Low-Dose-Rate and High-Dose-Rate Brachytherapy for Localized Prostate Cancer in ABO-Incompatible Renal Transplant Recipients.

BACKGROUND: Brachytherapy is one of the standard treatments for localized prostate cancer (CaP). However, the feasibility of brachytherapy for renal transplant recipients (RTRs) is still uncertain. MATERIALS AND METHODS: Between August 2007 and March 2018, all patients who had undergone low-dose-rate (LDR) brachytherapy or high-dose-rate (HDR) brachytherapy for clinically localized CaP at our institution were retrospectively identified (n = 394). Of these patients, 3 had a history of renal transplantation. We reviewed all available clinical data retrospectively. RESULTS: All of the RTRs received ABO-incompatible renal grafts from their spouses and had stable renal graft function before the diagnosis of CaP. The median age at diagnosis of CaP was 65 years (range, 60-67 years). The median time between transplantation and brachytherapy was 7 years (range, 4-10 years). In all of the patients, clinical stage was cT1cN0M0. Two patients received 125I LDR-brachytherapy (dose, 145 Gy) and 1 patient was treated by 192Ir HDR brachytherapy (dose, 19 Gy in 2 fractions) combined with external beam radiation therapy of 39 Gy in 13 fractions. The median follow-up period after brachytherapy was 44 months (range, 34-50 months). During the follow-up period, none of the patients developed disease progression including biochemical recurrence or clinically significant adverse events associated with radiation therapy. CONCLUSIONS: LDR brachytherapy and HDR brachytherapy are safe and technically feasible in RTRs with CaP, and oncological outcomes in RTRs do not appear to be inferior to those of patients who did not receive renal transplant.

Animal models of recurrent or bipolar depression.

Animal models of mental disorders should ideally have construct, face, and predictive validity, but current animal models do not always satisfy these validity criteria. Additionally, animal models of depression rely mainly on stress-induced behavioral changes. These stress-induced models have limited validity, because stress is not a risk factor specific to depression, and the models do not recapitulate the recurrent and spontaneous nature of depressive episodes. Although animal models exhibiting recurrent depressive episodes or bipolar depression have not yet been established, several researchers are trying to generate such animals by modeling clinical risk factors as well as by manipulating a specific neural circuit using emerging techniques.

Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus.

Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.

Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)-6 produced during remission phase.

T helper type 17 (Th17) cytokines have been implicated in the pathogenesis of neuromyelitis optica (NMO). As humanized anti-interleukin (IL)-6R (tocilizumab) immunoglobulin (Ig)G has been used as disease-modifying therapy for NMO, the objective of our study was to investigate the role of endogenous IL-6 on NMO-derived CD4(+) T cell behaviour. High production of IL-6, IL-17 and IL-21 by CD4(+) T-cells was detected in NMO patients. Further, IL-21 and IL-6 levels were related directly to the level of neurological disabilities. The addition of anti-IL-6R IgG not only reduced directly the production of these cytokines, but also almost abolished the ability of activated autologous monocytes in enhancing IL-6, IL-17 and IL-21 release by CD4(+) T cells. In contrast, the production of IL-10 was amplified in those cell cultures. Further, anti-IL-6R monoclonal antibodies (mAb) also potentiated the ability of glucocorticoid in reducing Th17 cytokines. Finally, the in-vivo and in-vitro IL-6 levels were significantly higher among those patients who experienced clinical relapse during 2-year follow-up. In summary, our results suggest a deleterious role of IL-6 in NMO by favouring, at least in part, the expansion of corticoid-resistant Th17 cells.

A novel Fe(II)/α-ketoglutarate-dependent dioxygenase from Burkholderia ambifaria has ß-hydroxylating activity of N-succinyl l-leucine.

An Fe(II)/α-ketoglutarate-dependent dioxygenase, SadA, was obtained from Burkholderia ambifaria AMMD and heterologously expressed in Escherichia coli. Purified recombinant SadA had catalytic activity towards several N-substituted l-amino acids, which was especially strong with N-succinyl l-leucine. With the NMR and LC-MS analysis, SadA converted N-succinyl l-leucine into N-succinyl l-threo-ß-hydroxyleucine with >99% diastereoselectivity. SadA is the first enzyme catalysing ß-hydroxylation of aliphatic amino acid-related substances and a potent biocatalyst for the preparation of optically active ß-hydroxy amino acids.

Location of main occluding areas and masticatory ability in patients with implant-supported prostheses.

BACKGROUND: The purpose of this study was to locate the main occluding area when the reduced posterior occlusal support was treated with an implant-supported prosthesis and to evaluate the subsequent improvement in the masticatory ability as compared with removable partial dentures. METHODS: Twenty-six patients with implant prostheses and 24 patients with removable partial dentures were recruited for this study. All patients had partially lost their posterior occlusal support. The first molar region in any quadrant was always included in the prosthetic region. Each subject was instructed to clench a piece of temporary stopping as a test food on the occluding area that was preferably used during mastication. The main occluding area was judged by locating the tooth on which the temporary stopping rested during clenching. Subjective masticatory ability was self-assessed by means of a questionnaire. RESULTS: The main occluding area of the subjects in the implant group was located more posterior compared with the removable partial denture group. The level of masticatory ability in the implant group was the same as that in the control group. CONCLUSIONS: The location of the main occluding area and the masticatory ability of the subjects with implants were equivalent to those with healthy natural dentition.

Intake of n-3 polyunsaturated fatty acids and non-alcoholic fatty liver disease: a cross-sectional study in Japanese men and women.

BACKGROUND/OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common condition, in which abnormal amounts of triglycerides accumulate in hepatocytes and is closely related to cardiovascular diseases and diabetes. Dietary fats contribute 15% of fat accumulation in the liver and regulate hepatic lipid metabolism. The supplementation of n-3 polyunsaturated fatty acids (n-3 PUFAs) improves NAFLD. The aim of this study is to assess the cross-sectional association between dietary n-3 PUFAs and NAFLD in Japanese men and women. SUBJECTS/METHODS: Participants were middle-aged, apparently healthy, 296 men and 496 women, who did not drink alcohol and who participated in a general health check-up program. Dietary information from the previous month was obtained by the brief-type self-administered diet history questionnaire. NAFLD was diagnosed if abdominal ultrasonography revealed the presence of fatty liver. RESULTS: The prevalence of NAFLD was 45.3% in men and 17.5% in women. In comparison with the first tertile, multivariate adjusted odds ratios (95% confidence intervals) for the presence of NAFLD in the second and third tertiles for men taking eicosapentaenoic acid (EPA) were 0.59 (0.31-1.14) and 0.45 (0.23-0.90), respectively, (P for linear trend=0.024), and the multivariate adjusted odds ratios (95% confidence intervals) for the presence of NAFLD in the second and third tertiles for men taking EPA+docosahexaenoic acid (DHA) were 0.44 (0.23-0.86) and 0.48 (0.24-0.95), respectively, (P for linear trend=0.035). However, there was no significant relation between NAFLD and each of these nutrients in women. CONCLUSIONS: Dietary EPA and EPA+DHA may be independent and preventive nutrients for NAFLD in Japanese men.

Effect of urotensin II on PC12 rat pheochromocytoma cells.

Urotensin II (U-II), initially identified as a cyclic peptide from fish urophysis, acts both as a strong vasoconstrictor and vasodilator in the vasculature via its receptor, G-protein coupled receptor 14. In addition, U-II and its receptor are co-expressed in the adrenal medulla, as well as in human pheochromocytomas, suggesting that this peptide may have some function in chromaffin cells. However, the precise role of U-II in these cells is unknown. In the present study, we initially demonstrate that U-II and its receptors mRNA are co-expressed in the rat pheochromocytoma cell line PC12. Moreover, U-II has not effect on tyrosine hydroxylase (TH), the rate-limiting enzyme involved in the biosynthesis of catecholamine, in terms of enzyme activity or at the mRNA level. However, U-II does induce an increase in the phosphorylation of TH specifically at Ser31 without affecting phosphorylation at the two other sites (Ser19 and Ser40). U-II also markedly activates extracellular signal-regulated kinases (ERKs) and p38, but not Jun N-terminal kinase. Blockade of the epidermal growth factor (EGF) receptor by AG1478 significantly reduces activation of ERK, suggesting that EGF receptor transactivation could act upstream of the ERK pathway in PC12 cells. Furthermore, U-II significantly increases dopamine secretion from PC12 cells. Finally, we show that U-II induced significant DNA synthesis in a ERKs and P38 mitogen-activated protein kinase-dependent manner. The results obtained indicate that U-II may exert its effects as a neuromodulator in chromaffin cells.

Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes.

There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.

Prognostic impact of FAS/CD95/APO-1 in urothelial cancers: decreased expression of Fas is associated with disease progression.

The death receptor Fas (Apo1/CD95) and Fas ligand (FasL) system is recognised as a major pathway for the induction of apoptosis in vivo, and antiapoptosis via its blockade plays a critical role in carcinogenesis and progression in several malignancies. However, the function of Fas-FasL system in urothelial cancer (UC) has not been elucidated. We therefore investigated the expression of Fas, FasL and Decoy receptor 3 for FasL (DcR3) in UC specimens and cell lines, and examined the cytotoxic effect of an anti-Fas-activating monoclonal antibody (mAb) in vitro. Immunohistochemical examinations of Fas-related molecules were performed on 123 UC and 30 normal urothelium surgical specimens. Normal urothelium showed Fas staining in the cell membrane and cytoplasm. In UC, less frequent Fas expression was significantly associated with a higher pathological grade (P < 0.0001), a more advanced stage (P = 0.023) and poorer prognosis (P = 0.010). Fas and the absence thereof were suggested to be crucial factors with which to select patients requiring more aggressive treatment. Moreover, low-dose anti-Fas-activating mAb sensitised resistant cells to adriamycin, and this synergistic effect could be applied in the development of new treatment strategy for UC patients with multidrug-resistant tumours.

A new walking orthosis for paraplegics: hip and ankle linkage system.

For paraplegics, two major disadvantages of hip-knee-ankle-foot orthotic systems that have a medial single hip joint are the short stride and horizontal rotation of the pelvis. The authors consider the pelvic rotation is caused by two factors; one is the lack of a mechanism to assist hip flexion, and the other is fixed ankle joints that cause instability when the step length becomes longer. Users must rotate their pelvis to initiate a swing in their legs and to achieve stability by making their two legs as parallel as possible in order to avoid losing balance. To overcome those disadvantages, the authors developed a new orthosis named "HALO" (Hip and Ankle Linked Orthosis), which has a linking mechanism that connects both ankle joints with a medial single hip joint. This new orthosis allows users to keep both feet always parallel to the floor while walking, and assists the swinging of the leg when the contralateral ankle is flexed dorsally by loading. Gait analysis revealed that the pelvic rotation with "HALO" either in parallel bars or with Lofstrand crutches was within 20 degrees, which was within the physiologically normal level.

A report of two cases of Werner's syndrome and review of the literature.

Two cases of Werner's syndrome are reported. The first case is that of a man with grey hair since his 20s, and alopecia since aged about 50 years. At the age of 53 years, Werner's syndrome was diagnosed, along with a malignant soft tissue tumour of the hand. The patient underwent ray amputation for the tumour. The subsequent histopathological diagnosis was synovial cell sarcoma, and the patient died of lung metastasis at 15 weeks postsurgery. The second case is that of a woman diagnosed with diabetes mellitus when aged 34 years. At 39 years, a bilateral cataract was diagnosed and at 40 years, diabetic gangrene of the left calcaneal region and calcaneal osteomyelitis necessitated left below-knee amputation. The incidence of Werner's syndrome in Japan is extremely high (1000 of the around 1300 cases reported worldwide) compared to other countries. Most patients develop malignant tumour or arteriosclerosis, the most important complications of this syndrome. The average life expectancy for patients with Werner's syndrome is 46 years. The incidence of epithelial cancer and mesenchymal sarcoma is 10 times that of the general population. The onset of symptoms of Werner's syndrome generally precedes any later symptoms of associated conditions, such as malignant tumour. Therefore, early recognition of Werner's syndrome is important to assist identification of malignant tumours at an early stage in this patient group.

Presence of a genistein-responsive inhibitory mechanism on interleukin-1alpha-induced NF-kappaB activation.

Interleukin 1 (IL-1) is known to activate the signal transduction machinery, including the transcription factor, nuclear factor kappa B (NF-kappaB). The activation mechanism of NF-kappaB has been studied intensively, while the negative regulatory mechanisms of NF-kappaB remain to be clarified. In the present study, we found that genistein, a tyrosine kinase inhibitor, augmented IL-1alpha-dependent NF-kappaB activation, suggesting the presence of a tyrosine kinase mediating a suppression signal on NF-kappaB. As determined by luciferase reporter gene assay using kappaB-responsive element, genistein enhanced IL-1alpha-induced NF-kappaB activation. Although genistein failed to increase luciferase activity at 1 and 3 h after IL-1alpha stimulation, it induced prolonged activation beginning at 6 h after the initial stimulation. We next examined whether genistein augmented the DNA-binding activity of NF-kappaB, using electrophoretic mobility shift assay. In the case of the control experiment, the binding of NF- kappaB to the kappaB-responsive element peaked at 30 min after IL-1alpha stimulation, and decreased thereafter. In contrast, treatment with genistein maintained the maximum binding activity for at least 2 h after stimulation. Moreover, genistein enhanced the IL-1alpha-dependent degradation of IkappaBalpha. Taken together, our results indicate that genistein augments IkappaB degradation, resulting in continuous NF-kappaB activation. This suggests the possibility that tyrosine kinase negatively regulates NF-kappaB.

Macrophage signaling, apoptosis, lectins and leukocyte trafficking.

The 10th International Symposium of the Molecular Cell Biology of Macrophages (Macrophages 2001) was held in Tokyo, Japan from 21-22 June 2001.

Sequential detection of alphafetoprotein-bearing cells in blood stem cell fraction of germ cell tumour patients.

High-dose chemotherapy with peripheral blood stem cell (PBSC) transplantation in advanced germ cell tumour (GCT) patients is widely applied. The aims of this study were: (1) To examine the presence of alphafetoprotein (AFP) bearing tumour cells in PBSC harvests from advanced GCT patients obtained after multiple cycles of induction chemotherapy. (2) To determine whether induction chemotherapy contributed to in vivo purging of the tumour. We evaluated cryopreserved PBSC samples from 5 patients with advanced stage II/III AFP producing GCT. PBSC were separated after the first, second and third cycles of induction chemotherapy. Those samples were analysed using the nested reverse transcription polymerase chain reaction (RT-PCR) method to detect AFP mRNA. Although, in all patients, AFP mRNA was detected in PBSC samples after the first or second cycle of induction chemotherapy, but was not detected in 3 of 4 samples after the third cycle of chemotherapy. Although it is not clear whether tumour cells contaminating PBSC fraction contribute to disease relapse, PBSC harvested after at least 3 cycles of induction chemotherapy might be recommended to avoid such a possibility.

Chicken pineal clock genes: implication of BMAL2 as a bidirectional regulator in circadian clock oscillation.

BACKGROUND: In a transcription/translation-based autoregulatory feedback loop of vertebrate circadian clock systems, a BMAL1-CLOCK heterodimer is a positive regulator for the transcription of the negative element gene Per. The chicken pineal gland represents a photosensitive clock tissue, but the pineal clock genes constituting the oscillator loop have been less well characterized. RESULTS: We identified expression of the Per2, Bmal1, Bmal2 and Clock genes in the chicken pineal gland. Messenger RNA levels of these genes exhibited overt circadian rhythms in the pineal cells, both in vivo and in culture. In vitro functional analyses revealed the formation of cBMAL1-cCLOCK and cBMAL2-cCLOCK heteromers. Both of the cBMAL-cCLOCK heteromers activated E-box element-dependent transcription, which was negatively regulated by cPER2 in luciferase assays. Co-expression of cCLOCK, cBMAL1 and cBMAL2 co-operatively activated E-box element-dependent transcription, and a greater level of expression of cBMAL2 inhibited the activation. In the cultured pineal cells, an over-expression of either cBMAL1 or cBMAL2 disrupted the circadian rhythm of melatonin production. CONCLUSION: The functional characterization of the chicken pineal clock molecules supports the key roles of BMAL1, BMAL2 and CLOCK which contribute to the E-box-dependent transcriptional regulation in the circadian clock system.

Frequency of PSA-mRNA-bearing cells in the peripheral blood of patients after prostate biopsy.

Transrectal ultrasound (TRUS) guided prostate biopsy is standard diagnostic procedure for prostate cancer (PCa). However, possibility of dissemination of cancer cells by biopsy is not negligible. To investigate this possibility, we examined prostate specific antigen (PSA)-bearing cells in peripheral blood of the 108 patients before and after prostate biopsy. Peripheral blood samples were obtained from 108 patients with elevated serum PSA (sPSA) levels, who had undergone sextant prostate biopsy using TRUS. The presence of PSA-mRNA bearing cells was examined using the nested RT-PCR method enabling detection of one LNCaP cell diluted in 1 ml of whole blood. Among 108 patients, 62 and 46 were diagnosed with benign prostatic hyperplasia (BPH) and PCa, respectively. PSA-mRNA was detected in 3 PCa cases but in no BPH patients before and after biopsy, and in 16 BPH (25.8%) and in 21 PCa (45.7%) patients only after biopsy (P< 0.01). The patients with positive mRNA before biopsy had higher sPSA (P< 0.001), and those after biopsy had higher sPSA and PSA density (PSAD) levels (P< 0.05). Positive PSA-mRNA cases had more cancer involved biopsy cores than the negative PSA-mRNA cases (P< 0.001). Although further investigations are needed, the present findings suggest that prostate biopsy might scatter prostate cells in the blood stream especially in cases with high sPSA and, thus, might contribute to tumour spreading in the cases of prostate cancer.

[Primary small cell carcinoma of the kidney: a case report].

A 43-year-old male visited our hospital with the complaint of right flank colicky pain. Computed tomographic (CT)-scan and angiography showed large renal tumor with liver invasion and tumor thrombosis in the vena cava. Multiple lung and bone tumors were also recognized. Percutaneous biopsy of the renal tumor revealed small cell carcinoma. Multiple lung masses were diagnosed as metastatic tumors according to the results of bronchoscopic biopsy. Chemotherapy including cisplatinum and etoposide was performed without success. He died 6 months after the diagnosis. Autopsy specimen revealed primary small cell carcinoma of the right kidney. To our knowledge, this is the seventh case as primary renal small cell carcinoma in the world literature.

Prognosis of acute poststreptococcal glomerulonephritis (APSGN) is excellent in children, when adequately diagnosed.

BACKGROUND: Recently, the prognosis of acute poststreptococcal glomerulonephritis (APSGN) has been reported as improved, compared with the results of previous studies. In an attempt to clarify this, we analyzed the clinical course of patients with APSGN. METHODS: A total of 220 children with acute nephritic syndrome were treated in the affiliated hospitals of our department, between January 1988 and December 1997. Among them, 138 children who were diagnosed with APSGN according to the presence of hematuria, transient hypocomplementemia and evidence of group A beta-hemolytic streptococcal infection, were studied. RESULTS: Serum creatinine and blood urea nitrogen levels at onset were 0.5 +/- 0.2 mg/dL and 20 +/-12 mg/dL, respectively. There were no patients with renal dysfunction (serum creatinine level > or = 1.5 mg/dL), but one patient with nephrotic syndrome. Blood pressure was well controlled in all patients and there were no patients with persistent hypertension. Serum complement levels were normalized within 12 weeks (100%), hematuria disappeared within 4 years (100%) and proteinuria disappeared within 3 years (100%) from the onset. CONCLUSIONS: These data indicate that the prognosis of APSGN during childhood is excellent, when adequately diagnosed and treated.

Antitumor effect of beta2-microglobulin in leukemic cell-bearing mice via apoptosis-inducing activity: activation of caspase-3 and nuclear factor-kappaB.

We have reported previously that beta2-microglobulin (beta2m) induces apoptosis in leukemic cells in vitro, and that an interaction between beta2m and HLA class I antigen induces apoptosis. Here we examined whether beta2m can induce apoptosis in leukemic cells in vivo and whether it has an antitumor effect in tumor-bearing mice. Daily administration of 50 or 250 microg of beta2m induced apoptosis and an antitumor effect on K562 leukemia cell-bearing mice in the same manner as tumor necrosis factor-alpha. In tumor tissues in beta2m-treated mice, both caspase-3 and nuclear factor-kappaB (NF-kappaB) were stained more strongly than in control mice by anti-caspase-3 and anti-NF-kappaB p65/Rel A polyclonal antibodies. We also observed the in vivo immunological effects of beta2m on lymphoid and hematopoietic organs, such as thymus, bone marrow, Peyer's patches, liver, and spleen in normal mice. Using antibodies against caspase-3 and NF-kappaB, immunohistochemical staining showed that no specific tissues were damaged or stained in normal mice. We conclude that beta2m stimulates caspase-3 and NF-kappaB pathways to induce apoptosis, making it a useful approach to a new therapy for leukemia.