Big mitogen-activated protein kinase 1 (BMK1)/extracellular signal regulated kinase 5 (ERK5) is involved in platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell migration

Big mitogen-activated protein kinase 1 (BMK1), also known as extracellular signal-regulated kinase 5 (ERK5), is a newly identified member of the mitogen-activated protein (MAP) kinase family. Recently, several studies have suggested that BMK1 plays an important role in the pathogenesis of cardiovascular disease. To clarify the pathophysiological significance of BMK1 in the process of vascular remodeling, we explored the molecular mechanisms of BMK1 activation in vascular smooth muscle cells (VSMCs). From the results of co-immunoprecipitation and immunoblotting analyses, it was found that platelet-derived growth factor (PDGF), a known potent mitogen, activated BMK1 and triggered the Gab1-SHP-2 interaction in rat aortic smooth muscle cells (RASMCs). The abrogation of SHP-2 phosphatase activity by transfection of the SHP-2-C/S mutant suppressed PDGF-stimulated BMK1 activation. Infection with an adenoviral vector expressing dominant-negative MEK5alpha, which can suppress PDGF-stimulated BMK1 activation to the control level, inhibited PDGF-induced RASMC migration. Moreover, we observed an increase of BMK1 activation in injured mouse femoral arteries. From these findings, it is suggested that BMK1 activation leads to VSMC migration induced by PDGF via Gab1-SHP-2 interaction, and that BMK1-mediated VSMC migration may play a role in the pathogenesis of vascular remodeling.     

Heart rate elevation precedes the development of metabolic syndrome in Japanese men: a prospective study.

This observational study of Japanese men without metabolic syndrome (MetS) (age: 41+/-8 years) was conducted to clarify whether or not heart rate elevation precedes the development of full-blown MetS. MetS was defined based on two modifications of the criteria of the Japanese Expert Committee on the Diagnosis and Classification of Metabolic Syndrome. Premetabolic syndrome subjects were defined as those having one component of MetS with increased body mass index (BMI). Among the subjects without MetS (n=1,859 when the BMI criterion was >or=25 and n=2,020 when the BMI criterion was >or=27.5), the incidence of progression to full-blown MetS by the time of the second examination at the end of the 3-year study period was higher in the subjects with premetabolic syndrome than in those without it. The receiver-operator characteristic curve analysis and binary logistic regression analysis revealed that the odds ratio (OR) of a heart rate >or=69 beats/min at the first examination for progression to full-blown MetS by the time of the second examination was significant in subjects with premetabolic syndrome (BMI>or=25: OR=3.64 [1.22-10.88]; BMI>or=27.5: OR=3.67 [1.28-10.55]; p<0.05). Thus, heart rate elevation appears to precede the development of full-blown MetS in subjects with premetabolic syndrome. Heart rate seems to be a simple and useful marker for predicting the progression to full-blown MetS of middle-aged Japanese men with premetabolic syndrome.     

The prognostic value of E-cadherin, α-, β- and γ-catenin in bladder cancer patients who underwent radical cystectomy

OBJECTIVES: To determine the value of the loss of expression of E-cadherin and cadherin associated molecules as useful markers for both prognosis and chemosensitivity in bladder cancer patients who have undergone radical cystectomy. PATIENTS AND METHODS: In 55 paraffin embedded specimens of radical cystectomy at our hospital from 1982 to 2000, the expression of E-cadherin, alpha-, beta- and gamma-catenin was examined by immunohistochemical staining. To evaluate the prognostic significance of these molecules, Kaplan-Meier survival curves were constructed and a statistical analysis was calculated by a log-rank test. A multivariate test (tumor stage, tumor grade, lymph node metastasis, configuration, the expression of E-cadherin, alpha-, beta- and gamma-catenin) was performed to detect prognostic markers. RESULTS: Normal expression was found in 33 cases (60.0%) for E-cadherin, 29 (52.7%) for alpha-catenin, 31 cases (56.4%) for beta-catenin, and 31 cases (56.4%) for gamma-catenin. The expression patterns for E-cadherin, alpha-, beta- and gamma-catenin were significantly correlated with each other (P < 0.01). Survival analysis showed a significant difference between normal and aberrant expression in each staining. A multivariate analysis revealed that the expression of alpha- catenin was an independent prognostic factor (P = 0.0191). In 23 patients that received adjuvant chemotherapy, there was a significant difference in survival between the normal and aberrant expression of alpha-catenin, but not other molecules. CONCLUSION: Alpha-catenin may not only be a good prognostic marker, but also one of key molecules that determine the chemosensitivities in patients with invasive bladder cancer.     

Chronic acid ingestion promotes renal stone formation in rats treated with vitamin D3

OBJECTIVE: Although hypercalciuria, a well-established adverse effect of vitamin D3, can be a risk factor of renal stone formation, the risk of nephrolithiasis has not been well defined. The consumption of a diet high in acid precursors is often cited as a risk factor for the development of calcium-based kidney stones. In the present study, we investigated the effect of chronic acid ingestion on kidney stone formation in rats treated with calcitriol (1-25[OH]2 D3). METHODS: Control rats (C-C), calcitriol-treated rats (C-V; three treatments of 0.5 microg of calcitriol per week) and acid-ingested (water containing 0.21 mol/L NH4Cl), calcitriol-treated (three treatments of 0.5 microg of calcitriol per week) rats (A-V) were fed in metabolic cages. After 1 month, urine, blood, kidney and bone samples were analyzed. RESULTS: The A-V rats exhibited elevated serum calcium concentrations, urinary calcium and phosphate excretion, urinary type I collagen cross-linked N-peptide (NTx)/creatinine values, mRNA expression of osteopontin in the kidney, and renal calcium contents as well as decreased bone mineral densities, compared with the C-C and C-V rats. Urinary citrate excretion was lower and NaDC-1 mRNA expression in the kidney was higher in the A-V rats than in the C-C and C-V rats. Calcium phosphate kidney stones were found in the A-V rats. CONCLUSIONS: The ingestion of NH4Cl, an acid precursor, promotes calcium phosphate kidney stone formation in calcitriol-treated rats. The chronic intake of a diet rich in acid precursors may be a risk factor for the development of kidney stones in subjects who are being treated with calcitriol.     

Effects of gender on prognosis of patients with known or suspected coronary artery disease undergoing contrast-enhanced dobutamine stress echocardiography.

BACKGROUND: Gender differences in the predictors of outcome among patients with known or suspected coronary artery disease (CAD) undergoing contrast-enhanced dobutamine stress echocardiography (CE-DSE) have not been completely determined. METHODS AND RESULTS: Follow-up (30+/-17 months) data for 581 men and 309 women with known or suspected CAD who underwent CE-DSE (mean age: 66 years) were obtained. Hard cardiac events included cardiac death and nonfatal myocardial infarction. Total cardiac events included hard cardiac events, unstable angina, congestive heart failure, and late revascularization (>3 months). Cardiac events occurred in 123 male and 50 female patients. Positive results for CE-DSE were associated with worse prognosis in both men and women (2-year total event free rate: 73.5% vs 88.2% in men, p<0.0001, 80.3% vs 91.3% in women, p<0.01). Addition of CE-DSE results, including abnormal left ventricular end-systolic volume response and left ventricular ejection fraction at peak stress <50%, to the clinical and rest echocardiography model provided incremental information for predicting total cardiac events (increase in chi-square value for the model from 60 to 72, p<0.001) in men and (increase in chi-square value for the model from 17 to 32, p<0.001) in women. CONCLUSIONS: CE-DSE provides incremental information for predicting future cardiac events in both men and women.     

The effect of intraosseous graft length on tendon-bone healing in anterior cruciate ligament reconstruction using flexor tendon

The current study was performed to understand the relationship between graft length placed within the bone tunnel and intraosseous graft healing in anterior cruciate ligament (ACL) reconstruction. Twenty-four adult beagle dogs were divided into two groups of 12 animals each. In each animal, ACL reconstruction using a 4-mm diameter autogenous flexor tendon graft was done in the left knee. In groups I and II, the graft having a length of 15 and 5 mm, respectively, was placed within the tibial tunnel. The proximal end of the graft was placed through the over-the-top route in all animals. In each group, five animals were sacrificed immediately after surgery, and the remaining seven were sacrificed at 6 weeks postoperatively. Biomechanical and histologic evaluations were performed. In pull out testing, the ultimate failure load and the linear stiffness of the graft-tibia complex harvested at 6 weeks were significantly greater than those harvested at the time-zero period. There were no significant differences in those parameters between groups I and II at 6 weeks. In each group, the perpendicular collagen fibers connecting the tendon to the bone tunnel wall were observed only in the narrow area located close to the intra-articular tunnel outlet. In conclusion, excessively long placement of the flexor graft within the bone tunnel does not result in an additional increase of anchoring strength and stiffness of the graft in ACL reconstruction.     

Human Tumor–infiltrating Lymphocytes Transfected with Tumor Necrosis Factor Gene Could Augment Cytotoxicity to Autologous Tumor Cells

Human tumor–infiltrating lymphocytes (TILs) derived from pleural or ascitic fluid were incubated with recombinant interleukin 2 and transfected with human tumor necrosis factor (TNF) a gene by the lipofection procedure. The resulting TILs secreted significant amounts of TNF in the culture supernatant and exhibited cytotoxicity against established cell lines, such as K562 and Daudi, and autologous tumor cells. The TNF gene–transfected TILs exhibited an augmented killing of autologous tumor cells.     

Scintigraphic detection of recurrence of medullary thyroid cancer

A case of recurrent medullary thyroid cancer (MTC) was evaluated with¹²³I-MIBG,^99mTc(V)-dimercaptosuccinic acid (DMSA), and²⁰¹Tl scintigraphy. This patient had been operated on for MTC in the right thyroid. Recently a left neck mass was noticed, and was suspected of being a. recurrence of MTC based on increased plasma calcitonin (CT) and carcinoembryonic antigen (CEA). He was operated on for the neck mass which revealed MTC, and papillary thyroid cancer was incidentally found in the left thyroid, but the CT and CEA levels remained high, and remaining MTC tumor was suspected. But the location of the tumor was unknown. Although^99mTc(V)-DMSA scintigraphy is generally believed to be superior in sensitivity to¹²³I-MIBG scintigraphy, it did not demonstrate the tumor site but²⁰¹Tl and¹²³I-MIBG did. Furthermore,¹²³I-MEBG scintigraphy has greater specificity for tumors which arise in the neural crest. Judging from the results of this case and cases reported in the literatures, both¹²³I-MIBG and^99mTc(V)-DMSA should be performed in the detection of recurrent MTC.