Is metabolic syndrome a risk factor for carotid atherosclerosis in normotensive and prehypertensive individuals?

AIM: We have investigated whether metabolic syndrome is a risk factor for carotid atherosclerosis also in normotensive or prehypertensive individuals. METHODS: We analyzed the data from 851 subjects who had a blood pressure of less than 140/90 mmHg and were not taking antihypertensive medication. Metabolic syndrome was defined according to three different criteria: Japan criteria (Japan-MetS); those of the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) (NCEP-MetS); and modified NCEP-ATP III criteria in which body mass index was used as a surrogate for waist circumference (modified NCEP-MetS). RESULTS: Japan-MetS, NCEP-MetS, and modified NCEP-MetS were found, respectively, in 1%, 4%, and 4%, of women, and in 10%, 5%, and 9%, of men. After the adjustment for gender and age, the association between MetS and carotid atherosclerosis did not reach statistical significance. CONCLUSION: Although the number of enrolled subjects was relatively small, these data may further support the importance of controlling blood pressure within the optimal range for the purpose of preventing atherosclerosis in individuals with metabolic syndrome.     

Anxiolytic-like profile of mirtazapine in rat conditioned fear stress model: Functional significance of 5-hydroxytryptamine 1A receptor and α1-adrenergic receptor

Mirtazapine is an antidepressant with a unique mechanism of action and has been categorized as a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA). Although numerous clinical trials suggested the usefulness of mirtazapine for not only major depressive disorders but also a variety of anxiety disorders, efficacy studies in animal anxiety models have been rarely reported. The present study investigated a potential anxiolytic-like profile of mirtazapine in rat conditioned fear stress model. A 5-hydroxytryptamine (5-HT) 1A receptor partial agonist, buspirone (1-5 mg/kg) exhibited a significant reduction in freezing time, and its maximal effect was reversed by a selective 5-HT_1A antagonist, WAY-100635 (1 mg/kg). Mirtazapine (1-10 mg/kg) also reduced the freezing time in a dose-related fashion, a substantial proportion (approx. 50%) of which was likewise antagonized by WAY-100635 (1 mg/kg). Mianserin (1-30 mg/kg), a structural analogue for mirtazapine, was ineffective. Furthermore, co-administration of α1 adrenoceptor antagonist, prazosin (0.03 mg/kg) completely reversed mirtazapine (10 mg/kg)-induced reduction of freezing time. These findings represent the first demonstration that the anxiolytic-like action of mirtazapine involves activation of 5-HT_1A receptor and α1 adrenoceptor to different extents, and are compatible with one aspect of mirtazapine's pharmacological profile as NaSSA.     

Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic

Rationale  Histamine H3 receptor functions as a presynaptic auto- and hetero-receptor on histaminergic and non-histaminergic neurons in the brain regulating the synaptic release of numerous neurotransmitters. Therefore, the ligands for this receptor have been proposed to be of therapeutic interest for the treatment of various neuropsychiatric disorders. At present, however, the psychopharmacological profiles of H3 ligands, particularly H3 agonists, have not been extensively studied. Objective  The present study investigated the anxiolytic-like profiles of H3-selective agonists in a variety of classical (benzodiazepine-sensitive) and atypical (antidepressant-effective) animal models of anxiety. Comparator drugs used were diazepam and both fluvoxamine and desipramine in the former and latter models, respectively. Results  H3 agonist R-α-methylhistamine and immepip were inactive in rat elevated plus maze test and Vogel type conflict test where diazepam (5 mg/kg) produced significant anxiolytic-like effects. Meanwhile, these H3 agonists (10–30 mg/kg) significantly reduced isolation-induced vocalizations in guinea pig pups and isolation-induced aggressive behavior in mouse resident–intruder test. Moreover, in rat conditioned fear stress test, R-α-methylhistamine (30 mg/kg) and immepip (10 mg/kg) significantly decreased freezing time, which were completely reversed by concomitant treatment with H3 antagonist, thioperamide (10 mg/kg). In contrast to the limited efficacy obtained with desipramine (30 mg/kg), fluvoxamine (20–60 mg/kg) exhibited anxiolytic-like effects in all the latter three atypical models. Conclusions  These data suggest that the H3 agonists may have anxiolytic-like effects similar to those of selective serotonin reuptake inhibitors but not benzodiazepine anxiolytics and represent a novel strategy for the treatment of some anxiety disorders in which selective serotonin reuptake inhibitors are prescribed.     

Association between serum albumin, carotid atherosclerosis, and metabolic syndrome in Japanese individuals

Serum albumin is a maker of nutritional status and possesses antioxidative properties. Here, we have sought to investigate the mode of association between serum albumin levels, metabolic syndrome, and carotid atherosclerosis by analyzing the data of the cross-sectional data from 8143 individuals who underwent general health screening test. After adjusting for age, total cholesterol, and smoking status, the highest quartile of serum albumin (>or=4.7 g/dL) was associated with increased prevalence of metabolic syndrome with an odds ratio of 1.80 (95% CI 1.41-2.23, P<0.0001) in women, and 1.60 (95% CI 1.44-1.78, P<0.0001) in men, when compared to the lowest serum albumin quartile (<4.3g/dL). By contrast, when compared with the lowest quartile, the highest quartile of serum albumin was associated with reduced prevalence of carotid plaque with an odds ratio of 0.62 (95% CI 0.42-0.91, P<0.001) in women, and 0.76 (95% CI 0.62-0.93, P<0.01) in men, and for carotid intima-media thickening with an odds ratio of 0.57 (95% CI 0.35-0.94, P<0.05) in women, and 0.71 (95% CI 0.55-0.92, P<0.01) in men. Our data showed that higher serum albumin was inversely associated with the prevalence of early carotid atherosclerosis, although it was positively associated with the prevalence of metabolic syndrome. Whether these observations are in part explained by the antioxidative properties of albumin requires further investigation.     

Targeted functional imaging of estrogen receptors with <Superscript>99m</Superscript>Tc-GAP-EDL

Purpose To evaluate the feasibility of using ^99mTc-glutamate peptide-estradiol in functional imaging of estrogen receptor-positive [ER(+)] diseases. Methods 3-Aminoethyl estradiol (EDL) was conjugated to glutamate peptide (GAP) to yield GAP-EDL. Cellular uptake studies of ^99mTc-GAP-EDL were conducted in ER(+) cell lines (MCF-7, 13762 and T47D). To demonstrate whether GAP-EDL increases MAP kinase activation, Western blot analysis of GAP-EDL was performed in 13762 cells. Biodistribution was conducted in nine rats with 13762 breast tumors at 0.5–4 h. Each rat was administered ^99mTc-GAP-EDL. Two animal models (rats and rabbits) were created to ascertain whether tumor uptake of ^99mTc-GAP-EDL was via an ER-mediated process. In the tumor model, breast tumor-bearing rats were pretreated with diethylstilbestrol (DES) 1 h prior to receiving ^99mTc-GAP-EDL. In the endometriosis model, part of the rabbit uterine tissue was dissected and grafted to the peritoneal wall. The rabbit was administered with ^99mTc-GAP-EDL. Results There was a 10–40% reduction in uptake of ^99mTc-GAP-EDL in cells treated with DES or tamoxifen compared with untreated cells. Western blot analysis showed an ERK1/2 phosphorylation process with GAP-EDL. Biodistribution studies showed that tumor uptake and tumor-to-muscle count density ratio in ^99mTc-GAP-EDL groups were significantly higher than those in ^99mTc-GAP groups at 4 h. Among ^99mTc-GAP-EDL groups, region of interest analysis of images showed that tumor-to muscle ratios were decreased in blocking groups. In the endometriosis model, the grafted uterine tissue could be visualized by ^99mTc-GAP-EDL. Conclusion Cellular or tumor uptake of ^99mTc-GAP-EDL occurs via an ER-mediated process. ^99mTc-GAP-EDL is a useful agent for imaging functional ER(+) disease.     

Climbing exercise enhances osteoblast differentiation and inhibits adipogenic differentiation with high expression of PTH/PTHrP receptor in bone marrow cells

We developed previously a mouse voluntary climbing exercise model as a physiological mechanical loading model and reported that climbing exercise increased bone formation, but its effect on adipogenesis is unknown. We assessed the effects of loading and PTH/PTHrP receptor (PTHR1) on bone marrow adipocyte differentiation in relation with osteoblast differentiation. 8-week-old C57BL/6J male mice were divided into ground control (GC) and climbing exercise (EX) group. Mice were housed in 100-cm towers and climbed up toward a bottle placed at the top of the cage to drink water. The values of bone volume and osteoblast number were significantly higher while those of marrow adipocyte volume and number were significantly lower in the 28dayEX group than 28dayGC group. The mRNA expression levels of adipocyte differentiation genes CCAAT/enhancer-binding proteins (C/EBP) beta and delta were lower in 4dayEX mice, while the adipocyte specific genes fatty acid binding protein (aP2) and phosphoenolpyruvate carboxykinase (PEPCK) expressions were lower in 7dayEX mice. In primary bone marrow cell cultures, the number of alkaline phosphatase-positive colony forming units-fibroblastic (ALP+ CFU-f) and Oil-red-O-positive cells were both increased in the 4dayEX group. Climbing exercise transiently increases both osteogenic and adipogenic potential in bone marrow stromal cells, and inhibits terminal adipocyte differentiation and promotes osteoblast differentiation. Immunoreactivity for the PTHR1 was intense on osteoblastic cell lineage in the endosteal tibial metaphysis. PTHR1 mRNA expression was increased in 4dayEX mice and PTHR1-positive cells were increased after 7 days in the experimental group. Ex vivo addition of PTHR1 antibody decreased and that of PTHrP(1-34) increased the number of ALP+ CFU-f in bone marrow cell cultures obtained at 4 days after the exercise, while the addition of PTHR1 antibody increased and PTHrP(1-34) decreased the number of Oil-red-O-positive cells. Our results indicate that climbing exercise enhanced osteoblast differentiation and inhibited terminal differentiation of adipocyte progenitors with high expression of PTHR1 in bone marrow cells.     

Dose escalation study of nedaplatin with 5-fluorouracil in combination with alternating radiotherapy in patients with head and neck cancer

BACKGROUND: This study, with a large number of patients, confirms that after administration of 5-fluorouracil (5FU), a higher dose of nedaplatin (NDP) can be safely administered rather than a single therapy of NDP, as demonstrated in a phase I study. METHODS: The subjects were 52 patients with stage II-IV (M0) head and neck cancer other than nasopharyngeal cancer. Alternating chemoradiotherapy was performed using the following method. Initially, chemotherapy was administered. For chemotherapy, 5FU at 700 mg/m2/24 h was intravenously administered for 5 days (days 1-5), and NDP was administered on day 6. We established three dose groups: level 1, 120 mg/m2; level 2, 140 mg/m2; and level 3, 150 mg/m2 (n = 13 or more per group). RESULTS: The maximum acceptable dose of NDP (150 mg/m2) was confirmed. The 5-year overall survival rates were 77% (95% CI: 66-90%) in all subjects and 75% (95% CI: 61-92%) in the stage III/IV patients. The 5-year progression-free survival rates were 73% (95% CI: 62-87%) in all subjects and 72% (95% CI: 57-89%) in the stage III/IV patients. CONCLUSIONS: After administration of 5FU, a higher dose of NDP can be safely administered. This alternating chemoradiotherapy showed potent antitumor effects. The efficacy of chemotherapy with NDP and 5FU should be compared to that of chemotherapy with CDDP and 5FU.     

A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras

The c-Met receptor tyrosine kinase has been implicated in cellular transformation induced by mutant Ras, a commonly activated proto-oncogene in non-small cell lung cancer (NSCLC). However, the role of c-Met has not been defined in K-ras-mutant NSCLC, a disease for which no effective targeted therapeutic options currently exist. To acquire a greater understanding of its role, we used genetic and pharmacologic approaches to inhibit c-Met in mice and cultured cells. In Kras(LA1) mice, which develop premalignant lung lesions that progress to multifocal lung adenocarcinomas owing to somatic mutations in K-ras, c-Met was expressed in multiple cell types within premalignant lung lesions, and high concentrations of HGF were detected in bronchoalveolar lavage samples. Short-term treatment with PHA-665752, a c-Met inhibitor, decreased the numbers of premalignant lung lesions and induced apoptosis in tumor cells and vascular endothelial cells within lesions. In cell culture, PHA-665752 induced apoptosis of a lung adenocarcinoma cell line derived from Kras(LA1) mice (LKR-13) and a murine lung endothelial cell line (MEC). c-Met depletion by siRNA transfection induced apoptosis of MECs but not LKR-13 cells. Collectively, these findings suggest that apoptosis was an on-target effect of PHA-665752 in MECs but not in LKR-13 cells. We conclude that PHA-665752 inhibited lung tumorigenesis in Kras(LA1) mice and may provide a novel therapeutic approach to the prevention of K-ras-mutant NSCLC.     

Surgical treatment of ossified cephalhematoma: a case report

We report a surgical case of ossified cephalhematoma which caused deformity of the skull. A boy was delivered with the aid of vacuum extractor at 40 gestational weeks. He presented with a big cephalhematoma in the left parietal region, and it remained and calcificated after 3 months. He was admitted after being diagnosed with ossified cephalhematoma. Plain skull radiograph showed a marginated radiolucent lesion with a protrusive outer table and a slightly invaginated inner table in the left parietal region. Plain CT scan showed a low density lesion between bony layers and the depressed inner table with irregular thickening. 3D-CT shows bony protrusion of the left parietal bone with thinning in the center. Magnetic resonance imaging revealed an old hematoma in the protruding bone and compression of the parietal lobe by the inner table. For cosmetic reasons and relief of compression of the brain, cranioplasty was performed at 7 months. The protruding bone was removed totally and was arranged to fit in the convex after being cut in pieces. Using bioabsorbable mini plates and screws, the bone was fixed firmly. For cranioplasty of a child, absorbable plates and screws are useful because of their non-interference with growth of the skull.