bluuebunny/crossref_metadata_2025 huggingface dataset:
AN INTRODUCTION TO BIO-INSPIRED ROBOT DESIGN
Authors: COIFFET PHILIPPE
Published: October 2005

After half a century of research and development, our requirements as far as robots are concerned now seem clear. People want robots to be mobile, intelligent, autonomous, able to cooperate with man and other machines, and to act within the world according to our wishes. Of course, that aim has still to be reached, and the means to reaching it cannot arise ex nihilo from the researcher's brain. However, one possible solution could be to take a look at the world around us and to ask ourselves the following question: are there, in the world, any entities that possess the characteristics we are looking for in robots? Indeed, there are billions of these entities. They are living beings in general, and animals and man in particular. Although bio-inspiration for robot design is not a new issue, it would appear that very few works have addressed the basic issues that might enable us to exploit this source of inspiration to the full. This paper aims to set out some basic premises which could then help designers to find adequate solutions. We should point out that, although the ideas presented in this paper come from observation and knowledge about living beings, the aim is neither to make living robots, nor to make an artificial real animal, and even less to make an artificial human. The goal consists in identifying the most important features of living beings that could be used to meet our requirements in the matter of robot design. It is obvious, moreover, that these needs or demands are not static, but may change according to the pace of new technological and scientific achievements. On the other hand, needs as far as robots are concerned may be formulated in terms of human (or animal) appearance, of mental and physical concerns or behavior, and not at all in terms of human (or animal) reality. Finally, the basic issue comes down to this: what "parts" of humans can be transferred to machines, and do these "parts" correspond to what is required nowadays of robots?
MEASURING POPULATION HEALTH: A Review of Indicators
Authors: Etches Vera , Frank John , Ruggiero Erica Di , Manuel Doug
Published: October 2005

▪ Abstract  This article reviews the historical development of population health indicators. We have long known that environmental, socioeconomic, early life conditions, individual actions, and medical care all interact to affect health. Present quantitative reporting on the impact of these factors on population health grew out of Bills of Mortality published in the 1500s. Since then, regular censuses, civil registration of vital statistics, and international classification systems have improved data quality and comparability. Regular national health interview surveys and application of administrative data contributed information on morbidity, health services use, and some social determinants of health. More recently, traditional health databases and datasets on “nonhealth” sector determinants have been linked. Statistical methods for map-making, risk adjustment, multilevel analysis, calculating population-attributable risks, and summary measures of population health have further helped to integrate information. Reports on the health of populations remain largely confined to focused areas. This paper suggests a conceptual framework for using indicators to report on all the domains of population health. Future ethical development of indicators will incorporate principles of justice, transparency, and effectiveness.
Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice
Authors: Kanda Naoki , Seno Hiroshi , Kawada Mayumi , Sawabu Tateo , Uenoyoma Yoshito , Nakajima Toshio , Konda Yoshitaka , Fukui Hirokazu , Takeuchi Toshiyuki , Chiba Tsutomu
Published: October 2005

Gastrin promotes gastric mucosal growth, and hypergastrinemia induces gastric mucosal hypertrophy. Recently, it has been reported that gastrin induces cyclooxygenase-2 (COX-2) in human gastric and colorectal cancer cell lines. However, whether COX-2 is involved in gastrin-induced gastric mucosal growth in vivo is unknown. We investigated the role of COX-2 in gastrin-induced gastric mucosal hypertrophy using gastrin transgenic mice. Hypergastrinemic mice [mice with mutated gastrin under the control of the β-actin promoter (ACT-GAS mice)] received the COX-2 inhibitor celecoxib (0, 200, or 500 mg/kg of diet) from 5 wk of age and were killed at 16 or 24 wk. Some ACT-GAS mice received celecoxib from 16 wk and were killed at 24 wk. Eighty-week-old ACT-GAS mice without celecoxib treatment were also examined. The thickness of the gastric mucosa, cell populations, COX-2 expression, and PGE2levels were evaluated. All ACT-GAS mice showed gastric mucosal hypertrophy, and four of six 80-wk-old ACT-GAS mice developed gastric cancer. COX-2 was expressed in interstitial cells of the hypertrophic gastric mucosa and gastric cancers. Moreover, PGE2levels in the gastric mucosa of ACT-GAS mice were significantly higher than those of normal mice. With treatment with celecoxib, PGE2levels, the gastric mucosal thickness, and the number of total gastric cells per gastric gland of ACT-GAS mice were significantly decreased. The decrease in gastric mucosal thickness was caused by a reduction of foveolar hyperplasia. The thickness of glandules and the number of Ki67-positive cells were not significantly changed. In conclusion, COX-2 contributes to gastrin-induced mucosal hypertrophy of the stomach.
Homocysteine causes cerebrovascular leakage in mice
Authors: Lominadze David , Roberts Andrew M. , Tyagi Neetu , Moshal Karni S. , Tyagi Suresh C.
Published: October 2005

Elevated plasma homocysteine (Hcy) is associated with cerebrovascular disease and activates matrix metalloproteinases (MMPs), which lead to vascular remodeling that could disrupt the blood-brain barrier. To determine whether Hcy administration can increase brain microvascular leakage secondary to activation of MMPs, we examined pial venules by intravital video microscopy through a craniotomy in anesthetized mice. Bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC) was injected into a carotid artery to measure extravenular leakage. Hcy (30 μM/total blood volume) was injected 10 min after FITC-BSA injection. Four groups of mice were examined: 1) wild type (WT) given vehicle; 2) WT given Hcy (WT + Hcy); 3) MMP-9 gene knockout given Hcy (MMP-9−/− + Hcy); and 4) MMP-9−/− with topical application of histamine (10−4 M) (MMP-9−/− + histamine). In the WT + Hcy mice, leakage of FITC-BSA from pial venules was significantly ( P < 0.05) greater than in the other groups. There was no significant leakage of pial microvessels in MMP-9−/− + Hcy mice. Increased cerebrovascular leakage in the MMP-9−/− + histamine group showed that microvascular permeability could still increase by a mechanism independent of MMP-9. Treatment of cultured mouse microvascular endothelial cells with 30 μM Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 μM) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation.
Patients with solid tumors treated with high-temperature whole body hyperthermia show a redistribution of naive/memory T-cell subtypes
Authors: Atanackovic Djordje , Pollok Kristina , Faltz Christiane , Boeters Ina , Jung Roman , Nierhaus Alexander , Braumann Klaus-Michael , Hossfeld Dieter Kurt , Hegewisch-Becker Susanna
Published: October 2005

An activation of the immune system might contribute to the therapeutic effect of whole body hyperthermia (WBH) in cancer patients. We explored immune and endocrine responses in patients undergoing high-temperature WBH. Identical parameters were investigated in a separate group of healthy volunteers undergoing physical exercise to rule out effects of sympathetic activation. Lymphocyte subpopulations, lymphocytic expression of a range of adhesion molecules, and serum concentrations of a variety of hormones and cytokines were assessed in cancer patients undergoing high-temperature (60 min at 41.0–41.8°C) WBH ( n = 25) and in a separate group of healthy volunteers ( n = 10) performing strenuous physical exercise. WBH induced an increase in human growth hormone (hGH), ACTH, and cortisol as well as in TNF-α, IL-6, IL-8, and IL-12R. We observed an increase in natural killer (NK) cells and CD56+NK T cells shortly after initiation of WBH. In contrast, we found a decrease in T cells expressing l-selectin (CD62L) or α4β7integrin adhesion molecules mediating homing to lymphatic tissues. Accordingly, we observed a decrease in CD45RA+CCR7+naive and CD45RA−CCR7+central memory T cells. Numbers of CD45RA−CCR7−memory effector and CD45RA+CCR7 terminally differentiated T cells, on the other hand, remained unchanged. No comparable changes were observed in the group of healthy volunteers. In conclusion, patients with solid tumors treated with WBH show an increase in NK and NK T cells. In a later phase, plasma concentrations of IL-8, hGH, and cortisol increase, correlated with an influx of neutrophils into the peripheral blood. The alterations in T-cell populations suggest that WBH may induce naive and central-memory T cells to enter lymphatic tissue to await antigen exposure and effector T cells to migrate into peripheral tissues to exert their effector function. Although the exercise group may not be an appropriate control to proof the effect of WBH, these changes were not seen in the healthy volunteers performing physical exercise.
Restraint stress augments postprandial gastric contractions but impairs antropyloric coordination in conscious rats
Authors: Nakade Yukiomi , Tsuchida Daisuke , Fukuda Hiroyuki , Iwa Masahiro , Pappas Theodore N. , Takahashi Toku
Published: October 2005

Central corticotropin-releasing factor (CRF) plays an important role in mediating restraint stress-induced delayed gastric emptying. However, it is unclear how restraint stress modulates gastric motility to delay gastric emptying. Inasmuch as solid gastric emptying is regulated via antropyloric coordination, we hypothesized that restraint stress impairs antropyloric coordination, resulting in delayed solid gastric emptying in conscious rats. Two strain gauge transducers were sutured onto the serosal surface of the antrum and pylorus, and postprandial gastric motility was monitored before, during, and after restraint stress. Antropyloric coordination, defined as a propagated single contraction from the antrum to the pylorus within 10 s, was followed by ≥20 s of quiescence. Restraint stress enhanced postprandial gastric motility in the antrum and pylorus to 140 ± 9% and 134 ± 9% of basal, respectively ( n = 6). The number of episodes of antropyloric coordination before restraint stress, 2.4 ± 0.4/10 min, was significantly reduced to 0.6 ± 0.3/10 min by restraint stress. Intracisternal injection of the CRF type 2 receptor antagonist astressin 2B (60 μg) or guanethidine partially restored restraint stress-induced impairment of antropyloric coordination (1.6 ± 0.3/10 min, n = 6). The restraint stress-induced augmentation of antral and pyloric contractions was increased by astressin 2B and guanethidine but abolished by atropine, hexamethonium, and vagotomy. Restraint stress enhanced postprandial gastric motility via a vagal cholinergic pathway. Restraint stress-induced delay of solid gastric emptying is due to impairment of antropyloric coordination. Restraint stress-induced impairment of antropyloric coordination might be mediated via a central CRF pathway.
Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain
Authors: Ogunshola O. O. , Djonov V. , Staudt R. , Vogel J. , Gassmann M.
Published: October 2005

Excessive erythrocytosis results in severely increased blood viscosity, which may have significant detrimental effects on endothelial cells and, ultimately, function of the vascular endothelium. Because blood-brain barrier stability is crucial for normal physiological function, we used our previously characterized erythropoietin-overexpressing transgenic (tg6) mouse line (which has a hematocrit of 0.8–0.9) to investigate the effect of excessive erythrocytosis on vessel number, structure, and integrity in vivo. These mice have abnormally high levels of nitric oxide (NO), a potent proinflammatory molecule, suggesting altered vascular permeability and function. In this study, we observed that brain vessel density of tg6 mice was significantly reduced (16%) and vessel diameter was significantly increased (15%) compared with wild-type mice. Although no significant increases in vascular permeability under normoxic or acute hypoxic conditions (8% O2for 4 h) were detected, electron-microscopic analysis revealed altered morphological characteristics of the tg6 endothelium. Tg6 brain vascular endothelial cells appeared to be activated, with increased luminal protrusions reminiscent of ongoing inflammatory processes. Consistent with this observation, we detected increased levels of intercellular adhesion molecule-1 and von Willebrand factor, markers of endothelial activation and damage, in brain tissue. We propose that chronic excessive erythrocytosis and sustained high hematocrit cause endothelial damage, which may, ultimately, increase susceptibility to vascular disease.
Sprint performance-duration relationships are set by the fractional duration of external force application
Authors: Weyand Peter G. , Lin Jennifer E. , Bundle Matthew W.
Published: October 2005

We hypothesized that the maximum mechanical power outputs that can be maintained during all-out sprint cycling efforts lasting from a few seconds to several minutes can be accurately estimated from a single exponential time constant ( kcycle) and two measurements on individual cyclists: the peak 3-s power output (Pmech max) and the maximum mechanical power output that can be supported aerobically (Paer). Tests were conducted on seven subjects, four males and three females, on a stationary cycle ergometer at a pedal frequency of 100 rpm. Peak mechanical power output (Pmech max) was the highest mean power output attained during a 3-s burst; the maximum power output supported aerobically (Paer) was determined from rates of oxygen uptake measured during a progressive, discontinuous cycling test to failure. Individual power output-duration relationships were determined from 13 to 16 all-out constant load sprints lasting from 5 to 350 s. In accordance with the above hypothesis, the power outputs measured during all-out sprinting efforts were estimated to within an average of 34 W or 6.6% from Pmech max, Paer, and a single exponential constant ( kcycle= 0.026 s−1) across a sixfold range of power outputs and a 70-fold range of sprint trial durations ( R2= 0.96 vs. identity, n = 105; range: 180 to 1,136 W). Duration-dependent decrements in sprint cycling power outputs were two times greater than those previously identified for sprint running speed ( krun= 0.013 s−1). When related to the respective times of pedal and ground force application rather than total sprint time, decrements in sprint cycling and running performance followed the same time course ( k = 0.054 s−1). We conclude that the duration-dependent decrements in sprinting performance are set by the fractional duration of the relevant muscular contractions.
Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression
Authors: Szalay László , Shimizu Tomoharu , Suzuki Takao , Yu Huang-Ping , Choudhry Mashkoor A. , Schwacha Martin G. , Rue Loring W. , Bland Kirby I. , Chaudry Irshad H.
Published: October 2005

Although studies indicate that 17β-estradiol administration after trauma-hemorrhage (T-H) improves cardiac and hepatic functions, the underlying mechanisms remain unclear. Because the induction of heat shock proteins (HSPs) can protect cardiac and hepatic functions, we hypothesized that these proteins contribute to the salutary effects of estradiol after T-H. To test this hypothesis, male Sprague-Dawley rats (∼300 g) underwent laparotomy and hemorrhagic shock (35–40 mmHg for ∼90 min) followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17β-estradiol (1 mg/kg body wt) was administered at the end of the resuscitation. Five hours after T-H and resuscitation there was a significant decrease in cardiac output, positive and negative maximal rate of left ventricular pressure. Liver function as determined by bile production and indocyanine green clearance was also compromised after T-H and resuscitation. This was accompanied by an increase in plasma alanine aminotransferase (ALT) levels and liver perfusate lactic dehydrogenase levels. Furthermore, circulating levels of TNF-α, IL-6, and IL-10 were also increased. In addition to decreased cardiac and hepatic function, there was an increase in cardiac HSP32 expression and a reduction in HSP60 expression after T-H. In the liver, HSP32 and HSP70 were increased after T-H. There was no change in heart HSP70 and liver HSP60 after T-H and resuscitation. Estradiol administration at the end of T-H and resuscitation increased heart/liver HSPs expression, ameliorated the impairment of heart/liver functions, and significantly prevented the increase in plasma levels of ALT, TNF-α, and IL-6. The ability of estradiol to induce HSPs expression in the heart and the liver suggests that HSPs, in part, mediate the salutary effects of 17β-estradiol on organ functions after T-H.
Effect of muscle fatigue on internal model formation and retention during reaching with the arm
Authors: Takahashi Craig D. , Nemet Dan , Rose-Gottron Christie M. , Larson Jennifer K. , Cooper Dan M. , Reinkensmeyer David J.
Published: October 2005

The motor system adapts to novel dynamic environments by forming internal models that predict the muscle forces needed to move skillfully. The goal of this study was to determine how muscle fatigue affects internal model formation during arm movement and whether an internal model acquired while fatigued could be recalled accurately after rest. Twelve subjects adapted to a viscous force field applied by a lightweight robot as they reached to a target. They then reached while being resisted by elastic bands until they could no longer touch the target. This protocol reduced the strength of the muscles used to resist the force field by ∼20%. The bands were removed, and subjects adapted again to the viscous force field. Their adaptive ability, quantified by the amount and time constant of adaptation, was not significantly impaired following fatigue. The subjects then rested, recovering ∼70% of their lost force-generation ability. When they reached in the force field again, their prediction of the force field strength was different than in a nonfatigued state. This alteration was consistent with the use of a higher level of effort than normally used to counteract the force field. These results suggest that recovery from fatigue can affect recall of an internal model, even when the fatigue did not substantially affect the motor system’s ability to form the model. Recovery from fatigue apparently affects recall because the motor system represents internal models as a mapping between effort and movement and relies on practice to recalibrate this mapping.
Early loss of proliferative potential of human peritoneal mesothelial cells in culture: the role of p16INK4a-mediated premature senescence
Authors: Książek Krzysztof , Piwocka Katarzyna , Brzezińska Agnieszka , Sikora Ewa , Zabel Maciej , Bręborowicz Andrzej , Jörres Achim , Witowski Janusz
Published: October 2005

Much has been learned about the mechanisms underlying cellular senescence. The pathways leading to senescence appear to vary, depending on the cell type and cell culture conditions. In this respect, little is known about senescence of human peritoneal mesothelial cells (HPMC). Previous studies have significantly differed in the reported proliferative lifespan of HPMC. Therefore, in the present study, we have examined how HPMC enter state of senescence under conditions typically used for HPMC culture. HPMC were isolated from omentum and grown into senescence. The cultures were assessed for the growth rate, the presence of senescence markers, activation of cell-cycle inhibitors, and the oxidative stress. HPMC were found to reach, on average, six population doublings before senescence. The terminal growth arrest was associated with decreased expression of Ki67 antigen, increased percentage of cells in the G1 phase, reduced early population doubling level cDNA-1 mRNA expression, and the presence of senescence-associated β-galactosidase. Compared with early-passage cells, the late-passage HPMC exhibited increased expression of p16INK4abut not of p21Cip1. In addition, these cells generated more reactive oxygen species and displayed increased presence of oxidatively modified DNA (8-hydroxy-2′-deoxyguanosine). These results demonstrate that early onset of senescence in omentum-derived HPMC may be associated with oxidative stress-induced upregulation of p16INK4a.
Cube Drawing Performances in Normal Ageing and Alzheimer’s Disease: Data from the PAQUID Elderly Population-Based Cohort
Authors: Gaestel Yann , Amieva Hélène , Letenneur Luc , Dartigues Jean-François , Fabrigoule Colette
Published: October 2005

To assess the influence of age and other sociodemographical variables, depressive symptomatology and the occurrence of Alzheimer’s disease (AD) on cube drawing, we examined the performance of 858 normal subjects and 17 incident AD patients in the PAQUID population-based study. Cube drawing was first performed on verbal command and, in case of failure, a model of a cube was given to the subjects to copy. Normal subjects had some difficulties in drawing a cube on verbal command, evidenced by 40% failure in the drawing-to-command condition, while only 17% still failed in the drawing-to-copy condition. Multivariate logistic regressions showed that age, gender, and educational level were associated with cube drawing failure in both conditions, but depressive symptomatology was only associated with persistent failure in the drawing-to-copy condition. Seventy-six point five percent of incident AD subjects failed in the drawing-to-command condition and 64.7% did not benefit from the presentation of the model. Analysis showed that persistent failure in the copy condition was the best level of differentiation between normal and AD subjects.
Effect of the Apolipoprotein E ε4 Allele on the Efficacy and Tolerability of Galantamine in the Treatment of Alzheimer’s Disease
Authors: Suh Guk-Hee , Jung Hee Yeon , Lee Chang Uk , Oh Byoung Hoon , Lee Sang-Kyu , Lee NamJin , Kim JaeHyun , Kee Baik Seok , Ko Daekwan , Kim Young-Hoon , Ju Young-Su , Hong InJa , Choi Sungku
Published: October 2005

Objective: To investigate the effect of the apolipoprotein E (ApoE) ε4 allele on the efficacy and tolerability of galantamine treatment. Methods: A total of 202 patients with mild to moderate Alzheimer’s disease participated in a 16-week, prospective, multi-center, randomized, double-blind galantamine trial in a Korean population. Patients were assessed at baseline and after 4, 8 and 16 weeks of randomized treatment using the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog/11), the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the Disability Assessment for Dementia Scale (DAD), the Behavioural Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) and adverse events. ApoE genotypes were determined for all subjects. Results: Of the 202 subjects, 115 carried at least one ApoE ε4 allele and 87 did not. In both ApoE ε4 carriers and ApoE ε4 noncarriers, significant improvements were detected relative to baseline on ADAS-cog/11, CIBIC-plus, DAD and BEHAVE-AD. ApoE ε4 noncarriers showed better improvement in mean total BEHAVE-AD score and mean psychosis (delusions and hallucinations) subscale score than ApoE ε4 carriers. The incidence of weight loss was significantly higher in ApoE ε4 carriers (n = 11; 9.6%) than in ApoE ε4 noncarriers (n = 1; 1.2%) during this 16-week study, even though 92% of patients who complained of weight loss completed this 16-week trial successfully. Conclusion: ApoE ε4 genotype does not affect galantamine-related improvements in cognition, global rating, function and behavior. Longer prospective studies with larger patient populations are required to confirm these new findings.
Balloon Valvuloplasty as an Initial Palliation in the Treatment of Newborns and Young Infants with Severely Symptomatic Tetralogy of Fallot
Authors: Wu En-Ting , Wang Jou-Kou , Lee Wen-Lee , Chang Chien-Chih , Wu Mei-Hwan
Published: October 2005

Background: Balloon valvuloplasty in infants with symptomatic tetralogy of Fallot (TOF) may increase the pulmonary flow and prompt the growth of pulmonary arteries. Method: From 1994 to 2002, percutaneous transluminal balloon valvuloplasty (PTPV) was performed in 22 consecutive newborns and young infants (<3 months of age) with TOF. The indication included severe hypoxemia (systemic oxygen saturation below 75%, 10 cases) and repeated hypoxic spells (12 cases). The age at PTPV was 8–88 days (38 ± 34, median 27) and the body weight 2–5 kg (3.45 ± 1.15, median 3). A balloon catheter (4– 7 mm in diameter and 2 cm in length) was used to dilate the pulmonary valve. Results: No major procedure-related complications occurred. The systemic oxygen saturation increased significantly (14 ± 9%). A subsequent palliative shunt operation was avoided in 12 patients (54.5%), but 10 still needed operation (median 11 days after the PTPV). The presence of recurrent hypoxic spells before PTPV was the most important indicator for PTPV failure (p = 0.02). Conclusion: PTPV was safe and effective for symptomatic newborns and young infants with TOF, but a palliative shunt operation was still needed due to short effect, especially in those with recurrent spells before the dilation.
Differential Effects of Fexofenadine on Arachidonic Acid Metabolism in Cultured Human Monocytes
Authors: Juergens Uwe R. , Darlath Wilfried , Stöber Meinolf , Racké Kurt , Tasci Selcuk , Gillissen Adrian , Vetter Hans
Published: October 2005

The relief of nasal congestion with the antihistamine fexofenadine in seasonal allergic rhinitis is thought to be due to its additional anti-inflammatory properties. The objective of this study was to evaluate the in vitro effects of fexofenadine on stimulated arachidonic acid metabolism. Human monocytes, isolated from blood and donated by 5 healthy volunteers, were either incubated for 20 h with 10 µg/ml lipopolysaccharide, with and without fexofenadine (10–8–10–3 mol/l, n = 8–19), or were incubated for 20 h, with and without fexofenadine, and then stimulated with 0.5 mg/ml zymosan for 2 h. Leukotriene B4 (LTB4), LTC4, LTD4 and LTE4, prostaglandin E2 (PGE2) and F2α(PGF2α) production was determined by enzyme immunoassay. Zymosan-stimulated production of LTC4, LTD4 and LTE4 was significantly inhibited by clinically relevant concentrations of fexofenadine HCl: 10–7mol/l (22% inhibition vs. control, p = 0.008) and 10–6 mol/l (24% inhibition vs. control, p = 0.020). Higher concentrations of fexofenadine (10–4 and 10–3 mol/l) inhibited LTB4 generation. Lipopolysaccharide-stimulated production of PGE2 was significantly inhibited by fexofenadine HCI 10–6 mol/l (26% inhibition, p = 0.035) and 10–5 mol/l (40% inhibition, p = 0.001). Higher concentrations of fexofenadine HCI (10–4 and 10–3 mol/l) significantly inhibited PGF2α production by 50% (p = 0.026) and 63% (p = 0.001), respectively. Fexofenadine, at both clinically relevant and higher concentrations, inhibits LTC4, LTD4, LTE4 and PGE2 in cultured human monocytes. These additional anti-inflammatory properties may underlie the relief of nasal congestion observed in clinical studies.
Clinical Features, Diagnosis and Molecular Studies of Familial Central Diabetes Insipidus
Authors: Davies J.H. , Penney M. , Abbes A.P. , Engel H. , Gregory J.W.
Published: October 2005

Background: Familial central diabetes insipidus (DI) is rare and is characterised by polydipsia and polyuria with a variable age of onset. The evaluation of arginine vasopressin (AVP) secretion in these individuals has been reported infrequently and only in adulthood. Objective: To describe the clinical features, diagnosis and molecular investigation of children affected by familial central DI. Methods: Functional studies of AVP secretion were undertaken in children from two kindreds with familial central DI. The AVP-neurophysin II (AVP-NPII) gene was also sequenced in symptomatic individuals. Results: In affected individuals, the result of the water deprivation test may be inconclusive. However, the hypertonic saline test identified both the severe and partial forms of AVP deficiency. A novel mutation of the AVP-NPII gene was identified by direct gene sequencing in both families. Conclusions: This report highlights the progressive decline in AVP secretion with increasing age in this disorder and the usefulness of mutational analysis in these families. In symptomatic individuals, the hypertonic saline test may be a useful second-line investigation for functional studies of AVP secretion where molecular diagnostics are unavailable.
Susceptibility Alleles and Haplotypes of Human Leukocyte Antigen DRB1, DQA1, and DQB1 in Autoimmune Polyglandular Syndrome Type III in Japanese Population
Authors: Hashimoto Kozo , Maruyama Hiroshi , Nishiyama Mitsuru , Asaba Koichi , Ikeda Yukio , Takao Toshihiro , Iwasaki Yasumasa , Kumon Yositaka , Suehiro Tadashi , Tanimoto Noriyasu , Mizobuchi Miki , Nakamura Tosihiro
Published: October 2005

Background: It has been reported that HLA class II haplotypes DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0901-DQA1*0302-DQB1*0303 are major susceptibility haplotypes for type 1 diabetes mellitus (DM) in Japanese population. However, little has been reported on the susceptibility HLA class II haplotypes in Japanese patients with autoimmune polyglandular syndrome type II and type III (APS III). Patients and Methods: HLA class II haplotypes of DRB1-DQA1-DQB1 in 31 patients with APS III, 14 patients with Hashimoto’s thyroiditis alone, and 15 patients with Graves’ disease alone were examined in Japanese population. APS III patients were divided into three groups (A, B, and C) depending on the combination of autoimmune endocrine diseases. Results: In 13 APS III patients with both Hashimoto’s thyroiditis and type 1 DM (group A), the haplotype frequencies of the HLA DRB1*0802-DQA1*0401-DQB1*0402 and DRB1*0901-DQA1*0302-DQB1*0303 were significantly higher than in the controls. In patients with Hashimoto’s thyroiditis alone, the haplotype frequency of DRB1*0901-DQA1*0302-DQB1*0303 was significantly higher than in controls, whereas the frequency of DRB1*0802-DQA1*0401-DQB1*0402 did not differ significantly from those in the controls. In 11 APS III patients with both Graves’ disease and type 1 DM (group B), the haplotype frequencies of HLA DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0802-DQA1*0301-DQB1*0302 were significantly higher than in controls. In patients with Graves’ disease alone, the haplotype frequency of DRB1*0803-DQA1*0103-DQB1*0601 were significantly higher than those in controls, suggesting that the susceptibility haplotypes for group B APS III differed from those for Graves’ disease alone. In 7 APS III patients with both autoimmune thyroid diseases and pituitary disorders (group C), the haplotype frequency of HLA DRB1*0405-DQA1*0303-DQB1*0401 was significantly higher than in controls. Conclusions: Susceptible HLA class II haplotypes of DRB1-DQA1-DQB1 for APS III differ between the Japanese and Caucasian populations. More interestingly, the susceptible HLA class II haplotypes differ among the three types of Japanese APS III and are not merely a combination of susceptibility haplotypes of each endocrine disease.
Nicotine Induces Proinflammatory Responses in Macrophages and the Aorta Leading to Acceleration of Atherosclerosis in Low-Density Lipoprotein Receptor−/−Mice
Authors: Lau Paul P. , Li Lan , Merched Aksam J. , Zhang Alan L. , Ko Kerry W.S. , Chan Lawrence
Published: October 2005

Objective—We investigated the molecular mechanism of nicotine-accelerated atherosclerosis in a hyperlipidemic low-density lipoprotein receptor−/−mouse model.

Methods and Results—Low-density lipoprotein receptor−/−mice received time-release nicotine or placebo pellets for 90 days. Aortic lesion size was 2.5 times larger in nicotine-treated than in placebo-treated mice (P<0.001). A mild increase in lipids was seen in treated mice. We quantified 18 different serum cytokines and found a significant increase of tumor necrosis factor α, interleukin 1β, and keratinocyte-derived chemokine in nicotine-treated mice. Among 107 nuclear factor κB (NF-κB) target genes screened from the aorta, we found that nicotine treatment upregulated only 4 atherogenic genes including vascular adhesion molecule 1 and cyclooxygenase 2 on day 60 and platelet-derived growth factor B and platelet 12-lipoxygenase on day 90. At the cellular level, nicotine induced tumor necrosis factor α and inducible nitric oxide synthase expression in RAW264.7 cells via the nicotinic acetylcholine receptors. Induction was confirmed in peritoneal macrophages isolated from nicotine-treated mice. Finally, we showed that preconditioned medium from nicotine-treated RAW264.7 cells activated NF-κB in human smooth muscle cells and vascular endothelial cells as evidenced by nuclear localization and electromobility shift assay.

Conclusions—Chronic nicotine exposure augments atherosclerosis by enhancing the production of proinflammatory cytokines by macrophages, which, in turn, activate atherogenic NF-κB target genes in the aortic lesions.
Glucocorticoid Receptor Regulates ATP-Binding Cassette Transporter-A1 Expression and Apolipoprotein-Mediated Cholesterol Efflux From Macrophages
Authors: Ayaori Makoto , Sawada Shojiro , Yonemura Atsushi , Iwamoto Noriyuki , Ogura Masatsune , Tanaka Nobukiyo , Nakaya Kazuhiro , Kusuhara Masatoshi , Nakamura Haruo , Ohsuzu Fumitaka
Published: October 2005

Objective—

The ATP-binding cassette transporter-A1 (ABCA1) regulates cholesterol efflux from cells and is involved in high-density lipoprotein metabolism and atherogenesis. The objective of this study was to investigate the effect of dexamethasone (Dex) and other glucocorticoid receptor (GR) ligands on apolipoprotein AI–mediated cholesterol efflux from macrophages and ABCA1 expression in them.

Methods and Results—

Dex, a GR agonist, decreased ABCA1 mRNA levels in a dose- and time-dependent fashion, and RU486, a GR antagonist, reversed the inhibitory effect of Dex. The effects of Dex and RU486 on ABCA1 protein levels and apolipoprotein AI–mediated cholesterol efflux from the macrophages were consistent with these changes in mRNA levels. Transfected RAW264.7, together with a human ABCA1 promoter–luciferase construct, inhibited transcriptional activity by Dex and overexpression of human GR. Transrepression by GR was not mediated by liver X receptor (LXR), because there were no differences in the effects of the GR ligands on promoter activity between a reporter construct with mutations at the LXR binding site and one without the mutations, and no changes were brought about in ABCG1 and ABCG4 expression by GR ligands.

Conclusions—

Our results showed that GR ligands affected ABCA1 expression and cholesterol efflux from macrophages, which are regulated by GR through a LXR-independent mechanism.
Expression of Neutrophil Gelatinase–Associated Lipocalin in Atherosclerosis and Myocardial Infarction
Authors: Hemdahl Anne-Louise , Gabrielsen Anders , Zhu Chaoyong , Eriksson Per , Hedin Ulf , Kastrup Jens , Thorén Peter , Hansson Göran K.
Published: October 2005

Objective—Neutrophil gelatinase-associated lipocalin (NGAL) modulates the activity of matrix metalloproteinase (MMP) 9, an important mediator of vascular remodeling and plaque instability in atherosclerosis. This study aimed to analyze the expression of NGAL in atherosclerotic plaques and myocardial infarction (MI).

Methods and Results—Atherosclerotic apolipoprotein E (apoE)−/−× low-density lipoprotein receptor (LDLR)−/−and C57BL/6J control mice were exposed to brief hypoxic stress (10 minutes of 10% oxygen). Expression of the mouse NGAL homolog (24p3) and MMP-9 was analyzed 48 hours later by quantitative RT-PCR, immunohistochemistry, and zymography. Hypoxic stress increased NGAL/24p3 mRNA in the cardiac vasculature. NGAL/24p3 was also increased in atherosclerotic plaques of apolipoprotein E−/−× LDLR−/−mice compared with C57BL/6J mice. Mice developing MI exhibited the highest plaque mRNA expression of NGAL/24p3 and MMP-9. Zymography revealed strong proteolytic activity in areas rich in 24p3 and MMP-9 protein. Immunohistochemistry performed on human carotid endarterectomy specimens and control tissue from the internal mammary artery showed colocalization of MMP-9 and NGAL with macrophages in the atherosclerotic plaques.

Conclusions—NGAL/24p3 is increased in atherosclerotic plaques and MI. Colocalization with MMP-9 in areas with high-proteolytic activity suggests a role for NGAL/24p3 in modulating the MMP-9-mediated remodeling of plaques and infarcted hearts.
The Glycoprotein VI-Phospholipase Cγ2 Signaling Pathway Controls Thrombus Formation Induced by Collagen and Tissue Factor In Vitro and In Vivo
Authors: Munnix Imke C.A. , Strehl Amrei , Kuijpers Marijke J.E. , Auger Jocelyn M. , van der Meijden Paola E.J. , van Zandvoort Marc A.M. , oude Egbrink Mirjam G.A. , Nieswandt Bernhard , Heemskerk Johan W.M.
Published: October 2005

Objective—

Both collagen and tissue factor can be initiating factors in thrombus formation. We investigated the signaling pathway of collagen-induced platelet activation in interaction with tissue factor–triggered coagulation during the thrombus-forming process.

Methods and Results—

In murine blood flowing over collagen, platelet exposure of phosphatidylserine and procoagulant activity, but not adhesion, completely relied on each of the following signaling modules: glycoprotein VI (GPVI), FcR γ-chain, Src kinases, adaptor protein LAT, and phospholipase Cγ2 (PLCγ2). On flow in the presence of tissue factor, these signaling components were essential for platelet aggregation and greatly enhanced fibrin clot formation. Collagen-stimulated thrombin generation relied on the presence and activity of GPVI, FcR γ-chain, Src kinase, LAT, and PLCγ2. The physiological importance of this GPVI pathway was shown in a FeCl
3
-induced in vivo murine thrombosis model. In both venules and arterioles, signaling through GPVI, FcR γ-chain, and Src kinases enhanced the formation of phosphatidylserine-exposing and fibrin-rich thrombi.

Conclusions—

The GPVI-PLCγ2 activation pathway regulates collagen-dependent coagulation in venous and arterial thrombus formation.
Cholesteryl Esters of Aggregated LDL Are Internalized by Selective Uptake in Human Vascular Smooth Muscle Cells
Authors: Llorente-Cortés Vicenta , Otero-Viñas Marta , Camino-López Sandra , Costales Paula , Badimon Lina
Published: October 2005

Objective—

Low-density lipoprotein (LDL) receptor-related protein (LRP1) mediates the internalization of aggregated LDL (agLDL)–LDL trapped in the arterial intima bound to proteoglycans–into human vascular smooth muscle cells (VSMC). LRP1-mediated agLDL uptake induces high-intracellular cholesteryl ester (CE) accumulation. The aim of this study was to characterize the mechanism of agLDL internalization in human VSMC.

Methods and Results—

The lipidic component of LDL was labeled with [
3
H] and the apolipoprotein component with [
125
I]. We found that >90% of intracellular CE derived from agLDL uptake was not associated with apoB100 degradation but was selectively taken up from agLDL. The inhibition of LRP1 expression by small interfering RNA treatment led to a decrease of 80±0.05% in agLDL-CE selective uptake. AgLDL induced intracellular CE accumulation without a concomitant CE synthesis. Cytosolic and cytoskeletal proteins were not required for CE transport. Electron and confocal microscopy experiments indicate that CE derived from agLDL accumulated in adipophilin-stained lipid droplets that were not removable by high-density lipoprotein.

Conclusions—

Taken together, these results demonstrate that LRP1 mediates the selective uptake of CE from agLDL and that CE derived from agLDL is not intracellularly processed but stored in lipid droplets in human VSMC.
Stimulation of Liver-Directed Cholesterol Flux in Mice by Novel N-Acetylgalactosamine–Terminated Glycolipids With High Affinity for the Asialoglycoprotein Receptor
Authors: Rensen Patrick C.N. , Sliedregt Leo A.J.M. , van Santbrink Peter J. , Ferns Michiel , Schifferstein Hendrik N.J. , van Leeuwen Steven H. , Souverijn John H.M. , van Berkel Theo J.C. , Biessen Erik A.L.
Published: October 2005

Objective—

Interventions that promote liver-directed cholesterol flux can suppress atherosclerosis, as demonstrated for scavenger receptor-BI overexpression in hypercholesterolemic mice. In analogy, we speculate that increasing lipoprotein flux to the liver via the asialoglycoprotein receptor (ASGPr) may be of therapeutic value in hypercholesterolemia.

Methods and Results—

A bifunctional glycolipid (LCO-Tyr-GalNAc
3
) with a high-nanomolar affinity for the ASGPr (inhibition constant 2.1±0.2 nmol/L) was synthesized that showed rapid association with lipoproteins on incubation with serum. Prior incubation of LCO-Tyr-GalNAc
3
with radiolabeled low-density lipoprotein or high-density lipoprotein (0.5 μg/μg of protein) resulted in a dramatic induction of the liver uptake of these lipoproteins when injected intravenously into mice (70±3% and 78±1%, respectively, of the injected dose at 10 minutes of low-density lipoprotein and high-density lipoprotein), as mediated by the ASGPr on hepatocytes. Intravenously injected LCO-Tyr-GalNAc
3
quantitatively incorporated into serum lipoproteins and evoked a strong and persistent (≥48 hour) cholesterol-lowering effect in normolipidemic mice (37±2% at 6 hours) and hyperlipidemic
apoE
−/−
mice (32±2% at 6 hours). The glycolipid was also effective on subcutaneous administration.

Conclusions—

LCO-Tyr-GalNAc
3
is very effective in promoting cholesterol uptake by hepatocytes and, thus, may be a promising alternative for the treatment of those hyperlipidemic patients who do not respond sufficiently to conventional cholesterol-lowering therapies.
Platelet Nitric Oxide Responsiveness
Authors: Willoughby Scott R. , Stewart Simon , Holmes Andrew S. , Chirkov Yuliy Y. , Horowitz John D.
Published: October 2005

Objectives—

Nitric oxide (NO) is critically important in the regulation of vascular tone and the inhibition of platelet aggregation. We have shown previously that patients with acute coronary syndromes (ACS) or stable angina pectoris have impaired platelet responses to NO donors when compared with normal subjects. We tested the hypotheses that platelet hyporesponsiveness to NO is a predictor of (1) cardiovascular readmission and/or death and (2) all-cause mortality in patients with ACS (unstable angina pectoris or non–Q-wave myocardial infarction).

Methods and Results—

Patients (n=51) with ACS had evaluation of platelet aggregation within 24 hours of coronary care unit admission using impedance aggregometry. Patients were categorized as having “normal” (≥32% inhibition of ADP-induced aggregation with the NO donor sodium nitroprusside; 10 μmol/L; n=18) or “impaired” (<32% inhibition of ADP-induced aggregation; n=33) NO responses. We then compared the incidence of cardiovascular readmission and death during a median of 7 years of follow-up in these 2 groups. Using a Cox proportional hazards model adjusting for age, sex, index event, postdischarge medical treatment, revascularization status, left ventricular systolic dysfunction, concurrent disease states, and cardiac risk factors, impaired NO responsiveness was associated with an increased risk of the combination of cardiovascular readmission and/or death (relative risk, 2.7; 95% CI, 1.03 to 7.10;
P
=0.041) and all-cause mortality (relative risk, 6.3; 95% CI, 1.09 to 36.7;
P
=0.033).

Conclusions—

Impaired platelet NO responsiveness is a novel, independent predictor of increased mortality and cardiovascular morbidity in patients with high-risk ACS.
What Does It Take to Make the Perfect Clot?
Authors: Monroe Dougald M. , Hoffman Maureane
Published: October 2005

The coagulation process has been conceptualized as being primarily dependent on adequate levels of the coagulation proteins. This concept was based on the clear relationship between the bleeding tendency and factor levels in hemophilia. The field is now evolving toward conceptualizing coagulation as being actively regulated by the specialized cellular components of the process. Rather than conceiving coagulation as only a “cascade” of proteolytic reactions, the coagulation reactions occur as overlapping steps on cell surfaces. Components of the old “extrinsic’” and “intrinsic” pathways of coagulation can be thought of as participating in the initiation and propagation of coagulation reactions, respectively. Thus, these pathways are not redundant as they are portrayed in the cascade model, but play distinct and complementary roles. Our understanding of how specific cellular features control the processes of hemostasis and thrombosis is developing rapidly. This review discusses some aspects of the cellular control of coagulation.
Low-Density Lipoprotein Cholesterol Determines Oxidative Stress and Endothelial Dysfunction in Saphenous Veins From Patients With Coronary Artery Disease
Authors: Al-Benna Sammy , Hamilton Carlene A. , McClure John D. , Rogers Paul N. , Berg Geoffrey A. , Ford Ian , Delles Christian , Dominiczak Anna F.
Published: October 2005

Objective—

There is evidence for a relationship between endothelial dysfunction and cardiovascular disease, but a causative role for oxidative stress remains to be determined.

Methods and Results—

We studied 188 patients with severe coronary artery disease (CAD), of whom 51 were age and sex matched with 51 healthy controls undergoing varicose vein surgery. Relaxation of saphenous vein to calcium ionophore, apocynin, and allopurinol was studied together with the markers of oxidative stress, total antioxidant capacity and reduced/oxidized glutathione ratio. Vascular superoxide levels were measured using lucigenin chemiluminescence and hydroethidine. Relaxation to calcium ionophore was decreased in CAD compared with control patients (maximum relaxation 26±2% versus 60±1%;
P
<0.001). Total superoxide production was increased (0.89±0.09 versus 0.56±0.06 nmol/mg per min;
P
=0.008), whereas superoxide inhibition with apocynin or allopurinol had a greater effect on vasorelaxation in CAD patients. Low-density lipoprotein (LDL) cholesterol predicted relaxation to calcium ionophore (
P
<0.001) and oxidative stress markers (
P
<0.001) in CAD patients.

Conclusions—

Endothelial dysfunction is associated with raised levels of superoxide and biomarkers of oxidative stress in saphenous veins from CAD patients. LDL cholesterol is a major determinant of endothelial dysfunction and oxidative stress in these patients. These results support intensive LDL cholesterol-lowering therapy as suggested by recent clinical trials.