Kazunari Fushimi

Pathogenesis of Morquio A syndrome: An autopsied case reveals systemic storage disorder

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase, which results in systemic accumulation of glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. Accumulation of these GAGs causes characteristic features as disproportionate dwarfism associated with skeletal deformities, genu valgum, pigeon chest, joint laxity, and kyphoscoliosis. However, the pathological mechanism of systemic skeletal dysplasia and involvement of other tissues remain unanswered in the paucity of availability of an autopsied case and successive systemic analyses of multiple tissues. We report here a 20-year-old male autopsied case with MPS IVA, who developed characteristic skeletal features by the age of 1.5 years and died of acute respiratory distress syndrome five days later after occipito-C1-C2 cervical fusion. We pathohistologically analyzed postmortem tissues including trachea, lung, thyroid, humerus, aorta, heart, liver, spleen, kidney, testes, bone marrow, and lumbar vertebrae. The postmortem tissues relevant with clinical findings demonstrated 1) systemic storage materials in multiple tissues beyond cartilage, 2) severely vacuolated and ballooned chondrocytes in trachea, humerus, vertebrae, and thyroid cartilage with disorganized extracellular matrix and poor ossification, 3) appearance of foam cells and macrophages in lung, aorta, heart valves, heart muscle, trachea, visceral organs, and bone marrow, and 4) storage of chondrotin-6-sulfate in aorta. This is the first autopsied case with MPS IVA whose multiple tissues have been analyzed pathohistologically and these pathological findings should provide a new insight into pathogenesis of MPS IVA.

Prostaglandin E2 downregulates TNF-α-induced production of matrix metalloproteinase-1 in HCS-2/8 chondrocytes by inhibiting Raf-1/MEK/ERK cascade through EP4 prostanoid receptor activation

Matrix metalloproteinase‐1 (MMP‐1, collagenase‐1) plays a pivotal role in the process of joint destruction in degenerative joint diseases. We have examined the regulation of MMP‐1 production in human chondrocytic HCS‐2/8 cells stimulated by tumor necrosis factor‐α (TNF‐α). In response to TNF‐α, MMP‐1 is induced and actively released from HCS‐2/8 cells. The induction of MMP‐1 expression correlates with activation of ERK1/2, MEK, and Raf‐1, and is potently prevented by U0126, a selective inhibitor of MEK1/2 activation. In contrast, SB203580, a selective p38 mitogen‐activated protein kinases (MAPK) inhibitor, had no effects on TNF‐α‐induced MMP‐1 release. A serine/threonine kinase, Akt was not activated in TNF‐α‐stimulated HCS‐2/8 cells. TNF‐α stimulated the production of PGE2 in addition to MMP‐1 in HCS‐2/8 cells. Exogenously added PGE2 potently inhibited TNF‐α‐induced both MMP‐1 production and activation of ERK1/2. The effects of PGE2 were mimicked by ONO‐AE1‐329, a selective EP4 receptor agonist but not by butaprost, a selective EP2 agonist. In contrast, blockade of endogenously produced PGE2 signaling by ONO‐AE3‐208, a selective EP4 receptor antagonist, enhanced TNF‐α‐induced MMP‐1 production. Furthermore, the suppression of MMP‐1 production by exogenously added PGE2 was reversed by ONO‐AE3‐208. Activation of EP4 receptor resulted in cAMP‐mediated phosphorylation of Raf‐1 on Ser259, a negative regulatory site, and blocked activation of Raf‐1/MEK/ERK cascade. Taken together, these findings indicate that Raf‐1/MEK/ERK signaling pathway plays a crucial role in the production of MMP‐1 in HCS‐2/8 cells in response to TNF‐α, and that the produced PGE2 downregulates the expression of MMP‐1 by blockage of TNF‐α‐induced Raf‐1 activation through EP4‐PGE2 receptor activation. J. Cell. Biochem. 100: 783–793, 2007.

Morphologic Changes in Contralateral Lumbar Foramen in Unilateral Cantilever Transforaminal Lumbar Interbody Fusion Using Kidney-type Intervertebral Spacers.

Study Design: A retrospective study of 58 patients undergoing cantilever transforaminal lumbar interbody fusion (c-TLIF). Objectives: To evaluate morphologic changes in the intervertebral foramen (IVF) on the side contralateral to spacer insertion in patients undergoing c-TLIF using plain x-ray films and computed tomography scan. Summary of Background Data: The morphologic changes in the contralateral lumbar foramen in c-TLIF using unilateral insertion of spacers have not been well studied. Materials and Methods: Fifty-eight consecutive patients with lumbar dysplastic changes or degenerative disk diseases underwent c-TLIF using 96 kidney-type spacers with local bone grafts. Radiographic findings (sagittal disk angle), computed tomography scan findings (coronal disk angle, disk height, foraminal height (FH), foraminal width, and cross-sectional area of IVF in contralateral lumbar foramen) were compared between preoperative period and 6 months after surgery. The correlations between contralateral lumbar foraminal dimensions and disk height, sagittal disk angle, and coronal disk angle were analyzed. Results: After c-TLIF, sagittal angle, disk height, FH, foraminal width, and cross-sectional area of the IVF were significantly increased. Increase in posterior disk height showed a positive correlation with increases in FH, foraminal width, and cross-sectional area of IVF (r=0.235–0.511). However, the increase in sagittal disk angle showed a negative correlation with changes in foraminal width and cross-sectional area of IVF (r=–0.256 to –0.206). Conclusions: Lumbar foraminal dimensions on the side contralateral to spacer insertion increased significantly after c-TLIF, suggesting that c-TLIF enables indirect decompression of the contralateral nerve root. Although increase in posterior disk height was shown to be an important factor to increase contralateral foraminal size, segmental lordosis was a risk factor for a decrease in contralateral foraminal size.

Repair of Pars Defects by Segmental Transverse Wiring for Athletes With Symptomatic Spondylolysis : Relationship Between Bony Union and Postoperative Symptoms

Study Design. Retrospective study of surgery for spondylolysis patients. Objective. To assess clinical outcome of bony union using multislice computed tomography after segmental wiring fixation. Summary of Background Data. How bony union affects surgical outcome of spondylolysis repair is unclear. Methods. Forty-four athletes with symptomatic spondylolysis (33 men and 11 women; mean age, 24.2 ± 5.4 years) who underwent segmental wiring fixation were evaluated retrospectively at a mean follow-up of 85 ± 17 months. The level of spondylolysis was L5 in 42 cases, and both L4 and L5 in 2 cases, giving a total of 46 operative levels of vertebrae. Bony union using axial and sagittal reconstruction images of computed tomography, the Japanese Orthopaedic Association (JOA) score for back pain, and complications were reviewed. State of bony union was classified as bilateral union, unilateral union, or nonunion. The total score and the improvement ratio of the JOA score were compared among the 3 groups. Results. Bilateral bony union was obtained in 29 cases (31 of 46 vertebrae, 67.4%). Six cases (13%) showed unilateral union, and 9 cases (19.6%) showed nonunion. JOA score increased significantly after surgery in all groups, average improvement rate was 78.9% in the bilateral group, 63.6% in the unilateral group, and 29.8% in the nonunion group; differences among the 3 groups were significant (P < 0.05). JOA score was significantly higher in the bilateral group than in the other 2 groups. Conclusion. Although symptoms were significantly ameliorated in all groups, the bilateral group showed the greatest improvement ratio in JOA score showing bony union to be an important factor in clinical outcome. However, there were a few exceptional cases with contradictory clinical and radiological outcomes. Thus, further studies are required to gain a better understanding of the other multiple factors affecting clinical outcome after spondylolysis repair.

The surgical treatment of pyogenic spondylitis using posterior instrumentation without anterior debridement

There have been few reports regarding the efficacy of posterior instrumentation alone as surgical treatment for patients with pyogenic spondylitis, thus avoiding the morbidity of anterior surgery. We report the clinical outcomes of six patients with pyogenic spondylitis treated effectively with a single-stage posterior fusion without anterior debridement at a mean follow-up of 2.8 years (2 to 5). Haematological data, including white cell count and level of C-reactive protein, returned to normal in all patients at a mean of 8.2 weeks (7 to 9) after the posterior fusion. Rigid bony fusion between the infected vertebrae was observed in five patients at a mean of 6.3 months (4.5 to 8) post-operatively, with the remaining patient having partial union. Severe back pain was immediately reduced following surgery and the activities of daily living showed a marked improvement. Methicillin-resistant Staphylococcus aureus was detected as the causative organism in four patients. Single-stage posterior fusion may be effective in patients with pyogenic spondylitis who have relatively minor bony destruction.

Cervical Symmetric Dumbbell Ganglioneuromas Causing Severe Paresis

We report an extremely rare case with bilateral and symmetric dumbbell ganglioneuromas of the cervical spine in an elderly patient. A 72-year-old man came by ambulance to our hospital due to progressive incomplete paraplegia. Magnetic resonance imaging demonstrated bilateral symmetric dumbbell tumors at the C1/2 level. We performed total resection of the intracanalar tumor, aiming at complete decompression of the spinal cord, and partial and subtotal resection of foraminal outside portions. Histopathological examination of the surgical specimen indicated the tumor cells to be spindle cells with the presence of ganglion cells and no cellular pleomorphism, suggesting a diagnosis of ganglioneuroma. Although the surgery was not curative, the postoperative course was uneventful and provided a satisfactory outcome. This is the fourth known case of cervical ganglioneuromas of the bilateral symmetric dumbbell type.

Failure of reconstruction surgery using anterior fibular strut grafting to correct postlaminectomy kyphosis

A patient with postlaminectomy kyphosis with a neurological deficit which developed following the initial surgical treatment is reported. A 49-year-old man, complaining of neck pain, sought treatment in 1995. An extramedullary cervical spinal tumor was diagnosed and C2-C4 laminectomy and resection of the tumor were performed. Recurrence of the tumor was seen 1 year later and a second tumor resection and radiation therapy were performed. One year after the second resection of the tumor, X-rays of the cervical spine revealed kyphosis. Anterior spinal fusion without instrumentation was performed followed by immobilization using a halo vest for 4 months. However, pseudoarthrosis and progression of the kyphosis occurred postoperatively. Iliac bone grafting at the pseudoarthrosis site and posterior internal fixation with lateral mass plates was performed. Bony fusion between the graft and C6 vertebra was obtained after these procedures, but the neurological deficits were not completely resolved. Clinicians who treat spinal cord tumors may learn from this treatment failure.

Comparison of Functional Recovery in the Very Early Period After Surgery Between Plate and Nail Fixation for Correction of Stable Femoral Intertrochanteric Fractures A Controlled Clinical Trial of 18 Patients

Purpose: This study aimed to compare the differences in functional recovery between patients undergoing plate and nail fixation in the very early period after surgery. Method: This study was designed as a controlled clinical trial that included 18 patients who were surgically treated with either dynamic hip screw as plate fixation or proximal femoral nail as nail fixation for stable intertrochanteric fractures. In particular, all patients selected for the study reported walking completely independently without the use of walking aids prior to sustaining their initial fracture. In all, 8 patients (mean age, 73.8 years; range, 65-89 years) were treated with plate fixation (group plate) and 10 patients (mean age, 79.7 years; range, 70-90 years) were treated with nail fixation (group nail). Functional evaluations were assessed every week after surgery using the Japanese Orthopaedic Association (JOA) hip functional scores and active range of motion (ROM) of the hip joint. Results: The recovery of activities of daily living (ADLs) according to JOA hip functional scores at week 4 after surgery was significantly better in group nail than in group plate (P = .03), whereas active ROM of hip flexion improved significantly in group plate than in group nail at weeks 3 and 4 after surgery (P = .04 and P = .02, respectively). Conclusions: The results suggested that nail fixation may provide a more rapid recovery of ADLs than that of plate fixation in the very early period after surgery. However, plate fixation may provide better ROM of hip flexion than that of nail fixation.

Intracranial subarachnoid hemorrhage following cervical laminoplasty: a report of two cases

ABSTRACT Intracranial hemorrhage is a rare complication of spinal surgery. Case 1 was a 58-year-old man who underwent cervical laminoplasty. No apparent iatrogenic dural rupture or cerebrospinal fluid leakage was observed. An hour after the surgery, the patient had convulsions and became restless thereafter. CT revealed an intracranial subarachnoid hemorrhage (SAH). The patient recovered normal consciousness the next morning. Case 2 was a 68-year-old woman who underwent cervical laminoplasty without postoperative cerebrospinal fluid leakage. Six days after the surgery, the patient continued to complain of nausea and headache. By 13 days, the patient reported relief from her symptoms. There was no evidence of cerebral aneurysm, or vascular malformation in both cases. Patients undergoing cervical laminoplasty might be at risk for developing SAH. Careful attention to intraoperative neck positioning, strict monitoring and control of perioperative blood pressure, and complete dural repair are essential measures for preventing SAH.

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury

Introduction Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. Methods and analysis The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). Ethics and dissemination The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. Trial registration number UMIN000018752.