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1.  18F-FDG PET/CT for Diagnosis of Osteosclerotic and Osteolytic Vertebral Metastatic Lesions: Comparison with Bone Scintigraphy 
Asian Spine Journal  2013;7(2):96-103.
Study Design
A retrospective study.
The aims of this study were to investigate the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in PET/computed tomography (CT) in the evaluation of spinal metastatic lesions.
Overview of Literature
Recent studies described limitations regarding how many lesions with abnormal 18F-FDG PET findings in the bone show corresponding morphologic abnormalities.
The subjects for this retrospective study were 227 patients with primary malignant tumors, who were suspected of having spinal metastases. They underwent combined whole-body 18F-FDG PET/CT scanning for evaluation of known neoplasms in the whole spine. 99mTc-methylene diphosphonate bone scan was performed within 2 weeks following PET/CT examinations. The final diagnosis of spinal metastasis was established by histopathological examination regarding bone biopsy or magnetic resonance imaging (MRI) findings, and follow-up MRI, CT and 18F-FDG PET for extensively wide lesions with subsequent progression.
From a total of 504 spinal lesions in 227 patients, 224 lesions showed discordant image findings. For 122 metastatic lesions with confirmed diagnosis, the sensitivity/specificity of bone scan and FDG PET were 84%/21% and 89%/76%, respectively. In 102 true-positive metastatic lesions, the bone scan depicted predominantly osteosclerotic changes in 36% and osteolytic changes in 19%. In 109 true-positive lesions of FDG PET, osteolytic changes were depicted predominantly in 38% while osteosclerotic changes were portrayed in 15%.
18F-FDG PET in PET/CT could be used as a substitute for bone scan in the evaluation of spinal metastasis, especially for patients with spinal osteolytic lesions on CT.
PMCID: PMC3669709  PMID: 23741546
18F-fluorodeoxyglucose positron emission tomography; Technetium Tc 99m (Sn)methylenediphosphonate; Positron emission tomography and computed tomography; Spine; Metastasis
2.  The Prevalence and Phenotype of Activated Microglia/Macrophages within the Spinal Cord of the Hyperostotic Mouse (twy/twy) Changes in Response to Chronic Progressive Spinal Cord Compression: Implications for Human Cervical Compressive Myelopathy 
PLoS ONE  2013;8(5):e64528.
Cervical compressive myelopathy, e.g. due to spondylosis or ossification of the posterior longitudinal ligament is a common cause of spinal cord dysfunction. Although human pathological studies have reported neuronal loss and demyelination in the chronically compressed spinal cord, little is known about the mechanisms involved. In particular, the neuroinflammatory processes that are thought to underlie the condition are poorly understood. The present study assessed the localized prevalence of activated M1 and M2 microglia/macrophages in twy/twy mice that develop spontaneous cervical spinal cord compression, as a model of human disease.
Inflammatory cells and cytokines were assessed in compressed lesions of the spinal cords in 12-, 18- and 24-weeks old twy/twy mice by immunohistochemical, immunoblot and flow cytometric analysis. Computed tomography and standard histology confirmed a progressive spinal cord compression through the spontaneously development of an impinging calcified mass.
The prevalence of CD11b-positive cells, in the compressed spinal cord increased over time with a concurrent decrease in neurons. The CD11b-positive cell population was initially formed of arginase-1- and CD206-positive M2 microglia/macrophages, which later shifted towards iNOS- and CD16/32-positive M1 microglia/macrophages. There was a transient increase in levels of T helper 2 (Th2) cytokines at 18 weeks, whereas levels of Th1 cytokines as well as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and macrophage antigen (Mac) −2 progressively increased.
Spinal cord compression was associated with a temporal M2 microglia/macrophage response, which may act as a possible repair or neuroprotective mechanism. However, the persistence of the neural insult also associated with persistent expression of Th1 cytokines and increased prevalence of activated M1 microglia/macrophages, which may lead to neuronal loss and demyelination despite the presence of neurotrophic factors. This understanding of the aetiopathology of chronic spinal cord compression is of importance in the development of new treatment targets in human disease.
PMCID: PMC3663759  PMID: 23717624
3.  Transplantation of Mesenchymal Stem Cells Promotes an Alternative Pathway of Macrophage Activation and Functional Recovery after Spinal Cord Injury 
Journal of Neurotrauma  2012;29(8):1614-1625.
Mesenchymal stem cells (MSC) derived from bone marrow can potentially reduce the acute inflammatory response in spinal cord injury (SCI) and thus promote functional recovery. However, the precise mechanisms through which transplanted MSC attenuate inflammation after SCI are still unclear. The present study was designed to investigate the effects of MSC transplantation with a special focus on their effect on macrophage activation after SCI. Rats were subjected to T9–T10 SCI by contusion, then treated 3 days later with transplantation of 1.0×106 PKH26-labeled MSC into the contusion epicenter. The transplanted MSC migrated within the injured spinal cord without differentiating into glial or neuronal elements. MSC transplantation was associated with marked changes in the SCI environment, with significant increases in IL-4 and IL-13 levels, and reductions in TNF-α and IL-6 levels. This was associated simultaneously with increased numbers of alternatively activated macrophages (M2 phenotype: arginase-1- or CD206-positive), and decreased numbers of classically activated macrophages (M1 phenotype: iNOS- or CD16/32-positive). These changes were associated with functional locomotion recovery in the MSC-transplanted group, which correlated with preserved axons, less scar tissue formation, and increased myelin sparing. Our results suggested that acute transplantation of MSC after SCI modified the inflammatory environment by shifting the macrophage phenotype from M1 to M2, and that this may reduce the effects of the inhibitory scar tissue in the subacute/chronic phase after injury to provide a permissive environment for axonal extension and functional recovery.
PMCID: PMC3353766  PMID: 22233298
bone marrow; macrophage; mesenchymal stem cell; spinal cord injury; transplantation
4.  Cutaneous squamous cell carcinoma (SCC) arising in stump of amputated finger in a patient with resected glossal SCC 
BMC Research Notes  2012;5:595.
Cutaneous squamous cell carcinoma (SCC) of the hands and fingers are sometimes locally aggressive; with higher rates of regional metastasis than other cutaneous SCC, although distant metastasis is rare.
Case presentation
We present the case of a 62–year-old Japanese man with double cancers: a tongue SCC and a cutaneous SCC. Swelling of the finger lesion developed gradually around the entire remaining middle finger after accidental amputation at the proximal interphalangeal joint. Histopathological examination of the tumor on the stump of the amputated finger indicated a well-differentiated SCC. The past history indicated surgery for SCC of the tongue 3 years earlier; with histopathology of moderately-differentiated SCC.
Since dedifferentiation is unlikely in metastatic tumors, the cutaneous SCC of the finger is unlikely to have originated from the tongue SCC. Alternatively, the double cancer may be two unrelated lesions or the tongue tumor could have originated from the cutaneous SCC.
PMCID: PMC3607937  PMID: 23111060
Squamous cell carcinoma; Finger amputation stump; Glossal tumor; Double cancer
5.  Clinical significance of MRI/18F-FDG PET fusion imaging of the spinal cord in patients with cervical compressive myelopathy 
18F-FDG PET is used to investigate the metabolic activity of neural tissue. MRI is used to visualize morphological changes, but the relationship between intramedullary signal changes and clinical outcome remains controversial. The present study was designed to evaluate the use of 3-D MRI/18F-FDG PET fusion imaging for defining intramedullary signal changes on MRI scans and local glucose metabolic rate measured on 18F-FDG PET scans in relation to clinical outcome and prognosis.
We studied 24 patients undergoing decompressive surgery for cervical compressive myelopathy. All patients underwent 3-D MRI and 18F-FDG PET before surgery. Quantitative analysis of intramedullary signal changes on MRI scans included calculation of the signal intensity ratio (SIR) as the ratio between the increased lesional signal intensity and the signal intensity at the level of the C7/T1 disc. Using an Advantage workstation, the same slices of cervical 3-D MRI and 18F-FDG PET images were fused. On the fused images, the maximal count of the lesion was adopted as the standardized uptake value (SUVmax). In a similar manner to SIR, the SUV ratio (SUVR) was also calculated. Neurological assessment was conducted using the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy.
The SIR on T1-weighted (T1-W) images, but not SIR on T2-W images, was significantly correlated with preoperative JOA score and postoperative neurological improvement. Lesion SUVmax was significantly correlated with SIR on T1-W images, but not with SIR on T2-W images, and also with postoperative neurological outcome. The SUVR correlated better than SIR on T1-W images and lesion SUVmax with neurological improvement. Longer symptom duration was correlated negatively with SIR on T1-W images, positively with SIR on T2-W images, and negatively with SUVmax.
Our results suggest that low-intensity signal on T1-W images, but not on T2-W images, is correlated with a poor postoperative neurological outcome. SUVmax of lesions showing increased signal intensity and SUVR measured on fusion MRI/PET scans are more sensitive parameters for predicting clinical outcome than signal intensity on the MRI scan.
PMCID: PMC3458200  PMID: 22854985
Cervical myelopathy; MRI; [18F]-Fluoro-deoxyglucose (FDG) positron emission tomography (PET); Fusion imaging; Spinal cord
6.  Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice 
Recent in vivo and in vitro studies in non-neuronal and neuronal tissues have shown that different pathways of macrophage activation result in cells with different properties. Interleukin (IL)-6 triggers the classically activated inflammatory macrophages (M1 phenotype), whereas the alternatively activated macrophages (M2 phenotype) are anti-inflammatory. The objective of this study was to clarify the effects of a temporal blockade of IL-6/IL-6 receptor (IL-6R) engagement, using an anti-mouse IL-6R monoclonal antibody (MR16-1), on macrophage activation and the inflammatory response in the acute phase after spinal cord injury (SCI) in mice.
MR16-1 antibodies versus isotype control antibodies or saline alone were administered immediately after thoracic SCI in mice. SC tissue repair was compared between the two groups by Luxol fast blue (LFB) staining for myelination and immunoreactivity for the neuronal markers growth-associated protein (GAP)-43 and neurofilament heavy 200 kDa (NF-H) and for locomotor function. The expression of T helper (Th)1 cytokines (interferon (IFN)-γ and tumor necrosis factor-α) and Th2 cytokines (IL-4, IL-13) was determined by immunoblot analysis. The presence of M1 (inducible nitric oxide synthase (iNOS)-positive, CD16/32-positive) and M2 (arginase 1-positive, CD206-positive) macrophages was determined by immunohistology. Using flow cytometry, we also quantified IFN-γ and IL-4 levels in neutrophils, microglia, and macrophages, and Mac-2 (macrophage antigen-2) and Mac-3 in M2 macrophages and microglia.
LFB-positive spared myelin was increased in the MR16-1-treated group compared with the controls, and this increase correlated with enhanced positivity for GAP-43 or NF-H, and improved locomotor Basso Mouse Scale scores. Immunoblot analysis of the MR16-1-treated samples identified downregulation of Th1 and upregulation of Th2 cytokines. Whereas iNOS-positive, CD16/32-positive M1 macrophages were the predominant phenotype in the injured SC of non-treated control mice, MR16-1 treatment promoted arginase 1-positive, CD206-positive M2 macrophages, with preferential localization of these cells at the injury site. MR16-1 treatment suppressed the number of IFN-γ-positive neutrophils, and increased the number of microglia present and their positivity for IL-4. Among the arginase 1-positive M2 macrophages, MR16-1 treatment increased positivity for Mac-2 and Mac-3, suggestive of increased phagocytic behavior.
The results suggest that temporal blockade of IL-6 signaling after SCI abrogates damaging inflammatory activity and promotes functional recovery by promoting the formation of alternatively activated M2 macrophages.
PMCID: PMC3310810  PMID: 22369693
Spinal cord injury; Interleukin (IL)-6/IL6 receptor (R); Alternatively activated macrophage; Arginase 1; Inducible nitric oxide synthase (iNOS); T helper (Th) cytokine
7.  Direct transplantation of mesenchymal stem cells into the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis 
Mesenchymal stem cells (MSCs) can differentiate into various connective tissue cells. Several techniques have been used for the clinical application of MSCs in articular cartilage repair; however, there are many issues associated with the selection of the scaffold material, including its ability to support cell viability and differentiation and its retention and degradation in situ. The application of MSCs via a scaffold also requires a technically demanding surgical procedure. The aim of this study was to test the outcome of intra-articular transplantation of mesenchymal stem cells suspended in hyaluronic acid (HA) in the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis (OA).
Commercially available human MSCs were cultured, labeled with carboxyfluorescein diacetate succinimidyl ester (CFDA-SE), suspended in either PBS or HA, and injected into the knee joints of 7-month-old animals. The control animals were injected with either PBS or HA alone. The animals were sacrificed at 1, 3, and 5 weeks post transplantation, the knee joints harvested, and fluorescent microscopic analysis was performed. Histological and immunohistochemical analysis were performed at 5 weeks post transplantation.
At 5 weeks post transplantation, partial cartilage repair was noted in the HA-MSC group but not in the other groups. Examination of CFDA-SE-labeled cells demonstrated migration, differentiation, and proliferation of MSC in the HA-MSC group. There was strong immunostaining for type II collagen around both residual chondrocytes and transplanted MSCs in the OA cartilage.
This scaffold-free and technically undemanding technique appears to result in the regeneration of articular cartilage in the spontaneous OA animal model. Although further examination of the long-term effects of transplantation is necessary, the findings suggest that intra-articular injection of HA-MSC mixture is potentially beneficial for OA.
PMCID: PMC3392826  PMID: 22314040
8.  Apoptosis of neurons and oligodendrocytes in the spinal cord of spinal hyperostotic mouse (twy/twy): possible pathomechanism of human cervical compressive myelopathy 
European Spine Journal  2011;21(3):490-497.
Cervical compressive myelopathy is the most serious complication of cervical spondylosis or ossification of the posterior longitudinal ligament (OPLL) and the most frequent cause of spinal cord dysfunction. There is little information on the exact pathophysiological mechanism responsible for the progressive loss of neural tissue in the spinal cord of such patients. In this study, we used the spinal hyperostotic mouse (twy/twy) as a suitable model of human spondylosis, and OPLL to investigate the cellular and molecular changes in the spinal cord. Mutant twy/twy mouse developed ossification of the ligamentum flavum at C2–C3 and exhibited progressive paralysis.
Materials and methods
The mutant twy/twy mice, aged 16 and 24 weeks, were used in the present study. The cervical spinal cord was analyzed histologically and immunohistochemically.
We observed that a significant correlation between the proportion of apoptotic oligodendrocytes in the compressed area of the spinal cord and the magnitude of cord compression. Immunohistochemical analysis indicated overexpression of TNFR1, CD95, and p75NTR in the twy/twy mice, which was localized by the immunofluorescence in the neurons and oligodendrocytes.
The expression of such factors seems to play at least some role in the apoptotic process, which probably contributes to axonal degeneration and demyelination in the twy/twy mice spinal cords with severe compression.
Electronic supplementary material
The online version of this article (doi:10.1007/s00586-011-2025-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3296863  PMID: 21935678
Apoptosis; Neurons; Spinal cord; Spinal hyperostotic mouse (twy/twy); Chronic compression
9.  Initiation and progression of ossification of the posterior longitudinal ligament of the cervical spine in the hereditary spinal hyperostotic mouse (twy/twy) 
European Spine Journal  2011;21(1):149-155.
Ossification of the posterior longitudinal ligament (OPLL) is a significantly critical pathology that can eventually cause serious myelopathy. Ossification commences in the vertebral posterior longitudinal ligaments, and intensifies and spreads with the progression of the disease, resulting in osseous projections and compression of the spinal cord. However, the paucity of histological studies the underlying mechanisms of calcification and ossification processes remain obscure. The pathological process could be simulated in the ossifying process of the ligament in mutant spinal hyperostotic mouse (twy/twy). The aim of this study is to observe that enlargement of the nucleus pulposus followed by herniation, disruption and regenerative proliferation of annulus fibrosus cartilaginous tissues participated in the initiation of ossification of the posterior longitudinal ligament of twy/twy mice.
Materials and methods
The mutant twy/twy mice (6 to 22-week-old) were used in the present study. The vertebral column was analyzed histologically and immunohistochemically.
We observed that the enlargement of the nucleus pulposus followed by herniation, disruption and regenerative proliferation of annulus fibrosus cartilaginous tissues participated in the initiation of ossification of posterior longitudinal ligament of twy/twy mice. In this regards, the cells of the protruded hyperplastic annulus fibrosus invaded the longitudinal ligaments and induced neovascularization and metaplasia of primitive mesenchymal cells to osteoblasts in the spinal ligaments of twy/twy mice.
Since genetic mechanisms could play a role in human OPLL, the age-related enlargement of the nucleus pulposus in the twy/twy mouse may primarily occur as a result of overproduction of mucopolysaccharide matrix material induced by certain genetic abnormalities.
Electronic supplementary material
The online version of this article (doi:10.1007/s00586-011-1971-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3252453  PMID: 21850419
Ossification of the posterior longitudinal ligament (OPLL); Twy/twy mouse; Nucleus pulposus herniation; Annulus fibrosus; Enchondral ossification
10.  The primary therapy chosen for patients with localized prostate cancer between the university hospital and its affiliated hospitals in Nara Uro-oncological research group registration 
BMC Urology  2011;11:6.
We investigated the differences between the preferential primary therapy conceived by the primary doctors and the primary therapy actually conducted for prostate cancer patients in Nara, Japan.
The distribution of primary therapy and clinical characteristics of 2303 prostate cancer patients - diagnosed between 2004 and 2006 at Nara Medical University and its 23 affiliated hospitals - were assessed. Moreover, the preferential primary therapy for the patients at each clinical stage (cT1-T3bN0M0) conceived by the primary doctors was investigated and compared to the actual therapy.
Of all patients, 51% received primary androgen deprivation therapy (PADT), 30% underwent radical prostatectomy (RP), and 14% received radiation therapy (RT). The preferential primary therapy for cT1-2N0M0 was RP (92%) while 38% of the patients actually received PADT (RP: 40%). For cT3aN0M0, the preferential primary therapy was both RP and external beam radiation therapy (EBRT) while 58% of the patients actually received PADT (RP: 16%, EBRT: 24%). For cT3bN0M0, the most preferential primary therapy was EBRT (46%) while 67% of the patients actually received PADT (EBRT: 21%). This trend was more notable in the affiliated hospitals than in the University hospital. The hospitals with lower volume of RP per year significantly conducted PADT compared with those with higher volume of RP.
PADT was commonly used to treat localized prostate cancer as well as locally advanced prostate cancer in Japan. There was a definite discrepancy between the preferential primary therapy conceived by the primary doctors and the actual therapy provided to the patients.
PMCID: PMC3095576  PMID: 21524283
11.  High prevalence of gastroesophageal reflux symptoms in patients with both acute and nonacute cough 
Although there have been many studies that showed a close association between gastroesophageal reflux disease (GERD) symptoms and chronic cough, it has been unknown whether acute cough is also associated with GERD. The aim of this study was to evaluate the relationship between GERD and respiratory symptoms in general practice. 1725 consecutive patients who first attended our hospital were enrolled in the present study. They were asked to respond the F-scale questionnaire regardless of their chief complaints. Over all, 656 (38%) patients were diagnosed as GERD and 226 (13%) had respiratory symptoms. Patients with respiratory symptoms had GERD symptoms more frequently than patients without respiratory symptoms (p < 0.05). Forty-three (37%) of 115 patients with acute cough and 48 (43%) of 111 with nonacute cough had GERD symptoms, suggesting that development of GERD is not associated with the period of respiratory symptoms. Patients with respiratory symptoms are at a significantly increased risk of developing GERD. Whether or not treatment for GERD or respiratory diseases is useful for the prevention of respiratory symptoms and GERD, respectively, should not be driving management decisions in primary care.
PMCID: PMC2840545  PMID: 20428407
acute cough; gastroesophageal reflux; chronic cough; F-scale
12.  Extensive Atrophic Gastritis Increases Intraduodenal Hydrogen Gas 
Objective. Gastric acid plays an important part in the prevention of bacterial colonization of the gastrointestinal tract. If these bacteria have an ability of hydrogen (H2) fermentation, intraluminal H2 gas might be detected. We attempted to measure the intraluminal H2 concentrations to determine the bacterial overgrowth in the gastrointestinal tract. Patients and methods. Studies were performed in 647 consecutive patients undergoing upper endoscopy. At the time of endoscopic examination, we intubated the stomach and the descending part of the duodenum without inflation by air, and 20 mL of intraluminal gas samples of both sites was collected through the biopsy channel. Intraluminal H2 concentrations were measured by gas chromatography. Results. Intragastric and intraduodenal H2 gas was detected in 566 (87.5%) and 524 (81.0%) patients, respectively. The mean values of intragastric and intraduodenal H2 gas were 8.5 ± 15.9 and 13.2 ± 58.0 ppm, respectively. The intraduodenal H2 level was increased with the progression of atrophic gastritis, whereas the intragastric H2 level was the highest in patients without atrophic gastritis. Conclusions. The intraduodenal hydrogen levels were increased with the progression of atrophic gastritis. It is likely that the influence of hypochlorhydria on bacterial overgrowth in the proximal small intestine is more pronounced, compared to that in the stomach.
PMCID: PMC2535789  PMID: 18795142

Results 1-12 (12)