Impact of pre-stent plaque debulking for chronic coronary total occlusions on restenosis reduction

BACKGROUND: While stenting improves the long-term angiographic outcomes of successfully recanalized chronic coronary total occlusions (CTO), the restenosis rate still remains high. The massive plaque burden in CTO is considered to be one of the causes of in-stent restenosis. METHODS: We examined the pre-stent plaque debulking strategy with high-speed rotational atherectomy (RA) for 50 CTO (Thrombolysis in Myocardial Infarction flow grade 0; estimated occlusive duration, 3 months). Angiographic follow-up results were compared to those of 120 consecutive CTO recanalized with primary stenting in which RA could be indicated retrospectively. Angiographic restenosis was defined as diameter stenosis > 50% at 6-month follow-up. RESULTS: RA could be performed safely in all lesions without any major complications. Adjunctive ballooning and stenting could be performed without high-pressure dilatation (8.4 +/- 1.7 atmospheres). Follow-up angiography was performed in 48 lesions 184 +/- 61 days after the procedure. There were no significant differences in baseline characteristics between the two groups; however, the implanted stent type was different. Quantitative coronary angiography revealed that diameter stenosis was smaller at follow-up (36.2 +/- 20.0% versus 52.2 +/- 26.7%; p = 0.0003) as well as post-procedure (7.8 +/- 11.5% versus 17.8 +/- 13.6%; p < 0.0001) compared with the control group. Angiographic restenosis was also significantly reduced (29.2% versus 52.5%; p = 0.0061). CONCLUSIONS: RA is a safe procedure for plaque debulking of CTO in selected cases. Plaque debulking of CTO facilitates subsequent stent expansion and may reduce the restenosis rate.     

Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice.

Chronic alcohol administration increases gut-derived endotoxin in the portal blood, which activates Kupffer cells and causes liver injury. Mice (C3H/HeJ) with mutations in toll-like receptor 4 (TLR4) are hyporesponsive to endotoxin. To test the hypothesis that TLR4 is involved in early alcohol-induced liver injury, the long-term intragastric ethanol feeding protocol developed by Tsukamoto and French for rats was adapted to mice. Animals with nonfunctional TLR4 and wild-type mice (C3H/HeOuJ) were compared. Two-month-old female mice were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 weeks. There was no difference in mean urine alcohol concentrations between the groups. Dietary alcohol significantly increased liver-to-body weight ratios and serum alanine transaminase (ALT) levels in wild-type mice (109 +/- 18 U/L) over high-fat controls (40 +/- 3 U/L), effects that were blunted significantly in mice with a mutation of TLR4 (55 +/- 9 U/L). While no significant pathologic changes were observed in high-fat controls, dietary ethanol caused steatosis, mild inflammation, and focal necrosis in wild-type animals (pathology score = 5.2 +/- 1.2). These pathologic changes were significantly lower in TLR4-deficient mice fed ethanol (score = 2.0 +/- 1.3). Endotoxin levels in the portal vein were increased significantly after 4 weeks in both groups fed ethanol. Moreover, ethanol increased tumor necrosis factor alpha (TNF-alpha) mRNA expression in wild-type, but not in TLR4-deficient, mice. These data are consistent with the hypothesis that Kupffer cell activation by endotoxin via TLR4 is involved in early alcohol-induced liver injury.     

Microsatellite instability in gallbladder carcinoma: two independent genetic pathways of gallbladder carcinogenesis

Although the genetic basis for gallbladder carcinogenesis has not been clarified, considerable evidence has shown that genetic alterations play an important role in the development and progression of human cancers. In this study, we analyzed 30 gallbladder carcinomas to investigate the role of genetic alterations in their tumorigenesis, and to study correlations with their clinicopathological features. Tissue samples were obtained from 30 patients with gallbladder carcinoma (11 men and 19 women; mean age, 62 years; age range, 38–80 years). Genomic DNAs were extracted from fresh tumor tissue. We examined loss of heterozygosity (LOH) in the p53, APC, DCC, RB, and NM23-H1 gene regions by polymerase chain reaction (PCR)-LOH assay using an automated fluorescent DNA sequencer employing four microsatellite markers (p53, APC, DCC, NM23-H1). Five additional microsatellite markers were used for the determination of microsatellite instability (MSI). LOH was found at p53 in 9 of 15 informative cases (60%), at DCC in 10 of 22 (45%), at APC in 5 of 15 (33%), at RB in 1 of 8 (13%), and at NM23-H1 in 1 of 15 (7%). MSI was observed in 5 of 30 cases (17%) in at least one chromosomal loci of these nine microsatellite markers. None of the patients with MSI-positive tumors showed lymph node metastasis, and there was an inverse correlation between MSI and the presence of LOH in gallbladder carcinoma. These results suggest that there are two independent genetic pathways in gallbladder carcinogenesis; that is, an MSI pathway and an LOH pathway. Received: December 24, 1999 / Accepted: May 26, 2000     

Evidence of estrogenic effect by the three-month-intervention of isoflavone on vaginal maturation and bone metabolism in early postmenopausal women

Objective of the present study is to determine the estrogenic effect of isoflavone on vaginal epithelia and bone metabolism in early postmenopausal women. Twenty-two postmenopausal women were randomly assigned to either a group that was given isoflavone extract (61.8 mg) for three months or a control group that was given placebo. We measured the L2-4 bone mineral density (BMD) before and 3 months after treatment by dual X-ray absorptiometry (DXA). Blood and urine samples were obtained from the women before and 3 months after treatment. We measured FSH using radioimmunoassay and, urinary pyridinoline and deoxypyridinoline levels by HPLC. For endocrine cytology, vaginal smears were collected before and 3 months after the treatment. Three months after the treatment, the serum FSH levels and the BMD values did not significantly differ between the two groups. Urinary excretion of isoflavone was significantly higher in the group given isoflavone compared with that given placebo (p<0.03). Numbers of parabasal and intermediate types of cells were significantly decreased (58.2 +/- 12.4% to 25.0 +/- 10.7%; p<0.05) and increased (24.1 +/- 8.7% to 63.7 +/- 10.7%; p<0.05), respectively in the isoflavone group, but remained unchanged in the control group. Urinary pyridinoline excretion was significantly decreased (49.6% vs. before, p<0.01 by paired t-test) in the isoflavone group. The intake of 60 mg of isoflavone daily for 3 months produced maturational changes of vaginal epithelia without affecting serum FSH levels, and could possibly slow down bone turnover rates as judged by decreased urinary pyridinoline excretion.     

Use of joint fluid analysis for determining cartilage damage in osteonecrosis of the knee

OBJECTIVE: To assess the value of joint fluid analysis for determining cartilage degradation and prognosis in spontaneous osteonecrosis (ON) of the knee. METHODS: Synovial fluid was obtained from 30 knees with spontaneous ON (26 medial femoral condyles, 4 medial tibial plateaus) as well as from 50 knees with medial compartmental osteoarthritis (OA) as a control. Levels of chondroitin 6-sulfate (C6S), C4S, and hyaluronic acid were measured with high-performance liquid chromatography. The lesion size, appearance of the articular cartilage, and results of magnetic resonance imaging (MRI) were compared with the results of joint fluid analysis. RESULTS: The mean +/- SD level of C6S was 82.2 +/- 36.6 nmoles/ml in joint fluid from ON knees, which was significantly higher than the levels in knees with grade 2 (47.2 +/- 20.0 nmoles/ml) and grade 3 (55.8 +/- 29.2 nmoles/ml) OA. The C6S:C4S ratio was highest in lesions with mild articular changes and reflected the macroscopic alteration of cartilage overlying the ON lesion. The concentration of C6S in the 9 knees with lesions that covered > or = 40% of the condyle (99.0 +/- 32.9 nmoles/ml) was higher than that in the 17 knees with lesions that covered <40% of the condyle (67.2 +/- 31.7 nmoles/ml). Knees with bone marrow edema on MRI had a higher level of C6S than did knees with a fibrous-like appearance. CONCLUSION: While radiologic staging was useful for indicating the size of the ON lesion, it was less valuable for determining articular cartilage damage. Joint fluid analysis may provide more precise information about articular cartilage degradation in ON, and the findings may also be of prognostic significance.     

Psychometric evaluation of the Nurse Competence Scale: A cross‐sectional study

Measuring nurses' competence for practice is critical for quality and safety improvement in nursing care and patient outcomes . While the Nurse Competence Scale is a widely used international measure of the generic nursing competence of nurses in various career stages, it has not been used in Thailand. This study involved the forward–backward translation of the scale into Thai and evaluation of its psychometric properties with 571 nurses at one public and one private hospital in Chiang Mai, Thailand. Participants also completed a demographic form. The content validity analysis revealed that the item‐level content validity index (I‐CVI) was .90, and the scale‐level content validity index (S‐CVI/Average) was .91. The principal component analysis with varimax rotation demonstrated that the six factor structure accounted for 58.45% of the total variance. The Mann–Whitney U‐test showed a significant difference between low and high work experience groups for all six factors, providing further support for the scale's construct validity. The reliability analysis showed an acceptable level of Cronbach's alphas in six factors ranging from .82 to .88. In conclusion, the Thai version demonstrated promising psychometric properties, but requires further testing with nurses in different settings before use in practice.     

Nonclinical Safety Profile of Tolvaptan

Purpose

In the present study, the nonclinical safety profile of tolvaptan was evaluated.

Methods

A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs.

Results

In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems. In general toxicity studies, a single dose of tolvaptan up to 2,000 mg/kg was not lethal in rats and dogs. Tolvaptan did not cause any target organ toxicity in rats after treatment for 26 weeks or in dogs after treatment for 52 weeks at oral doses of up to 1,000 mg/kg/day. The toxicities observed in the present studies were generally attributable to the exaggerated pharmacological action of tolvaptan. In reproductive and developmental toxicity studies in rats, fertility was not affected. Suppressed viability or growth observed in the prenatal and postnatal progeny occurred at the maternally toxic dose of 1,000 mg/kg/day. In rabbits, tolvaptan showed teratogenicity at 1,000 mg/kg/day, a dose that was maternally toxic causing abortion. Tolvaptan was not genotoxic or carcinogenic, and did not induce phototoxicity, antigenicity or immunotoxicity.

Conclusion

Nonclinical toxicity that precludes the safe administration of tolvaptan to humans was not observed. However, appropriate cautions should be taken in women of childbearing potential.

     

Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid

It is difficult to overestimate the importance of nucleoside triphosphates in cellular chemistry: They are the building blocks for DNA and RNA and important sources of energy. Modifications of biologically important organic molecules with fluorine are of great interest to chemists and biologists because the size and electronegativity of the fluorine atom can be used to make defined structural alterations to biologically important molecules. Although the concept of nonhydrolyzable nucleotides has been around for some time, the progress in the area of modified triphosphates was limited by the lack of synthetic methods allowing to access bisCF₂-substituted nucleotide analogs—one of the most interesting classes of nonhydrolyzable nucleotides. These compounds have “correct” polarity and the smallest possible steric perturbation compared to natural nucleotides. No other known nucleotides have these advantages, making bisCF₂-substituted analogs unique. Herein, we report a concise route for the preparation of hitherto unknown highly acidic and polybasic bis(difluoromethylene)triphosphoric acid 1 using a phosphorous(III)/phosphorous(V) interconversion approach. The analog 1 compared to triphosphoric acid is enzymatically nonhydrolyzable due to substitution of two bridging oxygen atoms with CF₂ groups, maintaining minimal perturbations in steric bulkiness and overall polarity of the triphosphate polyanion. The fluorinated triphosphoric acid 1 was used for the preparation of the corresponding fluorinated deoxynucleotides (dNTPs). One of these dNTP analogs (dT) was demonstrated to fit into DNA polymerase beta (DNA pol β) binding pocket by obtaining a 2.5 Å resolution crystal structure of a ternary complex with the enzyme. Unexpected dominating effect of triphosphate/Mg²⁺ interaction over Watson–Crick hydrogen bonding was found and discussed.     

Multiple lesions of adenocarcinoma with extensive dysplasia in long-segment Barrett’s esophagus treated with thoracoscopic surgery: a case report

In contrast to Western countries, in Japan esophageal adenocarcinoma and classic Barrett’s esophagus (long-segment Barrett’s esophagus) have been considered extremely uncommon. Although alternative therapeutic techniques such as endoscopic ablation, photodynamic therapy, and endoscopic mucosal resection have been improved, esophagectomy remains the gold standard treatment for high-grade dysplasia and/or early adenocarcinoma of the esophagus. Recently, minimally invasive operational procedures have been developed as a safe and feasible alternative technique to traditional open techniques, which has enabled us to expand the indication. In this report, we describe a Japanese case of multiple lesions of adenocarcinoma in long-segment Barrett’s esophagus, resected by thoracoscopic surgery. Our experience indicates that thoracoscopic esophagectomy could be one of the treatment options for multiple malignant or extensive precancerous lesions in long-segment Barrett’s esophagus.     

Establishment of a long-surviving murine model of myocardial infarction: Qualitative and quantitative conventional microscopic findings during pathological evolution

Summary Ongoing basic molecular analyses are being performed in mice, and a simple long-surviving murine model of myocardial infarction (MI) would be very useful in this regard. Although a few studies have included MI in mice by coronary artery ligation, the induction involves a complex technique and has a relatively high mortality rate. In addition, the identification of the basic pathological sequence is essential to the interpretation of experimental results. We developed a simple technique for the induction of MI in mice and examined qualitative and quantitative conventional microscopic findings during the pathological evolution over a 28-day observation period. Male BALB/c mice weighing approximately 25 – 30 g were anesthetized and then ventilated with a positive pressure ventilator. The heart was exposed by thoracotomy. Left coronary artery occlusion was performed by thermocoagulation using a thermocoagulation knife at the level of the tip of the left atrium. After establishing this surgical method, we used it to induce MI in 71 mice. The operative and postoperative mortality rates of this model were 5.6 % (4/71) and 12.6 % (9/71), respectively. In 3 (5.2%) of the 58 surviving mice, the area of infarct was not sufficient. The infarct area in the remaining 55 mice was 40 ± 9 % of the entire perimeter of the left ventricle. Conventional microscopic examinations with hematoxylin-eosin and Masson-trichrome staining disclosed that all of the characteristic histopathological features of MI occurred 1 – 2 days earlier than those in rats. Our surgical technique provides a sufficient infarct area, with an acceptable mortality rate. The present study clarified the histopathological sequence in this long surviving murine MI model. Received: 2 July 1998, Returned for revision: 19 August 1998, Revision received: 7 October 1998, Accepted: 7 October 1998