Detection of serum melanoma-associated antigen D4 in patients with squamous cell carcinoma of the esophagus.

Despite improvements in surgical techniques, perioperative management, and multidisciplinary therapy, treatment outcomes of patients with esophageal squamous cell carcinoma (ESCC) remain poor. Therefore, development of novel molecular biomarkers, which either predict patient survival or become therapeutic targets, is urgently required. In the present study, to facilitate early detection of ESCC and predict its clinical course, we investigated the relationship of the serum level of melanoma-associated antigen (MAGE)-D4 to patients' clinicopathological characteristics. Using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays, we determined the levels of MAGE-D4 mRNA and protein in cell lysates and conditioned medium of cultures, respectively, of nine ESCC cell lines. Further, we determined MAGE-D4 levels in serum samples collected from 44 patients with ESCC who underwent radical esophagectomy without neoadjuvant therapy as well as from 40 healthy volunteers. Samples of conditioned medium and cell lysates contained comparable levels of MAGE-D4 that correlated closely with the levels of MAGE-D4 mRNA. Preoperative MAGE-D4 levels in the sera of 44 patients with ESCC, which varied from 0 to 2,354 pg/mL (314 ± 505 pg/mL, mean ± standard deviation), were significantly higher compared with those of healthy volunteers. By setting the cutoff at the highest value for healthy volunteers (50 pg/mL), the MAGE-D4-positive group of patients was more likely to have shorter disease-specific and disease-free survival compared with those of the MAGE-D4-negative group, although the differences were not statistically significant. Our results indicate that the elevation of preoperative serum MAGE-D4 levels in some patients with ESCC was possibly caused by excess production of MAGE-D4 by tumor cells followed by its release into the circulation. Clinical implications of serum MAGE-D4 levels should be validated in a large population of patients with ESCC.

Salvage pharyngolaryngectomy with total esophagectomy following definitive chemoradiotherapy.

Historically, total pharyngolaryngectomy with total esophagectomy has been the standard radical surgical treatment for synchronous cancer of the thoracoabdominal esophagus and pharyngolaryngeal region, and for cancer of the cervical esophagus that has invaded as far as the thoracic esophagus. Although definitive chemoradiotherapy that enables preservation of the larynx has often been the first choice of treatment for cancers involving the cervical esophagus, total pharyngolaryngectomy with total esophagectomy is required as a salvage therapy for cases involving failure of complete remission or locoregional recurrence after chemoradiotherapy. However, salvage esophageal surgery after definitive high-dose chemoradiotherapy is generally associated with high morbidity and mortality. The aim of this study was to examine the short-term outcome of salvage total pharyngolaryngectomy with total esophagectomy. From 2001 to 2014, nine patients underwent salvage total pharyngolaryngectomy with total esophagectomy at the Department of Gastroenterological Surgery, Nagoya University. The mortality and morbidity rates were high at 22% and 89%, respectively. Four patients (44%) developed tracheal necrosis, which in two patients eventually led to lethal hemorrhage. Salvage total pharyngolaryngectomy with total esophagectomy is an uncommon and highly demanding surgical procedure that should be carefully planned and conducted in selected centers of excellence. Measures must be taken to preserve the tracheal blood supply, thus avoiding fatal complications.

Overexpression of melanoma-associated antigen D4 is an independent prognostic factor in squamous cell carcinoma of the esophagus.

To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. MAGE-D4 messenger RNA (mRNA) expression was analyzed in nine EC cell lines using quantitative reverse transcription polymerase chain reaction. In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative reverse transcription polymerase chain reaction. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P < 0.001). Patients with the highest MAGE-D4 mRNA expression in EC tissues (top quartile, n = 17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (≥65 years), lymphatic involvement, and high MAGE-D4 mRNA expression as significant prognostic factors; high MAGE-D4 mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039) and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4 mRNA profiling. Our results suggest that MAGE-D4 overexpression influences tumor progression, and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC.

Ischemic preconditioning and atenolol on lung injury after intestinal ischemia and reperfusion in rats.

The aim of this study was evaluate the beta blocker atenolol (AT) and ischemic preconditioning (IPC) strategies for tissue protection against systemic effects of intestinal ischemia (I) and reperfusion (R) injury. Forty-two rats were pretreated with AT (1.5 mg · kg(-1)), 0.9% saline solution (SS; 0.1 mL), or IPC and then subjected to prolonged occlusion of the superior mesenteric artery for 60 minutes leading to I followed or not by 120 minutes of R, according to the group. For IPC, 5 minutes of I prior to 10 minutes of R were established. After this process of I or I-R, the right lung of each animal was adequately prepared for staining with hematoxylin and eosin and subsequent histologic analysis for quantification of inflammatory infiltrate was done. The left lung was frozen and prepared for assessment of oxidative stress by the quantification of thiobarbituric acid-reactivity substances (TBARS). Histologic analysis showed an important inflammatory infiltrate in the I-R + SS (I-R + SS = 4.5), which was significantly (P < .05) reduced by IPC (I-R + IPC = 3.0) or AT (I-R + AT = 3.0). Likewise, the TBARS levels were decreased by both strategies (I-R + SS = 0.63; I-R + IPC = 0.23; I-R + AT = 0.38; P < .05). Our results showed that AT and IPC attenuate pulmonary lesions caused by intestinal I and R process.

Cardiac effect of ischemic preconditioning and heparin following intestinal ischemia and reperfusion in rats.

To study the role of heparin and ischemic preconditioning (IPC) in cardiac injury after intestinal ischemia (I) and reperfusion (R), 54 rats underwent 60 minutes of I, which was produced by occlusion of the superior mesenteric artery, and/or 120 minutes of R. The IPC group had the I procedure stimulation for 5 minutes and R for 10 minutes. The control group was subjected to sham surgery only, and the other groups were injected with saline solution (SS; 0.1 mL) or heparin (100 IU/kg) via the inferior cava vein 5 minutes before I and 5 minutes before R and 55 minutes after the R begins in I-R groups. In all animals, cardiac samples were stained with hematoxylin and eosin for optical microscopy analysis, and other sample was processed for lipid peroxidation determination. In I-R groups, both heparin and IPC showed significant protection compared to the SS group; conversely, in animals subjected only to I, no protection was observed. Moreover, when heparin was associated with IPC, I-R protection was compromised and the ischemic injury increased. Data showed that IPC and heparin attenuated cardiac dysfunction caused by intestinal I and I-R, but when used in association did not show beneficial effects.

Radical surgery for gastric carcinoma: it is not an issue of whether to perform D1 or D2. Dissect as many lymph nodes as possible and you will be rewarded.

In the current review article, evidences on radical surgery for gastric cancer reported in the literature are highlighted. The authors conclude that extended lymphadenectomy offers a statistically significant survival benefit. This benefit is only evident if the operative mortality is less than 2%, as obtained in centers of excellence with a high-volume experience of resection of gastric cancer. Lymphadenectomy should no longer be considered only as a tool for cancer-staging, but also as a beneficial therapeutic measure.

Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis.

Gastric cancer metastasised to the liver was found to overexpress HER2 at a significantly higher incidence than primary gastric cancers. The purpose of the present study was to investigate the possibility of molecular therapy targeting HER2 overexpression in gastric cancer liver metastasis. We developed three new HER2-overexpressing gastric cancer cell lines (GLM-1, GLM-2, GLM-4) without epidermal growth factor receptor (EGFR) mutations derived from such liver metastasis, two of which had HER2 gene amplifications. All these GLM series of cell lines were highly sensitive to gefitinib in vitro, a specific inhibitor of EGFR tyrosine kinase (Iressa) rather than anti-HER2 antibody trastuzumab (Herceptin), whereas most of the HER2 low-expressing counterparts were not. In these HER2-overexpressing GLM series, protein kinase B (Akt), but not extracellular signal-regulated kinase 1/2 (ERK1/2), was constitutively phosphorylated, and gefitinib efficiently inhibited this Akt phosphorylation, induced strong apoptosis in vitro and exhibited antitumour activity in tumour xenografts in nude mice. This gefitinib-mediated antitumour effect in xenograft was significantly potentiated by trastuzumab treatment. On the other hand, gefitinib-resistant cells (GLM-1R) exhibited increased EGFR expression, followed by constitutive activation of mitogen-activated protein kinase (MAPK) pathway. These results suggest that the antitumour effect of gefitinib is due to the effective inhibition of HER2-driven constitutive activation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway, and that the acquired resistance to gefitinib is due to the constitutive activation of Ras/MAPK pathway in compensation for PI3K/Akt pathway. Gastric cancer liver metastasis with HER2 overexpression would be a potential molecular target for gefitinib and trastuzumab.

PAI-1 expression levels in esophageal and colorectal cancers are closely correlated to those in corresponding normal tissues.

To investigate the mechanism of PAI-1 overexpression in esophageal and colorectal cancers, PAI-1 expression levels in these cancers were compared to those in corresponding normal tissues. Quantitative RT-PCR was performed for the PAI-1 gene in esophageal and colorectal cancer tissues and in the corresponding normal tissues and the association between PAI-1 expression levels in these tissues was evaluated. There was a significant correlation between esophageal and colorectal cancer and the corresponding normal PAI-1 expressions with a Spearman's rank correlation coefficient of 0.77 (p < 0.0001) and 0.81 (p < 0.0001), respectively. In previous studies, PAI-1 overexpression was found to be significantly associated with the malignancy of esophageal and colorectal cancers. Taken together, PAI-1 overexpression in esophageal and colorectal cancers might originate from higher PAI-1 expression in corresponding normal tissues and result in a malignant phenotype of these cancers.

Plasminogen activator inhibitor-1 as a potential marker for the malignancy of colorectal cancer.

To test the hypothesis that plasminogen activator inhibitor-1 (PAI-1) may serve as a candidate marker for the malignancy of colorectal cancer (CRC), we performed a quantitative RT-PCR for PAI-1 gene and evaluated the possible relationship between PAI-1 gene expression levels and clinicopathological findings in CRC. A significant increase in PAI-1 expression scores was observed in lymph node metastasis-positive CRCs (2.19 +/- 0.43) compared to negative ones (0.35 +/- 0.42) (P = 0.0037) as well as in distant metastasis-positive CRCs (3.50 +/- 1.18) compared to negative ones (0.99 +/- 0.30). The PAI-1 expression score markedly increased with the tumour stage (P = 0.0063; ANOVA test). Moreover, multivariate analysis revealed the PAI-1 expression score to be a strong and independent prognostic factor for CRC (P = 0.0432). These results suggested that PAI-1 might serve as a new parameter for the prediction of prognoses in CRC.

Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis.

AIM: Mizoribine (MZR) is a purine antimetabolic immunosuppressant agent that has few little severe adverse events. We studied whether maintenance therapy with MZR and prednisolone (PSL) in severe proliferative lupus nephritis patients could improve immunity, reduce proteinuria, prevent renal relapse, and reduce steroid dose. METHOD: Long-term maintenance therapy with MZR and PSL was evaluated in ten patients with biopsy-proven proliferative lupus nephritis. Patients with severe lupus nephritis, who had proteinuria of 0.5 g or more even after treatments with plasma exchange and/or pulse methyl prednisolone, were recruited. MZR at an average dose of 140 +/- 10 (100 - 200) mg was administered two to three times/day in combination with PSL. The average period for the MZR maintenance therapy was 89.7 +/- 5.5 (70 - 126) months. Urine protein excretion, serum hemolytic complement activity (CH50), C3, serum creatinine, general and biochemical blood examinations, anti-ds-DNA antibody were collected at each monthly medical examination. RESULTS: All patients were females, mean age 43.0 +/- 3.3 years. A significant decrease in proteinuria was noted two years after the combination therapy (p = 0.0016). Five patients experienced lupus nephritis relapse. Patients who did not experience relapses had their MZR combination therapy initiated earlier (p = 0.037) when compared with the patients who experienced relapses. Serum creatinine levels remained unchanged in all patients throughout treatment and follow-up, even during renal relapses. Levels of C3 and CH50 normalized as proteinuria decreased. None of the patients developed serious side effects during MZR treatment. A significant steroid-sparing effect was observed three years after initiating MZR (p = 0.0025). CONCLUSION: From our long-term observation, maintenance therapy with low-dose PSL combined with MZR can eliminate proteinuria and have steroid-sparing effect. Early initiation of the therapy can protect against renal relapses among severe proliferative lupus nephritis patients without serious side effects.

A clinical study of Japanese patients with ulcer induced by low-dose aspirin and other non-steroidal anti-inflammatory drugs.

BACKGROUND: The incidence and severity of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastro-duodenal ulcer have not been extensively studied in Japan. AIM: We performed a prospective study to clarify NSAIDs-induced gastro-duodenal injury, focusing especially on low-dose aspirin (L-A). METHODS: Two hundred and thirty-eight patients with bleeding peptic ulcers admitted to our hospital. History of taking NSAIDs and anti-ulcer drugs was obtained from all patients who underwent endoscopic examinations. The lesion scores of patients taking L-A were classified numerically from zero (no lesion) to five (ulcer). RESULTS: The NSAIDs were associated with 28.2% of hemorrhagic ulcers. The rates of patients using L-A, loxoprofen, diclofenac, and combination of two of these drugs were 27, 16, 10 and 9%, respectively. Co-administered anti-ulcer drugs were cytoprotective anti-ulcer drugs (27%), H2 receptor antagonists (16%), PPI (4%), and none (53%). In patients taking L-A, H2 receptor antagonists were used most frequently. The HP was positive in 63% of L-A-induced ulcer cases and in 69% of NSAIDs other than low-dose aspirin-induced ulcer cases. The lesion scores of patients taking L-A with H2 receptor antagonists or PPI were significantly lower than those of patients who were taking only L-A (P < 0.05). CONCLUSIONS: Approximately one-third of hospitalized patients with NSAIDs-induced hemorrhagic ulcer showed an association with L-A. Prospective randomized controlled trials including H2 receptor antagonists are required to establish preventive efforts aimed at L-A-induced gastro-duodenal injury.

Treatment of three pancreaticoduodenal artery aneurysms associated with coeliac artery occlusion and splenic artery aneurysm: a case report and review of the literature.

A case of three pancreaticoduodenal artery (PDA) aneurysms associated with coeliac artery occlusion and a concomitant splenic arterial aneurysm is described. Surgical treatment was used because it was anticipated that the hepatic blood supply would be obstructed completely if percutaneous transluminal embolization for three PDA aneurysms were performed. Splenectomy in continuity with the splenic artery aneurysm and PDA aneurysmectomies were performed, and infrarenal abdominal aorto-splenic artery bypass was accomplished using a 6mm ringed expanded polytetrafluoroethylene graft. The postoperative course was uneventful. Graft patency and successful aneurysm ablation were confirmed using MRA and intravenous DSA. Arterial histology revealed segmental arterial mediolysis. At 2-year follow-up, the patient was well and asymptomatic. A literature review of PDA aneurysms is presented.

Binding of Cu(II) or Zn(II) in a de novo designed triple-stranded alpha-helical coiled-coil toward a prototype for a metalloenzyme.

We previously reported the IZ-3adH peptide, which formed a triple-stranded coiled-coil after binding Ni(II), Cu(II), or Zn(II). In this paper, we report the peptide, IZ-3aH, having a new metal binding specificity. The IZ-3aH peptide was found to bind Cu(II) and Zn(II) and form a triple-stranded coiled-coil. However, it did not bind Ni(II). Metal ion titrations monitored by circular dichroism revealed that the dissociation constants, K(d) were 9 microm for Zn(II) and 10 microm for Cu(II). The bound Cu(II) ion has a planar tetragonal geometry, where the coordination positions are three nitrogens of the His residues and one H(2)O.

PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas.

BACKGROUND AND AIMS: Although it has been reported that intestinal metaplasia implicated in gastric carcinogenesis is induced by the ParaHox gene CDX2, it is unclear which genes are responsible for the formation of pseudopyloric glands and whether they play a role in gastric carcinogenesis. Pancreatic-duodenal homeobox 1 (PDX1) is also a ParaHox gene which contributes to the genesis and development of the pancreas, duodenum, and antrum. To clarify its significance for the formation of pseudopyloric glands and gastric carcinogenesis, we investigated expression of PDX1 and mucin in gastric carcinomas and surrounding mucosa. METHODS: Gastric carcinoma tissues from 95 patients were used for immunohistochemical analyses of PDX1, and mucins MUC6 and MUC5AC. RESULTS: PDX1 was found to be frequently expressed in pseudopyloric glands and intestinal metaplasia. MUC6 was more abundant than MUC5AC in pseudopyloric glands while higher levels of MUC5AC than MUC6 were evident in intestinal metaplasia. The frequency of PDX1 positive reactivity was higher in differentiated type carcinomas (39/43, 90.7%) and T1 carcinomas (42/43, 97.7%) than in undifferentiated type (33/52, 63.5%) and T2-4 (30/52, 57.7%) carcinomas. PDX1 and MUC6 double positive expression was observed in carcinomas, respectively, including the corpus, and also correlated with histological type and depth of invasion. In contrast, no link was apparent between PDX1 and MUC5AC double positive reactivity and histological type. CONCLUSION: Our study suggests that PDX1 plays an important role in the development of pseudopyloric glands, and that pseudopyloric glands may reflect a condition associated with gastric carcinogenesis.

[Non-compromised grafting policy in off-pump coronary artery bypass].

BACKGROUND: The off-pump coronary artery bypass (OPCAB) has been prevalent around the world. However the most optimal selection of graft conduits has still been controversial. METHODS: Between January 2002 and April 2003, 126 consecutive isolated coronary artery bypass procedures were attempted to performed without cardiopulmonary bypass. A mean age of the patients was 69.3 (47-90). Fifteen patients were operated on emergently and 16 were urgently, including 15 patients requiring preoperative intra-aortic balloon pumping (IABP). Five patients underwent reoperative coronary bypass. RESULTS: All procedures were completed without cardiopulmonary bypass. The mean number of grafts per patient was 3.23 (range, 1 to 6). The skeletonized arterial conduits were aggressively used [117 left internal mammary artery (LIMA) to 155 sites, 70 right internal mammary artery (RIMA) to 79 sites, 57 right gastro-epiploic artery (RGEA) to 82 sites and 49 saphenous vein (SV) to 91 sites]. Cardiac-related hospital mortality was none. Angiographic assessment of grafts demonstrated that patency of LIMA, RIMA, RGEA and SV were 98.6%, 100%, 100%, and 97.6% respectively. CONCLUSION: OPCAB with skeletonized in situ arterial conduits is secure and feasible.

Adhesive bonding of super-elastic titanium-nickel alloy castings with a phosphate metal conditioner and an acrylic adhesive.

The purpose of the current study was to evaluate the bonding characteristics of super-elastic titanium-nickel (Ti-Ni) alloy castings. Disk specimens were cast from a Ti-Ni alloy (Ti-50.85Ni mol%) using an arc centrifugal casting machine. High-purity titanium and nickel specimens were also prepared as experimental references. The specimens were air-abraded with alumina, and bonded with an adhesive resin (Super-Bond C & B). A metal conditioner containing a phosphate monomer (Cesead II Opaque Primer) was also used for priming the specimens. Post-thermocycling average bond strengths (MPa) of the primed groups were 41.5 for Ti-Ni, 30.4 for Ti and 19.5 for Ni, whereas those of the unprimed groups were 21.6 for Ti, 19.3 for Ti-Ni and 9.3 for Ni. Application of the phosphate conditioner elevated the bond strengths of all alloy/metals (P < 0.05). X-ray fluorescence analysis revealed that nickel was attached to the debonded resin surface of the resin-to-nickel bonded specimen, indicating that corrosion of high-purity nickel occurred at the resin-nickel interface. Durable bonding to super-elastic Ti-Ni alloy castings can be achieved with a combination of a phosphate metal conditioner and a tri-n-butylborane-initiated adhesive resin.

Cellular differentiation status of epithelial polyps of the colorectum: the gastric foveolar cell-type in hyperplastic polyps.

AIMS: The 'metaplastic' polyp of the colorectum, a synonym for the hyperplastic polyp, was named based only on features of the crypt epithelium. It is considered non-neoplastic, but the precise cellular differentiation status remains to be proven. METHODS AND RESULTS: Forty-eight hyperplastic polyps, 12 serrated adenomas, 45 tubular adenomas and five juvenile polyps were studied for their phenotypic expression using gastric (foveolar or pyloric gland cell), small intestinal (goblet cell), and colonic (goblet cell) cellular markers by immunohistochemical and mucin histochemical techniques. Gastric foveolar cell-type differentiation was significantly expressed in hyperplastic polyps, while colonic differentiation was also consistently preserved. Neither gastric pyloric-type nor small intestinal differentiation was observed. The same cell differentiation status as hyperplastic polyps was observed in serrated adenomas but not in tubular adenomas or juvenile polyps. CONCLUSIONS: A large proportion of hyperplastic polyps are composed of hybrid epithelium, with bidirectional differentiation to both gastric foveolar and colonic epithelial cells in the same crypt. Therefore hyperplastic polyps might be interpreted as the outcome of abnormal cell differentiation of stem cells. The same phenotypic expression suggests that hyperplastic polyps and serrated adenomas share the same cell lineage.

Two different inward rectifier K+ channels are effectors for transmitter-induced slow excitation in brain neurons.

Substance P (SP) excites large neurons of the nucleus basalis (NB) by inhibiting an inward rectifier K(+) channel (Kir). The properties of the Kir in NB (KirNB) in comparison with the G protein-coupled Kir (GIRK) were investigated. Single-channel recordings with the cell-attached mode showed constitutively active KirNB channels, which were inhibited by SP. When the recording method was changed from the on-cell to the inside-out mode, the channel activity of KirNB remained intact with its constitutive activity unaltered. Application of Gbeta(1gamma2) to inside-out patches induced activity of a second type of Kir (GIRK). Application of Gbeta(1gamma2), however, did not change the KirNB activity. Sequestering Gbeta(1gamma2) with Galpha(i2) abolished the GIRK activity, whereas the KirNB activity was not affected. The mean open time of KirNB channels (1.1 ms) was almost the same as that of GIRKs. The unitary conductance of KirNB was 23 pS (155 mM [K(+)](o)), whereas that of the GIRK was larger (32-39 pS). The results indicate that KirNB is different from GIRKs and from any of the classical Kirs (IRKs). Whole-cell current recordings revealed that application of muscarine to NB neurons induced a GIRK current, and this GIRK current was also inhibited by SP. Thus, SP inhibits both KirNB and GIRKs. We conclude that the excitatory transmitter SP has two types of Kirs as its effectors: the constitutively active, Gbetagamma-independent KirNB channel and the Gbetagamma-dependent GIRK.

Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats.

Neural progenitor cells, including neural stem cells, are a potential expandable source of graft material for transplantation aimed at repairing the damaged CNS. Here we present the first evidence that in vitro-expanded fetus-derived neurosphere cells were able to generate neurons in vivo and improve motor function upon transplantation into an adult rat spinal-cord-contusion injury model. As the source of graft material, we used a neural stem cell-enriched population that was derived from rat embryonic spinal cord (E14.5) and expanded in vitro by neurosphere formation. Nine days after contusion injury, these neurosphere cells were transplanted into adult rat spinal cord at the injury site. Histological analysis 5 weeks after the transplantation showed that mitotic neurogenesis occurred from the transplanted donor progenitor cells within the adult rat spinal cord, a nonneurogenic region; that these donor-derived neurons extended their processes into the host tissues; and that the neurites formed synaptic structures. Furthermore, analysis of motor behavior using a skilled reaching task indicated that the treated rats showed functional recovery. These results indicate that in vitro-expanded neurosphere cells derived from the fetal spinal cord are a potential source for transplantable material for treatment of spinal cord injury.