Kimura's disease: effects of age on clinical presentation.

BACKGROUND: Kimura's disease (KD) is known to be dominant among young Asian men, but it can also occur in middle- and advanced-aged people. The clinical characteristics of KD, especially by age, are not well known. AIM: This study was performed to investigate the effects of age on the clinical characteristics of KD. DESIGN: We conducted a case series study. METHODS: All case studies of patients diagnosed with KD were collected via a PubMed search of studies published until August 2018. The data were analyzed by age group. RESULTS: In total, 215 studies were reviewed (238 patients; mean age of 36 years). The male:female ratio was 4:1 overall, 17:1 in patients aged <20 years, 4:1 in patients aged 20-39 years and 2:1 in patients aged ≥40 years (P = 0.01). The percentage of patients with pruritus was 15.4% overall, 3.8% in patients aged <20 years, 15.5% in patients aged 20-39 years and 21.7% in patients aged ≥40 years (P = 0.02). The time to diagnosis was 5.3 years overall, 3.2 years in patients aged <20 years, 4.7 years in patients aged 20-39 years and 7.1 years in patients aged ≥40 years (P < 0.01). CONCLUSIONS: The proportion of female patients affected the incidence of pruritus, and the time to diagnosis increased as the patients' age increased. There were no significant age-related differences in region/race, complications, multiplicity, laterality, anatomical distribution, maximum size, eosinophil count, immunoglobulin E level, initial treatment, recurrence or outcomes. This may be useful information for the diagnosis of KD.

Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility.

Epithelial-to-mesenchymal transition (EMT) promotes cell motility, which is important for the metastasis of malignant cells, and blocks CD95-mediated apoptotic signaling triggered by immune cells and chemotherapeutic regimens. CD95L, the cognate ligand of CD95, can be cleaved by metalloproteases and released as a soluble molecule (cl-CD95L). Unlike transmembrane CD95L, cl-CD95L does not induce apoptosis but triggers cell motility. Electron paramagnetic resonance was used to show that EMT and cl-CD95L treatment both led to augmentation of plasma membrane fluidity that was instrumental in inducing cell migration. Compaction of the plasma membrane is modulated, among other factors, by the ratio of certain lipids such as sphingolipids in the membrane. An integrative analysis of gene expression in NCI tumor cell lines revealed that expression of ceramide synthase-6 (CerS6) decreased during EMT. Furthermore, pharmacological and genetic approaches established that modulation of CerS6 expression/activity in cancer cells altered the level of C16-ceramide, which in turn influenced plasma membrane fluidity and cell motility. Therefore, this study identifies CerS6 as a novel EMT-regulated gene that has a pivotal role in the regulation of cell migration.

Real-time monitoring of liver damage during experimental ischaemia-reperfusion using a nitric oxide sensor.

BACKGROUND: Hepatic ischaemia-reperfusion (IR) injury may lead to liver damage during liver surgery, and intrahepatic nitric oxide (NO) levels may play a role in this context. The aim of this study was to demonstrate real-time changes in intrahepatic NO concentration during IR and to correlate potential hepatic NO production with liver damage using a selective NO sensor. METHODS: Wistar rats were exposed to 15 min of hepatic ischaemia followed by reperfusion, after which changes in intrahepatic NO levels were measured using an NO sensor. Additionally, rats were exposed to five successive periods of IR, each consisting of 15 min ischaemia followed by 5 or 15 min reperfusion, and hepatic damage was evaluated by blood tests and histological examination. Hepatic expression of Akt, phosphorylated Akt, endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS was examined at different time points during and after IR by western blot and immunohistochemical analysis. RESULTS: During ischaemia, intrahepatic NO levels increased and reached a plateau at approximately 10 min. Repeated 15 min ischaemia-5 min reperfusion cycles reduced the maximum amount of NO produced during ischaemia gradually, and almost no NO production was observed during the fifth period of ischaemia. NO production following repeated ischaemia was proportional to the degree of hepatic viability. Phosphorylated eNOS was upregulated and correlated with the level of NO production during hepatic ischaemia. CONCLUSION: Intrahepatic NO levels decrease during repeated IR in rats. Real-time monitoring of intrahepatic NO levels is useful for the prediction of IR-related liver injury during experimental liver surgery.

Relationship between the localization of fibroblast growth factor 9 in prostate cancer cells and postoperative recurrence.

BACKGROUND: Fibroblast growth factor 9 (FGF9) enhances cell proliferation and invasiveness in several malignant diseases. The aim of the present study is to investigate the role of FGF9 in postoperative recurrence after radical prostatectomy. METHODS: Cell viability and invasion of LNCaP cells were assessed using MTT assay and Matrigel invasion assay, respectively, in the presence or absence of treatment with recombinant FGF9. Tissues obtained during a radical prostatectomy in 133 male patients were immunohistochemically stained using anti-FGF9 antibody. RESULTS: Cell viability and invasion of LNCaP was significantly enhanced by treatment with recombinant FGF9. Immunohistochemical staining detected FGF9-positive cells in 20 samples. The prevalence of FGF9-positive cells in cases with a Gleason score of 8 or higher was 34.2%, which was significantly higher than that in those with Gleason scores of 7 or lower (7.3%, P=0.0003), respectively. The 3-year biochemical relapse-free survival rate was 17.5% in cases with FGF9-positive cells, which was significantly lower than that in cases in which FGF9-positive cells were not detectable (75.5%, P < 0.0001). CONCLUSIONS: These results indicate that FGF9 can stimulate proliferation and invasion in prostate cancer cells, thus FGF9 could be a candidate of a predictive factor for recurrence after radical prostatectomy.

Lecithin-cholesterol acyltransferase (LCAT) deficiency without mutations in the coding sequence: a case report and literature review.

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by corneal opacities, normocytic anemia, dyslipidemia, and proteinuria progressing to chronic renal failure. In all FLD cases, a mutation has been found in the coding sequence of the LCAT gene. FLD is clinically distinguished from an acquired form of LCAT deficiency by the presence of corneal opacities. Here we describe a 36-year-old woman presenting with clinical, pathological, and laboratory data compatible with FLD. Her mother and elder sister had corneal opacities. However, genetic analysis revealed there were no mutations in the LCAT coding sequences and no alterations in LCAT mRNA expression. Furthermore, we were unable to find any underlying conditions that may lead to LCAT deficiency. The present case therefore demonstrates that LCAT deficiency may be caused by factors other than mutations in the coding sequence and we suggest that a translational or posttranslational mechanism may be involved.

Multifunctional transcription factor TFII-I is an activator of BRCA1 function.

BACKGROUND: The TFII-I is a multifunctional transcriptional factor known to bind specifically to several DNA sequence elements and to mediate growth factor signalling. A microdeletion at the chromosomal location 7q11.23 encoding TFII-I and the related family of transcription factors may result in the onset of Williams-Beuren syndrome, an autosomal dominant genetic disorder characterised by a unique cognitive profile, diabetes, hypertension, anxiety, and craniofacial defects. Hereditary breast and ovarian cancer susceptibility gene product BRCA1 has been shown to serve as a positive regulator of SIRT1 expression by binding to the promoter region of SIRT1, but cross talk between BRCA1 and TFII-I has not been investigated to date. METHODS: A physical interaction between TFII-I and BRCA1 was explored. To determine pathophysiological function of TFII-I, its role as a transcriptional cofactor for BRCA1 was investigated. RESULTS: We found a physical interaction between the carboxyl terminus of TFII-I and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous TFII-I and BRCA1 form a complex in nuclei of intact cells and formation of irradiation-induced nuclear foci was observed. We also showed that the expression of TFII-I stimulates the transcriptional activation function of BRCT by a transient expression assay. The expression of TFII-I also enhanced the transcriptional activation of the SIRT1 promoter mediated by full-length BRCA1. CONCLUSION: These results revealed the intrinsic mechanism that TFII-I may modulate the cellular functions of BRCA1, and provide important implications to understand the development of breast cancer.

Identification of DBC1 as a transcriptional repressor for BRCA1.

BACKGROUND: DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression. METHODS: A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied. RESULTS: We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1. CONCLUSION: These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue.

Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway.

Endometrial cancer is one of the tumor types in which either chromosomal instability (CIN) or microsatellite instability (MSI) may occur. It is known to possess mutations frequently in the Ras-PI3K (phosphatidylinositol 3'-kinase) pathway. We performed a comprehensive genomic survey in 31 endometrial carcinomas with paired DNA for chromosomal imbalances (25 by the 50K and 6 by the 250K single-nucleotide polymorphism (SNP) array), and screened 25 of the 31 samples for MSI status and mutational status in the Ras-PI3K pathway genes. We detected five or more copy number changes (classified as CIN-extensive) in 9 (29%), 1 to 4 changes (CIN-intermediate) in 17 (55%) and no changes (CIN-negative) in 5 (16%) tumors. Positive MSI was less common in CIN-extensive tumors (14%), compared with CIN-intermediate/negative tumors (50%), and multivariate analysis showed that CIN-extensive is an independent poor prognostic factor. SNP array analysis unveiled copy number neutral LOH at 54 loci in 13 tumors (42%), including four at the locus of PTEN. In addition to eight (26%) tumors with PTEN deletions, we detected chromosomal imbalances of NF1, K-Ras and PIK3CA in four (13%), four (13%) and six (19%) tumors, respectively. In all, 7 of the 9 CIN-extensive tumors harbor deletions in the loci of PTEN and/or NF1, whereas all the 10 MSI-positive tumors possess PTEN, PIK3CA and/or K-Ras mutations. Our results showed that genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability, and suggest that the degree of CIN is a useful biomarker for prognosis in endometrial carcinomas.

The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas.

BACKGROUND: The phosphatidylinositol 3'-kinase (PI3K)-AKT pathway is activated in many human cancers and plays a key role in cell proliferation and survival. A mutation (E17K) in the pleckstrin homology domain of the AKT1 results in constitutive AKT1 activation by means of localisation to the plasma membrane. The AKT1 (E17K) mutation has been reported in some tumour types (breast, colorectal, ovarian and lung cancers), and it is of interest which tumour types other than those possess the E17K mutation. METHODS: We analysed the presence of the AKT1 (E17K) mutation in 89 endometrial cancer tissue specimens and in 12 endometrial cancer cell lines by PCR and direct sequencing. RESULTS: We detected two AKT1 (E17K) mutations in the tissue samples (2 out of 89) and no mutations in the cell lines. These two AKT1 mutant tumours do not possess any mutations in PIK3CA, PTEN and K-Ras. INTERPRETATION: Our results and earlier reports suggest that AKT1 mutations might be mutually exclusive with other PI3K-AKT-activating alterations, although PIK3CA mutations frequently coexist with other alterations (such as HER2, K-Ras and PTEN) in several types of tumours.

Postoperative pain status after intraoperative systemic dexmedetomidine and epidural neostigmine in patients undergoing lower abdominal surgery.

BACKGROUND AND OBJECTIVES: To determine whether intraoperative systemic dexmedetomidine improves postoperative pain and interacts with epidural neostigmine to produce analgesic effects. METHODS: Sixty patients undergoing gynaecological surgery were randomly divided into four groups to receive epidural neostigmine and/or systemic dexmedetomidine: control (Group C), epidural neostigmine (Group N), systemic dexmedetomidine (Group D) and co-administered neostigmine and dexmedetomidine (Group ND). Epidural neostigmine (0.3 mg) was administered with 10 mL of 0.75% ropivacaine before the induction of general anaesthesia. Systemic dexmedetomidine (loading dose of 1 mug kg-1 over 10 min followed by 0.4 mug kg-1 h-1) was infused after the induction of general anaesthesia and continued until the end of surgery. The pain status of patients was assessed using the visual analogue scale at 2, 4, 6, 24 and 72 h postoperatively. RESULTS: Intraoperative systemic dexmedetomidine alone did not reduce postoperative pain scores. However, co-administered neostigmine and dexmedetomidine significantly decreased scores at 24 and 72 h (Group C: 3.0 [1.0-5.8] and 2.0 [0.3-3.0]; Group N: 1.5 [0.3-3.4] and 0 [0-1.3]; Group D: 3.5 [0-5.0] and 0 [0-1.4]; and Group ND: 0 [0-1.0]* and 0 [0-0]; median [interquartile range] *P = 0.0031, P = 0.0045 compared with Group C). CONCLUSIONS: The intraoperative systemic infusion of dexmedetomidine alone at doses causing sedation does not result in postoperative analgesic effects. However, the co-administration of systemic dexmedetomidine and epidural neostigmine at higher doses may be a useful method to improve postoperative pain although side-effects have to be evaluated.

Renal artery pseudoaneurysm occurring after laparoscopic partial nephrectomy.

Renal artery pseudoaneurysm (RAP) is rare, and has been reported after renal biopsy and percutaneous renal surgery. We report a case of RAP after laparoscopic partial nephrectomy for renal cell carcinoma.

Aqueous extract of Arbutus unedo inhibits STAT1 activation in human breast cancer cell line MDA-MB-231 and human fibroblasts through SHP2 activation.

Arbutus unedo L. has been for a long time employed in traditional and popular medicine as an astringent, diuretic, urinary anti-septic, and more recently, in the therapy of hypertension and diabetes. Signal transducer and activator of transcription 1 (STAT1) is a fascinating and complex protein with multiple yet contrasting transcriptional functions. Although activation of this nuclear factor is finely regulated in order to control the entire inflammatory process, its hyper-activation or time-spatially erroneous activation may lead to exacerbation of inflammation. The modulation of this nuclear factor, therefore, has recently been considered as a new strategy in the treatment of inflammatory diseases. In this study, we present data showing that the aqueous extract of Arbutus unedo's leaves exerts inhibitory action on interferon-gamma (IFN-gamma) elicited activation of STAT1, both in human breast cancer cell line MDA-MB-231 and in human fibroblasts. This down-regulation of STAT1 is shown to result from a reduced tyrosine phosphorylation of STAT1 protein. Evidence is also presented indicating that the inhibitory effect of this extract may be mediated through enhancement of tyrosine phosphorylation of SHP2 tyrosine phosphatase. The modulation of this nuclear factor turns out into the regulation of the expression of a number of genes involved in the inflammatory response such as inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1). Taken together, our results suggest that the employment of the Arbutus unedo aqueous extract is promising, at least, as an auxiliary anti-inflammatory treatment of diseases in which STAT1 plays a critical role.

Short-term effect of ovariectomy on osteoprogenitors in the healing rat mandibular incisor extraction socket.

UNLABELLED: OVX increased the percentage of AP-positive CFU-F in healing rat mandible. The increase of the number of osteoprogenitors was not significant in rat mandible-derived cultures but was in femur-derived ones. This suggests that the effect of OVX on osteoprogenitors is either smaller or develops later in mandible relative to femur. INTRODUCTION: Osteoprogenitors play an essential role in the regeneration process that leads to the successful integration of dental implants. However, it is unclear how systemic osteoporosis affects osteoprogenitors in oral bone. The present study was designed to determine the short-term effects of ovariectomy (OVX) on osteoprogenitors from the healing extraction socket in rat mandible. METHODS: Six-month-old rats were ovariectomized (n=8) and control rats were left intact (n=8). Two weeks post-OVX, the right mandibular incisor was extracted. Four weeks post-extraction, the basal mandibular bone between the 1st and 3rd molar in the healing extraction socket was used to determine the number of fibroblastic progenitors (CFU-F), alkaline phosphatase-positive fibroblastic progenitors (AP-positive CFU-F), Dex-dependent osteoprogenitors (CFU-O Dex) and Prog-dependent osteoprogenitors (CFU-O Prog) using colony assays (n=5). Osteocalcin mRNA expression was evaluated using in situ hybridization (n=3). Data were analyzed using two-way ANOVA or Student's t-test. RESULTS: OVX increased the percentage of AP-positive CFU-F in both mandible and femur. The number of CFU-O was increased only in femur. Osteocalcin mRNA expression in regenerating mandible was not statistically different between control and OVX animals. CONCLUSION: Our results suggest that the effect of OVX on osteoprogenitors is either smaller or develops later in mandible relative to femur.

Medial and adventitial macrophages are associated with expansive atherosclerotic remodeling in rabbit femoral artery.

Expansive vascular remodeling is considered a feature of vulnerable plaques. Although inflammation is upregulated in the media and adventitia of atherosclerotic lesions, its contribution to expansive remodeling is unclear. We investigated this issue in injured femoral arteries of normo- and hyperlipidemic rabbits fed with a conventional (CD group; n=20) or a 0.5% cholesterol (ChD group; n=20) diet. Four weeks after balloon injury of the femoral arteries, we examined vascular wall alterations, localization of macrophages and matrix metalloproteases (MMP)-1, -2, -9, and extracellular matrix. Neointimal formation with luminal stenosis was evident in both groups, while expansive remodeling was observed only in the ChD group. Areas immunopositive for macrophages, MMP-1, -2 and -9 were larger not only in the neointima, but also in the media and/or adventitia in the injured arterial walls of the ChD, than in the CD group. Areas containing smooth muscle cells (SMCs), elastin and collagen were smaller in the injured arterial walls of the ChD group. MMP-1, -2 and -9 were mainly localized in infiltrating macrophages. MMP-2 was also found in SMCs and adventitial fibroblasts. Vasa vasorum density was significantly increased in injured arteries of ChD group than in those of CD group. These results suggest that macrophages in the media and adventitia play an important role in expansive atherosclerotic remodeling via extracellular matrix degradation and SMC reduction.

Clinical efficacy of brachytherapy combined with external-beam radiotherapy and repeated arterial infusion chemotherapy in patients with unresectable extrahepatic bile duct cancer.

The objective of this study was to evaluate the clinical efficacy of brachytherapy combined with external-beam radiotherapy and repeated arterial infusion chemotherapy in improving stent patency and prognosis in patients with unresectable bile duct cancer as compared with brachytherapy alone. Seventeen patients were treated. Five patients received brachytherapy alone before stent placement. Twelve patients received brachytherapy combined with external-beam radiotherapy (n=5), repeated hepatic arterial infusion chemotherapy using an implanted catheter and port (n=1), or both (n=6). Mean survival was significantly improved in the group that received combined therapy as compared with the group that received brachytherapy alone (16.2 months vs. 4.6 months, p<0.01). Although stent occlusion rates were similar in the two groups (42% vs. 40%), there was a trend towards longer stent patency in the combined therapy group than in the brachytherapy group (22 months vs. 3.6 months, p<0.2). Radiation gastritis necessitating gastrectomy developed in 1 patient who received external-beam radiotherapy at more than 50 Gy. Brachytherapy combined with external-beam radiotherapy and repeated hepatic arterial infusion chemotherapy increases survival compared with brachytherapy alone in patients with unresectable bile duct cancer.

[Advanced hepatocellular carcinoma--feasibility and clinical impact of high-dose-rate brachytherapy on the treatment of lesions growing into biliary trees, portal veins and the vena cava].

This study was performed to evaluate the feasibility and clinical impact of intraluminal and endovascular high-dose-rate iridium-192 brachytherapy on the treatment of HCC lesions growing into biliary trees, portal veins and the inferior vena cava. HCCs involving biliary trees in 2 patients, the main and/or first-order portal veins in 3 patients, and the inferior vena cava in 2 patients. Brachytherapy was percutaneously performed with a 5F applicator, which was placed adjacent to the lesions. A mean total dose of 23 Gy (range, 5-7 Gy/fr) was irradiated (at a 5 mm radius) to the biliary or the portal venous tumors. A total dose of 10 Gy (5 Gy/fr) was given to the caval tumors. External-beam radiotherapy was combined in 2 patients with caval lesions, stent placement in 2 patients with biliary lesions and hepatic arterial infusion chemotherapy in 5 patients. There was no major complication except hemobilia, which ceased after placing a PTCD tube in the bile duct in one patient. All tumors were significantly reduced in size and remained controlled during the period of patients' survival. Complete tumor necrosis was histologically proved in 2 autopsy cases having biliary lesions. The median survival was 13 months. Intraluminal and endovascular high-dose-rate brachytherapy appears to be a feasible, and effective procedure to treat advanced HCCs invading biliary trees, portal veins and the vena cava.

The costing of carbon credits from ocean nourishment plants.

Ocean nourishment is a process for stimulating the sequestration of atmospheric carbon dioxide in the deep ocean by providing the nutrients needed to enhance the production of phytoplankton. The carbon dioxide sink thus created, can be used to generate tradeable carbon credits. The costs of sequestering carbon by the process of ocean nourishment have been estimated using as a basis, the previous experience in nitrogen fixing of Toyo Engineering Corporation. While there are uncertainties about the biological uptake efficiency, these introduce only a moderate uncertainty in our overall estimates of costs. The major determinants of the costs are the interest that must be paid on capital and the cost of the feedstock, natural gas. We have used for discussion purposes, an interest rate of 4-8% per annum and natural gas costs of US$0.5-$2 per GJ. The costs of carbon credits lie in the range US$6.70-$12.40 per tonne of carbon dioxide emissions sequestered. It should be noted that we have adopted the measure of carbon avoided by non-emission, because of the complex partitioning of anthropogenic carbon between the atmosphere, land and ocean.

[Female carrier of Duchenne muscular dystrophy presenting with secondary dilated cardiomyopathy: a case report].

A 48-year-old female carrier of Duchenne muscular dystrophy had developed congestive heart failure but had no skeletal muscle symptoms. She was admitted to our hospital complaining of palpitation in December 1998. Her three sons had Duchenne muscular dystrophy. Neurological examination was unremarkable with no evidence of muscle weakness. Serum creatine kinase level was slightly increased. Echocardiography showed severe left ventricular dysfunction. Coronary angiography showed no abnormalities. Left ventriculography showed generalized hypokinesis and left ventricular ejection fraction was 28%. Dystrophin immunostaining of the skeletal muscle biopsy specimen showed a mosaic pattern. The dystrophin negative fibers were scattered among positive fibers. Cardiomyopathy is the only clinical manifestation of dystrophin gene mutation in carriers. Beta-blocker therapy(carvedilol 5 mg/day) was effective in this patient.