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Background: Cervical traumatic spinal cord injury is a devastating condition. Current management (bony decompression) may be inadequate as after acute severe TSCI, the swollen spinal cord may become compressed against the surrounding tough membrane, the dura. DISCUS will test the hypothesis that, after acute, severe traumatic cervical spinal cord injury, the addition of dural decompression to bony decompression improves muscle strength in the limbs at 6 months, compared with bony decompression alone. Methods: This is a prospective, phase III, multicenter, randomized controlled superiority trial. We aim to recruit 222 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is change in the motor score at 6 months vs. admission; secondary outcomes assess function (grasp, walking, urinary + anal sphincters), quality of life, complications, need for further surgery, and mortality, at 6 months and 12 months from randomization. A subgroup of at least 50 patients (25/arm) also has observational monitoring from the injury site using a pressure probe (intraspinal pressure, spinal cord perfusion pressure) and/or microdialysis catheter (cord metabolism: tissue glucose, lactate, pyruvate, lactate to pyruvate ratio, glutamate, glycerol; cord inflammation: tissue chemokines/cytokines). Patients are recruited from the UK and internationally, with UK recruitment supported by an integrated QuinteT recruitment intervention to optimize recruitment and informed consent processes. Estimated study duration is 72 months (6 months set-up, 48 months recruitment, 12 months to complete follow-up, 6 months data analysis and reporting results). Discussion: We anticipate that the addition of duroplasty to standard of care will improve muscle strength; this has benefits for patients and carers, as well as substantial gains for health services and society including economic implications. If the addition of duroplasty to standard treatment is beneficial, it is anticipated that duroplasty will become standard of care. Trial registration: IRAS: 292031 (England, Wales, Northern Ireland) - Registration date: 24 May 2021, 296518 (Scotland), ISRCTN: 25573423 (Registration date: 2 June 2021); ClinicalTrials.gov number : NCT04936620 (Registration date: 21 June 2021); NIHR CRN 48627 (Registration date: 24 May 2021). [ABSTRACT FROM AUTHOR]

Background: It is unclear why AQP4-IgG primarily causes central nervous system lesions by activating complement, but generally spares peripheral AQP4-expressing organs. Objectives: To determine whether peripheral AQP4-expressing cells are protected from complement-mediated damage by expressing complement regulators. Methods: Human tissue and cultured human cells were immunostained for aquaporin-4 (AQP4), CD46, CD55 and CD59. We also determined the vulnerability to AQP4-IgG and complement-mediated damage of astrocytes cultured alone or co-cultured with endothelial cells. Results: In normal brain, astrocyte end-feet express AQP4, but are devoid of CD46, CD55 and CD59. Immunoreactivity for CD46, CD55 and CD59 is not increased in or around neuromyelitis optica lesions. In kidney AQP4 is co-expressed with CD46 and CD55, in stomach AQP4 is co-expressed with CD46 and in skeletal muscle AQP4 is co-expressed with CD46. Astrocytes cultured alone co-express AQP4 and CD59 but, in astrocyte-endothelial co-cultures, AQP4 is found in cell processes devoid of CD59. Astrocytes co-cultured with endothelial cells are more vulnerable to AQP4-IgG and complement-mediated lysis than astrocytes cultured alone. Conclusions: Complement regulators protect peripheral organs, but not the central nervous system, from AQP4-IgG and complement-mediated damage. Our findings may explain why neuromyelitis optica primarily damages the central nervous system, but spares peripheral organs. [ABSTRACT FROM AUTHOR]

Aquaporins are protein channels that facilitate the flow of water across plasma cell membranes in response to osmotic gradients. This review summarizes the evidence that aquaporins play key roles in tumor biology including tumor-associated edema, tumor cell migration, tumor proliferation and tumor angiogenesis. Aquaporin inhibitors may thus be a novel class of anti-tumor agents. However, attempts to produce small molecule aquaporin inhibitors have been largely unsuccessful. Recently, monoclonal human IgG antibodies against extracellular aquaporin-4 domains have become available and could be engineered to kill aquaporin-4 over-expressing cells in the malignant brain tumor glioblastoma. We conclude this review by discussing future directions in aquaporin tumor research. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. [ABSTRACT FROM AUTHOR]

MR scans from 65 patients with traumatic spinal cord injury were analysed; on admission 95% had evidence of cord compression – in 26% due to the dura, and in the remaining 74% due to extradural factors. Compression due to dural factors resolved with a half-life of 5.5 days. These findings suggest that bony decompression alone may not relieve spinal cord compression in the quarter of patients in whom dural factors are significant. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To develop a technique for continuously monitoring intraspinal pressure at the injury site (intraspinal pressure) after traumatic spinal cord injury. DESIGN: A pressure probe was placed subdurally at the injury site in 18 patients who had isolated severe traumatic spinal cord injury (American Spinal Injuries Association grades A-C). Intraspinal pressure monitoring started within 72 hours of the injury and continued for up to a week. In four patients, additional probes were inserted to simultaneously monitor subdural pressure below the injury and extradural pressure. Blood pressure was recorded from a radial artery catheter kept at the same horizontal level as the injured segment of the spinal cord. We determined the effect of various maneuvers on spinal cord perfusion pressure and spinal cord function and assessed using a limb motor score and motor-evoked potentials. SETTING: Neurosurgery and neuro-ICU covering a 3 million population in London. SUBJECTS: Patients with severe traumatic spinal cord injury. Control subjects without spinal cord injury (to monitor spinal cerebrospinal fluid signal and motor evoked potentials). INTERVENTIONS: Insertion of subdural spinal pressure probe. MEASUREMENTS AND MAIN RESULTS: There were no procedure-related complications. Intraspinal pressure at the injury site was higher than subdural pressure below the injury or extradural pressure. Average intraspinal pressure from the 18 patients with traumatic spinal cord injury was significantly higher than average intraspinal pressure from 12 subjects without traumatic spinal cord injury. Change in arterial PCO2, change in sevoflurane dose, and mannitol administration had no significant effect on intraspinal pressure or spinal cord perfusion pressure. Increase in inotrope dose significantly increased spinal cord perfusion pressure. Bony realignment and laminectomy did not effectively lower intraspinal pressure. Laminectomy was potentially detrimental by exposing the swollen spinal cord to compression forces applied to the skin. By intervening to increase spinal cord perfusion pressure, we could increase the amplitude of motor-evoked potentials recorded from below or just above the injury level in nine of nine patients with traumatic spinal cord injury. In two of two patients with American Spinal Injuries Association grade C traumatic spinal cord injury, higher spinal cord perfusion pressure correlated with increased limb motor score. CONCLUSIONS: Our findings provide proof-of-principle that subdural intraspinal pressure at the injury site can be measured safely after traumatic spinal cord injury. [ABSTRACT FROM AUTHOR]

Objectives: To develop a technique for continuously monitoring intraspinal pressure at the injury site (intraspinal pressure) after traumatic spinal cord injury. Design: A pressure probe was placed subdurally at the injury site in 18 patients who had isolated severe traumatic spinal cord injury (American Spinal Injuries Association grades A-C). Intraspinal pressure monitoring started within 72 hours of the injury and continued for up to a week. In four patients, additional probes were inserted to simultaneously monitor subdural pressure below the injury and extradural pressure. Blood pressure was recorded from a radial artery catheter kept at the same horizontal level as the injured segment of the spinal cord. We determined the effect of various maneuvers on spinal cord perfusion pressure and spinal cord function and assessed using a limb motor score and motor-evoked potentials. Setting: Neurosurgery and neuro-ICU covering a 3 million population in London. Subjects: Patients with severe traumatic spinal cord injury. Control subjects without spinal cord injury (to monitor spinal cerebrospinal fluid signal and motor evoked potentials). Interventions: Insertion of subdural spinal pressure probe. Measurements and Main Results: There were no procedure-related complications. Intraspinal pressure at the injury site was higher than subdural pressure below the injury or extradural pressure. Average intraspinal pressure from the 18 patients with traumatic spinal cord injury was significantly higher than average intraspinal pressure from 12 subjects without traumatic spinal cord injury. Change in arterial Pco2, change in sevoflurane dose, and mannitol administration had no significant effect on intraspinal pressure or spinal cord perfusion pressure. Increase in inotrope dose significantly increased spinal cord perfusion pressure. Bony realignment and laminectomy did not effectively lower intraspinal pressure. Laminectomy was potentially detrimental by exposing the swollen spinal cord to compression forces applied to the skin. By intervening to increase spinal cord perfusion pressure, we could increase the amplitude of motor-evoked potentials recorded from below or just above the injury level in nine of nine patients with traumatic spinal cord injury. In two of two patients with American Spinal Injuries Association grade C traumatic spinal cord injury, higher spinal cord perfusion pressure correlated with increased limb motor score. Conclusions: Our findings provide proof-of-principle that subdural intraspinal pressure at the injury site can be measured safely after traumatic spinal cord injury. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS and affects women of childbearing age. Most patients with NMO have circulating Abs, termed NMO-IgG, against the astrocytic water channel protein aquaporin-4. In the CNS, NMO-IgG causes complement-mediated astrocyte damage, inflammatory cell infiltration, and myelin loss. In this study, we show that aquaporin-4 is expressed in the syncytiotrophoblast of human and mouse placenta. Placental aquaporin-4 expression is high during mid-gestation and progressively decreases with advancing pregnancy. Intraperitoneally injected NMO-IgG binds mouse placental aquaporin-4, activates coinjected human complement, and causes inflammatory cell infiltration into the placenta and placental necrosis. There was no damage to maternal organs that express aquaporin-4, including the brain, spinal cord, kidneys, and skeletal muscle. In control experiments, no placentitis was found in mice injected with NMO-IgG without complement, non-NMO-IgG with human complement, or in aquaporin-4 null mice injected with NMO-IgG and human complement. The infiltrating cells were primarily neutrophils with a few scattered eosinophils and macrophages. NMO-IgG and human complement-induced placentitis caused fetal death, but some fetuses were born normal when lower amounts of NMO-IgG and human complement were injected. Sivelestat, a neutrophil elastase inhibitor, and aquaporumab, a nonpathogenic IgG that competes with NMO-IgG for aquaporin-4 binding, significantly reduced NMO-IgG and human complement induced placentitis and fetal death. Our data suggest that NMO-IgG can cause miscarriage, thus challenging the concept that NMO affects only the CNS. These findings have implications for the management of NMO during pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model. Methods: NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected. Results: We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions. Interpretation: Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy. ANN NEUROL 2012; [ABSTRACT FROM AUTHOR]

Background Bone graft substitutes are widely used in spinal surgery. Here, serious complications associated with the bone graft substitute GeneX are presented. GeneX contains tri-calcium phosphate and calcium sulphate. Methods GeneX was used in three patients who had spinal decompression and fusion. Mice were also injected with GeneX, demineralised bone matrix (DBX) or saline subcutaneously. After 24 h the extent of tissue damage and inflammation in tissue sections was quantified. To understand the licensing process for bone graft substitutes, the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) websites were accessed. Results All patients developed sterile pus in soft tissues adjacent to the GeneX followed by skin breakdown in two and pharyngeal perforation in one. In mice, GeneX produced moderate or severe skin damage compared with no or mild skin damage after DBX (p<0.05) or saline (p<0.05) injection. GeneX caused more inflammation in mouse dermis (1704±193 leucocytes/ mm², mean±SE) than DBX (537±266, p<0.01) or saline (136±19, p<0.01). The FDA and MHRA classify bone graft substitutes as medical devices. In contrast with drugs, medical devices do not need to undergo clinical safety tests before obtaining FDA 510(k) clearance for use in patients. Conclusion GeneX may cause soft tissue inflammation and destruction and should not be placed next to thin walled structures, such as skin or pharynx, because it may erode through these tissues. Bone graft substitutes should undergo mandatory detailed safety testing prior to approval. This could be achieved by reclassifying them as drugs. [ABSTRACT FROM AUTHOR]

Abstract: We reported recently that intracerebral administration of NMO-IgG with human complement produces neuromyelitis optica (NMO) lesions in mice. We examined the role of T cells in the formation of NMO lesions by comparing brain histopathology in wildtype and nude mice. Brains were co-injected with IgG from NMO patients and human complement. At 24h and 5days, wildtype vs. nude mouse brains had comparable inflammation (CD45 immunoreactivity), loss of myelin (Luxol Fast Blue staining) and loss of AQP4 immunoreactivity. We conclude that T cells are not required for the formation of NMO lesions in this mouse model. [Copyright &y& Elsevier]

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions. [ABSTRACT FROM PUBLISHER]

About 80% of the brain is water. This review discusses the importance of the three brain water-channel proteins (AQP1, AQP4, AQP9) in brain physiology. AQP1 is expressed in the choroid plexus and participates in forming cerebrospinal fluid. AQP4, found in astrocyte foot processes, glia limitans and ependyma, facilitates water movement into and out of the brain, accelerates astrocyte migration and alters neuronal activity. Recently, AQP4 autoantibodies were discovered in patients with neuromyelitis optica, a demyelinating disease, and are now being used to diagnose this condition. AQP9 is present in some glia and neurons, but its function is unclear. Finally, we discuss how the discovery of AQP activators and inhibitors will be the next major step in this field. [Copyright &y& Elsevier]

Aquaporin-1 (AQP1) is a water channel protein expressed widely in vascular endothelia, where it increases cell membrane water permeability. The role of AQP1 in endothelial cell function is unknown. Here we show remarkably impaired tumour growth in AQP1-null mice after subcutaneous or intracranial tumour cell implantation, with reduced tumour vascularity and extensive necrosis. A new mechanism for the impaired angiogenesis was established from cell culture studies. Although adhesion and proliferation were similar in primary cultures of aortic endothelia from wild-type and from AQP1-null mice, cell migration was greatly impaired in AQP1-deficient cells, with abnormal vessel formation in vitro. Stable transfection of non-endothelial cells with AQP1 or with a structurally different water-selective transporter (AQP4) accelerated cell migration and wound healing in vitro. Motile AQP1-expressing cells had prominent membrane ruffles at the leading edge with polarization of AQP1 protein to lamellipodia, where rapid water fluxes occur. Our findings support a fundamental role of water channels in cell migration, which is central to diverse biological phenomena including angiogenesis, wound healing, tumour spread and organ regeneration. [ABSTRACT FROM AUTHOR]

In a recent study, administration of granulocyte colony stimulating factor (G-CSF) increased neuromyelitis optica (NMO) lesions in mice. Here we report a patient whose first episode of NMO may have been exacerbated by inadvertent administration of G-CSF. Histological examination of brain and spinal cord samples from three other NMO patients revealed markedly increased expression of G-CSF in neurons located in and around the lesions, with little or no expression in multiple sclerosis lesions or normal white matter. Taken together, these cases support a detrimental role for G-CSF in NMO pathogenesis. [ABSTRACT FROM AUTHOR]

Purpose: We surveyed the treatment of acute spinal cord injuries in the UK and compared current practices with 10 years ago. Methods: A questionnaire survey was conducted amongst neurosurgeons, neuroanaesthetists, and neurointensivists that manage patients with acute spinal cord injuries. The survey gave two scenarios (complete and incomplete cervical spinal cord injuries). We obtained opinions on the speed of transfer, timing and aim of surgery, choice of anaesthetic, intraoperative monitoring, targets for physiological parameters, and drug treatments. Results: We received responses from 78.6% of UK units that manage acute spinal cord injuries (33 neurosurgeons, 56 neuroanaesthetists/neurointensivists). Most neurosurgeons operate within 12 h for incomplete (82%) and complete (64%) injuries. There is a significant shift from 10 years ago, when only 61% (incomplete) and 30% (complete) of neurosurgeons operated within 12 h. The preferred anaesthetic technique in 2022 is total intravenous anaesthesia (TIVA), used by 69% of neuroanaesthetists. Significantly more intraoperative monitoring is now used at least sometimes, including bispectral index (91%), non-invasive cardiac output (62%), and neurophysiology (73–77%). Methylprednisolone is no longer used by surgeons. Achieving at least 80 mmHg mean arterial blood pressure is recommended by 70% neurosurgeons, 62% neuroanaesthetists, and 75% neurointensivists. Conclusions: Between 2012 and 2022, there was a paradigm shift in managing acute spinal cord injuries in the UK with earlier surgery and more intraoperative monitoring. Variability in practice persists due to lack of high-quality evidence and consensus guidelines. [ABSTRACT FROM AUTHOR]

This study aims to determine the effect of neurogenic, inflammatory, and infective fevers on acutely injured human spinal cord. In 86 patients with acute, severe traumatic spinal cord injuries (TSCIs; American Spinal Injury Association Impairment Scale (AIS), grades A–C) we monitored (starting within 72 h of injury, for up to 1 week) axillary temperature as well as injury site cord pressure, microdialysis (MD), and oxygen. High fever (temperature ≥38°C) was classified as neurogenic, infective, or inflammatory. The effect of these three fever types on injury-site physiology, metabolism, and inflammation was studied by analyzing 2864 h of intraspinal pressure (ISP), 1887 h of MD, and 840 h of tissue oxygen data. High fever occurred in 76.7% of the patients. The data show that temperature was higher in neurogenic than non-neurogenic fever. Neurogenic fever only occurred with injuries rostral to vertebral level T4. Compared with normothermia, fever was associated with reduced tissue glucose (all fevers), increased tissue lactate to pyruvate ratio (all fevers), reduced tissue oxygen (neurogenic + infective fevers), and elevated levels of pro-inflammatory cytokines/chemokines (infective fever). Spinal cord metabolic derangement preceded the onset of infective but not neurogenic or inflammatory fever. By considering five clinical characteristics (level of injury, axillary temperature, leukocyte count, C-reactive protein [CRP], and serum procalcitonin [PCT]), it was possible to confidently distinguish neurogenic from non-neurogenic high fever in 59.3% of cases. We conclude that neurogenic, infective, and inflammatory fevers occur commonly after acute, severe TSCI and are detrimental to the injured spinal cord with infective fever being the most injurious. Further studies are required to determine whether treating fever improves outcome. Accurately diagnosing neurogenic fever, as described, may reduce unnecessary septic screens and overuse of antibiotics in these patients. [ABSTRACT FROM AUTHOR]

We describe a novel progressive neurological syndrome complicating traumatic spinal cord injury (TSCI). Based on clinical and radiological features, we propose the term 'Chronic Relapsing Ascending Myelopathy' (CRAM). We distinguish between the previously described sub-acute progressive ascending myelopathy (SPAM) and post-traumatic syringomyelia (PTS), which may lie on a spectrum with CRAM. A 60-year-old man sustained a T4 ASIA-A complete TSCI. Four months post-injury, he developed a rapidly progressive ascending sensory level to C4. Clinical and radiological evaluation revealed ascending myelopathy with progressive T2 hyper-intense cord signal change. He underwent cord detethering and expansion duroplasty. Following an initial dramatic resolution of symptoms, the patient sustained two relapses, each 1-month post-discharge characterised by recurrence of disabling ascending sensory changes, each correlating with the radiological recurrence of cord signal change. Symptoms and radiological signal change permanently resolved with more extensive detethering and expansion duroplasty. There is radiological and clinical resolution at 1-year follow-up. Acute neurological deterioration post-TSCI may be due to SPAM or may occur after years due to PTS. We propose CRAM as a previously unrecognised phenomenon. The radiological characteristics overlap with SPAM. However, CRAM presents later and, clinically, behaves like PTS, but without cord cystic change. Cord detethering with expansion duroplasty are an effective treatment. [ABSTRACT FROM AUTHOR]

The article presents the abstract of the research "Involvement of Aquaporin-4 in Astroglial Cell Migration and Glial Scar Formation," by Samira Saadoun, Marios C. Papadopoulos et al. The study identifies a novel role for aquaporin-4 in astroglial cell migration as occurs during glial scar formation. It cites that astroglial cell migration was enhanced by a small extracellular osmotic gradient which suggests that aquaporin-4 facilitates water influx on the edge of a migrating cell. It provides evidence for the involvement of aquaporin-4 in astroglial cell migration which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.

Objectives: To determine the feasibility of monitoring tissue oxygen tension from the injury site (pscto2) in patients with acute, severe traumatic spinal cord injuries.Design: We inserted at the injury site a pressure probe, a microdialysis catheter, and an oxygen electrode to monitor for up to a week intraspinal pressure (ISP), spinal cord perfusion pressure (SCPP), tissue glucose, lactate/pyruvate ratio (LPR), and pscto2. We analyzed 2,213 hours of such data. Follow-up was 6-28 months postinjury.Setting: Single-center neurosurgical and neurocritical care units.Subjects: Twenty-six patients with traumatic spinal cord injuries, American spinal injury association Impairment Scale A-C. Probes were inserted within 72 hours of injury.Interventions: Insertion of subarachnoid oxygen electrode (Licox; Integra LifeSciences, Sophia-Antipolis, France), pressure probe, and microdialysis catheter.Measurements and Main Results: pscto2 was significantly influenced by ISP (pscto2 26.7 ± 0.3 mm Hg at ISP > 10 mmHg vs pscto2 22.7 ± 0.8 mm Hg at ISP ≤ 10 mm Hg), SCPP (pscto2 26.8 ± 0.3 mm Hg at SCPP < 90 mm Hg vs pscto2 32.1 ± 0.7 mm Hg at SCPP ≥ 90 mm Hg), tissue glucose (pscto2 26.8 ± 0.4 mm Hg at glucose < 6 mM vs 32.9 ± 0.5 mm Hg at glucose ≥ 6 mM), tissue LPR (pscto2 25.3 ± 0.4 mm Hg at LPR > 30 vs pscto2 31.3 ± 0.3 mm Hg at LPR ≤ 30), and fever (pscto2 28.8 ± 0.5 mm Hg at cord temperature 37-38°C vs pscto2 28.7 ± 0.8 mm Hg at cord temperature ≥ 39°C). Tissue hypoxia also occurred independent of these factors. Increasing the Fio2 by 0.48 increases pscto2 by 71.8% above baseline within 8.4 minutes. In patients with motor-incomplete injuries, fluctuations in pscto2 correlated with fluctuations in limb motor score. The injured cord spent 11% (39%) hours at pscto2 less than 5 mm Hg (< 20 mm Hg) in patients with motor-complete outcomes, compared with 1% (30%) hours at pscto2 less than 5 mm Hg (< 20 mm Hg) in patients with motor-incomplete outcomes. Complications were cerebrospinal fluid leak (5/26) and wound infection (1/26).Conclusions: This study lays the foundation for measuring and altering spinal cord oxygen at the injury site. Future studies are required to investigate whether this is an effective new therapy. [ABSTRACT FROM AUTHOR]

We recently showed that, after traumatic spinal cord injury (TSCI), laminectomy does not improve intraspinal pressure (ISP), spinal cord perfusion pressure (SCPP), or the vascular pressure reactivity index (sPRx) at the injury site sufficiently because of dural compression. This is an open label, prospective trial comparing combined bony and dural decompression versus laminectomy. Twenty-one patients with acute severe TSCI had re-alignment of the fracture and surgical fixation; 11 had laminectomy alone (laminectomy group) and 10 had laminectomy and duroplasty (laminectomy+duroplasty group). Primary outcomes were magnetic resonance imaging evidence of spinal cord decompression (increase in intradural space, cerebrospinal fluid around the injured cord) and spinal cord physiology (ISP, SCPP, sPRx). The laminectomy and laminectomy+duroplasty groups were well matched. Compared with the laminectomy group, the laminectomy+duroplasty group had greater increase in intradural space at the injury site and more effective decompression of the injured cord. In the laminectomy+duroplasty group, ISP was lower, SCPP higher, and sPRx lower, (i.e., improved vascular pressure reactivity), compared with the laminectomy group. Laminectomy+duroplasty caused cerebrospinal fluid leak that settled with lumbar drain in one patient and pseudomeningocele that resolved completely in five patients. We conclude that, after TSCI, laminectomy+duroplasty improves spinal cord radiological and physiological parameters more effectively than laminectomy alone. [ABSTRACT FROM AUTHOR]

Background: Acute, severe traumatic spinal cord injury often causes fecal incontinence. Currently, there are no treatments to improve anal function after traumatic spinal cord injury. Our study aims to determine whether, after traumatic spinal cord injury, anal function can be improved by interventions in the neuro-intensive care unit to alter the spinal cord perfusion pressure at the injury site. Methods: We recruited a cohort of patients with acute, severe traumatic spinal cord injuries (American Spinal Injury Association Impairment Scale grades A–C). They underwent surgical fixation within 72 h of the injury and insertion of an intrathecal pressure probe at the injury site to monitor intraspinal pressure and compute spinal cord perfusion pressure as mean arterial pressure minus intraspinal pressure. Injury-site monitoring was performed at the neuro-intensive care unit for up to a week after injury. During monitoring, anorectal manometry was also conducted over a range of spinal cord perfusion pressures. Results: Data were collected from 14 patients with consecutive traumatic spinal cord injury aged 22–67 years. The mean resting anal pressure was 44 cmH2O, which is considerably lower than the average for healthy patients, previously reported at 99 cmH2O. Mean resting anal pressure versus spinal cord perfusion pressure had an inverted U-shaped relation (Ȓ2 = 0.82), with the highest resting anal pressures being at a spinal cord perfusion pressure of approximately 100 mmHg. The recto-anal inhibitory reflex (transient relaxation of the internal anal sphincter during rectal distension), which is important for maintaining fecal continence, was present in 90% of attempts at high (90 mmHg) spinal cord perfusion pressure versus 70% of attempts at low (60 mmHg) spinal cord perfusion pressure (P < 0.05). During cough, the rise in anal pressure from baseline was 51 cmH2O at high (86 mmHg) spinal cord perfusion pressure versus 37 cmH2O at low (62 mmHg) spinal cord perfusion pressure (P < 0.0001). During anal squeeze, higher spinal cord perfusion pressure was associated with longer endurance time and spinal cord perfusion pressure of 70–90 mmHg was associated with stronger squeeze. There were no complications associated with anorectal manometry. Conclusions: Our data indicate that spinal cord injury causes severe disruption of anal sphincter function. Several key components of anal continence (resting anal pressure, recto-anal inhibitory reflex, and anal pressure during cough and squeeze) markedly improve at higher spinal cord perfusion pressure. Maintaining too high of spinal cord perfusion pressure may worsen anal continence. [ABSTRACT FROM AUTHOR]

The pathogenesis of neuromyelitis optica (NMO) involves targeting of NMO-immunoglobulin G (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system. Prior work provided evidence for complement-dependent cytotoxicity (CDC) in NMO lesion development. Here, we show that antibody-dependent cellular cytotoxicity (ADCC), in the absence of complement, can also produce NMO-like lesions. Antibody-dependent cellular cytotoxicity was produced in vitro by incubation of mouse astrocyte cultures with human recombinant monoclonal NMO-IgG and human natural killer cells (NK-cells). Injection of NMO-IgG and NK-cells in mouse brain caused loss of AQP4 and GFAP, two characteristic features of NMO lesions, but little myelin loss. Lesions were minimal or absent following injection of: (1) control (non-NMO) IgG with NK-cells; (2) NMO-IgG and NK-cells in AQP4-deficient mice; or (3) NMO-IgG and NK-cells in wild-type mice together with an excess of mutated NMO-IgG lacking ADCC effector function. NK-cells greatly exacerbated NMO lesions produced by NMO-IgG and complement in an ex vivo spinal cord slice model of NMO, causing marked myelin loss. NMO-IgG can thus produce astrocyte injury by ADCC in a complement-independent and dependent manner, suggesting the potential involvement of ADCC in NMO pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system. Circulating autoantibodies (NMO-immunoglobulin [Ig]G) against astrocyte water channel aquaporin-4 (AQP4) cause complement- and cell-mediated astrocyte damage with consequent neuroinflammation and demyelination. Current NMO therapies, which have limited efficacy, include immunosuppression and plasma exchange. The objective of this study was to develop a potential new NMO therapy based on blocking of pathogenic NMO-IgG binding to its target, AQP4. Methods: We generated nonpathogenic recombinant monoclonal anti-AQP4 antibodies that selectively block NMO-IgG binding to AQP4. These antibodies comprise a tight-binding anti-AQP4 Fab and a mutated Fc that lacks functionality for complement- and cell-mediated cytotoxicity. The efficacy of the blocking antibodies was studied using cell culture, spinal cord slice, and in vivo mouse models of NMO. Results: In AQP4-expressing cell cultures, the nonpathogenic competing antibodies blocked binding of NMO-IgG in human sera, reducing to near zero complement- and cell-mediated cytotoxicity. The antibodies prevented the development of NMO lesions in an ex vivo spinal cord slice model of NMO and in an in vivo mouse model, without causing cytotoxicity. Interpretation: Our results provide proof of concept for a therapy of NMO with blocking antibodies. The broad efficacy of antibody inhibition is likely due to steric competition because of its large physical size compared to AQP4. Blocker therapy to prevent binding of pathogenic autoantibodies to their targets may be useful for treatment of other autoimmune diseases as well. ANN NEUROL 2012; [ABSTRACT FROM AUTHOR]

Background/Objective: We have recently developed monitoring from the injury site in patients with acute, severe traumatic spinal cord injuries to facilitate their management in the intensive care unit. This is analogous to monitoring from the brain in patients with traumatic brain injuries. This study aims to determine whether, after traumatic spinal cord injury, fluctuations in the monitored physiological, and metabolic parameters at the injury site are causally linked to changes in limb power. Methods: This is an observational study of a cohort of adult patients with motor-incomplete spinal cord injuries, i.e., grade C American spinal injuries association Impairment Scale. A pressure probe and a microdialysis catheter were placed intradurally at the injury site. For up to a week after surgery, we monitored limb power, intraspinal pressure, spinal cord perfusion pressure, and tissue lactate-to-pyruvate ratio. We established correlations between these variables and performed Granger causality analysis. Results: Nineteen patients, aged 22–70 years, were recruited. Motor score versus intraspinal pressure had exponential decay relation (intraspinal pressure rise to 20 mmHg was associated with drop of 11 motor points, but little drop in motor points as intraspinal pressure rose further, R2 = 0.98). Motor score versus spinal cord perfusion pressure (up to 110 mmHg) had linear relation (1.4 motor point rise/10 mmHg rise in spinal cord perfusion pressure, R2 = 0.96). Motor score versus lactate-to-pyruvate ratio (greater than 20) also had linear relation (0.8 motor score drop/10-point rise in lactate-to-pyruvate ratio, R2 = 0.92). Increased intraspinal pressure Granger-caused increase in lactate-to-pyruvate ratio, decrease in spinal cord perfusion, and decrease in motor score. Increased spinal cord perfusion Granger-caused decrease in lactate-to-pyruvate ratio and increase in motor score. Increased lactate-to-pyruvate ratio Granger-caused increase in intraspinal pressure, decrease in spinal cord perfusion, and decrease in motor score. Causality analysis also revealed multiple vicious cycles that amplify insults to the cord thus exacerbating cord damage. Conclusion: Monitoring intraspinal pressure, spinal cord perfusion pressure, lactate-to-pyruvate ratio, and intervening to normalize these parameters are likely to improve limb power. [ABSTRACT FROM AUTHOR]

In five patients with acute, severe thoracic traumatic spinal cord injuries (TSCIs), American spinal injuries association Impairment Scale (AIS) grades A–C, we induced cord hypothermia (33 °C) then rewarming (37 °C). A pressure probe and a microdialysis catheter were placed intradurally at the injury site to monitor intraspinal pressure (ISP), spinal cord perfusion pressure (SCPP), tissue metabolism and inflammation. Cord hypothermia–rewarming, applied to awake patients, did not cause discomfort or neurological deterioration. Cooling did not affect cord physiology (ISP, SCPP), but markedly altered cord metabolism (increased glucose, lactate, lactate/pyruvate ratio (LPR), glutamate; decreased glycerol) and markedly reduced cord inflammation (reduced IL1β, IL8, MCP, MIP1α, MIP1β). Compared with pre-cooling baseline, rewarming was associated with significantly worse cord physiology (increased ICP, decreased SCPP), cord metabolism (increased lactate, LPR; decreased glucose, glycerol) and cord inflammation (increased IL1β, IL8, IL4, IL10, MCP, MIP1α). The study was terminated because three patients developed delayed wound infections. At 18-months, two patients improved and three stayed the same. We conclude that, after TSCI, hypothermia is potentially beneficial by reducing cord inflammation, though after rewarming these benefits are lost due to increases in cord swelling, ischemia and inflammation. We thus urge caution when using hypothermia–rewarming therapeutically in TSCI. [ABSTRACT FROM AUTHOR]

In some centers, monitoring lumbar cerebrospinal fluid (CSF) is used to guide management of patients with acute traumatic spinal cord injuries (TSCI) and draining lumbar CSF to improve spinal cord perfusion. Here, we investigate whether the lumbar CSF provides accurate information about the injury site and the effect of draining lumbar CSF on injury site perfusion. In 13 TSCI patients, we simultaneously monitored lumbar CSF pressure (CSFP) and intraspinal pressure (ISP) from the injury site. Using CSFP or ISP, we computed spinal cord perfusion pressure (SCPP), vascular pressure reactivity index (sPRx) and optimum SCPP (SCPPopt). We also assessed the effect on ISP of draining 10 mL CSF. Metabolites at the injury site were compared with metabolites in the lumbar CSF. We found that ISP was pulsatile, but CSFP had low pulse pressure and was non-pulsatile 21% of the time. There was weak or no correlation between CSFP versus ISP (R = -0.11), SCPP(csf) versus SCPP(ISP) (R = 0.39), and sPRx(csf) versus sPRx(ISP) (R = 0.45). CSF drainage caused no significant change in ISP in 7/12 patients and a significant drop of <5 mm Hg in 4/12 patients and of ∼8 mm Hg in 1/12 patients. Metabolite concentrations in the CSF versus the injury site did not correlate for lactate (R = 0.00), pyruvate (R = -0.12) or lactate-to-pyruvate ratio (R = -0.05) with weak correlations noted for glucose (R = 0.31), glutamate (R = 0.61), and glycerol (R = 0.56). We conclude that, after a severe TSCI, monitoring from the lumbar CSF provides only limited information about the injury site and that lumbar CSF drainage does not effectively reduce ISP in most patients. [ABSTRACT FROM AUTHOR]

Background/objectives: We recently developed techniques to monitor intraspinal pressure (ISP) and spinal cord perfusion pressure (SCPP) from the injury site to compute the optimum SCPP (SCPPopt) in patients with acute traumatic spinal cord injury (TSCI). We hypothesized that ISP and SCPPopt can be predicted using clinical factors instead of ISP monitoring.Methods: Sixty-four TSCI patients, grades A-C (American spinal injuries association Impairment Scale, AIS), were analyzed. For 24 h after surgery, we monitored ISP and SCPP and computed SCPPopt (SCPP that optimizes pressure reactivity). We studied how well 28 factors correlate with mean ISP or SCPPopt including 7 patient-related, 3 injury-related, 6 management-related, and 12 preoperative MRI-related factors.Results: All patients underwent surgery to restore normal spinal alignment within 72 h of injury. Fifty-one percentage had U-shaped sPRx versus SCPP curves, thus allowing SCPPopt to be computed. Thirteen percentage, all AIS grade A or B, had no U-shaped sPRx versus SCPP curves. Thirty-six percentage (22/64) had U-shaped sPRx versus SCPP curves, but the SCPP did not reach the minimum of the curve, and thus, an exact SCPPopt could not be calculated. In total 5/28 factors were associated with lower ISP: older age, excess alcohol consumption, nonconus medullaris injury, expansion duroplasty, and less intraoperative bleeding. In a multivariate logistic regression model, these 5 factors predicted ISP as normal or high with 73% accuracy. Only 2/28 factors correlated with lower SCPPopt: higher mean ISP and conus medullaris injury. In an ordinal multivariate logistic regression model, these 2 factors predicted SCPPopt as low, medium-low, medium-high, or high with only 42% accuracy. No MRI factors correlated with ISP or SCPPopt.Conclusions: Elevated ISP can be predicted by clinical factors. Modifiable factors that may lower ISP are: reducing surgical bleeding and performing expansion duroplasty. No factors accurately predict SCPPopt; thus, invasive monitoring remains the only way to estimate SCPPopt. [ABSTRACT FROM AUTHOR]

The effect of traumatic spinal cord injury (TSCI) on spinal cord blood flow (SCBF) in humans is unknown. Whether intervention to achieve the recommended mean arterial pressure (MAP) guideline of 85–90 mm Hg improves SCBF is also unclear. Here, we use laser speckle contrast imaging intraoperatively to visualize blood flow at the injury site in 22 patients with acute, severe spinal cord injuries (American Spinal Injuries Association Impairment Scale, grades A–C). In 17 of 22 patients, injury-site metabolism was also monitored with a microdialysis catheter placed intradurally on the surface of the injured cord. We observed three different SCBF patterns, characterized by distinct injury-site metabolic signatures, which we term necrosis-penumbra, hyperperfusion, and patchy-perfusion. The necrosis-penumbra pattern, only observed in thoracic injuries, had a core of low blood flow (necrosis) with regions of intermediate blood flow on either side (penumbra). The hyperperfusion pattern, only observed in cervical injuries, had very high blood flow throughout the injury site. The patchy-perfusion pattern, found in cervical and thoracic injuries, had irregular regions of low, intermediate, and high blood flow. Though intervention to increase MAP by 20 mm Hg increased overall blood flow at the injury site, in 5 of 22 patients, blood flow increased in some regions, but, surprisingly, decreased in other regions. We term this phenomenon blood pressure–induced local steal. In 7 of 19 patients with MAP 85–90 mm Hg, parts of the injury site were only perfused in systole, but not in diastole, which we term diastolic ischemia. We conclude that acute, severe TSCI produces three pathological blood flow patterns at the injury site. Intervention to increase blood pressure may elicit potentially detrimental SCBF responses in some patients. [ABSTRACT FROM AUTHOR]

To guide management of patients with acute spinal cord injuries, we developed intraspinal pressure monitoring from the injury site. Here, we examine the complex fluctuations in the intraspinal pressure signal using network theory. We analyzed 7097 h of intraspinal pressure data from 58 patients with severe cord injuries. Intraspinal pressure signals were split into hourly windows. Each window was mapped into a visibility graph as follows. Vertical bars were drawn at 0.1 Hz representing signal amplitudes. Each bar produced a node, thus totalling 360 nodes per graph. Two nodes were linked with an edge if the straight line through the nodes did not intersect a bar. We computed several topological metrics for each graph including diameter, modularity, eccentricity, and small-worldness. Patients were followed up for 20 months on average. Our data show that the topological structure of intraspinal pressure visibility graphs is highly sensitive to pathological events at the injury site, including cord compression (high intraspinal pressure), ischemia (low spinal cord perfusion pressure), and deranged autoregulation (high spinal pressure reactivity index). These pathological changes correlate with long graph diameter, high modularity, high eccentricity and reduced small-worldness. In a multivariate logistic regression model, age, neurological status on admission, and average node eccentricity were independent predictors of neurological improvement. We conclude that analysis of intraspinal pressure fluctuations after spinal cord injury as graphs, rather than as time series, captures clinically important information. Our novel technique may be applied to other signals recorded from injured central nervous system (CNS); for example, intracranial pressure, tissue metabolite, and oxygen levels. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the effect of fever after acute, traumatic spinal cord injury on injury site metabolism and patient outcome.Design: Longitudinal cohort study. In 44 patients (London cohort), we determined the effect of fever on intrathecal injury site metabolism by analyzing 1,767 hours of intraspinal pressure and 759 hours of microdialysis data. We also determined the effect of fever burden, computed for the first 2 weeks in hospital, on neurologic outcome. A distinct cohort of 33 patients (Berlin cohort) was used to independently validate the effect of fever burden on outcome.Setting: ICUs in London and Berlin.Patients: Seventy-seven patients with acute, traumatic spinal cord injuries.Interventions: In the London patients, a pressure probe and a microdialysis catheter were placed intradurally on the surface of the injured cord for up to a week.Measurements and Main Results: Fever (> 37.5°C) occurs frequently (37% of the time) after spinal cord injury. High-grade fever (≥ 38°C) was associated with significantly more deranged metabolite levels than normothermia (36.5-37.5°C), that is, lower tissue glucose (median 2.0 vs 3.3 mM), higher lactate (7.8 vs 5.4 mM), higher glutamate (7.8 vs 6.4 µM), and higher lactate-to-pyruvate ratio (38.9 vs 29.3). High-grade fever was particularly detrimental on injury site metabolism when the peripheral leukocyte count was high. In the London and Berlin cohorts, high fever burden correlated with less neurologic improvement.Conclusions: Early after spinal cord injury, fever is associated with more deranged injury site metabolism than normothermia and worse prognosis. [ABSTRACT FROM AUTHOR]

The optimum spinal cord perfusion pressure (SCPP) after traumatic spinal cord injury (TSCI) is unknown. Here, we describe techniques to compute and display the optimum SCPP in real time. We recruited adults within 72 h of severe TSCI (American Spinal Injuries Association [ASIA] grades A-C). A pressure probe and a microdialysis catheter were placed on the injured cord. SCPP was computed as mean arterial pressure (MAP) minus intraspinal pressure (ISP), spinal pressure reactivity index (sPRx) as the running ISP/MAP correlation coefficient, and continuous optimum SCPP (cSCPPopt) as the SCPP that minimizes sPRx in a moving 4-h window. In 45 patients, we monitored ISP and blood pressure. In 14 patients, we also monitored injury site metabolism. cSCPPopt could be computed 45% of the time. Mean cSCPPopt varied by up to 60 mm Hg between patients. Each patient's cSCPPopt varied with time (standard deviation 10-20 mm Hg). Color-coded maps showing the sPRx/SCPP curve evolution enhanced visualization of cSCPPopt. Periods when SCPP ≈ cSCPPopt were associated with low injury site glucose, high pyruvate, and high lactate. Mean SCPP deviation from cSCPPopt correlated with worse neurological outcome at 9-12 months: ASIA grade improved in 30% of patients with <5 mm Hg deviation, 10% of patients with 5-15 mm Hg deviation, and no one with >15 mm Hg deviation. We conclude that real-time computation and visualization of cSCPPopt after TSCI are feasible. cSCPPopt appears to enhance glucose utilization at the injury site and varies widely between and within patients. Our data suggest that targeting cSCPPopt after TSCI might improve neurological outcome. [ABSTRACT FROM AUTHOR]

The management of patients having traumatic spinal cord injury would benefit from understanding and monitoring of spinal cord metabolic states. We hypothesized that the metabolism of the injured spinal cord could be visualized using Kohonen self-organizing maps. Sixteen patients with acute, severe spinal cord injuries were studied. Starting within 72 h of the injury, and for up to a week, we monitored the injury site hourly for tissue glucose, lactate, pyruvate, glutamate, and glycerol using microdialysis as well as intraspinal pressure and spinal cord perfusion pressure. A Kohonen map, which is an unsupervised, self-organizing topology-preserving neural network, was used to analyze 3366 h of monitoring data. We first visualized the different spinal cord metabolic states. Our data show that the injured cord assumes one or more of four metabolic states. On the basis of their metabolite profiles, we termed these states near-normal, ischemic, hypermetabolic, and distal. We then visualized how patients' intraspinal pressure and spinal cord perfusion pressure affect spinal cord metabolism. This revealed that for more than 60% of the time, spinal cord metabolism is patient-specific; periods of high intraspinal pressure or low perfusion pressure are not associated with specific spinal cord metabolic patterns. Finally, we determined relationships between spinal cord metabolism and neurological status. Patients with complete deficits have shorter periods of near-normal spinal cord metabolic states (7 ± 4% vs. 58 ± 12%, p < 0.01, mean ± standard error) and more variable injury site metabolic responses (metabolism spread in 70 ± 11 vs. 40 ± 6 hexagons, p < 0.05), compared with patients who have incomplete neurological deficits. We conclude that Kohonen maps allow us to visualize the metabolic responses of the injured spinal cord and may thus aid us in treating patients with acute spinal cord injuries. [ABSTRACT FROM AUTHOR]

Objective: There is lack of monitoring from the injury site to guide management of patients with acute traumatic spinal cord injury. Here, we describe a bedside microdialysis monitoring technique for optimizing spinal cord perfusion and drug delivery at the injury site.Methods: Fourteen patients were recruited within 72 hours of severe spinal cord injury. We inserted intradurally at the injury site a pressure probe, to monitor continuously spinal cord perfusion pressure, and a microdialysis catheter, to monitor hourly glycerol, glutamate, glucose, lactate, and pyruvate. The pressure probe and microdialysis catheter were placed on the surface of the injured cord.Results: Microdialysis monitoring did not cause serious complications. Spinal cord perfusion pressure 90 to 100mm Hg and tissue glucose >4.5mM minimized metabolic derangement at the injury site. Increasing spinal cord perfusion pressure by ∼10mm Hg increased the entry of intravenously administered dexamethasone at the injury site 3-fold.Interpretation: This study determined the optimum spinal cord perfusion pressure and optimum tissue glucose concentration at the injury site. We also identified spinal cord perfusion pressure as a key determinant of drug entry into the injured spinal cord. Our findings challenge current guidelines, which recommend maintaining mean arterial pressure at 85 to 90mm Hg for a week after spinal cord injury. We propose that future drug trials for spinal cord injury include pressure and microdialysis monitoring to optimize spinal cord perfusion and maximize drug delivery at the injury site. Ann Neurol 2016;80:522-531. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of spinal cord and optic nerve caused by pathogenic autoantibodies (NMO-IgG) against astrocyte aquaporin-4 (AQP4). We developed a high-throughput screen to identify blockers of NMO-IgG binding to human AQP4 using a human recombinant monoclonal NMO-IgG and transfected Fisher rat thyroid cells stably expressing human M23-AQP4. Screening of ~60,000 compounds yielded the antiviral arbidol, the flavonoid tamarixetin, and several plant-derived berbamine alkaloids, each of which blocked NMO-IgG binding to AQP4 without affecting AQP4 expression, array assembly, or water permeability. The compounds inhibited NMO-IgG binding to AQP4 in NMO patient sera and blocked NMO-IgG-dependent complement- and cell-mediated cytotoxicity with IC50 down to ~5 µM. Docking computations identified putative sites of blocker binding at the extracellular surface of AQP4. The blockers did not affect complement-dependent cytotoxicity caused by anti-GD3 antibody binding to ganglioside GD3. The blockers reduced by >80% the severity of NMO lesions in an ex vivo spinal cord slice culture model of NMO and in mice in vivo. Our results provide proof of concept for a small-molecule blocker strategy to reduce NMO pathology. Small-molecule blockers may also be useful for other autoimmune diseases caused by binding of pathogenic autoantibodies to defined targets. [ABSTRACT FROM AUTHOR]

Introduction Human African trypanosomiasis (sleeping sickness) affects up to half a million people every year in sub-Saharan Africa. Because current diagnostic tests for the disease have low accuracy, we sought to develop a novel test that can diagnose human African trypanosomiasis with high sensitivity and specificity. Methods We applied serum samples from 85 patients with African trypanosomiasis and 146 control patients who had other parasitic and non-parasitic infections to a weak cation exchange chip, and analyzed with surface-enhanced laser desorption-ionisation time-of-flight mass spectrometry. Mass spectra were then assessed with three powerful data-mining tools: a tree classifier, a neural network, and a genetic algorithm. Findings Spectra (2--100 kDa) were grouped into training (n=122) and testing (n=109) sets. The training set enabled data-mining software to identify distinct serum proteomic signatures characteristic of human African trypanosomiasis among 206 protein clusters. Sensitivity and specificity, determined with the testing set, were 100% and 98.6%, respectively, when the majority opinion of the three algorithms was considered. This novel approach is much more accurate than any other diagnostic test. Interpretation Our report of the accurate diagnosis of an infection by use of proteomic signature analysis could form the basis for diagnostic tests for the disease, monitoring of response to treatment, and for improving the accuracy of patient recruitment in large-scale epidemiological studies. [ABSTRACT FROM AUTHOR]