Altered Regulation of Renal Nitric Oxide and Atrial Natriuretic Peptide Systems in Lipopolysaccharide-induced Kidney Injury

Nitric oxide (NO) and atrial natriuretic peptide (ANP) may induce vascular relaxation by increasing the production of cyclic guanosine monophosphate (cGMP), an important mediator of vascular tone during sepsis. This study aimed to determine whether regulation of NO and the ANP system is altered in lipopolysaccharide (LPS)-induced kidney injury. LPS (10 mg.kg(-1)) was injected in the tail veins of male Sprague-Dawley rats; 12 hours later, the kidneys were removed. Protein expression of NO synthase (NOS) and neutral endopeptidase (NEP) was determined by semiquantitative immunoblotting. As an index of synthesis of NO, its stable metabolites (nitrite/nitrate, NOx) were measured using colorimetric assays. mRNA expression of the ANP system was determined by real-time polymerase chain reaction. To determine the activity of guanylyl cyclase (GC), the amount of cGMP generated in response to sodium nitroprusside (SNP) and ANP was calculated. Creatinine clearance decreased and fractional excretion of sodium increased in LPS-treated rats compared with the controls. Inducible NOS protein expression increased in LPS-treated rats, while that of endothelial NOS, neuronal NOS, and NEP remained unchanged. Additionally, urinary and plasma NOx levels increased in LPS-treated rats. SNP-stimulated GC activity remained unchanged in the glomerulus and papilla in the LPS-treated rats. mRNA expression of natriuretic peptide receptor (NPR)-C decreased in LPS-treated rats, while that of ANP and NPR-A did not change. ANP-stimulated GC activity reduced in the glomerulus and papilla. In conclusion, enhancement of the NO/cGMP pathway and decrease in ANP clearance were found play a role in the pathogenesis of LPS-induced kidney injury.     

Vasorelaxing Activity of Ulmus davidiana Ethanol Extracts in Rats: Activation of Endothelial Nitric Oxide Synthase

Ulmus davidiana var. japonica Rehder (Urticales: Ulmaceae) (UD) is a tree widespread in northeast Asia. It is traditionally used for anticancer and anti-inflammatory therapy. The present study investigated the effect of an ethanol extract of UD on vascular tension and its underlying mechanism in rats. The dried root bark of UD was ground and extracted with 80% ethanol. The prepared UD extract was used in further analysis. The effect of UD on the cell viability, vasoreactivity and hemodynamics were investigated using propidium iodide staining in cultured cells, isometric tension recording and blood pressure analysis, respectively. Low dose of UD (10~100μg/ml) did not affect endothelial cell viability, but high dose of UD reduced cell viability. UD induced vasorelaxation in the range of 0.1~10μg/ml with an ED(50) value of 2μg/ml. UD-induced vasorelaxation was completely abolished by removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. UD inhibited calcium influx induced by phenylephrine and high K(+) and also completely abolished the effect of L-NAME. Intravenous injection of UD extracts (10~100 mg/kg) decreased arterial and ventricular pressure in a dose-dependent manner. Moreover, UD extracts reduced the ventricular contractility (+dP/dt) in anesthetized rats. However, UD-induced hypotensive actions were minimized in L-NAME-treated rats. Taken together, out results showed that UD induced vasorelaxation and has antihypertensive properties, which may be due the activation of nitric oxide synthase in endothelium.     

Potential anti-cancer activity of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a histone deacetylase inhibitor, against breast cancer both in vitro and in vivo

Histone deacetylase (HDAC) is an attractive target for cancer therapy because it plays a key role in gene expression and carcinogenesis. N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) is a novel synthetic HDAC inhibitor (HDACI) that shows better pharmacological properties than a known HDACI present in the human fibrosarcoma cell: suberoylanilide hydroxamic acid (SAHA). Here, we investigate the anti-cancer activity of HNHA against breast cancer both in vitro and in vivo. HNHA arrested the cell cycle at the G(1) /S phase via p21 induction, which led to profound inhibition of cancer cell growth in vitro. In addition, HNHA-treated cells showed markedly decreased levels of VEGF and HIF-1α than SAHA and fumagillin (FUMA) when accompanied by increased histone acetylation. HNHA significantly inhibited tumor growth in an in vivo mouse xenograft model. HNHA-treated mice survived significantly longer than SAHA- and FUMA-treated mice. Dynamic MRI showed significantly decreased blood flow in the HNHA-treated mice, implying that HNHA inhibits tumor neovascularization. This finding was accompanied by marked reductions of proangiogenic factors and significant induction of angiogenesis inhibitors in tumor tissues. We have shown that HNHA is an effective anti-tumor agent in breast cancer cells in vitro and in breast cancer xenografts in vivo. Collectively, these findings indicate that HNHA may be a potent anti-cancer agent against breast cancer due to its multi-faceted inhibition of HDAC activity, as well as anti-angiogenesis activity.     

Clinicopathological parameters and biological markers predicting non-sentinel node metastasis in sentinel node-positive breast cancer patients

The value of complete axillary lymph node dissection (ALND) has been questioned in invasive breast cancer (IBC) patients with positive sentinel lymph nodes (SLNs) who have no non-sentinel lymph node (NSLN) metastases. Because biological markers have not been systematically studied in this setting, we sought to identify clinicopathological characteristics and biological markers for predicting NSLN metastases in SLN-positive IBC patients. Two hundred and five IBC patients who had at least one positive SLN and received SLN biopsy and ALND were included in our study. We examined the clinicopathological characteristics of their primary tumors, SLNs and NSLNs. We also evaluated the biological markers of the primary tumors by tissue microarray and immunohistochemistry. Of the 205 patients with SLN metastases, 89 patients (43.4%) had additional metastases in NSLNs. The following factors were found to be associated with NSLN metastases: peritumoral lymphovascular invasion (p=0.01), two or more metastatic SLNs (p<0.01), SLN metastasis >2.0 mm (p<0.01) and extra-nodal extension (p<0.01). Primary tumors >2.0 cm showed more NSLN metastases, but the association was statistically insignificant (p=0.08). In contrast, NSLN metastases were not associated with histologic grade, histologic type, presence of extensive intraductal component, presence of high grade ductal carcinoma in situ and number of harvested SLNs. Biological markers such as E-cadherin, CD44, cyclin D1, p21, ER, PR, c-erbB2, p53, Ki-67, luminal (CK7, CK18, CK19) and basal (CK5, p63) markers were not useful predictors of NSLN metastasis in IBC patients with SLN metastases. Multivariate analysis revealed that SLN metastasis >2.0 mm (p=0.01), two or more metastatic SLNs (p=0.03) and extranodal extension (p<0.01) were independent predictors of NSLN metastasis. For the prediction of NSLN metastasis in IBC patients with SLN metastases, light microscopic evaluation of the number, size and extranodal extension of metastatic SLNs by hematoxylin and eosin staining appeared to be critical. However, the biological markers of primary tumor characterized by immunohistochemical staining, such as luminal and basal markers, hormone receptors, E-cadherin, CD44, cyclin D1, p21, c-erb-B2, p53 and Ki-67, did not appear to be helpful predictors.     

Intramuscular lipoma of the sternocleidomastoid muscle

Intramuscular lipoma is a rare benign mesenchymal tumor that infiltrates the skeletal muscle. These lipomas are usually found on the extremity, but rarely occur in the head and neck. To our knowledge, only 4 cases of intramuscular lipoma in the sternocleidomastoid muscle have been reported in the literature. The recurrence rate of intramuscular lipoma is high, and it shows the pattern of infiltration to tissues, and thus different from general lipomas, its resection should include adjacent normal muscular tissues. In addition, although rare, concerning intramuscular lipoma that developed in the head and neck area, because important structures are present densely in a small space, it is important to establish a preoperative plan by determining the size and location of the tumor through preoperative clinical and radiologic tests. We had a case of intramuscular lipoma in sternocleidomastoid muscle and resected the mass completely including a portion of attached muscles. The postoperative course was uneventful, and no evidence of recurrence occurred after 6 months of follow-up.     

Submuscular fibrolipoma of the forehead

Fibrolipoma is a rare variant of lipoma with a mixture of fibrous connective tissue. Clinically, it presents as an asymptomatic, slowly growing mass with a smooth, firm, or soft consistency. Although fibrolipoma can occur in any part of the body, in the head region it mainly occurs in the oral cavity and sometimes in the lip, parotid gland, nose, and cheek. We present the first case of a 65-year-old man with a submuscular fibrolipoma of the forehead that showed no evidence of recurrence after excision.     

Use of separate single-tooth implant restorations to replace two or more consecutive posterior teeth: a prospective cohort study for up to 1 year

PURPOSE

The aim of this study was to evaluate the periodontal and prosthodontic complications of multiple freestanding implants in the posterior jaws for up to 1 year of function.

MATERIALS AND METHODS

Eight patients received 20 implants posterior to canines. Two or more implants were consecutively inserted to each patient. Single crowns were delivered onto the implants. Marginal bone loss, implant mobility, probing depth, and screw loosening were examined to evaluate the clinical success of such restorations for maximum 1 year of functional loading.

RESULTS

All the implants performed well during the observation period. Neither periodontal nor prosthodontic complications were found except a slight porcelain chipping. While the marginal bone level was on average 0.09 mm lower around the implant after 6 months of loading, it was 0.15 mm higher after 1 year.

CONCLUSION

Within the limits of this investigation, separate single-tooth implant restorations to replace consecutive missing teeth may clinically function well in the posterior jaw.     

Input-specific synaptic plasticity in the amygdala is regulated by neuroligin-1 via postsynaptic NMDA receptors

Despite considerable evidence for a critical role of neuroligin-1 in the specification of excitatory synapses, the cellular mechanisms and physiological roles of neuroligin-1 in mature neural circuits are poorly understood. In mutant mice deficient in neuroligin-1, or adult rats in which neuroligin-1 was depleted, we have found that neuroligin-1 stabilizes the NMDA receptors residing in the postsynaptic membrane of amygdala principal neurons, which allows for a normal range of NMDA receptor-mediated synaptic transmission. We observed marked decreases in NMDA receptor-mediated synaptic currents at afferent inputs to the amygdala of neuroligin-1 knockout mice. However, the knockout mice exhibited a significant impairment in spike-timing-dependent long-term potentiation (STD-LTP) at the thalamic but not the cortical inputs to the amygdala. Subsequent electrophysiological analyses indicated that STD-LTP in the cortical pathway is largely independent of activation of postsynaptic NMDA receptors. These findings suggest that neuroligin-1 can modulate, in a pathway-specific manner, synaptic plasticity in the amygdala circuits of adult animals, likely by regulating the abundance of postsynaptic NMDA receptors.