Subarachnoid haemorrhage: an unusual complication of implantation of an intrathecal baclofen pump.

STUDY DESIGN: Single case-report. OBJECTIVES: To describe subarachnoid haemorrhage; an unusual complication following implantation of an intrathecal baclofen pump in an adult with spinal cord injury. SETTING: Princess Royal Spinal Injuries Unit, Sheffield, UK. METHODS: Review of the medical notes and literature. RESULTS: A 77-year-old man with an incomplete ASIA-C spinal cord injury at C5 level sustained 2 years previously, developed subarachnoid haemorrhage following implantation of an intrathecal baclofen pump for the management of spasticity that was unresponsive to treatment with oral antispasticity agents. CONCLUSION: Subarachnoid haemorrhage can occur as a rare complication of insertion of Intrathecal baclofen pump. This need to be considered while evaluating patients who present with headache, confusion and seizures in the post operative period. SPONSORSHIP: Not applicable.

Orthodeoxia syndrome: a rare complication of ASD in spinal cord injury.

STUDY DESIGN: This is a single-subject case report. OBJECTIVES: The objective is to describe and discuss a rare presentation of orthodeoxia after spinal cord injury in a previously healthy adult with an asymptomatic and undiagnosed atrial septal defect. SETTING: This study was conducted at the Tertiary Care Spinal Injuries Center in Sheffield, UK. METHODS: An 81-year-old woman who was otherwise healthy and active sustained a polytrauma following a road traffic collision. Her injuries were managed conservatively. As a complication of epidural analgesia, she developed a complete thoracic paraplegia secondary to an epidural hematoma. She was found to have repeated episodes of severe deoxemia, without any significant postural hypotension when attempts were made to sit her up in bed. Detailed investigations were done to ascertain the cause for this deoxemia. RESULTS: Echocardiography revealed an atrial septal defect; agitated saline contrast transesophageal ultrasound done in various positions revealed interatrial defect with reversal of shunting when the patient was made to sit up in bed. CONCLUSION: Orthodeoxia is an uncommon finding in spinal injury patients. Detailed investigations at an early stage of rehabilitation need to be done to rule out cardiac causes after ruling out the common medical complications seen in the acute and subacute phases following spinal cord injury.

Superimposed myasthenia gravis in chronic spinal cord injury: a case report.

STUDY DESIGN: Case report. BACKGROUND/OBJECTIVE: Myasthenia gravis (MG) complicating spinal cord injury (SCI) is extremely rare. We report a patient with SCI developing MG leading to death. There are no similar articles at present on literature search. CASE REPORT: A 54-year-old man, paralysed at the T12 level (ASIA A) for 40 years, was admitted for surgical repair of his grade IV sacral pressure sore. During the admission he developed diplopia, fluctuating dysphagia and slurred speech. Elevated anti-acetylcholine receptor antibodies and single fibre electromyography confirmed the diagnosis of MG and pyridostigmine was commenced. His admission was complicated by intermittent episodes of unexplained tachycardia and tachypnoea. He succumbed following cardio respiratory within 6 weeks of admission. Post mortem examination was inconclusive of a definite cause of death. In the presence of SCI, it can be challenging to diagnose MG or its complications like myasthenic and cholinergic crisis. CONCLUSION: The case highlights the difficulty in diagnosis and management of MG in persons with SCI.

Mapping of the binding site for Mannheimia haemolytica leukotoxin within bovine CD18.

To map the site involved in Mannheimia haemolytica leukotoxin (LktA) binding and biological activity within bovine CD18, bovine x human CD18 chimeric constructs were generated and coexpressed with bovine CD11a in K562 cells. Studies with the chimeric leukocyte function-associated antigen 1 transductants demonstrate that the site required for LktA binding and biological effects resides within amino acid residues 500 and 600 of the extracellular region of bovine CD18.

Protective effect of dexamethasone in experimental bovine pneumonic mannheimiosis.

Clinical and experimental studies provide unequivocal evidence that neutrophils participate in the pathogenesis of lung injury in bovine pneumonic mannheimiosis (BPM). Since the inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 play a central role in the recruitment and activation of neutrophils, we hypothesize that pharmacological inhibition of their expression may prevent or reduce the inflammatory lung injury that is characteristic of the disease. The purpose of this study was to determine whether systemic therapy with dexamethasone sodium phosphate (DEX), a potent inhibitor of inflammatory cytokine synthesis, ameliorates disease development in an in vivo experimental model of BPM. Four experimental calves were treated intravenously with DEX (2 mg/kg 6 h prior to infection, 2 mg/kg immediately prior to infection, and 1 mg/kg every 12 h thereafter), while two placebo-treated control calves received dose-matched volumes of sterile saline. Disease was induced in the left lungs of the six calves by endobronchial administration of Mannheimia haemolytica. Clinical disease was characterized using a non-parametric scoring system, and the extent of gross pulmonary pathology affecting the left lung 48 h post-infection (PI) was determined using morphometric methods. Disease scores for DEX-treated calves were significantly lower than those for placebo-treated controls at all time points beyond 2 h PI (P<0.05) and the percent volume of the left lung exhibiting gross pneumonic lesions was significantly lower in DEX-treated calves (6.0+/-1.1%) as compared to controls (68.9+/-13.3%), P<0.05. In addition, histopathological lesions were less severe and extensive in DEX-treated calves. These findings indicate that pharmacological modulation of pulmonary inflammation may represent an alternative approach to control this disease. Successful implementation of this strategy will require additional research to identify drug agents that target the expression of cytokines and other inflammatory mediators without compromising host immune responses.

Pharmacological inhibition of Mannheimia haemolytica lipopolysaccharide and leukotoxin-induced cytokine expression in bovine alveolar macrophages.

The inflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1 beta (IL-1beta), and interleukin-8 (IL-8) are believed to contribute to the pathogenesis of lung injury in bovine pneumonic mannheimiosis (BPM) caused by Mannheimia (Pasteurella) haemolytica. Inflammatory cytokines may, therefore, represent therapeutic targets to be modulated for the purpose of treating or preventing this important disease of cattle. The purpose of this study was to evaluate the ability of six pharmacological agents to suppress the expression of TNFalpha, IL-1beta, and IL-8 genes and proteins in bovine alveolar macrophages (AM) exposed to M. haemolytica lipopolysaccharide (LPS) and leukotoxin (LktA) in vitro. The compounds tested included dexamethasone (DEX), tetrahydropapaveroline (THP), pentoxifylline (PTX), rolipram (ROL), SB203580 (SB), and thalidomide (THL). Cytokine expression was induced by the addition of purified M. haemolytica LPS and LktA to AM cell cultures following pretreatment with inhibitor compounds. Secretion of TNFalpha, IL-1beta, and IL-8 proteins into the cell culture supernatant was measured using enzyme-linked immunosorbent assays, and steady-state accumulation of cytokine-specific mRNA was measured by northern blot analysis. Dose-dependent inhibition of cytokine secretion occurred in response to pretreatment of AM with DEX (TNFalpha, IL-1beta, IL-8), THP (TNFalpha, IL-1beta, IL-8), PTX (TNFalpha, IL-1beta, IL-8), ROL (TNFalpha, IL-1beta), and SB (TNFalpha, IL-8). Significant dose-dependent inhibition of cytokine mRNA expression occurred in response to pretreatment with DEX (TNFalpha, IL-1beta, IL-8), THP (TNFalpha, IL-1beta, IL-8), and PTX (TNFalpha). DEX was the most effective inhibitor by far; pretreatment with this compound yielded greater than 95% inhibition of cytokine gene and protein expression over a broad range of concentrations. These findings demonstrate that DEX, THP, PTX, ROL, and SB are capable of suppressing inflammatory cytokine secretion by bovine AM in vitro. If pulmonary cytokine secretion may be similarly inhibited in vivo, anti-cytokine therapy may represent a novel strategy for the management of BPM.

Biological effects of two genetically defined leukotoxin mutants of Mannheimia haemolytica.

Mannheimia(Pasteurella)haemolytica serotype 1 is the primary causative agent responsible for bovine pneumonic mannheimiosis, also known as shipping fever in cattle. The bacterium produces a variety of virulence factors, foremost of which is the exotoxic leukotoxin. The leukotoxin is a calcium-dependent cytolysin that is a member of the RTX (repeats in toxin) family and exhibits a narrow cell-type and species specificity and has biological effects only on ruminant leukocytes and platelets. The genetic organization of the leukotoxin is comprised of four genes: lktC, lktA, lktB and lktD. The lktA structural gene encodes the protoxin (pro-LktA) and lktC encodes a transacylase that post-translationally modifies the inactive pro-LktA to a biologically active wild-type leukotoxin (LktA). The LktA has been implicated as the key factor that contributes to the pathogenesis of lung injury associated with the disease and considerable efforts have been employed in abrogating toxin function while retaining immunogenicity, with an eye towards design of attenuated vaccines. We hypothesized that the pro-LktA retains the ability to cause biological effects on target cells as has been reported in the case of the closely related RTX toxin alpha-hemolysin (HlyA). We also examined the biological effects of an amino-terminal truncation mutant leukotoxin DeltaLktA on target cells. Thus the objectives of our study were to investigate whether two different mutant leukotoxins, one a nonacylated pro-LktA, and the other lacking 344 amino acids at the N-terminal end of the LktA protein; DeltaLktA, are capable of (i). binding to the beta2-integrin leukotoxin receptor, (ii). inducing the elevation of second messenger intracellular calcium ([Ca(2+)](i)), and (iii). inducing inflammatory gene expression, reactive oxygen metabolites (ROMs) and cytolysis in target cells. Our results demonstrate that neither acylation nor the amino terminal 344 amino acids are required for LktA binding but are essential for LktA-induced [Ca(2+)](i) elevation, generation of ROM, generation of the inflammatory cytokine IL-8 and cytolysis in target cells.

A comparison of heparin/warfarin and enoxaparin thromboprophylaxis in spinal cord injury: the Sheffield experience.

OBJECTIVES: To compare the safety and effectiveness of two different thromboprophylactic protocols in the management of patients with spinal cord injury - one using heparin/warfarin and the other using enoxaparin. STUDY DESIGN: Retrospective. SETTING: Princess Royal Spinal Injuries Unit, Sheffield, UK. METHODS: Retrospective review of two cohorts of patients with acute spinal injury admitted to a supra-regional spinal injuries centre and treated with different pharmacological agents. One group received heparin/warfarin in combination with antiembolism stockings and mechanical measures for thromboprophylaxis whereas the second group received enoxaparin in combination with the other measures. Patients who developed clinical symptoms suggestive of deep vein thrombosis or pulmonary embolism were investigated as appropriate. RESULTS: Four of the 101 patients on heparin/warfarin developed symptoms of venous thromboembolism compared to 13 of the 72 who were on enoxaparin. Of the 13, three had been on 40 mg of enoxaparin daily and 10 on 20 mg enoxaparin daily. Six patients on enoxaparin and one patient on warfarin developed thromboembolic complications after they had been mobilised and the anticoagulant discontinued. Eight patients on warfarin prophylaxis and three patients on enoxaparin developed haemorrhagic complications necessitating cessation of therapy. CONCLUSION: This study suggests that the traditional protocol of warfarin/heparin for thromboprophylaxis in spinal cord injury patients remains a safer option than enoxaparin.

Neuropathic lumbar spondylolisthesis--a rare trigger for posture induced autonomic dysreflexia.

STUDY DESIGN: Case report. OBJECTIVES: Description of a rare trigger for autonomic dysreflexia. SETTING: Princess Royal Spinal Injuries Unit, Sheffield. METHODS AND RESULTS: A case of Charcot's spine (neuropathic spinal arthropathy) in a woman with a traumatic T5 paraplegia is described. She developed symptoms of autonomic dysreflexia, brought on by changes in posture. The postural variation was attributable to a freely mobile neuropathic spondylolisthesis at the L4/5 level. A laminectomy performed for the implantation of a sacral anterior root stimulator was identified as a causative factor in the development of the neuropathic joint. Surgical stabilisation and fusion resulted in amelioration of her symptoms. CONCLUSION: Neuropathic spine is a rare cause of autonomic dysreflexia that should be considered when other more common factors have been excluded. The development of Charcot's spine in the spinal cord injured population is facilitated by surgical procedures involving the vertebrae.

Mannheimia haemolytica leukotoxin activates a nonreceptor tyrosine kinase signaling cascade in bovine leukocytes, which induces biological effects.

The leukotoxin (LktA) produced by Mannheimia haemolytica binds to bovine lymphocyte function-associated antigen 1 (LFA-1) and induces biological effects in bovine leukocytes in a cellular and species-specific fashion. We have previously shown that LktA also binds to porcine LFA-1 without eliciting any effects. These findings suggest that the specificity of LktA effects must entail both binding to LFA-1 and activation of signaling pathways which are present in bovine leukocytes. However, the signaling pathways leading to biological effects upon LktA binding to LFA-1 have not been characterized. In this context, several reports have indicated that ligand binding to LFA-1 results in activation of a nonreceptor tyrosine kinase (NRTK) signaling cascade. We designed experiments with the following objectives: (i) to determine whether LktA binding to LFA-1 leads to activation of NRTKs, (ii) to examine whether LktA-induced NRTK activation is target cell specific, and (iii) to determine whether LktA-induced NRTK activation is required for biological effects. We used a biologically inactive mutant leukotoxin (DeltaLktA) for comparison with LktA. Our results indicate that LktA induces tyrosine phosphorylation (TP) of the CD18 tail of LFA-1 in bovine leukocytes. The DeltaLktA mutant does not induce TP of the CD18 tail, albeit binding to bovine LFA-1. LktA-induced TP of the CD18 tail was attenuated by an NRTK inhibitor, herbimycin A; a phosphatidylinositol 3'-kinase (PI 3-kinase) inhibitor, wortmannin; and a Src kinase inhibitor, PP2, in a concentration-dependent manner. Furthermore, LktA induces TP of the CD18 tail in bovine, but not porcine, leukocytes. Moreover, LktA-induced intracellular calcium ([Ca2+]i) elevation was also inhibited by herbimycin A, wortmannin, and PP2. Thus, our data represent the first evidence that binding of LktA to bovine LFA-1 induces a species-specific NRTK signaling cascade involving PI 3-kinase and Src kinases and that this signaling cascade is required for LktA-induced biological effects.