Sustained activation of ERK signaling in astrocytes is critical for neuronal injury‐induced monocyte chemoattractant protein‐1 production in rat corticostriatal slice cultures

We previously demonstrated that N‐methyl‐d ‐aspartate (NMDA) treatment (50 μm , 3 h) induced astrocytic production of monocyte chemoattractant protein‐1 (MCP‐1, CCL2), a CC chemokine implicated in ischemic and excitotoxic brain injury, in rat corticostriatal slice cultures. In this study, we investigated the signaling mechanisms for NMDA‐induced MCP‐1 production in slice cultures. The results showed a close correlation between NMDA‐induced neuronal injury and MCP‐1 production, and an abrogation of NMDA‐induced MCP‐1 production in NMDA‐pretreated slices where neuronal cells had been eliminated. These results collectively indicate that NMDA‐induced neuronal injury led to astrocytic MCP‐1 production. NMDA‐induced MCP‐1 production was significantly inhibited by U0126, an inhibitor of extracellular signal‐regulated kinase (ERK). Immunostaining for phosphorylated ERK revealed that transient neuronal ERK activation was initially induced and subsided within 30 min, followed by sustained ERK activation in astrocytes. Treatment with U0126 during only the early phase (U0126 was washed out at 15 or 30 min after NMDA administration) suppressed early activation of ERK in neuronal cells, but not later activation of ERK in astrocytes. In this case, MCP‐1 production was not suppressed, suggesting that activation of neuronal ERK is not necessary for MCP‐1 production. In contrast, delayed application of U0126 at 3 h after the beginning of NMDA treatment inhibited MCP‐1 production to the same degree as that observed when U0126 was applied from 3 h before NMDA administration. These findings suggest that sustained activation of the ERK signaling pathway in astrocytes plays a key role in neuronal injury‐induced MCP‐1 production.     

Effect of itraconazole on the cornea in a murine suture model and penetrating keratoplasty model

AIM: To investigate the anti-(lymph)angiogenic and/or anti-inflammatory effect of itraconazole in a corneal suture model and penetrating keratoplasty (PK) model. METHODS: Graft survival, corneal neovascularization, and corneal lymphangiogenesis were compared among itraconazole, amphotericin B, dexamethasone, phosphate buffered saline (PBS) and surgery-only groups following subconjunctival injection in mice that underwent PK and corneal suture. Immunohistochemical staining and analysis were performed in each group. Real-time polymerase chain reaction (RT-PCR) was performed to quantify the expression of inflammatory cytokines (TNF-alpha, IL-6) and vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGFR-2, and VEGFR-3. RESULTS: In the suture model, the itraconazole group showed less angiogenesis, less lymphangiogenesis, and less inflammatory infiltration than the PBS group (all P<0.05). The itraconazole group showed reduced expression of VEGF-A, VEGFR-2, TNF-alpha, IL-6 than the PBS group (all P<0.05). In PK model, the two-month graft survival rate was 28.57% in itraconazole group, 62.50% in dexamethasone group, 12.50% in PBS group, 0 in amphotericin B group and 0 in surgery-only group. Graft survival in the itraconazole group was higher than that in the amphotericin, PBS and surgery-only group (P=0.057, 0.096, 0.012, respectively). The itraconazole group showed less total angiogenesis and lymphangiogenesis than PBS group (all P<0.05). CONCLUSION: Itraconazole decrease neovascularization, lymphangiogenesis, and inflammation in both a corneal suture model and PK model. Itraconazole has anti-(lymph)-angiogenic and anti-inflammatory effects in addition to its intrinsic antifungal effect and is therefore an alternative treatment option in cases where steroids cannot be used.     

Separation and characterization of the molecular species of thrombomodulin in the plasma of diabetic patients.

Thrombomodulin (TM) and its molecular species have been identified as markers of vascular endothelial cells (EC). In the present study, using high-performance liquid chromatography (HPLC) in 7 normal subjects, 5 chronic glomerulonephritis (GN) patients, and 25 diabetes mellitus (DM) patients, the TM molecular species separated from plasma showed seven heterogeneous fragments of 94, 74, 48, 36, 27, 14, and 12 kDa. Comparing the diabetic patients and healthy subjects, it was found that plasma TM generally, and its 74-kDa molecular species particularly, were increased in diabetic patients and the increase became more apparent as the disease progressed in severity. Comparing the patients with diabetic nephropathy and those with nephritis of the same degree of renal dysfunction, both groups had increased levels of TM, but the distribution of the molecular species differed; that is, the 74-kDa form increased in the diabetic patients and the 12-kDa species increased markedly in the nephritis patients. Glycation of the various TM molecular species increased more in the diabetic patients than in healthy subjects. There was a significantly positive correlation between the HbA(1c) and the 74-kDa TM molecular species in diabetic patients. These findings suggest that a fluctuation in the blood glucose level is significantly related to vascular EC damage in DM.     

Extranodal NK/T‐cell lymphoma,nasal type,manifesting as rapidly progressive dementia without any mass or enhancing brain lesion

Among the many potential etiologies for rapidly progressive dementia (RPD), primary central nervous system extranodal NK/T‐cell lymphoma, nasal‐type (ENKL) is a rare entity. We present the first reported case of autopsy‐proven RPD due to ENKL without any mass or enhancing lesion of the brain. A 54‐year‐old immunocompetent man presented with RPD, myoclonus and ataxia. The mini‐mental state examination (MMSE) score was 22/30. His brain MRI revealed progressive brain atrophy without gadolinium enhancement or mass lesion. Five months after the initial evaluation, cognitive impairment further worsened with an MMSE score of 3/30. At the advanced stage, lumbar MRI showed swollen cauda equina with gadolinium enhancement. The number of Epstein‐Barr virus (EBV) DNA in cerebrospinal fluid had gradually increased. Twelve months after onset, the patient died of respiratory failure. Pathological findings revealed that lymphoma cells had diffusely invaded the meninges, parenchyma of the brain, spinal cord and cauda equina. Cells were positive for CD3, CD56 and EBV‐encoded small RNAs and negative for CD20. No evidence of malignancy was identified in the visceral organs. This report indicates that ENKL should be recognized as one of the rare causes of RPD. Early testing for EBV‐DNA in cerebrospinal fluid and imaging of cauda equina would be useful diagnostic tools.     

Iron deficiency down-regulates the Akt/TSC1-TSC2/mammalian Target of Rapamycin signaling pathway in rats and in COS-1 cells

Iron deficiency (ID) is one of the most commonly known forms of nutritional deficiencies. Low body iron is thought to induce neurologic defects but may also play a protective role against cancer development by cell growth arrest. Thus, ID may affect cellular pathways controlling cell growth and proliferation, the mechanism of which is still not fully understood. The serine/threonine protein kinase Akt and its downstream target, the mammalian Target of Rapamycin (mTOR), is known to play a crucial role in the regulation of cell growth and survival. Therefore, we hypothesized that Akt/mTOR pathway could be influenced by ID. Three-week-old male Wistar-strain rats were divided into 3 groups and the 2 groups had free access to a control diet (C group) or an iron-deficient diet (D group). The third group (PF group) were pair-fed the control diet to the mean intake of the D group. After 4 weeks, rats were killed and their brains were sampled. In separate experiments, COS-1 cells were cultured with or without the iron chelator deferoxamine. Western blots of brain samples and COS-1 lysates were used to analyze the expression and phosphorylation state of Akt, TSC2, mTOR, and S6 kinase proteins implicated in the Akt/mTOR pathway. Using 2 different ID models, we show for the first time that iron deficiency depresses Akt activity in rats and in COS-1 cells, leading to a decrease in mTOR activity.     

Four-hydroxyphenylpyruvic acid oxidase deficiency with normal fumarylacetoacetase: a new variant form of hereditary hypertyrosinemia

Enzymatic studies on the liver of an infant are described-a case of hypertyrosinemia without hepatic dysfunction. His parents were siblings and the mother had hypertyrosinemia. Excessive amounts of 4-hydroxyphenylpyruvic acid (pHPP), 4-hydroxyphenylacetic acid (pHPL), and 4-hydroxyphenylacetic acid (pHPA) were found to be excreted in the patient's urine as well as in the urine of the mother and the inhibitor of porphobilinogen synthetase was not found. Soluble tyrosine aminotransferase (s-TAT), separated from that of the mitochondrial form (m-TAT) by DE 52 column chromatography, was normal in the patient's liver, both quantitatively and qualitatively. The activities of fumarylacetoacetase in the patient's liver and in the peripheral leucocytes from the parents were normal. The activity of pHPP oxidase in the patient's liver was approximately 5% of the control and the enzyme had a high Km value for pHPP (controls: 0.06 +/- 0.01 mM, patient: 0.23 +/- 0.03 mM). From these results, the patient was thought to be different from previously described types of tyrosinemia and perhaps representative of a new variant form. This is the first report concerning 4-hydroxyphenylpyruvic acid oxidase deficiency alone. Mild metal retardation and mild hypertyrosinemia may be offered as typical clinical features of the disease.     

Minimal curettage,multiple drilling,and continuous decompression through a cannulated screw for treatment of calcaneal simple bone cysts in children

This report concerns a series of 12 patients with simple bone cysts of the calcaneus, who were treated between 1988 and 2000 by a minimal surgical intervention of curettage, multiple drilling and continuous decompression through insertion of a cannulated screw. Inserted screws were made of titanium in 8 cases and ceramics in 4 cases. The mean operative time was 58.8 +/- 25.4 minutes, and complete healing was achieved in 11 cases after 9.2 +/- 6.4 months. One patient needed an additional surgery for replacement of a titanium screw. Final results were excellent after a mean follow up of 91 +/- 52.1 months. This series of patients represents one of the largest reported series of calcaneal simple bone cyst in conjunction with long-term follow-up. Our technique of minimal curettage, drilling and continuous decompression with a cannulated screw insertion is considered to be a good option for management of simple bone cysts of the calcaneus.     

Main pancreatic duct dilatation: a sign of high risk for pancreatic cancer

BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma remains very poor, but is better in patients with a small tumor without local infiltration. The identification of the sign of high risk for pancreatic cancer will lead to early detection and improvement of the prognosis of this disease. The purpose of this study was to evaluate the main pancreatic duct dilatation as a sign of high risk for pancreatic cancer. METHODS: The diameter of the main pancreatic duct was measured by ultrasonography. The proportion of cases with main pancreatic duct dilatation was retrospectively examined in a pre-cancer group (39 subjects in whom pancreatic cancer developed more than 1 year later and surgically resected) and in a control group (10 244 subjects). Then the proportions in both groups were compared using the odds ratio. RESULTS: The proportion of cases with a slight dilatation (>/=2 mm in diameter) of the main pancreatic duct was 65% in the pre-cancer group, more than 4 years before the resection of the pancreatic cancer. In contrast, it was 5.35% in the age-matched control subjects. The odds ratio of 32.5 (95% confidence interval: 10.9-107.3) shows a significant association between the main pancreatic duct dilatation and the pre-cancer condition. Moreover, the proportion and the mean diameter of the dilated duct in the pre-cancer group increased with time. CONCLUSION: Slight dilatation of the main pancreatic duct appears to be a sign of high risk for pancreatic cancer. The systematic examination of high-risk subjects is recommended for the early detection of pancreatic cancer.     

Psychoeducation for the families of patients with eating disorders and changes in expressed emotion: A preliminary study

Psychosocial variables such as expressed emotion (EE) have prognostic significance, and family psychoeducation has been developed to aid in the treatment of various psychiatric disorders. This study reports relationships among EE, family factors, and symptoms observed while conducting multifamily psychoeducation for eating disorders. Group sessions were held once a month for the relatives of patients with DSM-IV eating disorders, and the group met for five sessions that included both education and problem-solving. Thirty-seven relatives volunteered to participate in our program, and of these, 28 completed the program. EE (as measured by the Five-Minute Speech Sample [FMSS]), family function (as measured by the Family Adaptability and Cohesion Evaluation Scales [FACES]), the family's mental state (as measured by the Profile of Mood States [POMS]), and patient's symptoms (as measured by the Eating Disorder Evaluation Scales [EDES] and Global Assessment of Functioning [GAF] on clinician evaluations, and by the Anorexic Behavior Observation Scale [ABOS] assessment of the family) were administered at both the first and final sessions. The rates of high-EE relatives tended to decrease (especially high emotional overinvolvement [EOI]), and families' assessment of symptoms was also significantly improved. Twice-repeated multivariate analysis of variance (MANCOVA) showed that EOI, ABOS, and POMS scores were changed significantly during the sessions. Psychoeducation for the family members of patients with eating disorders might help lower distress and encourage positive interactions within the family. EE is an important measure in evaluations of psychoeducation. However, a randomized, controlled trial is needed to clarify the efficacy of this treatment.