issue—Kashmir. While most of this research is focused on the dynamics of already established realpolitik scholarship, less is known about how it contributed to make this dyad exceedingly dangerous in the post–Cold War era. The present effort attempts to account for the “action-reaction conundrum” by illuminating how the traditional realist practices are performing contrary to their security maximization objectives in the India-Pakistan rivalry. In order to bring the two states out of their prolonged security dilemma, what is needed is a way forward through the transformation of the Line of Control on the basis of an approach that combines the Westphalian state and an alternative paradigm. This article concludes by discussing the steps required to move in this direction, that is, toward Indo-Pakistani coexistence and a progressive future for South Asia more generally.
Analyses of China's Indian Ocean forays have been sporadic, seasonal, and restricted. Often, these are triggered by and remain limited to reporting new assets and technologies in China's naval modernisation and fail to appreciate their larger vision, deeper stimuli and also their complex linkages to China's political compulsions, economic motives and social moorings. Even at the most visible level, the survival of China's communist regime remains premised not on its military modernisation but on continued smooth trade-led development that needs assured access to and safety of sea lanes and unlimited markets and resources. The naval component of China's Indian Ocean policy, therefore, needs to be put in perspective and these analyses need to explore China's forays into the Indian Ocean in terms of its larger and concerted initiatives in building a maritime infrastructure both across the Indian Ocean littoral and also in expanding its ocean-faring and ocean-exploring claims and capabilities. What is also necessary to appreciate is how, in the face of new threats of maritime terrorism and the expanding US presence on China's periphery, China feels not only isolated but even targeted. All of this makes China far more assertive in accessing the Indian Ocean with obvious implications for its neighbours especially peer-powers like India that share several of China's proclivities. India, however, must carefully sidestep from falling prey to popular binaries of friend-or-foe formulations and focus not just on narrower and surface level trends in China's naval build-up, but expand its appreciation and engage China across the whole spectrum of maritime sectors and thereby maximise mutual benefits and lasting stable maritime equations with China.
Edema of the spinal cord, secondary to an impact injury produced in cats, was measured chemically. One day after injury a decrease in percentage dry weight and potassium concentration and an increase in sodium concentration were seen in the injured cord. By the second day these changes had spread to adjacent tissue. Edema was maximal between the third and sixth day and had begun to recede by the ninth day. A net loss of potassium, not directly related to the edematous changes, was observed throughout the analyzed cord starting on the third day and persisting on the ninth day after injury, when edema was regressing. Dexamethasone, started 48 hours before 5 or 24 hours after injury had only minimal effect on edema but prevented loss of potassium from the injured cord. Six days after injury this effect was statistically significant in all three groups of dexamethasone treated animals. All treated animals showed significantly better functional recovery than the untreated cats. On the sixth postinjury day the funtional state of all animals was highly correlated with the potassium content of the spinal cord. Thus, the beneficial effect of dexamethasone may be related to the postulated role of steroid treatment in the maintenance of structural integrity of cellular elements in traumatized tissues. This could result in a better functional state of the injured cord, as well as in the maintenance of the normal content of potassium, the principal intracellular ion.
The ESR spectra of the free radicals formed by the autoxidation of serotonin, 5-hydroxyindole, and 5-hydroxytryptophan in 1 N NaOH are presented. The analysis of the hyperfine splitting constants in H2O and D2O characterize these free radicals as semiquinone-imines, the one-electron oxidation product of the corresponding indole. At alkaline pH, autoxidation of these compounds ultimately leads to solid precipitate and unresolved ESR spectra characteristic of polymeric material. The reduction of cytochrome c at pH 7.4 by a wide variety of indoles correlates with the amplitude of the ESR signal in 1 N NaOH, as do other processes thought to be related to 5-hydroxyindole free radical formation. Relative to the rate of cytochrome c reduction, neither serotonin nor the serotonin free radical appears to react with oxygen to form superoxide. In the presence of NAD(P)H, the serotonin radical most probably oxidizes NAD(P)H to form the NAD(P). radical. The NAD(P). radical then reacts with oxygen to form superoxide, which ultimately reduces cytochrome c.
Loss of latency due to membrane lipid peroxidation induced in vitro was studied in highly purified rat liver lysosomes. Enriched fractions of lysosomes were isolated by free flow electrophoresis. Lipid peroxidation of lysosomes, assayed as malondialdehyde formation, was catalyzed by a radical generating system consisting of dihydroxyfumaric acid and Fe3+-ADP. The peroxidation reaction occurred readily at 37 degrees C and reached a plateau at 10 min; however, the loss of lysosomal latency, determined as increased percentage free beta-N-acetylglucosaminidase activity, occurred more gradually and reached a maximum after 30 min. Scavengers of superoxide, hydrogen peroxide, singlet oxygen, and hydroxyl radicals did not inhibit the peroxidation reaction nor prevent the loss of lysosomal latency. However, preincubation of the lysosomes with alpha-tocopherol effectively blocked the induction of peroxidation and substantially reduced the loss of lysosomal latency. These results indicate that the lysosomal membrane is susceptible to free radical-induced lipid peroxidation; further, this process may be the immediate cause of the subsequent disintegration of the lysosome. The nature of the protective effect of alpha-tocopherol is unclear but may be due to its interaction with the unsaturated membrane lipids and the subsequent interruption of the chain-reaction initiated by free radicals.
The hypothesis that the paravertebral sympathetic ganglia play a role in spinal blood flow regulation was tested in cats. Five cats were subjected to paravertebral sympathectomy, two to combined sympathectomy-adrenalectomy, three to adrenalectomy alone, and five controls received no treatment. Laminectomy was carried out to expose the T4–10 cord, and autoregulation was tested by measuring blood flow from the lateral columns with the hydrogen clearance technique during manipulation of systemic pressure with intravenous saline infusion and nitroprusside administration. The cord was then contused at T-7 with a 400 gm-cm impact injury. Posttraumatic blood flow was recorded, and neurophysiological function was assessed with somatosensory evoked potential (SEP) monitoring.
Before injury, blood flow in the untreated (control) group had no consistent relationship with mean systemic pressure over the range 80 to 160 mm Hg. In contrast, in all cats with paravertebral sympathectomy, whether accompanied by adrenalectomy or not, blood flows increased with systemic pressure (correlation coefficient 0.86, p < 0.01). After injury, the control and adrenalectomized cats showed blood flow decreases of > 60% to 4 to 6 ml/100 gm/min (p < 0.01) by 2 to 3 hours. However, cats with paravertebral sympathectomy maintained blood flow above 9 ml/100 gm/min for up to 3 hours after injury. All the sympathectomized cats recovered their SEP by the 3rd hour after injury, compared with none of the controls.
Thus, in the absence of the paravertebral sympathetic ganglia, spinal blood flow autoregulation was impaired and the typical posttraumatic loss in blood flow did not occur. The sympathectomy also protected the spinal cords from the neurophysiological loss usually seen in 400 gm-cm injury. The data suggest the need for caution in using acetylcholine blocking agents to paralyze animals in experimental spinal injury, since these agents alter sympathetic activity and may influence the injury process. The spinal cord is an excellent model in which to investigate sympathetic regulation of central nervous system blood flow.
The Sino-Pakistani relationship illustrates a truly relational identity. It involves two relational selves constituting each other, and the formation of the China-Pakistan Economic Corridor (CPEC) independently constituting each of them. Both the study and the presentation of this relational identity are only possible under an epistemology of relationality, as opposed to the epistemology of the self-interested actor. The article enlists the anthropological notion of post-Chineseness, which typologises relationality in accordance with how Pakistan and China identify each other in their strategic choice of relationship. It finds that China has moved from its expectations of Pakistan as being an owner of physical Chineseness, through hybrid Chineseness, and ultimately progressing to moral Chineseness under the CPEC. By contrast, Pakistan's self-positioning vis-a` -vis China has shifted from the ownership of physical Chineseness, via experiential Chineseness, to moral Chineseness. Among them, experiential Chineseness is the most relevant element in explaining the changing bilateral relationships under the epistemology of relationality. It is the spontaneous rise of intimacy, or friendship, made possible by the long-term process of a collegial working relationship. © The Author(s) 2018. Published by Oxford University Press on behalf of The Institute of International Relations, Tsinghua University. All rights reserved.
Since the establishment of diplomatic relations in 1951, Pakistan's desire for strategic parity with India and China's efforts to propel Pakistan as a strategic balancer to India have been the overarching factors for the emergence of a security centric Sino–Pak relationship. Over the years, it has diversified into an economic-centric relationship. Although military and technological transactions continue to dominate the economic relationship, China began gradually pledging increased investment in Pakistan's economy and infrastructure. China became the primary investor for building the Gwadar deep-sea port in 2002. Both sides signed a free trade agreement and agreed to link China's rail network to Gwadar Port through the Karakoram Highway in 2008. The commitment to develop Gwadar Port is a good indicator of the steady expansion of Chinese maritime interests and strategic influence in India's neighbourhood.
This paper attempts to analyse the significance and implications of the development of Gwadar Port for Pakistan, India and the region as a whole.
Does Narendra Modi bring anything substantively new to Indian foreign policy? This article assesses Modi's record towards Pakistan and China, arguing that he has significantly changed the course of India's diplomacy, at two levels—bilateral diplomacy and coalition diplomacy. India has traditionally followed a policy of slow-to-anger, prudential bilateral diplomacy and, in the name of non-alignment, reluctant coalition-building against both powers. Under Modi, New Delhi has adopted a more assertive stance bilaterally and has actively sought to recruit third parties into a diplomatic coalition against Pakistan and China. Modi's assertive bilateralism has translated into an insistence that anti-terrorism is the only subject of discussion and that the Kashmir dispute with Pakistan is off the table. In the case of Beijing, assertive bilateralism has meant reversing India's traditional stance of normalization of relations leading to a border settlement by arguing that quicker progress on a settlement must be the condition for any further diplomatic normalization. Modi's coalition diplomacy has entailed an active engagement with the US, the Gulf countries and even China against Pakistan, and with the US, Australia, Japan, Vietnam and the Indian Ocean states against China. The objective is not alliance-building but rather the application of diplomatic pressures against India's two rivals. Modi's diplomacy has been marked by a cooperation–defection cycle with both powers, signalling a willingness to cooperate on India's terms and defect when it does not get its way. Not surprisingly, relations with both Pakistan and China have come under considerable strain.
India is often perceived as a regional power, but a closer look reveals that it is in a disadvantageous position vis-à-vis China in South Asia. The first reason is that Indian governments never had the political, economic, and military capacities to pursue their regional power ambitions with their neighbours in the long run. South Asian countries could always play the China card in order to evade India’s influence. Second, India’s new South Asia policy with the focus on trade and connectivity has improved regional cooperation since 1991. But China remains an economically more attractive and politically more reliable partner for India’s neighbours.
Rising powers such as Brazil, China, India, Russia, and Turkey are increasingly claiming heightened profiles in international politics. Although differing in other respects, rising states have a strong desire for recognition and respect. This pioneering volume on status features contributions that develop propositions on status concerns and illustrate them with case studies and aggregate data analysis. Four cases are examined in depth: the United States (how it accommodates rising powers through hierarchy), Russia (the influence of status concerns on its foreign policy), China (how Beijing signals its status aspirations), and India (which has long sought major power status). The authors analyze status from a variety of theoretical perspectives and tackle questions such as: How do states signal their status claims? How are such signals perceived by the leading states? Will these status concerns lead to conflict, or is peaceful adjustment possible?
China's economic growth leads to an increasingly ambitious ocean development strategy. In addition, China has been more assertive in the South China Sea territorial disputes. In view of the exacerbating “China threat” perception, Chinese leaders attempt to maintain a balance: while building a modern navy, China avoids its deployment in maritime law enforcement and the handling of minor territorial conflicts. Efforts have also been made to de-escalate such conflicts while establishing a deterrence effect. Given such context, the recent Sino-Filipino conflict over the Scarborough Shoal is now presented as a model of the way China asserts its sovereignty claims in territorial disputes. This article considers Chinese foreign policy from a traditional realism approach based on content analysis of existing documents, literature and interviews of Chinese academics in the field. It observes how China's neighbours remain suspicious of Beijing's intentions. It concludes that China's relations with ASEAN have been adversely affected by the recent confrontation, demonstrating its problem of maintaining a balance in the pursuit of multiple foreign policy objectives.
• We postulated that damage to the endothelial lining of the spinal cord vasculature is a major factor in the pathogenesis of the characteristic lesion of the spinal cord (progressive, central, hemorrhage necrosis) that occurs after acute trauma. Endothelial damage may occur as a result of primary injury to the vessels or after arterial spasm. This damage results in deposition of platelets and formation of thrombi on the exposed subendothelial tissues and embolization of such thrombi to smaller vessels of the spinal cord parenchyma.
A review of the literature on experimental spinal cord trauma indicates the advantages of using a reproducible and quantifiable form of injury. Studies to date indicate that contusion of the spinal cord, creating either transitory traumatic paraplegia or permanent traumatic paraplegia, results in structural, vascular, physiological, and biochemical changes, each of which may be altered by various treatment methods.
In 2011, the concept of the Indo-Pacific began to appear in India's foreign policy discourse. This article argues that rather than signalling a dramatic shift in India's foreign policy, however, the way in which the Indo-Pacific has been interpreted by the Indian leadership suggests significant continuity as well as change, which is contrary to the goals of the concept's most fervent proponents in India. The article seeks to develop a framework for understanding ideational change and continuity in foreign policy by theorising the interplay between ideas, political and economic flux, and social expectations related to effective and legitimate state-building. It is argued that the Indo-Pacific concept has instigated a new emphasis on regional architecture-building to manage the ongoing regionalisation in the area between the Indian and Pacific Oceans as a result of heightened trade flows and production and investment linkages. Yet, the Indo-Pacific concept, like the new policy ideas on regional engagement that preceded it—the Look East policy and the ‘extended neighbourhood’—has been articulated in ways that are also compatible with long-standing ideas—such as non-alignment—about what constitutes appropriate international behaviour. This reflects the nature of the broader state project that has emerged since 1990, which, while encompassing a new focus on economic growth and competitiveness as being essential to effective state-building, continues to prioritise older ideas about what constitutes effective and legitimate state-building.
One of the greatest events in the first decades of the 21st century is the simultaneous emergence of China and India as economic powers. Indeed, China and India have become the twin engines for global growth today. The two Asian giants share much in common such as ancient civilizations, a colonial past, current challenges, and future potentials. However, since the 1960s the two nations have had a rocky, and sometimes explosive, relationship. What makes Sino-Indian relations so complex and difficult? What is the current status of the relationship? What can both sides do to improve the relationship? This paper examines major current developments in Sino-Indian relations and explores ways to further promote bilateral ties. The study suggests that despite impressive progress in their relations, the two countries still suffer from a deep-rooted trust deficit. To step out of the classic security dilemma and move the relationship to a higher level, the two countries need to translate their commitments into actions.
This article updates the arguments about the South Asian regional security complex (RSC) given in Buzan and Wæver’s (2003) Regions and Powers (RaP). In terms of the South Asian RSC itself, there have been lots of events, but little in the way of structural change from the analysis in RaP. In terms of South Asia’s regional context, the picture is mixed. In relation to the Gulf, there has been a minimal structural change. However, in relation to East Asia, there are more signs of interaction between the South and East Asian regional security complexes, mainly hinging on the rise of China. This is not yet sufficient to talk of the two having merged, but a wider Asian supercomplex is clearly emergent and becoming stronger. In terms of South Asia’s position in the global system, India’s claim for great power status is now plausible, though the role of the United States in both East and South Asia remains similar. But, the global level itself is probably moving towards a scenario in which a system, containing several great powers and no superpowers, becomes more regionalized. This trend has deep roots, and the key question for India is what balance it wants to establish through its engagement with its own region, the wider East Asian region, and at the global level.
Using disposable Bio-Rad columns packed with Sephadex G-10, the methods for isolation and determination of NA, DA, 5HT, 5HIAA, and GABA from the same brain tissue are described. Preparation and maintenance of the columns requires a minimum amount of time, and once prepared, the columns can be easily regenerated by washing the resin with 3 ml of 0.01 N NH3 and 6 ml of 0.01 N HCl. Brain tissues are prepared by homogenizing in 1 ml of 0.4 N HCLO4. After centrifugation, the supernatant is poured onto the resin. The columns can be placed directly on top of test tubes (15 × 150 mm) to allow collection of the eluate. GABA (96–98%) is removed in the first 2.2 ml of acid washed through the columns. NA and DA (100%) are contained in 2.8 ml of acid eluate. 5HT (94–98%) is washed from the column with 4 ml of an acid-ethanol solution. Finally, 5HIAA (100%) is removed with 2.0 ml of Na2CO3 solution. All determinations were made fluorimetrically.Also, a manual method, using Bio-Rad columns packed with G-10 resin, for isolating NA, DA, HVA, DOPAC and GABA from the same brain tissue is given as a modification of the semiautomated methods of Westernik and Korf (1976). The procedures for column preparation, maintenance, and regeneration are identical for both methods described in this paper. However, after homogenizing the brain tissue in HCLO4, a KOH/HCOOH buffer is added to precipitate excess perchlorate ions. This procedure appears to destroy about 8–10% of the catecholamines and metabolites present in the homogenate.These methods provide recovery values, reproducibility, and sensitivity compatible with cation exchange and some solvent extraction methods.
✓ A controlled series of adult mongrel dogs were rendered paraplegic by traumatizing the thoracic spinal cord. Those animals treated with local hypothermia, whether immediately or after a delay, recovered to a significantly greater degree than the untreated group. Spinal cord pO2 studies revealed a marked fall in the pO2 at the area of maximal injury over a 30-min period. The severe hypoxia lasted at least 7 hours. Pathological studies showed the varying degrees of injury produced. It is postulated that local hypothermia may be effective in altering the clinical recovery by decreasing the tissue metabolism at the site of injury.
alpha-L-Fucosidase (alpha-L-fucoside fucohydrolase, EC 3.2.1.51) has been purified to apparent homogeneity (about 22 000-fold over the crude homogenate) from monkey brain. Values of kinetic constants for the purified enzyme were as follows: pH optimum, 5.0; Km, 0.22 mM; V, 913 mumol/mg per h. alpha-L-Fucose was a competitive inhibitor (Ki, 0.275 mM) of the enzyme. Evidence for the involvement of sulphydryl group(s) and carboxyl group containing amino acid(s) in the catalytic process is presented. The purified enzyme was a tetramer of molecular weight of 285 000 of identical subunits of 73 500 held together by non-covalent forces. Gel filtration studies revealed the presence of three molecular forms of the activity in the purified preparation which appeared to be the tetramer, dimer and monomer. The existence of three types of activities was also aupported by a triphasic heat inactivation profile of the enzyme at 50 or 55 degrees C and the distinctly different pH activity profiles of the differentially heat-inactivated enzymes. Immunodiffusion studies using antibody developed against purified monkey brain alpha-L-fucosidase showed that the monkey brain enzyme had only partial immunological identity with the enzymes from the non-neural tissues of monkey as well as the human and rat liver and the rat brain. However, the monkey brain and liver enzymes appeared to be similar to the human brain and liver enzymes, respectively.
The specific activity of the membrane-bound enzyme, Na+-K+-activated adenosine triphosphatase (ATPase), has been shown to be decreased following experimental impact injury (400 gm-cm) to the spinal cord in dogs. The prompt and significant (p less than 0.01) fall in activity was evident as early as 5 minutes after injury, and remained at 56% to 67% of control for the 1-hour period studied. This decrease was most prominent in the central core of the traumatized segments of spinal cord. Central core samples, excised immediately adjacent to the trauma site, gave values for the Na+-K+-activated enzyme intermediate to those of the trauma and control sites. For these same samples, the activity of the Mg+2-dependent ATPase did not change appreciably. No alterations were observed in the tissue surrounding the zone of maximum injury at these early time periods. The relationship of membrane-bound enzyme alterations to blood flow, clotting mechanisms, and abnormal free radical reactions are briefly discussed.
Blood flow in the dorsolateral funiculus of the cat thoracic spinal cord was studied after severe experimental cord injury, using a modification of the hydrogen clearance technique. Autoregulation was intact during the initial 60 to 90 minutes after cord injury, but was then lost coincident with the onset of ischemia. The data suggest that the ischemic response to spinal cord injury is mediated both by the loss of autoregulation and by relative vasoconstriction of the resistance vessels. Therapeutic intervention aimed at maintaining perfusion during the early posttraumatic period may prove of value in reversing or limiting some elements of dysfunction due to the secondary injury of ischemia.
Spinal cord damage was induced in dogs by a 400 gm-centimeter force injury to assess an early release of lyosomal enzymes from traumatized cord. In whole cord homogenates, an early decrease in total acid phosphatase and beta-glucuronidase was observed, approaching control levels by 2 hr. With acid phosphatase, total activity increased to 117% of control by 4 hr. Beta-glucuronidase showed no significant change in free activity at any time up to 4 hr. Dissected gray and white matter trauma samples displayed free, soluble, and total activities similar to controls. Cisternal CSF showed increased beta-glucuronidase and acid phosphatase activity at 30 and 60 min, while lumbosacral values were decreased. By 2 hr, acid phosphatase was increased in lumbar fluid and remained elevated for the 24-hr interval studied. Cisternal CSF protein was unchanged throughout the 24-hr period, while lumbosacral values increased at 4 and 24 hr. In traumatized adjacent and control cord segments a significant drop in total acid phosphatase activity in the trauma core samples was noted by 30 min and remained lower than control for the 24-hr period. The early drop in total activity in the area of maximal injury suggests enzyme inactivation by free radicals or some unknown inhibitor. The late increase in acid phosphatase activity in surrounding white matter may be due to accumulation of lysosomes within axis cylinders of partially injured nerve fibers. It is concluded that lysosomal enzyme release does not appear to play a role in the early phases of the pathophysiologic process of spinal cord trauma.
Endothelial changes leading to edema formation are examined in the primate spinal cord (Macaca mulatta) following a lesion created by a 20-gm weight falling 15 cm onto the exposed dura. Intravascular perfusion of a paraformaldehydeglutaraldehyde solution followed by carbon black provides adequate fixation of vascular structures and glial elements. Myelin is poorly preserved. Ultrastructural alterations of the blood-brain barrier consist of loss of integrity of the endothelial tight junctions. Edema caused by vascular disruption and parenchymatous extravasation of intravascular contents is observed along with glial swelling. Interglial gap junctions persist in areas of marked cellular seperation and do not impede the migration of edema fluid.
As in brain, another, obviously hydrostatic, type of oedema develops in the acutely injured spinal cord of the rabbit in addition to vasogenic oedema. The authors arrived at this finding by means of fluorescent tracer studies histological examinations, and measurements of tissue water, sodium and potassium. Longitudinal spread of vasogenic oedema remained limited to the zone of the epicentre and its surroundings. Hyperhydration, which appears gradually in the remote segments and is associated with increased sodium content, has the characteristics of plasma-ultrafiltrate.
Highly sensitive enzymatic assays, microdissection techniques, and histochemical methods were used to investigate the effects of blunt trauma on rabbit spinal cord serotonin, norepinephrine, and dopamine concentrations. Within 5 minutes after trauma, norepinephrine and serotonin in gray matter decreased considerably at the lesion center. In white matter, norepinephrine decreased or was unchanged, but at the lesion edges serotonin increased. No changes in dopamine concentration were detected. Substantial changes in monoamines do occur after spinal cord trauma and serotonin may play a role in injury development.
The T-13 spinal cord segment of dogs was compressed both acutely and chronically by means of a balloon catheter. The vascular permeability to protein was assessed using Evans blue albumin (EBA), and the dorsal column evoked potential recorded to monitor conduction failure. With acute compression sufficient to cause conduction failure there was a marked leakage of EBA from the intermediate gray matter, which spread into the dorsolateral white matter. The degree of edema was similar whether the compression was maintained or released. Chronic compression maintained over 4 to 5 hours did not increase vascular permeability, but following release of compression leakage of EBA occurred in the same cord locations observed with leakage from acute compressions. This increased permeability following release of chronic compression may result from reactive hyperemia. Dorsal column conduction returned after the release of both acute and chronic compression. The extravasated EBA was present both in the extracellular space and within cells. The results and their clinical application are discussed.
In order to evaluate the pathogenetic importance of platelet aggregates in cerebrovascular disease, a platelet count ratio method was used to study 66 patients with transient ischemic attacks (TIAs). Thirty normal subjects and 22 patients without thromboembolic disorders were also included as controls. The mean platelet aggregate ratio of the TIA group was 0.75 +/- 0.03 SEM which was significantly lower than that of normal subjects (0.90 +/- 0.02) or patients controls (0.88 +/- 0.01) (P less than 0.01). Seventeen patients with TIA were then treated with aspirin (1,200 mg) and dipyridamole (200 mg) daily. The platelet aggregate ratios were normalized in 13 patients. Of four patients who did not respond to this regimen, one did respond to sulfinpyrazone. When sulfinpyrazone was discontinued, recurrence of symptoms was preceded by an increase in platelet aggregates. These findings suggest that platelet aggregates may play an important role in the pathogenesis of cerebrovascular insufficiency. The determination of platelet aggregates appears useful in selecting patients for antiplatelet therapy.
Spinal cord blood flow (SCBF) was measured in dogs before and following acute injury with 300 or 500 g-cm force (GCF). In addition, the responses to high and low PaCO2 and low PaO2 levels were studied. The hydrogen clearance technique was used and 0.3 mm platinum electrodes were placed in grey matter, central white matter or peripheral white matter of the L2 segment. The pre-trauma flows were: grey matter 12.5 ± 2.7; central white matter 14.4 ± 3.6 and peripheral white matter 15.1 ± 4.2 ml/100 g/min.
✓ Identification of central nervous system edema is based on increased water content in relation to nonvolatile residue per unit weight. Nonvolatile residue in spinal cord tissue following impact trauma was determined to ascertain the magnitude and persistence of edema. High and low thoracic laminectomies were carried out on each of 17 rhesus monkeys. The lower exposed cord was traumatized with a calibrated blow of 300 gm cm. All upper exposed cords and the lower exposed cord in one monkey served as nontraumatized controls. At time intervals of 5 minutes to 20 days after trauma, cord segments were removed and assayed for water content. Increased tissue water was evident within 5 minutes and persisted for 15 days. By the 20th day it had essentially subsided. Increased tissue water content in the traumatized segment reached a maximum of 7.4% over control values at 5 days and then gradually diminished. These findings support the concept that edema following spinal trauma is unrelated to secondary effects of ...
Abstract— Lipid peroxide formation as measured by the thiobarbituric acid reaction was demonstrated in subcellular fractions of rat brain. The ascorbic acid induced nonenzymic lipid peroxidation was distributed in all the subcellular fractions with a maximum in microsomes. The NADPH dependent enzymic lipid peroxidation occurred mainly in microsomes and to a smaller extent in synaptosomes; NADH could replace NADPH for the enzymic lipid peroxidation under the assay conditions employed. Fe2+ but not Fe3+ stimulated the NADPH or NADH dependent lipid peroxide formation. The optimum conditions with respect to pH, ascorbic acid or NADPH concentration, time of incubation and protein concentration were studied. Heating the microsomes at 100oCdid not influence the ascorbate-induced lipid peroxidation but completely abolished the NADPH linked peroxidation. Several heavy metal ions, surface active agents and EDTA were inhibitory to lipid peroxidation. The effect of thiol agents indicated that -SH groups were involved in the enzymic lipid peroxidation. Studies on subcellular fractions of developing rat brain showed an increasing trend in lipid peroxidation with the advancing age of the animal. No significant difference in lipid peroxidation was observed between brains from normal rats and those from rats affected by experimental allergic encephalomyelitis.
Concentrations of norepinephrine (NE), dopamine (DA), serotonin (5 HT), and histamine (HIST) were determined in spinal cords of 5 groups of cats. One group underwent laminectomy only; a 2nd untreated group received a 400 gm cm impact at the T 9 level. These were compared with 3 groups treated with epsilon aminocaproic acid (EACA), methyl prednisolone sodium succinate (MP), and a combination of EACA and MP after similar trauma. The biogenic amines were measured in three 1 cm segments of the cord, rostral, middle, and caudal, 1 hr after trauma. There was no change in NE concentration in any of the 3 segments after impact compared with laminectomized controls, nor was the NE concentration in the impacted (middle) area higher than that in the rostral or caudal sites. Although the NE content of the cord in treated animals decreased compared to that of laminectomized controls, the decrease was not significant. The concentration of DA, however, significantly increased after impact and significantly decreased after treatment with EACA and EACA plus MP. There was no significant change in 5 HT levels, but the level of HIST increased significantly after impact and was lowered by treatment with EACA and EACA with MP. The implications of these changes in biogenic amines in spinal cord trauma are discussed.
Vascular permeability and the spread of protein-rich fluid has been assessed in experimental injury to the canine thoracic cord. Concussive injuries of 500 and 200 gram-centimetre force (GCF) were produced and the leakage of Evans blue albumin (EBA) studied with fluorescent microscopy. In dogs subjected to a 500 GCF injury, the leakage occurred initially in the central, intermediolateral grey matter, and dorsal horns, immediately after trauma. Veins and venules were primarily affected. Vessels in the outer white matter had EBA in the vessel wall which only rarely spread into the neuropil. Extensive centrifugal and longitudinal spread occurred and EBA reached the pia mater in approximately 6 hr. A similar but less extensive lesion was present in the segments rostral and caudal to the point of trauma. Blood flow was still present in the outer oedematous white matter 6 hr after trauma, as shown by the presence of Thioflavine S in blood vessels. This was injected intravenously immediately prior to death to assess vascular perfusion, The abnormal permeability decreased rapidly after trauma. Six hr after injury leakage of EBA from vessels was minimal. In dogs subjected to a 200 GCF injury the localisation of leakage was similar but decreased in severity.
Large intravenous doses of methylprednisolone sodium succinate are associated with biochemical and electrophysiological effects in the cat spinal cord which may be of therapeutic value in the treatment of spinal cord injury. The potentially beneficial effects of large doses of the glucocorticoid include: 1) an enhancement of spinal cord (Na + + K+)-ATPase activity; 2) an attenuation of lipid peroxide formation; 3) a hyperpolarization of motor neuron resting membrane potentials; and 4) an accelerated impulse conduction along the myelinated portion of the motor axon. Each of these is apparent with spinal cord tissue levels of methylprednisolone around 1.3 micrograms/gm wet weight, which are rapidly obtained following a single intravenous dose of 30 mg/kg. The half-life of methylprednisolone in cat spinal cord following a single intravenous administration, as well as the duration of its pharmacological actions, is roughly 3 hours. The data suggest that, in order to be of therapeutic value in the treatment of acute spinal cord trauma, early intervention with high-dose intravenous methylprednisolone (30 to 40 mg/kg) is necessary, followed by intravenous maintenance dosing of 15 to 20 mg/kg every 2 to 3 hours. The rationale and duration for this regimen are discussed.
Posttraumatic spinal cord blood flow (SCBF) was assessed after elevating the mean systemic arterial pressure (mSAP) with a blood transfusion, or with an infusion of dopamine. The effect of the anesthetic agent, gamma hydroxybutyrate, was also assessed. Flows were measured using the 14C-antipyrine autoradiographic method. Animals were injured at T-1 by acute compression of the spinal cord with a clip exerting a pressure of 175 gm. Uninjured animals, with mSAP's of 120.0 +/- 17.0 mm Hg, had gray and white matter flows of 74.2 +/- 22.3 and 18.7 +/- 6.7 ml/100 gm/min, respectively, while injured untreated animals had mSAP's of 82.5 +/- 14.1 mm Hg and gray and white matter flows of 13.3 +/- 12.1 and 3.9 +/- 3.9 ml/100 gm/min, respectively, at the injury site. Blood transfusion raised the mSAP's to 127.5 +/- 13.7 mm Hg in the injured animals and doubled the flows in gray and white matter to 25.6 +/- 30.2 and 6.3 +/- 6.4 ml/100 gm/ml, respectively. Dopamine did not have as beneficial an effect as blood transfusion on either the mSAP (101.0 +/- 16.7 mm Hg) or the SCBF (gray and white matter flows of 18.4 +/- 12.4 and 5.8 +/- 5.9 ml/100 gm/min). Gamma hydroxybutyrate (GHB) had almost no effect on the mSAP or SCBF of normal animals, and in injured animals produced only a unilateral increase in flow on the less severely injured side, without affecting the mSAP.
The purpose of this study was to determine the effect of treatment with the synthetic glucocorticoid, methylprednisolone, on the microvasulature and metabolism of the traumatized spinal cord. Spinal cords of cats were compressed with a 170-gm weight for 5 minutes and were treated with either high-dose methylprednisolone (HDMP, 15 mg/kg/24 hrs) or megadose methylprednisolone (MDMP,60 mg/kg/24 hrs). Animals were sacrificed at 2, 8, or 24 hours following injury. Treatment with HDMP resulted in substantial preservation of injured spinal cord microvascular perfusion at 8 hours as compared with injured untreated cats. Compression trauma caused a partial derangement of energy metabolism and a shift toward anaerobic glycolysis in both treated and untreated groups for the entire 24-hour postinjury period. Tissue levels of adenosine triphosphate, phosphocreatine, and total adenylates in the HDMP-treated cats sacrificed at 8 hours after trauma were significantly elevated over untreated controls, but those in the 2- and 24-hour groups were not. Concentration of energy intermediates in MDMP-treated cat were either equal to or below those of injured untreated animals al all three postinjury time period. The postinjury metabolite pattern and concentrations seen in this study possibly result from differing levels of blood flow and neuronal activity in the injured untreated, HDMP-, and MDMP-treated spinal cords. Better tissue perfusion in the HDMP-treated cats might be expected to result in an improved tissue energy state in these animals. However, intensive high-dose glucocorticoid treatment has been demonstrated to augment spinal cord monosynaptic and polysynaptic reflex transmission and primary afferent excitability. Furthermore, acute single intravenous dose studies have shown this direct neuronal action to be dose-related. Thus, additional high-energy phosphate molecules that may be reformed as a result of HDMP treatment were perhaps used as the energy source for any increased neuronal activity caused by steroid administration. The beneficial effects of glucocorticoid treatment in experimental spinal cord trauma might derive from preserved cellular structural integrity. This could result in increased levels of neuronal activity, energy utilization, and production in treated as compared with untreated tissue.
A specific gravity, column gradient method was coupled with a tissue punch technique to measure regional edema in the traumatized spinal cord of the cat at 1 and 2 hours after a 500-g/cm impact injury. A significant increase in water content was observed at the injury site in the posterior, anterior, and lateral white columns by 1 hour after injury and extended 2 mm above and below the site by 2 hours after injury.
Inside China's Global Spending Spree
- See Scott Cendrowski
See Scott Cendrowski, "Inside China's Global Spending Spree," Fortune, December 12, 2016,
https://fortune.com/longform/china-belt-road-investment/ (accessed May 2, 2017).
China's Rise and US Hegemony: Renegotiating Hegemonic Order in East Asia
- See World Bank
See World Bank, "World Bank National Account Data: China, 2018," https://data.worldbank.
org/indicator/NY.GDP.MKTP.CD?locations=CN (accessed October 10, 2019); Rosemary
Foot, "China's Rise and US Hegemony: Renegotiating Hegemonic Order in East Asia?" International Politics (2019). doi:10.1057/s41311-019-00189-5 (accessed November 2, 2019).
We employ Robert Gilpin's definition that a hegemon is a state that has a preponderance of power in the international system
We employ Robert Gilpin's definition that a hegemon is a state that has a preponderance of
power in the international system. See Robert Gilpin, War and Change in World Politics
(Cambridge: Cambridge University Press, 1981).
The South China Sea Dispute and the Growing Sino-American Rivalry
- Susanna Lobo
J. Susanna Lobo, "The South China Sea Dispute and the Growing Sino-American Rivalry," World Focus, 39, no. 4 (2018): 141-7.
Somewhat similar equations were at play during the Cold War wherein the Indo-Soviet relationship factored in the US' relations with India and, on the other hand, Pakistan's revisionist policies did not allow India to forge close ties with the US. See Surinder Mohan and J. Susanna Lobo
- Surinder Mohan
Surinder Mohan, "Re-examining the Rivalry Paradigm: The India-Pakistan Conflict" (Ph.D.
Thesis, New Delhi, University of Delhi, 2016), 258-60. Somewhat similar equations were at
play during the Cold War wherein the Indo-Soviet relationship factored in the US' relations
with India and, on the other hand, Pakistan's revisionist policies did not allow India to forge
close ties with the US. See Surinder Mohan and J. Susanna Lobo, "The Politics of Foreign Aid:
Impact of Superpowers Economic Assistance on India and Pakistan during the Cold War,"
Bandung: Journal of the Global South, 7, no. 1 (2020): 52-79. https://doi.org/10.1163/
21983534-00701004.