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Objective: To investigate whether postischemic administration of minocycline attenuates hind-limb motor dysfunction and gray and white matter injuries after spinal cord ischemia. Design: A prospective, randomized, laboratory investigation. Setting: Laboratory in university, single institution. Participants: Male New Zealand White rabbits. Intervention: Spinal cord ischemia was induced by an occlusion of the infrarenal aorta for 15 minutes. The groups were administered minocycline 1 hour after reperfusion (M-1; n = 8), minocycline 3 hours after reperfusion (M-3; n = 8), saline 1 hour after reperfusion (control [C]; n = 8), or saline and no occlusion (sham; n = 4). Minocycline was administered intravenously at 10 mg/kg 6 times at 12-hour intervals until 60 hours after the initial administration. Measurement and Main Results: Hind-limb motor function was assessed using the Tarlov score. For histologic assessments, gray and white matter injuries were evaluated 72 hours after reperfusion using the number of normal neurons and the percentage of areas of vacuolation, respectively. Motor function 72 hours after reperfusion was significantly better in group M-1 than in group C. The number of neurons in the anterior horn was significantly larger in group M-1 than in groups M-3 or C but did not differ significantly between groups M-3 and C. No significant difference was noted in the percentage of areas of vacuolation among the ischemia groups. Conclusions: Minocycline administration beginning at 1 hour after reperfusion improved hind-limb motor dysfunction and attenuated gray matter injury in a rabbit spinal cord ischemia model. [Copyright &y& Elsevier]

We previously demonstrated using restriction landmark genomic scanning-based 2-dimensional genome electrophoresis method decreased results of 16 primary hepatocellular carcinomas (HCCs) revealed reduction of intensity of 60 NotI-landmark spots, and increase in five spots that were frequently observed in HCCs. Most frequently decreased spot (14/16 HCCs) was identified to it corresponds to a gene encoding SSI-1, a JAK-binding protein (SSI-1/SOCS-1/JAB) that regulated the JAK/STAT signal transduction pathway. This signaling pathway is important for relaying signals from various cytokines outside the cell to the inside. Expression level of SOCS-1 messenger RNA was markedly suppressed in 50% of HCCs (4/8). Loss of heterozygosity at the SSI-1 gene, was found in all cases with aberrant expression. Methylation analysis of the CpG-rich regions of SSI-1 gene revealed hypermethylation of these regions. In an additional series of methylation analysis using 30 HCCs, 16 (53%) showed hypermethylation of the gene. These results indicate that the SSI-1 gene is silenced in a substantial portion of HCC though the combined mechanisms of methylation of either 5′ or exon CpG rich regions and by a chromosomal loss of the remaining allele. [Copyright &y& Elsevier]

Background and purpose The aim of this study was to evaluate chronologic changes in lower urinary tract symptoms (LUTS), health-related (HR) quality of life (QOL), and disease-specific QOL during the first 12 months after salvage radiotherapy (SRT) for biochemical recurrence of prostate cancer in patients who underwent radical prostatectomy. Materials and methods In 81 patients who received SRT (70 Gy/35fr/7 weeks), International Prostate Symptom Score (IPSS), 36-Item Short Form scores, and UCLA-Prostate Cancer Index (UCLA-PCI) were recorded before, during, and immediately after SRT, and 1–12 months after the completion of SRT. Results The total IPSS and storage symptom-related sum were significantly increased following initiation of SRT, and returned to the baseline 6 months after SRT. For three of eight domains of HRQOL, and the physical component summary score showed transient deterioration in the period between completion of SRT and 1 month following SRT. The UCLA-PCI for urinary function/bother and bowel function/bother was affected until 1–6 months after SRT. Conclusions This is the first report to concurrently evaluate detailed chronologic changes in LUTS and QOL in patients who received SRT. Knowledge of changes in LUTS and QOL outcomes associated with SRT may influence treatment recommendations and enable patients to make better-informed decisions. [ABSTRACT FROM AUTHOR]

Objective: To assess whether the phosphorylated Fas-associated death domain protein (FADD) at 194 serine (p-FADD) is valuable as a marker of biochemical recurrence in hormone-naive patients who had undergone radical prostatectomy. Materials and Methods: We used radical prostatectomy specimens from 106 patients. None of the patients had received neoadjuvant or adjuvant therapy. The percentage of positive p-FADD cells (nuclear staining) was immunohistochemically evaluated. The correlation between FADD phosphorylation and the clinicopathologic parameters was assessed. The correlation between the biochemical recurrence-free rate and the p-FADD expression level was analyzed using the Kaplan-Meier method. Results: Overall, 39 patients developed biochemical recurrence. We investigated the expression of p-FADD in 106 patients with prostate cancer using immunohistochemistry. We compared our findings with the clinicopathologic parameters, including the follow-up data. Patients with a greater positive p-FADD rate had a significantly lower biochemical recurrence rate than those with a lower positive p-FADD rate (P < .001). A significant inverse correlation was found between the positive p-FADD rate and the Gleason score. Conclusion: A low expression of p-FADD could be a predictor of biochemical recurrence in hormone-naive patients who have undergone radical prostatectomy. [ABSTRACT FROM AUTHOR]

Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal α-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the study: The present study was conducted to assess the effects of intraperitoneal administration of n-propyl gallate (PG) on hippocampal neuronal survival after forebrain ischemia. Methods: Forty male Sprague-Dawley rats were randomly assigned to one of 6 groups. Animals in the PG-I-10, PG-I-8 and PG-S groups received intraperitoneal injection of PG (100mg/kg) 72, 48, 24h and 30min before severe (10min) or moderate (8min) ischemia or sham operation, respectively, while animals in the V-I-10, V-I-8 and V-S groups received the vehicle (10% DMSO) in the same manner. Forebrain ischemia was produced by bilateral carotid occlusion combined with hypotension (35mmHg) under isoflurane anesthesia. Animals were killed 7 days after reperfusion. Histological assessments were performed using hematoxylin and eosin staining. In separate groups of animals that received PG or vehicle, m-RNA levels of hypoxia-inducible factor 1α (HIF-1α), erythropoietin (EPO) and vascular endothelial growth factor (VEGF) were measured using the reverse transcription-PCR protocol. Results: The number of normal neurons was significantly higher in the PG-I-8 group compared with that in the V-I-8 group, whereas it was similar between the PG-I-10 and V-I-10 groups. Animals that received PG had significantly higher levels of HIF-1α, EPO and VEGF expression compared with those that received vehicle. Conclusion: The results indicated that intraperitoneal administration of PG may have neuroprotective effects in a model of moderate, but not severe, forebrain ischemia in rats. [Copyright &y& Elsevier]

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this study was to prospectively assess the variations in health-related quality of life (HR-QoL) in patients who underwent low–dose rate prostate brachytherapy using iodine-125 seed source during the first year after seed implantation. Methods and Materials: Between July 2004 and December 2006, 109 patients underwent low–dose rate brachytherapy. The Medical Outcomes study 36-Item Short Form; the University of California, Los Angeles-Prostate Cancer Index; and the International Index of Erectile Function-5 were evaluated before and at 1, 3, 6, and 12 months after seed implantation. Results: In Medical Outcomes study 36-Item Short Form analyses and the HR-QoL scores were well preserved during the first year after seed implantation. In the University of California, Los Angeles-Prostate Cancer Index analyses, the urinary function and bother scores showed significant decrease during 6 months after seed implantation. The bowel function and bother scores showed significant decrease at 3 months after seed implantation. The sexual function score showed significant decrease at 3, 6, and 12 months after seed implantation, whereas the sexual bother score showed no change during the first year. The International Index of Erectile Function-5 score dramatically decreased at 1, 3, 6, and 12 months after seed implantation. Conclusions: The general HR-QoL in the patients who underwent seed implantation was well preserved during the first year after seed implantation, whereas the urinary, bowel, and sexual function and bother scores showed transient deterioration during the first year after seed implantation. Especially, sexual function showed significant deterioration in Japanese men after seed implantation. [ABSTRACT FROM AUTHOR]

Abstract: The two-vein occlusion (2VO) model is known to be useful for ischemic penumbra studies in vivo. It was applied here to examine sequential changes of regional cerebral blood flow (CBF) and cerebral venous infarction in normal (Long–Evans Tokushima Otsuka, LETO) and diabetic (Otsuka Long–Evans Tokushima Fatty, OLETF) rats. The aim of our study was to examine and compare the ischemic pathogenesis related to regional changes in cerebral blood flow (CBF) induced with 2VO in diabetic OLETF and non-diabetic LETO rats. Two cortical veins were occluded photochemically by using rose bengal dye in 10 OLETF and 10 LETO rats. All animals were killed with perfusion fixation at 48 h after 2VO. Bax and Bcl-2 staining was performed along with the terminal deoxynucleotidyl transderase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay to examine the relationship to single-cell death. Smooth muscle actin and Van Gieson''s elastic staining were done for assessment of thickening of the vessel walls. Not only the volume of cerebral cortex affected by 2VO-induced venous infarction was increased in diabetic OLETF rats, but we also observed significantly reduced CBF at 90 min after 2VO, coupled with increased apoptosis in and around ischemic lesions. Morphologically, OLETF rats demonstrated marked thickening of the walls in the small cerebral vessels with perivascular fibrosis, indicating more severe cerebral microvascular atherosclerotic changes as compared to their non-diabetic LETO counterparts. The OLETF rat thus appears to be an excellent animal model for studying the diabetic enhancement of venous ischemia induced by 2VO. [Copyright &y& Elsevier]

Objectives: To evaluate the chronologic changes in the International Prostate Symptom Score (IPSS), uroflowmetric parameters, and prostate volume (PV) in patients who received low-dose-rate brachytherapy. Methods: Between July 2004 and December 2006, 110 patients received low-dose-rate brachytherapy. Of the 110 patients, 82 were treated with seed implantation alone and 28 with combined external beam radiotherapy. The IPSS, uroflowmetric parameters, and PV were evaluated before seed implantation and at 1, 3, 6, and 12 months after seed implantation. Results: The mean IPSS showed a significant increase at 1 and 6 months after seed implantation and had returned to baseline 12 months later. The maximal flow rate, voided volume, and postvoid residual urine volume showed transient deterioration at 1 and 6 months after seed implantation and had returned to the baseline 12 months later. The mean PV compared with the baseline PV showed a significant 3.8-cm decrease (11.2%) at 12 months after implantation. The patients who did not receive neoadjuvant hormonal therapy had a 5.9-cm decrease in PV (20.2%) 12 months later. In contrast, those who received neoadjuvant hormonal therapy had no change in PV after seed implantation. Conclusions: This is the first report to evaluate the chronologic changes in subjective parameters (IPSS) and objective parameters (uroflowmetry) and PV, concurrently. The changes in subjective parameters correlated with the changes in objective parameters during the first 12 months after seed implantation. The change in the PV was different after seed implantation in patients with or without neoadjuvant hormonal therapy. [Copyright &y& Elsevier]

Abstract: It has been reported that delta opioid agonists can have neuroprotective efficacy in the central nervous system. This study was conducted to test the hypothesis that a delta opioid receptor (DOR) agonist, [d-Ala2, d-Leu5] enkephalin (DADLE), can improve neuron survival against experimental forebrain ischemia in rats. Using male rats (n =125), intraperitoneal injection of DADLE (0, 0.25, 1, 4, 16mgkg−1) was performed 30min before ischemia. Ten minutes interval forebrain ischemia was provided by the bilateral carotid occlusion combined with hypotension (35mmHg) under isoflurane (1.5%) anesthesia. All animals were neurologically and histologically evaluated after a recovery period of 1 week. As histological evaluation, percentages of ischemic neurons in the CA1, CA3, dentate gyrus (DG) were measured. During the recovery period, 27 rats died because of apparent upper airway obstruction, seizure, or unidentified causes. There were no differences in the motor activity score among the groups. Ten minutes forebrain ischemia induced approximately 75, 20, and 10% neuronal death in the CA1, CA3, and DG, respectively. Any doses of DADLE did not attenuate neuronal injury in the hippocampus after ischemia. Pre-ischemic treatment of DORs agonism with DADLE did not provide any neuroprotection to the hippocampus in rats subjected to forebrain ischemia. [Copyright &y& Elsevier]

The Otsuka–Long–Evans Tokushima Fatty rat represents a model for spontaneous non-insulin-dependent type II diabetes mellitus (DM), characterized by diastolic dysfunction and associated with abnormal calcium handling and decrease in sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) expression. The aim of this study was to examine whether SERCA2a gene transfer can restore the energetic deficiency and left ventricular (LV) function in this model. DM rats were randomized to receive adenovirus carrying either the SERCA2a gene (DM + Ad.SERCA2a) or the β-galactosidase gene (DM + Ad.βGal) or saline (DM + saline). LV mechanoenergetic function was measured in cross-circulated heart preparations 3 days after infection. In DM, end-systolic pressure at 0.1 ml intraballoon water (ESP0.1) was low and end-diastolic pressure at 0.1 ml intraballoon water (EDP0.1) was high (22 mm Hg), compared with non-DM (EDP0.1 12 mm Hg). In DM + Ad.SERCA2a, however, ESP0.1 was increased over 200 mm Hg and EDP0.1 was decreased to 7 mm Hg. LV relaxation rate was fast in DM + Ad.SERCA2a, but slow in the other DM groups. There was no difference in relation between cardiac oxygen consumption per beat and systolic pressure–volume area among all groups. Finally, the oxygen cost of LV contractility in DM was about three times as high as that of normal. In DM + Ad.SERCA2a, the oxygen cost decreased to control levels, but in DM + Ad.βGal/DM + saline it remained high. In DM failing hearts, the high oxygen cost indicates energy wasting, which contributes to the contractile dysfunction observed in diabetic cardiomyopathy. SERCA2a gene transfer transforms this inefficient energy utilization into a more efficient state and restores systolic and diastolic function to normal.Molecular Therapy (2006) 13, 987–996; doi: 10.1016/j.ymthe.2006.01.002 [ABSTRACT FROM AUTHOR]

Summary: We investigated the promotor hypermethylation status of multiple genes in 49 oral squamous cell carcinomas (OSCC), using the methylation-specific PCR (MSP) assay. The genes examined included p16 INK4a , p14 ARF , RB1, p21 Waf1 , p27 Kip1 , PTEN, p73, 0 6 -MGMT, and GST-P. Detailed clinicopathological data, such as patient age, sex, tobacco use, alcohol consumption, lesion site, degree of tumor differentiation, tumor size, presence of lymph node metastasis, and clinical stage, were collected for all 49 samples. Overall, gene methylation was detected in 46.9% (23/49) of samples and was closely correlated with tobacco use or/and alcohol consumption. Of the genes investigated, p16 INK4a , p14 ARF , 0 6 -MGMT, RB1, PTEN, and p27 Kip1 were found to be methylated in 34.7%, 20.4%, 12.2%, 10.2%, 6.1%, and 4.1% of these 49 tumors, respectively, but methylation of p21 Waf1 , p73, and GST-P was not detected at all. Methylation frequencies were much higher for each gene when computed among informative cases only. Concurrent promotor hypermethylation of p16 INK4a and p14 ARF correlated significantly with tumor size, lymph node metastasis, and stage III/IV advanced OSCC; p14 ARF hypermethylation, in particular, was significantly associated with both lymph node metastasis and late clinical stage. Our results suggest that DNA methylation of multiple genes, especially hypermethylation of the p14 ARF promoter, is common in OSCC and is associated with the use of tobacco and/or alcohol consumption. For this type of cancer, the data further implicates gene methylation as playing an important role in tumor progression. [Copyright &y& Elsevier]

Summary: As combinations of genetic and/or epigenetic alterations occurring during salivary gland carcinogenesis are largely unknown, we here analyzed 36 salivary gland carcinomas (SGCs) for changes in INK4a/ARF, RB1, p21, p27, PTEN, p53, MDM2 and O6-MGMT genes using methylation specific PCR (MSP), loss of heterozygosity (LOH) assays and mutational analysis with immunohistochemistry (IHC), as well as histone H3 and H4 acetylation status. The RB1 gene was found to be the most frequently methylated (41.7% of cases), while methylation of p27Kip1 and O6-MGMT were less frequent 8.3% and 5.6%, respectively). Two other genes, p21Waf1 and PTEN, were unmethylated in the SGCs examined. RB1 methylation significantly correlated with loss of expression as determined by IHC (P=0.03), and also a poor prognosis (P=0.02). p53 mutations were found in 8 cases (22.2%), coupled with p14ARF hypermethylation in two cases. LOH in INK4a/ARF and the RB1 locus was observed in 33.3% and 28.6% of the lesions, respectively. There was no correlation between 9p21 LOH and methylation of the INK4a/ARF gene. Promoter hypermethylation of RB1 coupled with LOH was evident in three samples immuno-negative for RB1. Acetylation of histone H3 and H4 was detected in 6 and 5 cases, respectively. These findings indicate that epigenetic silencing of tumour suppressor genes via promoter hypermethylation might be crucial for salivary gland carcinogenesis, particularly in the RB1 gene. Thus epigenetic events including methylation and acetylation as well as genetic alterations may have important contributions. [Copyright &y& Elsevier]

Recent evidence suggested that cyclooxygenase-2 (COX-2) expression in the peripheral nerve early after nerve injury might be involved in the development of neuropathic pain. Although previous investigators have demonstrated that COX-2 is expressed in peripheral nerve at a late phase (2–4 weeks) after nerve injury, COX-2 up-regulation at an early phase after nerve injury has not been determined. Using immunohistochemistry, we observed biphasic increases of COX-2 expression after L5 single spinal nerve injury. The first increment of COX-2 positive cells was noted 1 day after nerve injury and these cells co-expressed the Schwann cell marker S-100. A second increment was noted after 7–14 days and these cells co-expressed the macrophage marker ED-1. These results suggested that the cellular sources of COX-2 expression might be different between the early and late phases after nerve injury. [Copyright &y& Elsevier]

To clarify the role of cyclooxygenase in the peripheral nerve on the development of neuropathic pain, we investigated the effects of peri-sciatic administration of indomethacin on the development of allodynia in a model of L5 single spinal nerve injury. Peri-sciatic administration of indomethacin (1 mg/kg) was performed 3, 24, or 72 h after nerve injury (n=6/each). In rats with indomethacin 3 or 24 h after nerve injury, ipsi-lateral paw withdrawal thresholds 7–35 days after nerve injury were significantly higher compared with those in the control group (n=6: without peri-sciatic treatment) (P<0.05). However, such efficacy was no longer apparent when indomethacin was administered 72 h after nerve injury. These results suggest that peri-sciatic administration of indomethacin early (less than 24 h) after nerve injury can attenuate the development of allodynia. [Copyright &y& Elsevier]

Abstract: Bardet–Biedl syndrome (BBS) is an autosomal recessive disorder characterized by rod–cone dystrophy, polydactyly, central obesity, mental retardation, and hypogonadism. Although many organs are involved in BBS, hyperammonemia caused by portal hypertension has been reported previously in only a single patient. We describe the second such patient with BBS and hyperammonemia, associated with fluctuating mental impairment. The patient was a 17-year-old boy with BBS. Esophageal, gastric, and rectal varices and mild hepatic dysfunction started to develop at 5 years of age. A liver biopsy showed dilated portal veins with mild fibrosis in portal tract. From the age of 17 years, he often had forced laughter with apparently normal consciousness. Laboratory examinations revealed hyperammonemia (112.2mg/ml). Oral medication lowered the blood ammonia level to 69.9mg/ml, reduced the frequency of forced laughter, and improved his IQ. Patients with BBS may have additional diseases or conditions that affect mental status, such as hyperammonemia. Physicians should explore the underlying causes of these conditions and treat such patients, who already have a compromised quality of life. [Copyright &y& Elsevier]

Purpose: High-neutrophil to lymphocyte ratio (NLR) values have been shown to be associated with a poor prognosis in many human malignant tumors. We evaluated the correlation of the NLR with other variables in patients with muscle-invasive bladder cancer after radical cystectomy (RC); in particular, we evaluated chronological changes in the postoperative NLR.Methods: We included the data from a total of 110 patients who underwent RC for muscle-invasive bladder cancer. The NLR was calculated using complete blood counts determined before RC. Kaplan-Meier and Cox proportional regression analyses of recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were performed to identify significant prognostic variables.Results: The median patient age was 72 years (41-91 years). In univariate analysis, the pretreatment NLR (≥2.6 vs.<2.6) was associated with RFS (hazard ratio [HR] = 2.41, P = 0.008), CSS (HR = 2.89, P = 0.006), and OS (HR = 2.73, P = 0.002). In multivariate analysis, an NLR≥2.6 and an infiltrative growth pattern at the tumor invasion front were significantly associated with RFS (HR = 2.61, P = 0.023), CSS (HR = 2.58, P = 0.08), and OS (HR = 2.77, P = 0.004). Postoperative chronological analysis revealed that the NLR of 68 patients without recurrence remained low during follow-up, whereas the NLR of the remaining 42 patients with recurrence increased significantly in the last visit before recurrence was detected radiographically (P< 0.01).Conclusions: The NLR and tumor growth pattern were strong predictors of prognosis for patients undergoing RC. Our results suggest that an increase in the NLR during follow-up after RC is a potential marker for the early detection of recurrence. [ABSTRACT FROM AUTHOR]

Abstract: Plasmacytoid urothelial carcinoma is a rare malignant neoplasm in the urinary bladder. A 46-year-old man presented with gross hematuria and increased serum concentrations of both carbohydrate antigen (CA) 19-9 and beta-human chorionic gonadotropin (β-hCG). The tumor was composed of conventional urothelial carcinoma and plasmacytoid variant, both positive for epithelial markers. In addition, plasmacytoid tumor cells were positive for an accepted marker of plasma cell origin, CD138. CA19-9 was mainly expressed in conventional urothelial carcinoma cells, and β-hCG was mainly produced by plasmacytoid tumor cells. This is the first report, to our knowledge, indicating β-hCG can be produced by plasmacytoid bladder cancer cells lacking trophoblastic features. [Copyright &y& Elsevier]