bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure
Authors: Weber Christopher R. , Piacentino Valentino , Houser Steven R. , Bers Donald M.
Published: October 2003

Background—

Sarcolemmal Na/Ca exchange (NCX) regulates cardiac Ca and contractility. NCX function during the cardiac cycle is determined by intracellular [Ca] and [Na] ([Ca]
i
, and [Na]
i
) and membrane potential (E
m
), which all change in human heart failure (HF). Therefore, changes in NCX function may contribute to abnormal Ca regulation in human HF.

Methods and Results—

We assessed the cellular bases of differences in NCX function in ventricular myocytes from failing (F) and nonfailing (NF) human hearts. Allosteric activation of NCX by [Ca]
i
was comparable in F and NF myocytes (
K
1/2
=150±31 nmol/L, n=7). The steady-state relation between [Ca]
i
and NCX current (
I
NCX
) was used to infer the local submembrane [Ca]
i
([Ca]
sm
) that is sensed by NCX dynamically during the action potential (AP) and Ca transient (37°C). This involved “tail”
I
NCX
measurement during abrupt repolarization of APs and Ca transients, where peak inward
I
NCX
indicates [Ca]
sm
. This allows inference of the direction of Ca transport by the NCX during the AP. In NF myocytes, NCX extrudes Ca for most of the AP. Three factors shift the direction of NCX-mediated Ca transport (to favor more Ca influx) in F versus NF myocytes, as follows: (1) reduced [Ca]
sm
, (2) prolonged AP duration, and (3) elevated [Na]
i
.

Conclusions—

These results show that Ca entry through NCX may limit systolic dysfunction due to reduced sarcoplasmic reticulum Ca stores in HF but could contribute to slow decay of the [Ca]
i
transient and to diastolic dysfunction.
Predictors of Improved Renal Function After Percutaneous Stent-Supported Angioplasty of Severe Atherosclerotic Ostial Renal Artery Stenosis
Authors: Zeller Thomas , Frank Ulrich , Müller Christian , Bürgelin Karlheinz , Sinn Lutz , Bestehorn Hans-Peter , Cook-Bruns Nancy , Neumann Franz-Josef
Published: October 2003

Background—

Percutaneous stent-supported angioplasty is a treatment option for atherosclerotic ostial renal artery stenosis. Improvement of renal function by such intervention, however, is controversial and thought to be limited to specific subsets, such as nondiabetic patients and bilateral stenoses. In this prospective study, we investigated predictors for improvement of renal function and blood pressure after renal artery stent placement.

Methods and Results—

The study included 215 consecutive patients with ostial renal artery stenosis of ≥70% diameter stenosis undergoing stent-supported angioplasty. The primary end point was decrease in serum creatinine concentration at 1 year; the secondary end point, decrease in average mean arterial blood pressure assessed by 24-hour monitoring. One-year follow-up was complete in 191 surviving patients. In 52% (99/191) of the patients, serum creatinine concentration decreased during 1-year follow-up. Median serum creatinine concentration dropped significantly from 1.21 mg/dL (quartiles: 0.92, 1.60 mg/dL) at baseline to 1.10 mg/dL (quartiles: 0.88, 1.50 mg/dL) at 1 year (
P
=0.047). On average, mean arterial blood pressure decreased significantly, from 102±12 mm Hg (mean±SD) at baseline to 92±10 mm Hg at 1 year (
P
<0.001). Significant independent predictors of improved renal function were baseline serum creatinine (odds ratio [95% CI], 2.58 [1.35 to 4.94],
P
=0.004) and left ventricular function (OR 1.51 [1.04 to 2.21],
P
=0.032). Female sex, high baseline mean blood pressure, and normal renal parenchymal thickness were independent predictors for decreased mean blood pressure.

Conclusions—

Stent-supported angioplasty for severe ostial renal artery stenosis improves renal function and blood pressure in a broader spectrum of patients than previously thought.
Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI)
Authors: Britten M.B. , Abolmaali N.D. , Assmus B. , Lehmann R. , Honold J. , Schmitt J. , Vogl T.J. , Martin H. , Schächinger V. , Dimmeler S. , Zeiher A.M.
Published: October 2003

Background—

Experimental and initial clinical studies suggest that transplantation of circulating blood– (CPC) or bone marrow–derived (BMC) progenitor cells may beneficially affect postinfarction remodeling processes after acute myocardial infarction (AMI). To relate functional characteristics of the infused cells to quantitative measures of outcome at 4-month follow-up, we performed serial contrast-enhanced MRI and assessed the migratory capacity of the transplanted progenitor cells immediately before intracoronary infusion.

Methods and Results—

In 28 patients with reperfused AMI receiving either BMCs or CPCs into the infarct artery 4.7±1.7 days after AMI, serial contrast-enhanced MRI performed initially and after 4 months revealed a significant increase in global ejection fraction (from 44±10% to 49±10%;
P
=0.003), a decrease in end-systolic volume (from 69±26 to 60±28 mL;
P
=0.003), and unchanged end-diastolic volumes (122±34 versus 117±37 mL;
P
=NS). Infarct size, measured as late enhancement (LE) volume, decreased significantly, from 46±32 to 37±28 mL (
P
<0.05). There was a significant correlation between the reduction in LE volume and global ejection fraction improvement. The migratory capacity of transplanted cells as assessed ex vivo toward a gradient of vascular endothelial growth factor for CPCs and stromal cell derived factor-1 for BMCs was closely correlated with the reduction of LE volume. By multivariate analysis, migratory capacity remained the most important independent predictor of infarct remodeling.

Conclusions—

Analysis of serial contrast-enhanced MRI suggests that intracoronary infusion of adult progenitor cells in patients with AMI beneficially affects postinfarction remodeling processes. The migratory capacity of the infused cells is a major determinant of infarct remodeling, disclosing a causal effect of progenitor cell therapy on regeneration enhancement.
Sirolimus-Eluting Stent Implantation in ST-Elevation Acute Myocardial Infarction
Authors: Saia Francesco , Lemos Pedro A. , Lee Chi-Hang , Arampatzis Chourmouzios A. , Hoye Angela , Degertekin Muzaffer , Tanabe Kengo , Sianos Georgios , Smits Pieter C. , McFadden Eugene , Hofma Sjoerd H. , van der Giessen Willem J. , de Feyter Pim J. , van Domburg Ron T. , Serruys Patrick W.
Published: October 2003

Background—

Sirolimus-eluting stents (SES) have recently been proven to reduce restenosis and reintervention compared with bare stents. Safety and effectiveness of SES in acute myocardial infarction remain unknown.

Methods and Results—

Since April 16, 2002, a policy of routine SES implantation has been instituted in our hospital, with no clinical or anatomic restrictions, as part of the RESEARCH (Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital) registry. During 6 months of enrollment, 96 patients with ST-elevation acute myocardial infarction underwent percutaneous recanalization and SES implantation; these patients comprise the study population. The incidence of major adverse cardiac events (death, nonfatal myocardial infarction, reintervention) was evaluated. Six-month angiographic follow-up was scheduled per protocol. At baseline, diabetes mellitus was present in 12.5% and multivessel disease in 46.9%. Primary angioplasty was performed in 89 patients (92.7%). Infarct location was anterior in 41 (42.7%) of the cases, and 12 patients (12.5%) had cardiogenic shock. Postprocedural TIMI-3 flow was achieved in 93.3% of the cases. In-hospital mortality was 6.2%. One patient (1.1%) had reinfarction and target lesion reintervention the first day as a result of distal dissection and acute vessel occlusion. During follow-up (mean follow-up of 218±75 days), 1 patient died (1.1%), no patient had recurrent myocardial infarction, and there were no additional reinterventions. No early or late stent thromboses were documented. At angiographic follow-up (70%), late loss was −0.04±0.25, and no patient presented angiographic restenosis.

Conclusions—

In this study, sirolimus-eluting stent implantation for patients with ST-elevation acute myocardial infarction was safe without documented angiographic restenosis at 6 months.
Role of Endothelium-Derived Hyperpolarizing Factor in Human Forearm Circulation
Authors: Inokuchi Kosuke , Hirooka Yoshitaka , Shimokawa Hiroaki , Sakai Koji , Kishi Takuya , Ito Koji , Kimura Yoshikuni , Takeshita Akira
Published: October 2003

Endothelium-derived hyperpolarizing factor (EDHF) contributes to endothelium-dependent relaxation of isolated arteries, but it is not known whether this also occurs in the case of humans in vivo. The present study examined the role of EDHF in human forearm circulation. Forearm blood flow (FBF) was measured by strain-gauge plethysmography in 31 healthy, normal subjects (mean±SE age, 23±2 years; 24 men and 7 women). After oral administration of aspirin (486 mg), we infused
N
G
-monomethyl-
l
-arginine (8 μmol/min for 5 minutes) into the brachial artery. We used tetraethylammonium chloride (TEA, 1 mg/min for 20 minutes), a K
Ca
channel blocker, as an EDHF inhibitor, and nicorandil as a direct K
+
channel opener. TEA significantly reduced FBF (
P
<0.05) but did not change systemic arterial blood pressure. Furthermore, TEA significantly inhibited the FBF increase in response to substance P (0.8, 1.6, 3.2, and 6.4 ng/min, n=8) and bradykinin (12.5, 25, 50, and 100 ng/min, n=8; both
P
<0.001), whereas it did not affect the FBF increase in response to acetylcholine (4, 8, 16, and 32 μg/min, n=8), sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 μg/min, n=8), or nicorandil (0.128, 0.256, 0.512, and 1.024 mg/min, n=8). These results suggest that EDHF contributes substantially to basal forearm vascular resistance, as well as to forearm vasodilatation evoked by substance P and bradykinin in humans in vivo.
Mechanisms Mediating the Vasoactive Effects of the B
1
Receptors of Bradykinin
Authors: Duka Irena , Duka Arvi , Kintsurashvili Ekaterina , Johns Conrado , Gavras Irene , Gavras Haralambos
Published: October 2003

Bradykinin normally exerts its vasodilatory effect via the B
2
receptor (B
2
R), but in this receptor’s absence, the B
1
receptor becomes expressed and activated. To explore the mechanism of B
1
R-mediated vasodilation, 8 groups of B
2
R gene–knockout mice received a 2-week infusion of a B
1
R antagonist (300 μg · kg
−1
· d
−1
) or vehicle (groups 1 and 2), B
1
R antagonist or vehicle plus NO inhibition with
Nω
-nitro-
l
-arginine methyl ester (groups 3 and 4), B
1
R antagonist or vehicle plus cyclooxygenase inhibition with indomethacin (groups 5 and 6), or B
1
R antagonist or vehicle plus blockade of vasoconstricting prostaglandin (PG) H
2
and thromboxane A
2
(TxA
2
) with SQ29548 (groups 7 and 8). The B
1
R antagonist produced significant (
P
<0.05) blood pressure increases of 17.7±3.1 mm Hg in group 1 and 10.4±3 mm Hg in group 3, whereas their vehicle-treated respective control groups 2 and 4 had no significant blood pressure changes. Indomethacin abolished the capacity of the B
1
R antagonist to raise blood pressure, as did blockade of the receptors of PGH
2
and TxA
2
. Injection with the B
1
R agonist produced a hypotensive response (12±1.3 mm Hg), which was further accentuated by TxA
2
blockade (21.7±4.1 mm Hg). Analysis of B
1
R gene expression by reverse transcription–polymerase chain reaction (PCR) in cardiac and renal tissues revealed marked expression at baseline, with further upregulation by 1.5- to 2-fold after various manipulations. Expression of the TxA
2
receptor gene in renal tissue by quantitative real-time PCR was significantly lower in mice treated with the B
1
R antagonist, consistent with increased levels of agonist for this receptor. The data confirm that the B
1
R becomes markedly expressed in the absence of B
2
R and suggest that it contributes to vasodilation by inhibiting a vasoconstricting product of the arachidonic acid cascade acting via the PGH
2
/TxA
2
receptor.
G-Protein β
3
-Subunit Gene 825T Allele and Hypertension
Authors: Sartori Michelangelo , Semplicini Andrea , Siffert Winfried , Mormino Paolo , Mazzer Alberto , Pegoraro Fabrizio , Mos Lucio , Winnicki Mikolaj , Palatini Paolo
Published: October 2003

The 825T allele of the
GNB3
gene has been associated with essential hypertension and obesity in cross-sectional studies. We have therefore planned a longitudinal cohort study to assess whether the
GNB3
825T allele is predictive of blood pressure increase in young subjects with grade I hypertension. We genotyped at the
GNB3
825 locus 461 participants of the Hypertension and Ambulatory Recording Venetia Study (HARVEST) study (age, 18 to 45 years) at low cardiovascular risk, according to 1999 ISH/WHO criteria. The study end point was eligibility for antihypertensive medication, that is, progression to grade II hypertension during the first year of observation or office systolic blood pressure ≥150 mm Hg and/or office diastolic blood pressure ≥95 mm Hg in two later consecutive visits during follow-up. At baseline, there was no statistically significant difference among genotypes with respect to body mass index, blood pressure, and heart rate. During follow-up (mean, 4.7 years), 113 (51.1%) patients with CC genotype and 145 (60.4%) patients with TT/TC genotype reached the end point. According to survival analysis, the patients carrying the 825T allele had an increased risk of reaching the blood pressure end point (CI, 1.108 to 1.843;
P
=0.006). In young patients with grade I hypertension, the 825T allele is associated with increased risk of progression to more severe hypertension requiring antihypertensive therapy. The
GNB3
825T allele may be considered a genetic marker of predisposition for hypertension.
Working Procedures Before Panels, the Appellate Body and other Adjudicating Bodies of the WTO
Authors:   Monnier
Published: October 2003

No Abstract
Procedural Developments in International Criminal Courts
Authors:   Wierda
Published: October 2003

No Abstract
Towards an International Criminal Procedure by Christoph J.M. Safferling (Book Review)
Authors:   Cholmeley,   Claypoole
Published: October 2003

No Abstract
Egotism and Delinquent Behavior
Authors: Costello Barbara J. , Dunaway R. Gregory
Published: October 2003

A recent work by Baumeister, Smart, and Boden suggested that “threatened egotism” is an important cause of violent behavior. Challenging the view that low self-esteem causes violence, Baumeister et al. held that those with inflated levels of self-esteem are likely to react violently when faced with ego threats. This article presents a preliminary test of the threatened egotism hypothesis with a sample of junior high and high school students in a small Southern city. The results show that egotism is positively associated with violent and nonviolent delinquency and that this relationship holds when a number of important predictors of delinquency are controlled, including social control and self-control. These results provide some support for the threatened egotism hypothesis and suggest that further research in this area is warranted.
Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial
Authors: Kemmeren Jeanet M. , Algra Ale , Meijers Joost C. M. , Tans Guido , Bouma Bonno N. , Curvers Joyce , Rosing Jan , Grobbee Diederick E.
Published: October 2003

A plausible mechanism to explain thrombotic risk differences associated with the use of second- and third-generation oral contraceptives (OCs), particularly in carriers of factor VLeiden, is still lacking. In a double-blind trial, 51 women without and 35 women with factor VLeiden were randomized to either a second- (30 μg ethinylestradiol/150 μg levonorgestrel) or third- (30 μg ethinylestradiol/150 μg desogestrel) generation OC. After 2 cycles of use and a wash-out of 2 cycles, the participants continued with the corresponding progestagen-only preparation. Hemostatic variables that probe the activity of the anticoagulant protein C system were determined. Compared with levonorgestrel, desogestrel-containing OCs significantly decreased protein S and increased activated protein C (APC) resistance in both groups. OCs with desogestrel had the most pronounced effects in carriers of factor VLeiden. Progestagen-only preparations caused changes of anticoagulant parameters opposite to those of combined OCs, which in a number of cases were more pronounced with levonorgestrel. Our data show that progestagens in combined OCs counteract the thrombotic effect of the estrogen component. The higher thrombotic risk associated with third-generation OCs compared with second-generation OCs may be explained by the fact that desogestrel appeared less antithrombotic than levonorgestrel, especially in women with factor VLeiden. (Blood. 2004;103:927-933)
ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein
Authors: Chevallier Nathalie , Corcoran Connie M. , Lennon Christine , Hyjek Elizabeth , Chadburn Amy , Bardwell Vivian J. , Licht Jonathan D. , Melnick Ari
Published: October 2003

The multiplicity of transcription factors involved in hematologic malignancies suggests a complicated scenario in which many different molecular mechanisms lead to malignant transformation. We hypothesized that some of these proteins might physically and functionally interact and thus mechanistically link different diseases. The ETO protein of t(8;21) acute myeloid leukemia (AML) is an excellent candidate as a common factor because it is normally expressed in human hematopoietic cells, it binds to histone deacetylases (HDACs), and it interacts with the PLZF protein of t(11;17) acute promyelocytic leukemia. To determine whether ETO functionally links a broader range of disease entities, we asked whether ETO forms a complex with the Bcl-6 oncoprotein of B-cell lymphomas. We found that ETO and Bcl-6 are coexpressed in normal and malignant lymphoid tissue, where they interact and colocalize in nuclear speckles. ETO binds to the fourth zinc finger of Bcl-6, enhances Bcl-6 repression of artificial and endogenous genes in an HDAC-dependent manner, and forms a complex with Bcl-6 on the promoters of its endogenous target genes in B-cell lymphoma cells. Therefore, ETO is a bona fide corepressor that links the transcriptional pathogenesis of acute leukemias and B-cell lymphomas and offers a compelling target for transcriptional therapy of hematologic malignancies.
Transfer of allogeneic CD62L– memory T cells without graft-versus-host disease
Authors: Chen Benny J. , Cui Xiuyu , Sempowski Gregory D. , Liu Congxiao , Chao Nelson J.
Published: October 2003

The major challenge in allogeneic hematopoietic cell transplantation is how to transfer allogeneic T-cell immunity without causing graft-versus-host disease (GVHD). Here we report a novel strategy to selectively prevent GVHD by depleting CD62L+ T cells (naive and a subset of memory T cells). In unprimed mice, CD62L– T cells (a subset of memory T cells) failed to proliferate in response to alloantigens (which the mice have never previously encountered) and were unable to induce GVHD in allogeneic hosts. CD62L– T cells contributed to T-cell reconstitution by peripheral expansion as well as by promoting T-cell regeneration from bone marrow stem/progenitor cells. CD62L– T cells from the animals previously primed with a tumor cell line (BCL1) were able to inhibit the tumor growth in vivo but were unable to induce GVHD in the third-party recipients. This novel technology may allow transfer of allogeneic recall antitumor and antimicrobial immunity without causing GVHD.
Physiologic variations in granulocytic surface antigen expression: impact of age, gender, pregnancy, race, and stress
Authors: Elghetany M Tarek , Lacombe Francis
Published: October 2003

There is a growing interest in the use of granulocytic surface markers for the diagnosis of some inherited and acquired disorders, such as Shwachman-Diamond syndrome and myelodysplastic syndromes. Understanding the impact of physiologic factors, such as age, gender, pregnancy, race, and stress on granulocytic surface markers is essential for appropriate interpretation of results. Some surface markers show marked variations at the very early and the very late stages in life. Fetal granulocytes tend to have a lower expression of CD11b, CD11c, CD18, and CD32. Term neonatal granulocytes are frequently associated with a lower expression of CD10, CD11b, CD13, CD33, and CD62L and a higher expression of CD55 and CD64. Elderly individuals have shown a higher expression of CD64. Pregnancy is associated with temporary changes in granulocytic surface markers, such as a lower expression of CD16 and a higher CD64, partially mimicking an inflammatory response. Stress also has an impact on some surface markers, particularly adhesion molecules, such as CD62L and CD54. These factor need to be taken in consideration for the optimal interpretation of granulocytic surface marker studies.
In Vitro and in Vivo Regulation of Antioxidant Response Element-Dependent Gene Expression by Estrogens
Authors: Ansell P. J. , Espinosa-Nicholas C. , Curran E. M. , Judy B. M. , Philips B. J. , Hannink M. , Lubahn D. B.
Published: October 2003

Understanding estrogen’s regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17β-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nm) of 17β-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17β-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17β-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.
Protection by the Chinese prescription Wen-Pi-Tang against renal tubular LLC-PK1 cell damage induced by 3-morpholinosydnonimine
Authors: Yokozawa Takako , Rhyu Dong Young , Cho Eun Ju
Published: October 2003

We investigated the effects of Wen-Pi-Tang extract on the protective mechanisms of renal tubular LLC-PK1 cells, as renal tubular cells are the most vulnerable renal tissue to oxidative stress. Exposure to 800 μM 3-morpholinosydnonimine (SIN-1) resulted in a marked increase in cellular peroxynitrite (ONOO−), which converted nonfluorescent dihydrorhodamine 123 to fluorescent rhodamine 123, a detectable probe for the long-lived ONOO−. In addition, it resulted in apoptotic cell death, assessed by a DNA fragmentation assay. However, treatment with Wen-Pi-Tang extract, at concentrations of 50 and 100 μg mL−1 together with SIN-1 protected renal tubular cells against ONOO− through scavenging ONOO− and inhibiting apoptotic cell death in a dose-dependent manner. Moreover, treatment with Wen-Pi-Tang extract both before and after exposure to SIN-1 was also protective: it reduced cellular ONOO− levels, increased cell viability and decreased the DNA fragmentation rate. These results suggest that Wen-Pi-Tang would have protective activity against ONOO−-induced renal tubular injury through the inhibition of ONOO− production and apoptotic cell death by both preventing and treating renal injury. Furthermore, morphological characteristics of apoptosis were observed in SIN-1 treated tubular cells, while the addition of Wen-Pi-Tang extract with SIN-1 attenuated these morphological changes. ONOO− generated by SIN-1 also disturbed the cell cycle by decreasing the cellular G2/M phase ratio, while Wen-Pi-Tang extract regulated the cell cycle by G2/M phase arrest.
Protective effect of Asteracantha longifolia extract in mouse liver injury induced by carbon tetrachloride and paracetamol
Authors: Hewawasam R P , Jayatilaka K A P W , Pathirana C , Mudduwa L K B
Published: October 2003

This study was conducted to investigate the protective effect of Asteracantha longifolia Linn (Acanthaceae) plant extract on carbon tetrachloride (CCl4)- and paracetamol-induced acute hepatotoxicity in mice. Hepatotoxicity was induced by the administration of a single intraperitoneal dose of CCl4 (0.5 mL kg−1 CCl4 in olive oil) in one model and in the other by administration of paracetamol1 (300 mg kg−1 in saline) orally, after a 16-h fast. An aqueous extract of the whole plant (0.9 g kg−1) was used on a pre- and post-treatment basis. Asteracantha reduced the alanine aminotransferase (ALT) level by 69.32% (P < 0.001) and increased the liver reduced glutathione level by 64.65% (P < 0.001) in the pre-treated group, 4 days after the administration of CCl4. A similar pattern was observed in the pre-treated group 4 h after the administration of paracetamol with a reduction in serum levels of ALT, aspartate aminotransferase and alkaline phosphatase enzymes by 65.04, 55.79 and 45.75% respectively (P < 0.001). Plant extract also increased the glutathione concentration of the liver significantly (P < 0.001). Histopathological studies also provided supportive evidence for results from the biochemical analysis with marked improvement in liver architecture being observed in the Asteracantha-treated groups. Pre-treatment showed better results than post-treatment in both hepatotoxic models. Overall results indicate that the aqueous extract of Asteracantha longifolia possesses hepatoprotective effects on CCl4- and paracetamol-induced hepatotoxicity in mice.
Sho-saiko-to and Saiko-keisi-to, the traditional Chinese and Japanese herbal medicines, altered hepatic drug-metabolizing enzymes in mice and rats when administered orally for a long time
Authors: Nose Mitsuhiko , Tamura Masayo , Ryu Nobukazu , Mizukami Hajime , Ogihara Yukio
Published: October 2003

As the consumption of herbal remedies has increased, the opportunity that such herbal medicines are co-administered with other drugs has also risen gradually and we are, therefore, very much concerned about herb–drug interactions. We examined the effects of pre-administration of Kampo medicines (Sho-saiko-to, Saiko-keishi-to, Shigyaku-san and Dai-saiko-to) on the pentobarbital-induced sleeping time in mice and rats, to clarify the possibility that they could affect the drug-metabolizing enzymes. The administration of Sho-saiko-to and Saiko-keishi-to for 4 weeks significantly shortened the pentobarbital-induced sleeping time in mice and the administration of Sho-saiko-to for 2 weeks significantly reduced the sleeping time in rats. Furthermore, we tried to identify the molecular species of rat cytochrome P450s (CYPs) affected by Sho-saiko-to and Saiko-keishi-to by competitive RT-PCR. The oral administration of Sho-saiko-to for 2 weeks up-regulated the mRNA expression of CYP2B, CYP3A1, CYP2E1 and CYP4A1 in rats. The treatment with Saiko-keishi-to for 2 weeks also up-regulated the mRNA expression of CYP2B, CYP3A1 and CYP4A1. Sho-saiko-to and Saiko-keishi-to may potentially influence the drug-metabolizing enzymes in man, and would thus require much attention when used in the clinical situation.
Accessibility of solid core tablet for dissolution in an asymmetric triple-layer matrix system
Authors: Yang Libo , Fassihi Reza
Published: October 2003

The importance of glassy matrix surface area to ensure constant drug release and the effect of barrier layer thickness on the duration of linear release in an asymmetric triple-layer tablet with zero-order release kinetics were investigated. Poly(ethylene oxide) of different molecular weights and hydroxypropylmethylcellulose K4M were the major polymeric constituents, and verapamil hydrochloride was used as a drug model. The contribution of diffusion and polymer relaxation towards drug release was evaluated based on drug release data using a non-linear regression analysis algorithm. The results demonstrated that application of barrier layers to the central core tablet enables polymer relaxation to be the predominant mechanism in controlling drug release and leads to the often desired zero-order release kinetics. The duration of linear release from the asymmetric triple-layer tablet depends on the barrier layer thickness and composition. It was further indicated that the magnitude of diffusion and polymer relaxation in controlling drug release is affected by the accessibility of the drug core tablet for dissolution, as well as the inherent swelling and erosion characteristics of the release rate-controlling polymer.
Intratumoural chemotherapy with 5-fluorouracil for palliation of bronchial cancer in patients with severe airway obstruction
Authors: Çelikoǧlu Firuz , Çelikoǧlu Seyhan I
Published: October 2003

Patients with tracheal or major airway obstruction owing to inoperable carcinomas are at risk of developing respiratory failure or postobstructive pneumonia. In such cases, there is an urgency to restore the airway. Bronchoscopic interventional procedures for palliation of malignant airway obstruction are becoming more common in clinical practice. However, as current interventional methods may be unavailable or are contraindicated, we have investigated the use of direct intratumoural injection with 5-fluorouracil for tumour regression to open the airway. In this study, 65 patients who presented with greater than 50% obstruction of at least one major airway were treated with 5-fluorouracil injection directly into the endobronchial tumour or area of infiltrated bronchial mucosa through a flexible fiber-optic bronchoscope. The pretreatment luminal opening for this cohort of 65 patients ranged from 0% (totally obstructed) to 40%, with an overall mean luminal opening of 22% (78% occlusion). There was a positive response to intratumoural injection in 56 of 65 patients, and a large reduction in the size of tumours by endoscopic evaluation in the majority of cases. Overall, the mean pretreatment luminal opening of 22.0% was significantly improved to a mean post-treatment luminal opening of 58.5%, an increase in the opening of the airways of 36.5%. The increase in the diameter of the airway lumen was more than 50% for 34 of 65 patients, and 23 showed a 25–50% improvement. The results were of obvious immediate clinical benefit. Statistical analysis of all patient data by a Wilcoxon matched-pairs/sign-ranked test confirmed the significant benefit achieved (P < 0.001). The therapy was well tolerated, with no systemic side-effects or any serious complications. The results of this study suggest that in patients with life-threatening airway obstruction, intratumoural injection of anticancer drugs should be regarded as an important new therapeutic approach and an integral part of interventional bronchoscopic management. This study further encourages more general consideration of intratumoural drug injection as a minimally invasive therapeutic method for the treatment of lung cancer and various inoperable cancers.
The effects of the phytoestrogenic isoflavone genistein on the hepatic disposition of preformed and hepatically generated gemfibrozil 1-O-acyl glucuronide in the isolated perfused rat liver
Authors: Lucas Anthony N , Brogan Léonie R , Nation Roger L , Milne Robert W , Evans Allan M , Shackleford David M
Published: October 2003

Foods and complementary medicines contain phytoestrogenic isoflavones such as genistein, which undergo hepatic glucuronidation and excretion into bile and can potentially interfere with the hepatic elimination of other compounds. To investigate this potential, livers from Sprague-Dawley rats were perfused in single-pass mode with preformed gemfibrozil 1-O-acyl glucuronide (GG) (1 μM, n = 12) for 60 min followed by a 30-min washout phase, or with gemfibrozil (1 μM n = 10) for 120 min. Half of each group of livers were co-perfused with genistein (10 μM) throughout the experiment. Perfusate and bile were analyzed for GG and gemfibrozil by HPLC. Co-perfusion with genistein significantly (P < 0.05) decreased the biliary extraction ratio of preformed GG from a mean of 0.82 to 0.65 and the first-order rate constant for transport of GG into bile from 0.054 + 0.010 to 0.032 + 0.008 min−1, but increased the first-order rate constant for sinusoidal efflux of GG from 0.128 + 0.023 to 0.227 + 0.078 min−1. Co-perfusion with genistein also significantly decreased the biliary extraction ratio of hepatically generated GG from 0.95 + 0.01 to 0.83 + 0.05. The findings confirm that genistein increases the potential for hepatic and systemic exposure to hepatically generated glucuronides, which may be important for patients on conventional drugs who consume isoflavones.
AXR3andSHY2interact to regulate root hair development
Authors: Knox Kirsten , Grierson Claire S. , Leyser Ottoline
Published: October 2003

Signal transduction of the plant hormone auxin centres on the regulation of the abundance of members of the Aux/IAA family of transcriptional regulators,of which there are 29 in Arabidopsis. Auxin can influence Aux/IAA abundance by promoting the transcription of Aux/IAA genes and by reducing the half-life of Aux/IAA proteins. Stabilising mutations, which render Aux/IAA proteins resistant to auxin-mediated degradation, confer a wide range of phenotypes consistent with disruptions in auxin response. Interestingly, similar mutations in different family members can confer opposite phenotypic effects. To understand the molecular basis for this functional specificity in the Aux/IAA family, we have studied a pair of Aux/IAAs, which have contrasting roles in root hair development. We have found that stabilising mutations in AXR3/IAA17 blocks root hair initiation and elongation, whereas similar mutations in SHY2/IAA3 result in early initiation of root hair development and prolonged hair elongation,giving longer root hairs. The phenotypes resulting from double mutant combinations, the transient induction of expression of the proteins, and the pattern of transcription of the cognate genes suggest that root hair initiation is controlled by the relative abundance of SHY2 and AXR3 in a cell. These results suggest a general model for auxin signalling in which the modulation of the relative abundance of different Aux/IAA proteins can determine which down-stream responses are induced.
C. elegansankyrin repeat protein VAB-19 is a component of epidermal attachment structures and is essential for epidermal morphogenesis
Authors: Ding Mei , Goncharov Alexandr , Jin Yishi , Chisholm Andrew D.
Published: October 2003

Elongation of the epidermis of the nematode Caenorhabditis elegansinvolves both actomyosin-mediated changes in lateral epidermal cell shape and body muscle attachment to dorsal and ventral epidermal cells via intermediate-filament/hemidesmosome structures. vab-19 mutants are defective in epidermal elongation and muscle attachment to the epidermis. VAB-19 is a member of a conserved family of ankyrin repeat-containing proteins that includes the human tumor suppressor Kank. In epidermal cells,VAB-19::GFP localizes with components of epidermal attachment structures. In vab-19 mutants, epidermal attachment structures form normally but do not remain localized to muscle-adjacent regions of the epidermis. VAB-19 localization requires function of the transmembrane attachment structure component Myotactin. vab-19 mutants also display aberrant actin organization in the epidermis. Loss of function in the spectrin SMA-1 partly bypasses the requirement for VAB-19 in elongation, suggesting that VAB-19 and SMA-1/spectrin might play antagonistic roles in regulation of the actin cytoskeleton.
Caspase-independent cell engulfment mirrors cell death pattern inDrosophilaembryos
Authors: Mergliano Jaime , Minden Jonathan S.
Published: October 2003

Programmed cell death plays an essential role during Drosophilaembryonic development. A stereotypic series of cellular changes occur during apoptosis, most of which are initiated by a caspase cascade that is triggered by a trio of proteins, RPR, HID and GRIM. The final step in apoptosis is engulfment of the cell corpse. To monitor cell engulfment in vivo, we developed a fluorogenic β-galactosidase substrate that is cleaved by an endogenous, lysosomal β-galactosidase activity. The pattern of cell engulfment in wild-type embryos correlated well with the known pattern of apoptosis. Surprisingly, the pattern of cell engulfment persisted in apoptosis-deficient embryos. We provide evidence for a caspase-independent engulfment process that affects the majority of cells expected to die in developing Drosophila embryos.
Multimodal tangential migration of neocortical GABAergic neurons independent of GPI-anchored proteins
Authors: Tanaka Daisuke , Nakaya Yohei , Yanagawa Yuchio , Obata Kunihiko , Murakami Fujio
Published: October 2003

Neuronal migration is crucial for the construction of neuronal architecture such as layers and nuclei. Most inhibitory interneurons in the neocortex derive from the basal forebrain and migrate tangentially; however, little is known about the mode of migration of these neurons in the cortex. We used glutamate decarboxylase (Gad)67-green fluorescent protein (GFP) knock-in embryonic mice with expression of GFP in gamma-aminobutyric acid (GABA)-ergic neurons and performed time-lapse analysis. In coronal slices, many GFP-positive neurons in the lower intermediate zone (IZ) and subventricular zone (SVZ) showed robust tangential migration from lateral to medial cortex,while others showed radial and non-radial migration mostly towards the pial surface. In flat-mount preparations, GFP-positive neurons of the marginal zone(MZ) showed multidirectional tangential migration. Some of these neurons descended toward the cortical plate (CP). Intracortical migration of these neurons was largely unaffected by a treatment that cleaves glycosylphosphatidylinositol (GPI) anchors. These findings suggest that tangential migration of cortical interneurons from lateral to medial cortex predominantly occurs in the IZ/SVZ and raise the possibility that a part of the pial surface-directed neurons in the IZ/SVZ reach the MZ, whereby they spread into the whole area of the cortex. At least a part of these neurons may descend toward the CP. Our results also suggest that intracortical migration of GABAergic neurons occurs independent of GPI-anchored proteins.
Embryonic handedness choice inC. elegansinvolves the Gαprotein GPA-16
Authors: Bergmann Dominique C. , Lee Monica , Robertson Barbara , Tsou Meng-Fu B. , Rose Lesilee S. , Wood William B.
Published: October 2003

The mechanism by which polarity of the left-right (LR) axis is initially established with the correct handedness is not understood for any embryo. C. elegans embryos exhibit LR asymmetry with an invariant handedness that is first apparent at the six-cell stage and persists throughout development. We show here that a strong loss-of-function mutation in a gene originally designated spn-1 affects early spindle orientations and results in near randomization of handedness choice. This mutation interacts genetically with mutations in three par genes that encode localized cortical components. We show that the spn-1 gene encodes the Gαprotein GPA-16, which appears to be required for centrosomal association of a Gβ protein. We will henceforth refer to this gene as gpa-16. These results demonstrate for the first time involvement of heterotrimeric G proteins in establishment of embryonic LR asymmetry and suggest how they might act.
Methane to Hydrogen by Means of Redox of Modified Iron Oxides
Authors: Takenaka Sakae , Son Van Tho Dinh , Yamada Chisa , Otsuka Kiyoshi
Published: October 2003

CH4 can be converted to pure H2 by means of repeated reduction of modified iron oxides (Cu–Cr–FeOx) with CH4 and subsequent oxidation of the reduced oxides with H2O.
Synthesis and Structures of Cyclic Ethynylphosphine Ligands
Authors: Shiozawa Rie , Sakamoto Kenkichi
Published: October 2003

Twelve-membered cyclic diethynylphosphine derivatives (R12SiC≡C–R2PC≡C)2 (1a: R1 = R2 = Ph; 1b: R1 = Ph, R2 = t-Bu; 1c: R1 = i-Pr, R2 = Ph) have been synthesized as a novel cyclic phosphine ligand including potentially reactive acetylene and silane moieties. Compounds 1a and 1b were formed as a mixture of cis- and trans-isomers, while an only trans-isomer was obtained for 1c. X-ray structural analysis revealed planar skeletal structures of the trans-isomers of 1a–c.
A Convenient Synthesis of MAPO-36 (ATS) by Dry-gel Conversion (DGC) Technique
Authors: Saha Shyamal Kumar , Kubota Yoshihiro , Sugi Yoshihiro
Published: October 2003

MAPO-36 (ATS topology), which is one of the metalloaluminophosphate molecular sieves, was successfully synthesized by means of dry-gel conversion (DGC) technique.
Preparation and Catalytic Application of Transition Metal (Fe, V, or Cu) Oxides Homogeneously Dispersed in the Wall of Mesoporous Nb2O5
Authors: Yamashita Tomohiro , Lu Daling , Kondo Junko N , Hara Michikazu , Domen Kazunari
Published: October 2003

Fe, V, or Cu oxide was mixed in mesoporous Nb2O5, at a few atom percent, and their extremely high dispersion was confirmed by elemental analysis in about 5-nm spots using TEM–EDS. These mesoporous Nb2O5 showed characteristic selectivity for cyclohexene oxidation depending on the kind of the doped metal oxide.
A Clinical Audit into the Success Rate of Inferior Alveolar Nerve Block Analgesia in General Dental Practice
Authors: Keetley Andrew , Moles David R
Published: October 2003

Aims and objectives

The aim of this study was to produce some observational evidence of the success rate of inferior alveolar nerve block (IDB) analgesia that is achieved in general dental practice. The objective was to help provide some measure of expected failure rates and help dental practitioners in their self-appraisal of this crucial basic skill.

Method

Up to 100 consecutive IDB analgesia procedures for four dentists were recorded. In a subdivision of this study 200 consecutive IDBs for a fifth dentist were recorded. This dentist had the greatest experience of giving IDB analgesia of the dentists in this study. In this part of the study the dentist made a note if he anticipated that the procedure would fail. The reason for this was that it was felt that experienced dental practitioners could predict when failure was about to occur. The level of facial nerve palsy was also recorded.

Results

Overall, 533 of 580 (91.9%) local anaesthetic administrations were deemed to be successful. The only factor that significantly affected the likelihood of success was the practitioner administering the local anaesthetic, and this was only borderline statistically significant. In order to be certain that the other factors did not affect the outcome, the data were re-analysed using the technique of Poisson regression. This technique investigated the effects of each of the factors in turn while controlling for the differences in success that can be attributed to the different practitioners. The regression analyses also did not detect any differences in success that could be attributed to any of the other recorded factors. The incidence of facial palsy was 0.3%.

Conclusion

This paper gives an insight into the possible success rates to be encountered by general dental practitioners when they administer IDB analgesia. The only recorded factor that could be shown to affect the chance of a successful local analgesic was the operator. The incidence of facial nerve palsy at 0.3% may be more common than has previously been considered.
Barriers to the Use of Dental Services by Individuals from Minority Ethnic Communities Living in the United Kingdom: Findings from Focus Groups
Authors: Newton Jonathon T , Thorogood Nicky , Bhavnani Vanita , Pitt Jill , Gibbons David E , Gelbier Stanley
Published: October 2003

Objective

To describe the barriers identified by individuals from minority ethnic communities resident in the United Kingdom to their use of dental services.

Method

Focus group discussions were held with individuals from minority ethnic groups. Data were analysed using the technique of content analysis on the basis of categories defined by the researchers.

Findings

Barriers to regular attendance identified by participants included: language, a mistrust of dentists, cost, anxiety, cultural misunderstandings, concern about standards of hygiene. The type of barrier identified differed between ethnic groups, though mistrust of dentists was common to all groups.

Conclusions

The findings confirm previous research identifying barriers to the use of dental services. However, for the first time in the United Kingdom, it has been suggested that the nature of the perceived barriers varies across ethnic groups. These findings have implications for attempts to increase use of dental services among individuals from minority ethnic communities.
Thoracoscopy: A new era for surgical anatomy
Authors: Satyapal K.S. , Singh B. , Partab P. , Ramsaroop L. , Pather N.
Published: October 2003

In this new era of minimal access surgery, advances in optics and illumination have established thoracoscopic sympathectomy as a pre‐eminent procedure, including a safe and efficient technique for upper limb sympathectomy. The success of thoracoscopy will doubtless ensure that a greater number of these procedures will be carried out and will put some of the daunting technical challenges posed by traditional open surgical procedures to rest. The thoracoscopic era affords the surgical anatomist a new challenge: to move the teaching of living anatomy to a higher level. Clin. Anat. 16:538–541, 2003. © 2003 Wiley‐Liss, Inc.
Electrostatic Calculation of the Substituent Effect: An Efficient Test on Isolated Molecules
Authors: Exner Otto , Böhm Stanislav
Published: October 2003

The energy of a disubstituted molecule has often been approximated by simple electrostatic formulas that represent the substituents as poles or dipoles. Herein, we test this approach on a new model system that is more direct and more efficient than testing on acid–base properties. The energies of 27 1,4‐derivatives of bicyclo[2.2.2]octane were calculated within the framework of the density functional theory at the B3LYP/6‐311+G(d,p) level; interaction of the two substituents was evaluated in terms of isodesmic homodesmotic reactions. This interaction energy, checked previously on some experimental gas‐phase acidities, was considered to be accurate and served as reference to test the electrostatic approximation. This approximation works well in the qualitative sense as far as the sign and the order of magnitude are concerned: beginning with the strongest interaction between two poles, a weaker interaction between pole and dipole, and the weakest between two dipoles. However, all the electrostatic calculations yield energies that are too small, particularly for weak interaction, and this fundamental defect is not remedied by some possible improvements. In particular, variation of the effective permittivity would require a physically impossible value less than unity. The explanation must lie in a more complex distribution of electron density than anticipated in the electrostatic model. It also follows that possible conclusions about the transmission of substituent effects “through space” have little validity.