Protective effects of diphenyleneiodonium,an NADPH oxidase inhibitor,on lipopolysaccharide‐induced acute lung injury

NADPH oxidase (NOX) plays an important role in inflammatory response by producing reactive oxygen species (ROS). The inhibition of NOX has been shown to induce anti‐inflammatory effects in a few experimental models. The aim of this study was to investigate the effects of diphenyleneiodonium (DPI), a NOX inhibitor, on lipopolysaccharide (LPS)‐induced acute lung injury (ALI) in a rat model. Sprague‐Dawley rats were intraperitoneally administered by DPI (5 mg/kg) 30 minutes after intratracheal instillation of LPS (3 mg/kg). After 6 hours, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The NOX activity in lung tissue was significantly increased in LPS‐treated rats. It was significantly attenuated by DPI. DPI‐treated rats showed significant reduction in the intracellular ROS, the number of inflammatory cells, and cytokines (TNF‐α and IL‐6) in BALF compared with LPS‐treated rats. In lung tissue, DPI‐treated rats showed significantly decreased malondialdehyde content and increased activity of glutathione peroxidase and superoxide dismutase compared with LPS‐treated rats. Lung injury score, myeloperoxidase activity, and inducible nitric oxide synthase expression were significantly decreased in DPI‐treated rats compared with LPS‐treated animals. Western blotting analysis demonstrated that DPI significantly suppressed LPS‐induced activation of NF‐κB and ERK1/2 and SAPK/JNK in MAPK pathway. Our results suggest that DPI may have protective effects on LPS‐induced ALI thorough anti‐oxidative and anti‐inflammatory effects which may be due to inactivation of the NF‐κB, ERK1/2, and SAPK/JNK pathway. These results suggest the therapeutic potential of DPI as an anti‐inflammatory agent in ALI.     

Self-limiting extravasation in the unused urinary bladder

Patients being evaluated as potential renal transplant recipients routinely undergo voiding cystourethrography. Eight patients were encountered in whom extraperitoneal extravasation was noted from the region of the ureterovesical junction during voiding (seven patients) or during filling (one patient). Extravasation was bilateral in six patients and unilateral in two. The patients neither experienced symptoms related to the extravasation, required treatment, nor had sequelae. Five of the eight patients have subsequently received renal transplants and their bladders were observed to be normal at surgery. Cystoscopy was also performed in two of these five patients and was unremarkable. After transplantation, these patients' bladders functioned normally and gave rise to no symptoms.     

Inhibitory activity of diacylglycerol acyltransferase by tanshinones from the root of Salvia miltiorrhiza

The inhibitory activity of tanshinones from Salvia miltiorrhiza was tested on rat liver diacylglycerol acyltransferase (DGAT). Cryptotanshinone (1) and 15,16-dihydrotanshinone I (3) exhibited potent DGAT inhibitory activities dose-dependently with IC50 values of 10.5 microg/ml and 11.1 microg/ml. However, tanshinone IIA (2) and tanshinone I (4) showed very weak inhibition (IC50 value: > 250 microg/ml). A dihydrofuran moiety was seemed to be responsible for the stronger inhibitory activity.     

Isolation of Acyl-CoA:cholesterol acyltransferase inhibitor from Persicaria vulgaris

In the course of our search for Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors from natural sources, a new type of ACAT inhibitor was isolated from the methanol extract of Persicaria vulgaris. On the basis of spectral evidence, the structure of the active compound was identified as pheophorbide A. Pheophorbide A inhibited ACAT activity with an IC 50 value of 1.1 microg/ml in an enzyme assay using rat liver microsomes with a dose dependent fashion.     

Mechanisms of relaxant action of a pyranocoumarin from Peucedanum japonicum in isolated rat thoracic aorta

The CHCl(3) -soluble fraction obtained from the MeOH extract of Peucedanum japonicum Thunb. inhibited phenylephrine-induced vasoconstriction in isolated rat thoracic aorta. We isolated a vasorelaxing compound, as one of the bioactive components, which was identified as (+)- cis-4'- O-acetyl-3'- O-angeloylkhellactone (1), a pyranocoumarin, and examined the mechanisms of vasorelaxant effect caused by 1. This compound (1) (10(-6)-10(-4) M) concentration-dependently relaxed the isolated rat thoracic aorta pre-contracted with phenylephrine (PE). This vasorelaxant potency was diminished by endothelial removal (by 20%), L- N(G)-nitro-arginine or methylene blue (MB), but not indomethacin treatment. These findings indicate that the vasorelaxant effect of 1 was partially endothelium dependent and mediated by nitric oxide and cyclic GMP pathway. To determine if the effect of 1 was mediated through the activation of some of the receptors known to lead to vascular relaxation, the effects of atropine, triprolidine and propranolol were determined. 1-induced vasorelaxation was not affected by atropine, triprolidine and propranolol. Compound 1 inhibited high potassium (80 mM)-induced, calcium-dependent contractions in a concentration-dependent manner. But it slightly relaxed the rat aorta precontracted with PE in the presence of nifedipine, a blocker of voltage-operated calcium channels. Tetraethylammonium (TEA, a non-specific (K+) channel blocker) did not affect the vasodilatory effect of 1 against PE-induced contraction. Mechanisms of the vasorelaxant effect of 1 were multiple, including endothelium dependence and Ca(2+) channel blockade.     

Inhibition of LFA-1/ICAM-1-mediated cell adhesion by stilbene derivatives from Rheum undulatum

Six stilbenes were isolated from the methanol extract of Rheum undulatum rhizomes by bioactivity-guided fractionation. The structures of the compounds were determined by spectroscopic analysis (¹H-, ¹³C-NMR and MS), to be desoxyrhapontigenin (1), rhapontigenin (2), trans-resveratrol (3), piceatannol (4), piceatannol-3′-O-β-D-glucopyranoside (5) and isorhapontin (6). Compounds 1–4 inhibited the direct binding between sICAM-1 and LFA-1 of the THP-1 cells in a dose-dependent manner with IC₅₀ values of 50.1, 25.4, 33.4 and 45.9 μM, respectively. On the other hand, the other compounds 5 and 6 with a glucose moiety in each molecule did not show any inhibitory activity in the cell adhesion assay (IC₅₀ values of >100.0 μM). Compounds 2, 3 and 4 also had an inhibitory effect on direct binding between sVCAM-1 and VLA-4 of THP-1 cells. This suggests that the stilbenes from Rheum undulatum rhizomes are good candidates for therapeutic strategies towards inflammation.     

Cost-effectiveness of counseling and pedometer use to increase physical activity in the Netherlands: a modeling study

Background

Counseling in combination with pedometer use has proven to be effective in increasing physical activity and improving health outcomes. We investigated the cost-effectiveness of this intervention targeted at one million insufficiently active adults who visit their general practitioner in the Netherlands.

Methods

We used the RIVM chronic disease model to estimate the long-term effects of increased physical activity on the future health care costs and quality adjusted life years (QALY) gained, from a health care perspective.

Results

The intervention resulted in almost 6000 people shifting to more favorable physical-activity levels, and in 5100 life years and 6100 QALYs gained, at an additional total cost of EUR 67.6 million. The incremental cost-effectiveness ratio (ICER) was EUR 13,200 per life year gained and EUR 11,100 per QALY gained. The intervention has a probability of 0.66 to be cost-effective if a QALY gained is valued at the Dutch informal threshold for cost-effectiveness of preventive intervention of EUR 20,000. A sensitivity analysis showed substantial uncertainty of ICER values.

Conclusion

Counseling in combination with pedometer use aiming to increase physical activity may be a cost-effective intervention. However, the intervention only yields relatively small health benefits in the Netherlands.     

Clock-hour laminar displacement and age in primary open-angle glaucoma and normal tension glaucoma

Background: To find out the relationship between laminar displacement and age between patients with primary open‐angle glaucoma and normal tension glaucoma. Design: Retrospective study conducted at a tertiary university hospital Participants or Samples: Twenty‐six eyes of 26 primary open‐angle glaucoma patients and 52 eyes of 52 normal tension glaucoma patients. Methods: Patients were scanned with a Stratus optical coherence tomography apparatus to measure the retinal nerve fibre layer thickness and to visualize the cross‐sectional laminar displacement of 12 clock‐hour segments, 30 degrees each. Depth1 was defined as the longest distance between the retinal pigment epithelium and the anterior laminar cribrosa surface, which represents the amount of laminar displacement. Main Outcome Measure: Partial correlation coefficients adjusted by mean deviation and intraocular pressure between (i) retinal nerve fibre layer thickness and age, and (ii) Depth1 and age. Results: In the primary open‐angle glaucoma group, strong negative correlations (approximately ?0.343 ～ ?0.738) were found between Depth1 and age. Eight of 12 clock‐hour segments' correlations were significant after Bonferroni correction (α = 0.0021; 24 comparisons). However, no significant correlations were found between Depth1 and age in the normal tension glaucoma group. When the correlation coefficients were compared between the two groups, eight clock‐hour segments showed significant differences after Bonferroni correction. Conclusions: The significantly different correlation between laminar displacement and age between primary open‐angle glaucoma and normal tension glaucoma patients may suggest a different role of the lamina cribrosa to the disease.     

Design of the sex hormones and physical exercise (SHAPE) study

Background  

Physical activity has been associated with a decreased risk for breast cancer. The biological mechanismn(s) underlying the association between physical activity and breast cancer is not clear. Most prominent hypothesis is that physical activity may protect against breast cancer through reduced lifetime exposure to endogenous hormones either direct, or indirect by preventing overweight and abdominal adiposity. In order to get more insight in the causal pathway between physical activity and breast cancer risk, we designed the Sex Hormones and Physical Exercise (SHAPE) study. Purpose of SHAPE study is to examine the effects of a 1-year moderate-to-vigorous intensity exercise programme on endogenous hormone levels associated with breast cancer among sedentary postmenopausal women and whether the amount of total body fat or abdominal fat mediates the effects.     

Efficacy and tolerance of diltiazem in primary pulmonary hypertension. Apropos of a case

The Authors report a case of a serious and symptomatic primary pulmonary hypertension, where the intravenous administration of Diltiazem, at a dosage of 0.3 mg/kg, resulted in an important improvement of haemodynamic parameters. This improvement was confirmed 4 months later on chronic oral therapy with Diltiazem, at a dosage of 180 mg per day. Six months after the beginning of therapy, the patient is totally asymptomatic. Even though further controls are needed, Diltiazem may represent an active drug in the treatment of primary pulmonary hypertension.