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The aim of the present study was to investigate metabolite alterations in the hippocampal formation as they relate to aggression in high-functioning adults with autism. We measured concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine plus phosphocreatine (Cr+PCr) in the hippocampal formation by proton magnetic resonance spectroscopy in 12 non-medicated male subjects with autism and 12 age- and sex-matched controls. Aggression was scored in the autistic subjects using the Buss-Perry Aggression Questionnaire. The concentrations of Cho and Cr+PCr in the hippocampal formation in autistic subjects were significantly higher than the corresponding values in control subjects, and a significant positive correlation was observed between the concentrations of these metabolites in the hippocampal formation and scores on the Buss-Perry Aggression Questionnaire in autistic subjects. Results suggest that high-functioning adult subjects with autism have abnormal metabolite concentrations in the hippocampal formation, which may in part account for their aggression.

The neurobiological basis for autism remains poorly understood. We hypothesized that adipokines, such as adiponectin, may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of adiponectin are altered in subjects with autism. We measured serum levels of adiponectin in male subjects with autism (n=31) and age-matched healthy male subjects (n=31). The serum levels of adiponectin in the subjects with autism were significantly lower than that of normal control subjects. The serum adiponectin levels in the subjects with autism were negatively correlated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction. This study suggests that decreased levels of serum adiponectin might be implicated in the pathophysiology of autism., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: The neurobiological basis of autism remains poorly understood. To examine the role played by serum cytokines in brain development, we hypothesized that Platelet-Derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) may be associated with pathophysiology of autism. In this study, we screened serum levels of these growth factors in young male subjects with autism., Methods: We measured serum levels of PDGF subtypes and VEGF in the 31 male children with autism (6-19 years old) and 31 healthy age- and gender-matched subjects., Results: The serum levels of PDGF-BB in male children with autism (N=31, 5624.5+/-1651.8 pg/mL [mean+/-SD]) were significantly higher (two-tailed Student's t-test: p=0.0188) than those of normal control subjects (N=31, 4758.2+/-1521.5 pg/mL [mean+/-SD]). There was a significant and positive correlation (Pearson's r=0.5320, p=0.0010) between the serum levels of PDGF-BB and the Autism Diagnostic Interview-Revised (ADI-R) domain C scores, which represent stereotyped patterns of behavior in the children with autism. However, there were no marked or significant correlations between serum PDGF-BB levels and clinical variables, including the other ADI-R scores and Intellectual Quotient (IQ) scores by WAIS-R. There were no significant change and correlations with clinical variables in serum PDGF-AA, PDGF-AB, and VEGF levels in the children with autism., Conclusions: Increased levels of serum PDGF-BB homodimers might be implicated in the pathophysiology of autism., (Copyright 2009 Elsevier Inc. All rights reserved.)

Fatty acid-binding protein (FABP) gene family encode fatty acid-binding proteins and consist of at least 12 members, of which FABP7, 5 and 3 are expressed in the brain. We previously showed that FABP7 is associated with schizophrenia and bipolar disorder. Recently, genetic overlap between autism and schizophrenia has been reported. Therefore, in this study, we set out to examine the possible roles of brain-expressed FABPs in autism, focusing primarily on potentially functional polymorphisms (that is, missense polymorphisms). First, we resequenced the three genes using 285 autism samples. We identified 13 polymorphisms, of which 7 are novel. Of the novel single-nucleotide polymorphisms (SNPs), two are missense mutations, namely, 376G>C (Val126Leu) in FABP7 and 340G>C (Gly114Arg) in FABP5. Second, we tested for the genetic association of four missense SNPs with autism and schizophrenia, but failed to detect significant results. Finally, as a web-based algorithm predicts that the 8A>G (Asp3Gly; rs17848124) in FABP3 is 'probably damaging', we estimated the possible impact of this SNP, and found that the loss of charge and salt bridge, caused by the Asp3-to-Gly3, may affect stability of the FABP3 protein. Future searches for associated phenotypes with missense SNPs using larger samples are highly warranted.

A man in his seventies visited our hospital due to positive a fecal occult blood test. Colonoscopy showed a submucosal tumor in the rectum covered with reddish and irregular mucosa. Pathological examination of the biopsy specimen revealed well differentiated adenocarcinoma. The tumor was resected, and pathological examination showed carcinoid and adenocarcinoma components coexisting and mixed with each other. Because a previous colonoscopy had shown a submucosal tumor with a smooth surface, this case was diagnosed as a collision tumor of adenocarcinoma which developed on a carcinoid.

Aim: The safety and efficacy, and the dose-limiting toxicity (DLT) of the chemotherapeutic agent gemcitabine administered in conjunction with radiotherapy in patients with locally advanced pancreatic cancer are not yet established. Here, we evaluated the safety and efficacy, DLT, and maximum tolerated dose of gemcitabine with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Tumor response and time to progression were also assessed., Patients and Methods: Patients with previously untreated pancreatic cancer (n = 12) received gemcitabine intravenously on days 1, 8, and 15. Concurrent radiation therapy was initiated on day 1 (40 Gy in 2 Gy/day x 20 fractions, days 1-5, 8-12, 15-19, 22-26). Patients received limited-field irradiation with three-dimensional radiotherapy. Dose escalation included dose levels 1-3 (gemcitabine 400, 600, and 800 mg/m(2))., Results: No patient developed DLT in this study. Of the 12 patients, there were 11 sustained responses, 0 partial responses, and 1 progressive disease. Two patients with a sustained response underwent surgery after re-evaluation. The median progression-free survival was 8 months, not including the patients that underwent surgery., Conclusion: Weekly gemcitabine at a dose of 800 mg/m(2) with concurrent radiation therapy in patients with locally advanced pancreatic cancer was well tolerated. and IAP.

Context: Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown., Objective: To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems., Design: Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 ((11)C)-labeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652) and 2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane ([(11)C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables., Setting: Participants recruited from the community., Participants: Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects., Results: Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = -0.61; P = .004)., Conclusions: The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

Bone morphogenic proteins (BMPs) may have neurotrophic functions but there is limited evidence of these functions in the peripheral nervous system. We therefore investigated the expression of BMPs and BMP receptors (BMPRs) in normal and injured peripheral nerves. In 10 of 15 Sprague-Dawley rats, a 3-mm segment of sciatic nerve was resected at the trifurcation in the thigh. One day (n = 5) and 7 days (n = 5) after transection, proximal and distal stumps were removed and immunohistochemically analyzed for BMP-2, -7, BMPR-1A, -1B, and -2. The other five animals served as normal controls. In normal nerves, BMP-2 expression was localized at Ranvier's node, and BMP-7 and BMPR-1B were expressed in several axon-Schwann cell units, whereas other receptors were not expressed. After nerve transection, BMP-7 expression was upregulated at both proximal and distal stumps along with Schwann cell columns during Wallerian degeneration. BMPRs were also upregulated compared with the normal nerve. The upregulation in BMP expression after nerve transection suggests that BMPs may play a role in the healing response of the peripheral nerve.

The paired box 6 (PAX6) is a transcription factor expressed early in development, predominantly in the eye, brain and pancreas. Mutations in PAX6 are responsible for eye abnormalities including aniridia, and it is also known that some PAX6 mutations result in autism with incomplete penetrance. We resequenced all the exons and flanking introns of PAX6 in 285 autistic patients in the Japanese, with the possibility that novel mutations may underlie autism. Fifteen different polymorphisms were identified: 13 are novel, and 2 were previously reported (rs667773 and rs3026393). Among the novel ones, there is one missense mutation that was found in a patient: 136C>G (Leu46Val) (single nucleotide polymorphism ID "ss130452457" is temporarily assigned). Leu46 is extremely conserved from fly to human, and we did not detect Val46 in 2120 nonautistic subjects. The autistic patient carrying this heterozygous mutation showed reduced vision, photophobia and eyelid ptosis, but no other ocular abnormality such as aniridia. Our findings suggest the necessity of further studies on the causal relationship between PAX6 and autism.

Purpose: To investigate the utility of palmar bowing of the flexor retinaculum (PBFR) on magnetic resonance imaging (MRI) as an adjunct to presurgical evaluation of carpal tunnel syndrome (CTS)., Materials and Methods: The CTS group comprised 48 women with CTS diagnosed from clinical history, physical examination, and electrophysiological findings. Another 21 healthy women with no symptoms of CTS served as controls. The CTS group was divided into four subgroups based on symptom duration. CTS patients were preoperatively assessed for symptom severity using a Likert scale. In both groups, palmar bowing of the flexor retinaculum (PBFR) was measured on MRI. Furthermore, relationships with disease duration, subjective symptom severity, and electrophysiological findings were assessed in the CTS group., Results: Although PBFR increased significantly in all CTS groups when compared to the control group, PBFR in patients who complained of severe pain tended to exceed that in patients with mild to moderate pain. Statistical analysis showed a positive correlation between PBFR and pain severity. In contrast, PBFR did not reflect median nerve function., Conclusion: PBFR as seen on MRI seems to correlate significantly with patients' subjective reports of pain severity.

A 47-year-old man who was diagnosed as Crohn's disease at the age of 27 became aware of a mass on the forehead. CT and PET scan revealed many scattered tumors in his body. The CEA level was 4424 ng/ml. Primary lesion was not detected by the surveillance of whole gastro-intestinal tract. Liver tumor biopsy samples were histologicaly analyzed and were diagnosed as adenocarcinoma. Further immunohistochemical analysis revealed that the biopsy material had colonic character determined by positive CK20 and negative CK7 staining. Therefore, we performed 12 cycles of mFOLFOX6 chemotherapy. It was effective with the reduced size of tumors and the decreased level of CEA.

Purpose: Interstitial cells of Cajal (ICC) play important roles in autonomic gut motility as electrical pacemakers and mediators of neural regulation of smooth muscle functions. Insufficiency of ICC has been reported in a wide range of gut dysmotilities. Thus, restoration of ICC may be a therapeutic modality in these diseases. Here we provide evidence that transplanted bone marrow (BM) cells can restore gut dysmotility in part via transdifferentiation to ICC., Methods: Bone marrow cells obtained from Kit insufficient W/W(v) mice or syngeneic GFP-transgenic mice with wild-type Kit were transferred to W/W(v) recipients. Whole gut transit time and gastric emptying were examined 5 and 6 weeks after BM transplantation, respectively, and ICCs were identified in whole mounts, frozen sections and transmission electron immunomicroscopy of the gut smooth muscle layers using specific antibodies., Results: Transplantation of wild-type BM into W/W(v) mice significantly improved whole gut transit time and gastric emptying. Fluorescent immunohistochemistry revealed GFP(+)Kit(+) cells in the myenteric plexus, deep muscular plexus, and submucosal plexus smooth muscle layers of the stomach, small intestine, and colon, respectively. In the whole mounts, GFP(+)Kit(+) cells were bipolar and spindle shaped, and transmission electron immunomicroscopy showed GFP(+) cells rich in mitochondria and endoplasmic reticulum between gut smooth muscle layers, suggesting the presence of GFP(+) cells with morphological characteristics of ICC., Conclusions: These results suggest that BM contains cells that may incorporate into ICC networks and improve dysmotility in W/W(v) mice. Thus, BM transplantation may become to a new therapeutic modality for gut dysmotilities due to ICC insufficiency.

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selected, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were considered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA; modest haplotype association was also observed. The SNPs that showed associations were related to early developmental abnormalities (ADI-R&#95;D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA group was significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children; STX1A might influence the serotonergic system during this stage of neurodevelopment, as implied by the association with ADI-R&#95;D.

Background: The involvement of bone marrow (BM) in tumor-stroma reactions or tumor development has not been examined in a cancer allograft, which has otherwise been appropriate for assessing therapeutic modalities. We investigated the fate of BM-derived cells in colon cancer allografts and liver metastases in mice., Methods: C57BL/6 mice were irradiated and rescued by BM transplantation from green fluorescent protein (GFP)-transgenic mice. MC38 colon cancer cells were stably transfected with the pDsRed gene in order to identify tumor cells by fluorescence. These were inoculated into the mice to generate subcutaneous allografted tumors or liver metastases. The tumors were observed under confocal microscopy and fluorescent immunohistochemistry to determine the fate of tumor versus BM-derived cells., Results: GFP-positive (GFP(+)) cells were consistently identified as vimentin(+), alpha-smooth muscle actin (alphaSMA)(+), spindle-shaped stromal cells in both the subcutaneous tumors and the liver metastases. GFP(+) cells of leukocyte lineage also infiltrated the tumors. Neither GFP(+) CD31(+) endothelial cells nor GFP(+) DsRed(+) cells were detected in the tumor., Conclusions: BM-derived cells frequently and consistently infiltrated the tumor allografts and metastases as interstitial cells and leukocytes. Cells derived from the fusion of BM cells and tumor cells were not observed. This model may be appropriate for the clarification of the effects of anticancer therapies and the study of BM-derived cells in tumor-host interactions.

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. SerT expression in Drosophila is regulated by robo; it plays a vital role in mammalian neurodevelopment also. Here, we examined the associations of ROBO3 and ROBO4 with autism, in a trio association study using DNA from 252 families recruited to AGRE. Four SNPs of ROBO3 (rs3923890, P = 0.023; rs7925879, P = 0.017; rs4606490, P = 0.033; and rs3802905, P = 0.049) and a single SNP of ROBO4 (rs6590109, P = 0.009) showed associations with autism; the A/A genotype of rs3923890 showed lower ADI-R&#95;A scores, which reflect social interaction. Significant haplotype associations were also observed for ROBO3 and ROBO4. We further compared the mRNA expressions of ROBO1, ROBO2, ROBO3, and ROBO4 in the lymphocytes of 19 drug-naïve autistic patients and 20 age- and sex-matched controls. Expressions of ROBO1 (P = 0.018) and ROBO2 (P = 0.023) were significantly reduced in the autistic group; the possibility of using the altered expressions of ROBO as peripheral markers for autism, may be explored. In conclusion, we suggest a possible role of ROBO in the pathogenesis of autism. Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment. To the best of our knowledge, this is the first report relating ROBO with autism.

Background: Previous studies have reported the association between advanced paternal age at birth and the risk of autistic-spectrum disorder in offspring, including offspring with intellectual disability., Aims: To test whether an association between advanced paternal age at birth is found in offspring with high-functioning autistic-spectrum disorder (i.e. offspring without intellectual disability)., Method: A case-control study was conducted in Japan. The participants consisted of individuals with full-scale IQ>or=70, with a DSM-IV autistic disorder or related diagnosis. Unrelated healthy volunteers were recruited as controls. Parental ages were divided into tertiles (i.e. three age classes). Odds ratios and 95% confidence intervals were estimated using logistic regression analyses, with an adjustment for age, gender and birth order., Results: Eighty-four individuals with autistic-spectrum disorder but without intellectual disability and 208 healthy controls were enrolled. Increased paternal, but not maternal, age was associated with an elevated risk of high-functioning autistic-spectrum disorder. A one-level advance in paternal age class corresponded to a 1.8-fold increase in risk, after adjustment for covariates., Conclusions: Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.

Immune dysfunction has been proposed as a mechanism for the pathophysiology of autistic-spectrum disorders. The selectin family of adhesion molecules plays a prominent role in immune/inflammatory responses. We determined the serum levels of three types of soluble-form selectin (sP, sL and sE) in 15 men with high-functioning autism and 22 age-matched healthy controls by enzyme-linked immunosorbent assay. Levels of sP-selectin and sL-selectin were significantly lower in patients than in controls. Furthermore, sP-selectin levels were negatively correlated with impaired social development during early childhood.

Mesenchymal stem cells (MSCs) are attractive cell sources in regenerative medicine. We examined the effects of topical MSCs implantation on an experimental model of inflammatory bowel disease. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in vitro, were characterized by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and differentiation assays. Experimental colitis was induced by intraluminal instillation of 2,4,6-trinitrobonzene sulfonic acid (TNBS) in the colons of male rats. The putative MSCs and unselected fresh bone marrow cells were injected into the colonic submucosa surrounding the area exposed to TNBS. The healing process of the injury was examined macroscopically and immunohistologically. Multipotent MSCs positive for CD29 and CD90, and negative for CD31 and CD34, were implanted into colon tissue surrounding the lesion; a majority of the engrafted cells were positive for vimentin. The implantation significantly accelerated healing of the damaged mucosa compared with vehicle-injected controls. The MSCs expressed vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 in vitro and after the implantation. In conclusion, we found that MSCs were successfully topically implanted in the colon and that they were associated with accelerated healing of TNBS-induced colitis. The beneficial effects of the MSCs might be mediated, at least in part, by their ability to differentiate into colonic interstitial cells and by their ability to provide VEGF and TGF-beta1 to the injured area.

Freiberg's infraction is a rare disorder that arises mostly in adolescent athletes. We describe a 77-year-old woman with the collapse of second metatarsal head with similar clinical appearance to Freiberg's infraction. Radiological findings at initial visit of our hospital were normal. Her condition was obscure and magnetic resonance imaging showed the subchondral insufficiency fracture with bone marrow edema to the second metatarsal head. Despite the conservative treatment, the second metatarsal head collapsed. She was surgically treated with an osteochondral autograft without complications relating surgery. Furthermore, the histological findings showed that the site of collapse was considered to be secondary lesions resulting from the subchondral insufficiency fracture.

Abrogating tolerance against unidentified antigens is a critical step in the pathogenesis of ulcerative colitis (UC). T cell anergy, one of the main mechanisms of tolerance, has been shown to be induced by E3 ubiquitin ligases, such as gene related to anergy in lymphocytes (GRAIL), Itch, and c-Cbl in mice. However, it is not well known whether these E3 ligases play roles in human diseases. The pathophysiological role of the E3 ligases in patients with UC was investigated. At first, the expression of GRAIL, Itch, and c-Cbl in human anergic T cells was analyzed by quantitative RT-PCR and Western immunoblotting. Next, the mRNA expression of the E3 ligases was analyzed in peripheral CD4+ T cells of 20 patients with UC and 10 healthy volunteers (HV). mRNA expression was analyzed in patients with active UC before and after treatment with prednisolone and leukocytapheresis. Anergic human CD4+ T cells expressed significantly higher levels of GRAIL, Itch, and c-Cbl than nonanergic cells. GRAIL expression was significantly higher in patients with UC in remission than in patients with active disease and in HV (P < 0.01). The level of GRAIL expression was also significantly increased in patients with active disease whose clinical activity index scores improved after treatment (P < 0.05). There were no significant differences in Itch and c-Cbl expression among patients with active UC, patients with UC in remission, and HV. These data suggest that GRAIL plays an important role in maintaining remission in patients with UC.

It is generally believed that trauma from child abuse or bone fragility from diseases such as osteogenesis imperfecta accounts for most cases of multiple rib fractures. We report an infant with unexplained fractures from the right 3rd rib through to the 8th rib who had undergone resection of a large cervical tumor and had been admitted to a neonatal intensive care unit. Neither trauma nor bone fragility disease was found in the patient during the detailed investigation conducted by the Malpractice Investigative Committee.

Background and Aims: Patients with inflammatory bowel disease (IBD) share several immunologic similarities with rheumatoid arthritis (RA). Patients with RA have significantly increased levels of serum agalactosyl immunoglobulin G (IgG). Our aim was to investigate the clinical significance of analyzing the oligosaccharide structure of serum IgG in patients with IBD., Methods: Serum IgG oligosaccharide structures were analyzed using high-performance liquid chromatography in 60 patients with Crohn's disease (CD), 58 patients with ulcerative colitis (UC), 27 healthy volunteers (HV), and 15 disease controls (DC). The activity and mRNA level of beta-1,4-galactosyltransferase (Beta4GalT) in antibody-secreting cells were investigated in these subjects., Results: The agalactosyl fraction of the fucosylated IgG oligosaccharides (G0F/G2F) in CD and UC was significantly greater than that in HV and DC (P < 0.001). The percentage of subjects with a high G0F/G2F in CD, UC, HV, and DC was 72%, 33%, 0%, and 0%, respectively. G0F/G2F, which is significantly correlated with disease severity in both CD and UC, had higher sensitivity to diagnose IBD compared with anti-Saccharomyces cerevisiae antibody. Moreover, G0F/G2F was significantly correlated with the prognosis of UC patients: patients with a high G0F/G2F did not maintain long-term remission. The activity and mRNA level of Beta4GalT were significantly elevated in UC but not in CD., Conclusions: G0F/G2F is a potentially effective diagnostic marker of disease activity in both CD and UC, and of the clinical course in UC. A pathophysiologic difference between CD and UC was also demonstrated.

Objective: Intra-articular injection of hyaluronan (HA) is frequently used to treat knee osteoarthritis (OA). We studied whether HA injections induced significant changes in levels of biochemical markers in synovial fluid (SF). In addition, we investigated the possibility of predicting the effectiveness of HA based on these biochemical markers., Methods: Twenty-eight patients with knee OA underwent five weekly intra-articular injections of HA. Knee pain was measured on visual analog scale (VAS) before and after the five injections. Levels of biochemical markers, including chondroitin 6-sulfate (C6S), chondroitin 4-sulfate (C4S), keratan sulfate (KS), and tenascin-C (TN-C), were determined before and after the five injections. Correlations between the biochemical markers before HA injection and the improvement of VAS after the five injections were evaluated., Results: After HA injections, levels of C6S, C4S, and KS decreased significantly. Inverse correlations were observed between the levels of TN-C and C4S before HA injection and improvement of VAS after the five injections. In contrast, no significant correlation was seen between levels of C6S and KS before injections and improvement of VAS after the five injections., Conclusion: The reduction in C6S, C4S, and KS levels after HA injections reflects that HA could help maintain normal cartilage metabolism. Our findings suggest that HA injections are effective in patients whose knees contain low levels of TN-C and C4S, reflecting an early stage of OA and limited synovitis.

Mesenchymal stem cells (MSCs), a subpopulation of adult somatic stem cells, are an attractive stem cell source in regenerative medicine because of their multipotentiality. We examined the effects of MSC transplantation on gastric ulcer healing. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in culture, were characterized by flow cytometry and reverse transcription-polymerase chain reaction. Gastric ulcers were induced by serosal application of acetic acid on the anterior wall of the stomach in female rats. Either MSCs (labeled with PKH67; 1x10(7) cells) or vehicle was injected into the gastric wall surrounding the ulcer. The healing process of the ulcer and the influence of anti-vascular endothelial growth factor (VEGF) antibody were examined. CD29-positive, CD90-positive, CD34-negative, and CD45-negative MSCs expressed mRNAs for VEGF and hepatocyte growth factor (HGF). The MSCs were transplantable to the gastric tissue surrounding the ulcer, where a majority of the engrafted cells were positive for vimentin. The transplantation significantly accelerated gastric ulcer healing compared with controls. The engrafted MSCs also expressed VEGF and HGF. Administration of anti-VEGF neutralizing antibody dose dependently reduced the MSC-induced promotion of ulcer healing. In conclusion, MSC transplantation accelerated gastric ulcer healing, possibly through the induction of angiogenesis in the gastric mucosa via the secretion of VEGF. The beneficial effects of MSCs might be mediated not only by their differentiation into gastric interstitial cells, but also by their ability to supply angiogenic factors.

Musashi-1 (Msi-1), a mammalian neural RNA-binding protein, has been found to play important roles in the maintenance of stem cell states and differentiation in neural stem cells and mouse intestinal cells. We explored Msi-1 expression and its potential implications in the human stomach. Reverse transcription-PCR revealed that Msi-1 levels were significantly higher in the corpus than in antrum in Helicobacter pylori (Hp)-infected patients (n = 49) (P < 0.00001) in paired biopsy samples, whereas they were low and comparable at these two sites in Hp-negative patients (n = 31). Msi-1 levels were significantly higher in the Hp-infected corpus (n = 107) than in the Hp-negative corpus (n = 69) (P < 0.00000001). Immunohistochemistry and in situ hybridization demonstrated that Msi-1 was expressed at the base and neck/isthmus region of the fundic glands and partly co-expressed in Ki-67-positive cells in the corpus and antrum. Msi-1 levels correlated with Hp density (P < 0.05). Based on these results, we conclude that Hp infection strongly induces Msi-1 in the corpus. Given its expression in dividing cells, Msi-1 may modulate the state of gastric progenitor cells.

To examine the pathomechanism of entrapment neuropathy associated with diabetes with special emphasis on the roles of mast cells and Tenascin-C using a rat model of Streptozotocin-induced diabetes. The roles of mast cells and Tenascin-C in development of tarsal tunnel syndrome were analyzed electrophysiologically and histologically in 20 male Ws/Ws-/-rats (mast cell deficient) and 20 of their male wild type counterparts (12-16 weeks old; 250-300 g). Rats were assigned randomly to one of the following three groups; diabetic group and nondiabetic group reared in cages with a wire grid flooring; non-diabetic group in cages with sawdust covered plastic flooring. No significant role for mast cells in entrapment neuropathy was found in the rats with streptozotocin-induced diabetes. Distal latency was prolonged in diabetic rats compared with nondiabetic rats, and positively correlated with increases in blood glucose levels. Tenascin-C expression levels in the endoneurium at the tarsal tunnel in diabetic rats were found to be correlated with distal latency. The anti-alpha-smooth muscle actin (alpha-SMA) positive myofibroblast was scattered in nerve fascicles overexpressing Tenascin-C. It seems likely that Tenascin-C expressing myofibroblasts constrict axons by inducing collagen contraction of the endoneurium. Our data indicate that metabolic and phenotypic abnormalities of endoneurium and perineum lie behind the vulnerability of diabetic patients to entrapment neuropathy.

Background: The therapeutic potential of bone marrow (BM)-derived cells in ulcers is not known. This study aimed to clarify (1) cell types that are derived from the BM which infiltrate ulcers; (2) whether BM-derived cells or gastric myofibroblasts can be used for cell transplantation to treat ulcers; and (3) the phenotypes of such transplantable cells., Methods: (1) Wild-type mice were transplanted with BM cells of green fluorescent protein (GFP)-transgenic mice. Acetic acid-induced gastric ulcers were produced in mice after BM transplantation. (2) BM cells and gastric myofibroblasts were isolated from GFP-transgenic mice. Bone marrow cells attached to plastic dishes were selected for expansion. Gastric ulcers were induced, and BM-derived cells, myofibroblasts, or phosphate-buffered saline were injected around ulcers. The ulcer healing process was examined macroscopically and histologically. (3) Expression of growth factors and cytokines in transplantable cells was examined by reverse transcriptase-polymerase chain reaction., Results: (1) GFP-positive cells with interstitial phenotypes were observed at the ulcerated area. (2) Ulcer healing was significantly promoted by the injection of BM-derived cells compared to controls on day 7, but not on day 3. The BM-derived cells were observed in the tissue surrounding the ulcer. However, myofibroblasts were not found. (3) The BM-derived cells expressed hepatocyte growth factor, transforming growth factor-beta(1), and other stromal factors before transplantation, and had mesenchymal phenotypes after transplantation., Conclusions: BM-derived cells are involved in the ulcer healing. BM-derived cells, but not myofibroblasts, are locally implantable to ulcers. Thus, BM-derived cells can be transplanted to accelerate ulcer healing.

Background: Accumulating evidence suggests that the immune system plays a role in the pathophysiology of autism, and that the adhesion molecules play an important role in the process of inflammation. This study was undertaken to determine whether serum levels of the adhesion molecules in subjects with high-functioning autism are altered as compared with those of normal controls., Methods: Seventeen male subjects with high-functioning autism and 22 male age-matched unrelated healthy control subjects were enrolled. Serum levels of the soluble forms of platelet-endothelial adhesion molecule (PECAM-1), intracellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) were measured., Results: Levels of PECAM-1, but not ICAM-1, in the subjects with autism were significantly lower than those of control subjects. VCAM-1 showed a weak trend for a lowered level. There was a negative correlation between serum levels of PECAM-1 and head circumference at birth in the autistic subjects., Conclusions: These results suggest that PECAM-1 plays a role in the pathophysiology of high-functioning autism.

Background/aims: Toll-like receptor 4 (TLR4), which requires a helper molecule, MD-2, is a main receptor for lipopolysaccharide (LPS) from gram-negative bacteria. The expression of TLR4 in H. pylori infection in human gastric mucosa, however, is unclear. The aim of this study was to determine the effect of H. pylori infection on the TLR4 and MD-2 expression in human gastric mucosa., Methodology: Biopsy samples from the antrum and corpus were obtained from 45 patients (25 patients without H. pylori infection including 5 patients with successful eradication of H. pylori, and 20 patients with H. pylori infection). These samples were used for TLR4, MD-2 mRNA expression study and immunohistochemical study., Results: In patients without H. pylori infection, the expressions of TLR4 and MD-2 were bigger in the corpus mucosa than in the antral mucosa. In patients with H. pylori infection, the expressions of TLR4 and MD-2 significantly increased in the antral and corpus mucosa. Immunohistochemical study revealed similar results as the TLR4 mRNA expression. After the eradication of H. pylori, the expressions of TLR4 and MD-2 were the same levels in both sites as those in patients without H. pylori infection., Conclusions: The results indicated that H. pylori infection significantly increased TLR4 and MD-2 expressions in the antral and corpus mucosa.

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-beta (TGFbeta) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGFbeta1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGFbeta1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism.

Cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colorectal cancers. For treatment of advanced cancers, combination of COX-2 inhibitors and chemotherapy has been attempted, but the results are still controversial. In the present study, the effects of the COX-2 inhibitor celecoxib on the anticancer potential of chemotherapy, and its mechanisms of action were investigated in point of the angiogenesis, using an advanced cancer model in mice. BALB/c mice were inoculated with colon 26 cells. After the allograft grew up to 5 mm in diameter, the animals received celecoxib, 5FU, or a combination of 5FU and celecoxib (5FU/celecoxib). After 21-days of the treatment, 5FU/celecoxib significantly inhibited the tumor growth and the tumor vessel density compared with the other groups. Celecoxib, 5FU or 5FU/celecoxib significantly suppressed the VEGF content in tumor tissues. 5FU/celecoxib also enhanced IFN-gamma levels in tumor tissue, which could be involved in the potent antitumor effects of 5FU/celecoxib. This hypothesis was proven, because in IFN-gamma knockout (IFN-gamma(-/-)) mice, the inhibitory effects of 5FU/celecoxib on angiogenesis and tumor growth were significantly impaired compared with that in wild type mice. These results suggest that celecoxib enhances the antitumor effect of 5FU against an advanced colon cancer model by suppressing angiogenesis. In addition to VEGF, IFN-gamma has pivotal roles in tumor suppression induced by celecoxib.

The podosome and invadopodium are dynamic cell-adhesion structures that degrade the extracellular matrix (ECM) and promote cell invasion. We recently reported that the actin-binding protein caldesmon is a pivotal regulator of podosome formation. Here, we analyzed the caldesmon's involvement in podosome/invadopodium-mediated invasion by transformed and cancer cells. The ectopic expression of caldesmon reduced the number of podosomes/invadopodia and decreased the ECM degradation activity, resulting in the suppression of cell invasion. Conversely, the depletion of caldesmon facilitated the formation of podosomes/invadopodia and cell invasion. Taken together, our results indicate that caldesmon acts as a potent repressor of cancer cell invasion.

This study used a choice reaction-time paradigm to test the perceived impairment of facial affect recognition in Asperger's disorder. Twenty teenagers with Asperger's disorder and 20 controls were compared with respect to the latency and accuracy of response to happy or disgusted facial expressions, presented in cartoon or real images and in static or moving conditions. Group analysis revealed that the Asperger group did not differ significantly from the control group in speed and accuracy for both affects and in all presentation modalities. Individual analysis, however, revealed that the proportion of participants exhibiting a happy face advantage was smaller in the Asperger group than in the control group. The results did not support the notion of impairment in facial affect recognition in terms of speed and accuracy in Asperger's disorder. Findings also revealed that the absence of happy face advantage was more prevalent in individuals with Asperger's disorder.

Geranylgeranylacetone (GGA) effectively protects the gastric mucosa against noxious agents. The precise mechanisms underlying the gastroprotective actions of GGA are not known. To elucidate the precise mechanism of GGA, the effect of GGA treatment on COX-2 expression in rat gastric epithelial (RGM1) cells was investigated. We used a prostaglandin E2 (PGE2) enzyme-linked immunoassay kit and Western blot analysis to measure PGE2 production and COX-2 induction by GGA treatment in serum-starved RGM1 cells. Gel-shift assay, Western blot analysis, and a reporter assay were performed to determine which COX-2 promoter was involved in GGA-induced COX-2 expression. GGA treatment dose dependently increased COX-2 expression and PGE2 production. The nuclear factor (NF)-kappaB sites of the COX-2 gene promoter were critical for GGA-mediated COX-2 expression. GGA induces COX-2 expression and increases PGE2 production in serum-starved RGM1 cells via activation of the NF-kappaB sites of COX-2 gene promoters.

Background: The neurobiological basis for autism remains poorly understood. Given the role of growth factors in brain development, we hypothesized that epidermal growth factor (EGF) may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of EGF are altered in adult subjects with high-functioning autism., Methods: We measured serum levels of EGF in the 17 male subjects with high-functioning autism and 18 age-matched healthy male subjects., Results: The serum levels of EGF in the subjects with high-functioning autism (72.4 +/- 102.8 pg/mL [mean +/- SD]) were significantly lower (Mann-Whitney U = 22.0, p < .001) than those of normal control subjects (322.3 +/- 122.0 pg/mL [mean +/- SD]). However, there were no correlations between serum EGF levels and clinical variables in the subjects with autism., Conclusions: This study suggests that decreased levels of EGF might be implicated in the pathophysiology of high-functioning autism.

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of autism. In this study, we examined the SNP- and haplotypic-association of BDNF with autism in a trios-based association study (the Autism Genetic Resource Exchange). We also examined the expression of BDNF mRNA in the peripheral blood lymphocytes of drug-naïve autism patients and control subjects. In the TDT of autism trios, the SNP haplotype combinations showed significant associations in the autism group. BDNF expression in the drug-naïve autistic group was found to be significantly higher than in the control group. We suggest that BDNF has a possible role in the pathogenesis of autism through its neurotrophic effects on the serotonergic system.

We report a 72-year-old woman with a type-1 intra-osseous ganglion in the proximal humerus, extending to the bone surface. We conducted a systemic review of intra-osseous ganglion cases in Japan to identify clinical features and pathogenesis of this condition. The anatomical distribution between intra-osseous ganglia without a communicating soft tissue ganglion (type 1) and those with (type 2) is different. The origins of intra-osseous ganglia vary and depend on their anatomical location. They can arise from within the bone or in the adjacent soft tissue, and can progress to a type-2 lesion in either an outside-in or inside-out fashion.

Background: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism., Methods: Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects., Results: The serum levels (503.5+/-160.5 pg/mL (mean+/-SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0, p<0.001) lower than those (817.6+/-232.4 pg/mL (mean+/-SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients., Conclusions: This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism.

Background and Aim: Cytotoxin-associated gene A (CagA) protein from H. pylori was reported to be injected into host gastric epithelial cells via a bacterial type IV secretion system, thereby modifying signal transduction. It is classified into two major subtypes, Western and East Asian. The present study aimed to compare the effects of East Asian-type and Western-type CagA on host cell growth., Methods: A tetracycline (tet)-off system and cagA genes from Western and East Asian-type H. pylori (NCTC 11637 and F32) were transfected into untransformed rat gastric mucosal (RGM1) cells to establish RGM1-CagA cell lines in which CagA expression could be controlled by tetracycline. These cell lines were used to investigate the effect of CagA protein expression on cell growth with BrdU and water-soluble tetrazolium reagent (WST-8) assays. CagA expression, phosphorylation and extracellular signal-regulated kinase (ERK) activation were examined with immunoprecipitation and Western blotting analysis., Results: 5-Bromo-2'deoxyuridine (BrdU) and WST-8 assays demonstrated significant increases in DNA replication and RGM1 cell growth after CagA protein expression. ERK phosphorylation was enhanced when CagA protein was expressed in RGM1-CagA cells. Moreover, the East Asian-type CagA showed a significantly greater effect on ERK activation and host cell growth than the Western type. PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor, suppressed ERK phosphorylation and the CagA protein-induced increase in RGM1-CagA cell growth., Conclusions: CagA protein expression induces an increase in RGM1-CagA cell proliferation via the mitogen-activated protein kinase (MAPK) signal pathway. The East Asian-type CagA showed a significantly greater effect on cell growth than the Western type, suggesting that the East Asian CagA-positive strain may have an important role in pathogenesis.

Background: The neurobiological basis for autism remains poorly understood. Given the key role of transforming growth factor-beta1 (TGF-beta1) in brain development, we hypothesized that TGF-beta1 plays a role in the pathophysiology of autism. In this study, we studied whether serum levels of TGF-beta1 are altered in patients with autism., Methods: We measured serum levels of TGF-beta1 in 19 male adult patients with autism and 21 age-matched male healthy subjects using enzyme-linked immunosorbent assay (ELISA)., Results: The serum levels (7.34+/-5.21 ng/mL (mean+/-S.D.)) of TGF-beta1 in the patients with autism were significantly (z=-5.106, p<0.001) lower than those (14.48+/-1.64 ng/mL (mean+/-S.D.)) of normal controls. However, there were no marked or significant correlations between serum TGF-beta1 levels and other clinical variables, including Autism Diagnostic Interview-Revised (ADI-R) scores, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), aggression, Theory of Mind, and Intellectual Quotient (IQ) in patients., Conclusions: These findings suggest that decreased levels of TGF-beta1 may be implicated in the pathophysiology of autism.

Bone-marrow-derived cells (BMDCs) transdifferentiate into various types of gastrointestinal cells. The precise transdifferentiation of BMDCs in gut regeneration, however, is controversial. In this study, we examined the transdifferentiation of BMDCs in the regeneration of damaged colonic epithelia. Lethally irradiated wild-type female mice (C57BL/6) were rescued by bone marrow transplantation from male green fluorescent protein transgenic mouse donors. Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in the drinking water for 5 days on day 28 after the bone marrow transplantation. The mice were killed on day 25 after DSS administration. BMDC phenotypes were examined by confocal microscopy and fluorescence immunohistochemistry. BMDCs were frequently observed in the vimentin-positive colonic interstitial cells, which also expressed alpha-smooth muscle actin and had a spindle-like morphology, but did not express leukocyte common antigen. Green-fluorescent-protein-positive cells were rarely or less frequently found in Ki-67-positive proliferating cells, cytokeratin-positive epithelial cells, or CD31-positive endothelial cells. BMDCs frequently transdifferentiated into subepithelial myofibroblasts and fibroblasts, and often continued to reside in the colonic subepithelia after the experimental colitis had healed. In conclusion, our data indicate the fate of BMDCs, which might be involved in the healing process of the colon after DSS-induced colitis. Our data show that BMDCs contribute to colonic interstitial cells after the colitis has healed. Understanding the fate of BMDCs may be important for stem cell therapy by BMDCs., ((c) 2007 S. Karger AG, Basel.)

Background: Precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the major role of glutamate in brain development, we have hypothesized that glutamatergic neurotransmission plays a role in the pathophysiology of autism. In this study, we studied whether amino acids (glutamate, glutamine, glycine, D-serine, and L-serine) related to glutamatergic neurotransmission are altered in serum of adult patients with autism., Methods: We measured serum levels of amino acids in 18 male adult patients with autism and age-matched 19 male healthy subjects using high-performance liquid chromatography., Results: Serum levels (mean = 89.2 microM, S.D. = 21.5) of glutamate in the patients with autism were significantly (t = -4.48, df = 35, p < 0.001) higher than those (mean = 61.1 microM, S.D. = 16.5) of normal controls. In contrast, serum levels of other amino acids (glutamine, glycine, d-serine, l-serine) in the patients with autism did not differ from those of normal controls. There was a positive correlation (r = 0.523, p = 0.026) between serum glutamate levels and Autism Diagnostic Interview-Revised (ADI-R) social scores in patients., Conclusions: The present study suggests that an abnormality in glutamatergic neurotransmission may play a role in the pathophysiology of autism.

Background: The precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the key role of brain-derived neurotrophic factor (BDNF) in brain development, we hypothesized that BDNF may play a role in the pathophysiology of autism. In this study, we studied whether serum levels of BDNF are altered in patients with autism., Methods: We measured serum levels of BDNF in 18 adult male patients with autism and 18 age-matched healthy male control subjects., Results: The serum levels of BDNF in patients with autism (25.6+/-2.15 ng/ml (mean+/-S.D.)) were significantly (z = -4.42, p < 0.001) lower than those of normal controls (61.6+/-10.9 ng/ml (mean+/-S.D.)). Nevertheless, we found no correlations between BDNF levels and clinical variables in autistic patients., Conclusions: This study suggests that reduced BDNF levels may play a role in the pathophysiology of autism.

We report a case of a locked thumb metacarpophalangeal joint secondary to metacarpal head fracture. As fractures of the radial condyle are not readily seen in routine X-rays, other imaging modalities, including CT, should be considered if the patient complains of limited extension after hyperextension injury of the thumb.

We report 4 cases of a congenitally stiff metacarpophalangeal joint of the small finger that were treated satisfactorily with surgical release.