bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium channels are required during in vivo sodium chloride hyperosmolarity to stimulate increase in intestinal endothelial nitric oxide production
Authors: Zani Brett G. , Bohlen H. Glenn
Published: August 2004

NaCl hyperosmolarity increases intestinal blood flow during food absorption due in large part to increased NO production. We hypothesized that in vivo, sodium ions enter endothelial cells during NaCl hyperosmolarity as the first step to stimulate an increase in intestinal endothelial NO production. Perivascular NO concentration ([NO]) and blood flow were determined in the in vivo rat intestinal microvasculature at rest and under hyperosmotic conditions, 330 and 380 mosM, respectively, before and after application of bumetanide (Na+-K+-2Cl− cotransporter inhibitor) or amiloride (Na+/H+ exchange channel inhibitor). Suppressing amiloride-sensitive Na+/H+ exchange channels diminished hypertonicity-linked increases in vascular [NO], whereas blockade of Na+-K+-2Cl− channels greatly suppressed increases in vascular [NO] and intestinal blood flow. In additional experiments we examined the effect of sodium ion entry into endothelial cells. We proposed that the Na+/Ca2+ exchanger extrudes Na+ in exchange for Ca2+, thereby leading to the calcium-dependent activation of endothelial nitric oxide synthase (eNOS). We blocked the activity of the Na+/Ca2+ exchanger during 360 mosM NaCl hyperosmolarity with KB-R7943; complete blockade of increased vascular [NO] and intestinal blood flow to hyperosmolarity occurred. These results indicate that during NaCl hyperosmolarity, sodium ions enter endothelial cells predominantly through Na+-K+-2Cl− channels. The Na+/Ca2+ exchanger then extrudes Na+ and increases endothelial Ca2+. The increase in endothelial Ca2+ causes an increase in eNOS activity, and the resultant increase in NO increases intestinal arteriolar diameter and blood flow during NaCl hyperosmolarity. This appears to be the major mechanism by which intestinal nutrient absorption is coupled to increased blood flow.
Basal myosin light chain phosphorylation is a determinant of Ca2+ sensitivity of force and activation dependence of the kinetics of myocardial force development
Authors: Olsson M. Charlotte , Patel Jitandrakumar R. , Fitzsimons Daniel P. , Walker Jeffery W. , Moss Richard L.
Published: August 2004

It is generally recognized that ventricular myosin regulatory light chains (RLC) are ∼40% phosphorylated under basal conditions, and there is little change in RLC phosphorylation with agonist stimulation of myocardium or altered stimulation frequency. To establish the functional consequences of basal RLC phosphorylation in the heart, we measured mechanical properties of rat skinned trabeculae in which ∼7% or ∼58% of total RLC was phosphorylated. The protocol for achieving ∼7% phosphorylation of RLC involved isolating trabeculae in the presence of 2,3-butanedione monoxime (BDM) to dephosphorylate RLC from its baseline level. Subsequent phosphorylation to ∼58% of total was achieved by incubating BDM-treated trabeculae in solution containing smooth muscle myosin light chain kinase, calmodulin, and Ca2+ (i.e., MLCK treatment). After MLCK treatment, Ca2+ sensitivity of force increased by 0.06 pCa units and maximum force increased by 5%. The rate constant of force development ( ktr) increased as a function of Ca2+ concentration in the range between pCa 5.8 and pCa 4.5. When expressed versus pCa, the activation dependence of ktr appeared to be unaffected by MLCK treatment; however, when activation was expressed in terms of isometric force-generating capability (as a fraction of maximum), MLCK treatment slowed ktr at submaximal activations. These results suggest that basal phosphorylation of RLC plays a role in setting the kinetics of force development and Ca2+ sensitivity of force in cardiac muscle. Our results also argue that changes in RLC phosphorylation in the range examined here influence actin-myosin interaction kinetics differently in heart muscle than was previously reported for skeletal muscle.
Flow-conditioned HUVECs support clustered leukocyte adhesion by coexpressing ICAM-1 and E-selectin
Authors: Burns Michael P. , DePaola Natacha
Published: August 2004

Endothelial sequestration of circulating monocytes is a key event in early atherosclerosis. Hemodynamics is proposed to regulate monocyte-endothelial cell interactions by direct cell activation and establishment of flow environments that are conducive or prohibitive to cell-cell interaction. We investigated fluid shear regulation of monocyte-endothelial cell adhesion in vitro using a disturbed laminar shear system that models in vivo hemodynamics characteristic of lesion-prone vascular regions. Human endothelial cell monolayers were flow conditioned for 6 h before evaluation of monocyte adhesion under static and dynamic flow conditions. Results revealed a distinctive clustered cell pattern of monocyte adhesion that strongly resembles in vivo leukocyte adhesion in early- and late-stage atherosclerosis. Clustered monocyte cell adhesion correlated with endothelial cells coexpressing intercellular adhesion molecule-1 (ICAM-1) and E-selectin as result of a flow-induced, selective upregulation of E-selectin expression in a subset of ICAM-1-expressing cells. Clustered monocyte cell adhesion assayed under static conditions exhibited a spatial variation in size and frequency of occurrence, which demonstrates differential regulation of endothelial cell adhesiveness by the local flow environment. Dynamic adhesion studies conducted with circulating monocytes resulted in clustered cell adhesion only within the disturbed flow region, where the monocyte rate of motion is sufficiently low for cell-cell interaction. These studies provide evidence and reveal mechanisms of local hemodynamic regulation of endothelial adhesiveness and endothelial monocyte interaction that lead to localized monocyte adhesion and potentially contribute to the focal origin of arterial diseases such as atherosclerosis.
Heat stress induces a biphasic thermoregulatory response in mice
Authors: Leon Lisa R. , DuBose David A. , Mason Clifford W.
Published: August 2004

Previous animal models of heat stress have been compromised by methodologies, such as restraint and anesthesia, that have confounded our understanding of the core temperature (Tc) responses elicited by heat stress. Using biotelemetry, we developed a heat stress model to examine Tcresponses in conscious, unrestrained C57BL/6J male mice. Before heat stress, mice were acclimated for >4 wk to an ambient temperature (Ta) of 25°C. Mice were exposed to Taof 39.5 ± 0.2°C, in the absence of food and water, until they reached maximum Tcof 42.4 ( n = 11), 42.7 ( n = 12), or 43.0°C ( n = 11), defined as mild, moderate, and extreme heat stress, respectively. Heat stress induced an ∼13% body weight loss that did not differ by final group Tc; however, survival rate was affected by final Tc(100% at 42.4°C, 92% at 42.7°C, and 46% at 43°C). Hypothermia (Tc< 34.5°C) developed after heat stress, with the depth and duration of hypothermia significantly enhanced in the moderate and extreme compared with the mild group. Regardless of heat stress severity, every mouse that transitioned out of hypothermia (survivors only) developed a virtually identical elevation in Tcthe next day, but not night, compared with nonheated controls. To test the effect of the recovery Ta, a group of mice ( n = 5) were acclimated for >4 wk and recovered at Taof 30°C after moderate heat stress. Recovery at 30°C resulted in 0% survival within ∼2 h after cessation of heat stress. Using biotelemetry to monitor Tcin the unrestrained mouse, we show that recovery from acute heat stress is associated with prolonged hypothermia followed by an elevation in daytime Tcthat is dependent on Ta. These thermoregulatory responses to heat stress are key biomarkers that may provide insight into heat stroke pathophysiology.
Determinants of fat oxidation during exercise in healthy men and women: a cross-sectional study
Authors: Venables Michelle C. , Achten Juul , Jeukendrup Asker E.
Published: August 2004

The aim of the present study was to establish fat oxidation rates over a range of exercise intensities in a large group of healthy men and women. It was hypothesised that exercise intensity is of primary importance to the regulation of fat oxidation and that gender, body composition, physical activity level, and training status are secondary and can explain part of the observed interindividual variation. For this purpose, 300 healthy men and women (157 men and 143 women) performed an incremental exercise test to exhaustion on a treadmill [adapted from a previous protocol (Achten J, Venables MC, and Jeukendrup AE. Metabolism 52: 747–752, 2003)]. Substrate oxidation was determined using indirect calorimetry. For each individual, maximal fat oxidation (MFO) and the intensity at which MFO occurred (Fatmax) were determined. On average, MFO was 7.8 ± 0.13 mg·kg fat-free mass (FFM)−1·min−1 and occurred at 48.3 ± 0.9% maximal oxygen uptake (V̇o2 max), equivalent to 61.5 ± 0.6% maximal heart rate. MFO (7.4 ± 0.2 vs. 8.3 ± 0.2 mg·kg·FFM−1·min−1; P < 0.01) and Fatmax (45 ± 1 vs. 52 ± 1% V̇o2 max; P < 0.01) were significantly lower in men compared with women. When corrected for FFM, MFO was predicted by physical activity (self-reported physical activity level), V̇o2 max, and gender ( R2 = 0.12) but not with fat mass. Men compared with women had lower rates of fat oxidation and an earlier shift to using carbohydrate as the dominant fuel. Physical activity, V̇o2 max, and gender explained only 12% of the interindividual variation in MFO during exercise, whereas body fatness was not a predictor. The interindividual variation in fat oxidation remains largely unexplained.
Living and Dying for Sex
Authors: Bowen Richard L. , Atwood Craig S.
Published: August 2004

A mechanistic understanding of aging has yet to be described; this paper puts forth a new theory that has the potential to explain aging in all sexually reproductive life forms. The theory also puts forth a new definition of aging – any change in an organism over time. This definition includes not only the changes associated with the loss of function (i.e. senescence, the commonly accepted definition of aging), but also the changes associated with the gain of function (growth and development). Using this definition, the rate of aging would be synonymous with the rate of change. The rate of change/aging is most rapid during the fetal period when organisms develop from a single cell at conception to a multicellular organism at birth. Therefore, ‘fetal aging’ would be determined by factors regulating the rate of mitogenesis, differentiation, and cell death. We suggest that these factors also are responsible for regulating aging throughout life. Thus, whatever controls mitogenesis, differentiation and cell death must also control aging. Since life-extending modalities consistently affect reproduction, and reproductive hormones are known to regulate mitogenesis and differentiation, we propose that aging is primarily regulated by the hormones that control reproduction (hence, the Reproductive-Cell Cycle Theory of Aging). In mammals, reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis hormones. Longevity inducing interventions, including caloric restriction, decrease fertility by suppressing HPG axis hormones and HPG hormones are known to affect signaling through the well-documented longevity regulating GH/IGF-1/PI3K/Akt/Forkhead pathway. This is exemplified by genetic alterations in Caenorhabditis elegans where homologues of the HPG axis pathways, as well as the daf-2 and daf-9 pathways, all converge on daf-16, the homologue of human Forkhead that functions in the regulation of cell cycle events. In summary, we propose that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence.
Uncontrolled Crying: Characteristics and Differences from Normative Crying
Authors: Grinblat Neta , Grinblat Einat , Grinblat Joseph
Published: August 2004

Background: Uncontrolled crying (UC) is a prevalent poststroke phenomenon of elderly patients, socially disabling and interfering with rehabilitation. There are many differences in opinions and nonclarity in the literature relating to UC. Objective: To examine two basic questions regarding UC that have as yet not been experimentally studied: typical situations where UC occurs and how UC differs from normative crying (NC). Methods: Crying episodes of elderly patients suffering from poststroke UC were documented. From 235 crying documented episodes, instructions for further follow-up documentation were received. According to these instructions, 1,098 crying episodes were documented. Using the ‘truncated pyramid’ model developed during this study, 47 crying situations typical of poststroke UC processed into seven categories were identified. Based on these findings, we compared UC and NC. Results: UC and NC were found to differ in all tested variables: crying situations, content areas of crying situations, crying frequency, crying frequency of men as compared with that of women, and crying frequency when alone as compared with the crying frequency in the presence of others. Conclusions: UC should be approached as an entity totally different from NC within a wide range of variables. The study’s findings assist in understanding UC, the reasons for its disabling effect, and the need for exploring ways to aid elderly patients suffering from poststroke UC. The situations typical of UC and their categories found in this study may serve as additional clinical and research means for these purposes.
Effects of Lesopitron on the Central Nervous System Arising from Its Interaction with 5-HT1A Receptors
Authors: Fisas M. Angels , Farré Antonio , Camarasa Jorge , Escubedo Elena
Published: August 2004

Lesopitron acts as a ligand for central serotonin 5-HT1A receptors. Ki obtained from [3H]8-OH-DPAT competition studies was 104.8 ± 10.6 nmol/l. As lesopitron did not affect the binding of [3H]paroxetine, involvement of the serotonin reuptake system in the effects of lesopitron is rejected. Lesopitron inhibits haloperidol-induced catalepsy that is the consequence of its action on 5-HT1A autoreceptors. The ability of lesopitron to induce 5-HT syndrome reflects post-synaptic 5-HT1A receptor activation and the reversion of 8-OHDPAT-induced 5-HT syndrome by lesopitron suggests a partial agonist effect on this receptor-type. Lesopitron induced a hypothermic effect due to the enhanced activation of post-synaptic 5-HT1A receptors. The agonist effect of lesopitron on 5-HT1A receptors and its marked hypothermic effect is an added value for this drug and a stimulus to the study of its possible neuroprotective action.
Pharmacological Study of IQM-97,423, a Potent and Selective CCK1 Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis
Authors: Latorre M. , Bartolomé-Nebreda J.M. , García-López M.T. , González-Muñiz R. , Herranz R. , Del Río J. , Cenarruzabeitia E.
Published: August 2004

The pharmacological profile of the new CCK1 receptor antagonist IQM-97,423, (4aS,5R)-2-benzyl-5-(tert-butylaminocarbonyl-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine, was examined in in vitro and in vivo studies and compared with typical CCK1 antagonists such as devazepide and lorglumide. IQM-97,423 showed a high affinity at [3H]-pCCK8-labeled rat pancreatic CCK1 receptors, and was virtually devoid of affinity at brain CCK2 receptors. IQM-97,423 antagonized CCK8S-stimulated α-amylase release from rat pancreatic acini with a potency similar to devazepide and much higher than lorglumide. In the guinea pig isolated longitudinal muscle-myenteric plexus preparation, IQM-97,423 produced a full antagonism of the contractile response elicited by CCK8S and a weaker effect on the contraction elicited by CCK4, suggesting a selective antagonism at CCK1 receptors. The protective effect of IQM-97,423 and devazepide was tested in two models of acute pancreatitis in rats, induced by injection of cerulein or by combined bile and pancreatic duct obstruction. The new compound fully prevented the cerulein-induced increase in plasma pancreatic enzymes and in pancreas weight with a potency similar to devazepide. In common bile-pancreatic duct ligature-induced acute pancreatitis, IQM-97,423 partially prevented, like devazepide, the increase in plasma pancreatic enzyme activity and in pancreas weight. Consequently, the pyridopyrimidine derivative IQM-97,423 is a potent and highly selective CCK1 receptor antagonist with preventive effects in two experimental models of acute pancreatitis and a potential therapeutic interest.
Aggravation of Inflammatory Bowel Disease by Cyclooxygenase-2 Inhibitors in Rats
Authors: Singh Vijay Pal , Patil Chandrashekhar S. , Jain Naveen K. , Kulkarni Shrinivas K.
Published: August 2004

The objective of the present study was to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor in in-vivo dextran sodium sulfate (DSS)-stimulated distal colon tissues of the rat. Longitudinal colon tissue sections from DSS-treated rats exhibited noticeable inflammation, altered contraction, increased myleoperoxidase activity, and oxidative stress. When the animals were pretreated with celecoxib, a selective COX-2 inhibitor, the flare of the colon was further worsened in terms of all the parameters studied. There was a reduction in PGE2 levels on chronic administration of celecoxib in DSS-treated animals. The results of the present study suggest that COX-2 enzyme and prostaglandins derived from COX-2 might play a defensive role in protecting ulceration of the colon akin to that seen in the upper gastrointestinal tract.
Prostaglandin Analogs and Blood-Aqueous Barrier Integrity: A Flare Cell Meter Study
Authors: Cellini M. , Caramazza R. , Bonsanto D. , Bernabini B. , Campos E.C.
Published: August 2004

Purpose: To study, with an objective method, inflammation of the anterior segment of the glaucomatous eye after treatment with latanoprost, travoprost and bimatoprost. Materials and Methods: Sixty patients with chronic open-angle glaucoma aged between 38 and 76 years (mean 64.0 ± 12.2) were randomly assigned to latanoprost 0.005, travoprost 0.004 and bimatoprost 0.03%. The study period lasted 6 months. Intraocular pressure (IOP) was measured every 2 weeks. We studied the intraocular inflammation before and after 3 and 6 months of therapy with an instrument composed of a He-Ne laser beam system, a photomultiplier mounted on a slitlamp microscope and a computer. This flare meter allows objective determination of the flare and the number of cells in the aqueous of the anterior chamber. Results: At the baseline, IOP was 26.4 ± 3.6 mm Hg. After 3 months of treatment, mean IOP in the latanoprost group was 17.9 ± 0.3 mm Hg (p < 0.001) with a mean cellularity of 12.638 ± 3.284 photons/ms (p < 0.001). The travoprost group had an IOP of 17.2 ± 0.3 mm Hg (p < 0.001) with a cellularity of 9.719 ± 1.927 photons/ms (0.001). Finally, IOP in the bimatoprost group was 17.6 ± 0.5 mm Hg (p < 0.001) with a cellularity of 6.138 ± 1.475 photons/ms (p < 0.032). After 6 months of treatment, IOP in the latanoprost group was 18.1 ± 0.3 (p < 0.001), in the travoprost group 17.3 ± 0.3 (p < 0.001) and in the bimatoprost group 17.7 ± 0.5 mm Hg (p < 0.001), whereas cellularity was 11.838 ± 3.218 (p < 0.001), 8.950 ± 3.692 (p < 0.001) and 7.617 ± 2.603 photons/ms (p < 0.001), respectively. After 3 months, the travoprost (p < 0.013) and the bimatoprost groups (p < 0.001) had less flare compared with the latanoprost group and this remained so even at 6 months. When we compared the travoprost group with the bimatoprost group, we found significantly less flare at 3 months in the bimatoprost group (p < 0.001) but not at 6 months (p < 0.246). Conclusions: The flare meter analysis shows that the eyes treated with bimatoprost and travoprost have a less significantly broken blood-aqueous barrier and their anterior chamber is also significantly less inflamed.
Antifungal Activity of Intraocularly Used Liquids against Aspergillus
Authors: Economou-Stamatelopoulou Calliope , Roussopoulos George P. , Prouskas John C. , Apostolopoulos Michael
Published: August 2004

The antifungal effectiveness of liquids used as intraocular tamponading agents in vitrectomy was tested against a strain of Aspergillus niger. This microorganism is a frequent causative factor of endophthalmitis. The strain belonged to the ATCC collection (A. niger ATCC 16404). The samples tested were: (a) perfluorocarbons: perfluorodecalin and perfluoroctane, (b) silicone oils: Siloil 1,000 and Siloil 5,000, and (c) balanced salt solutions: BSS and BSS Plus. The experiment consisted in inoculating the samples with the microorganism, in preserving the samples in 25°C in the dark, and in taking small amounts of each product for counting surviving microorganisms at t = 0 and then after 1 day, and 1, 2, 3 and 4 weeks. Among the samples tested, perfluorocarbons and silicone oils conform to the standards. No increase, and in some samples decrease, in the number of microorganisms is observed during the second week, while the number drops to zero at the end of the experiment. Therefore, the use of these liquids is safe.
Posterior Vitreous Detachment: Clinical Correlations
Authors: Hayreh Sohan Singh , Jonas Jost B.
Published: August 2004

Background: To evaluate the frequency of, and the factors which are primarily and secondarily associated with, posterior vitreous detachment (PVD), and to correlate the presence of PVD with various demographic and ophthalmic entities. Methods: The clinical prospective observational cohort study included 1,481 subjects (740 women, 741 men) with a mean age of 63.45 ± 14.97 years (mean ± SD; range, 10.3–94.9 years) and a mean spherical equivalent refractive error of +0.68 ± 2.13 dpt (range, –14.25 to +13.50 dpt). The presence of PVD was assessed by indirect and direct ophthalmoscopy, fundus biomicroscopy and by using a Hruby lens upon pharmacologically dilated pupil. Main outcome measures were frequency of PVD, association with age, refractive error, cataract surgery, diabetes mellitus, arterial hypertension, history of ocular trauma, vitreous hemorrhage, various retinal disorders, nonarteritic anterior ischemic optic neuropathy (AION) and open-angle glaucoma. Results: The occurrence of PVD was significantly correlated with increasing age (p < 0.001), myopic refractive error (p < 0.001), female gender (p < 0.001), and surgical aphakia (p < 0.001). PVD occurred significantly more often bilaterally than unilaterally (p < 0.001). Patients with unilateral PVD were significantly (p < 0.001) younger than the patients with bilateral PVD. PVD was seen significantly (p = 0.038) less frequently in AION than in the remaining study population. The frequency of PVD was lower in eyes with than without diabetic retinopathy (p = 0.095), optic disc neovascularization (p = 0.07) and retinal neovascularization (p = 0.09). There was no significant association between the presence of PVD and macular hole, macular edema, retinal vascular occlusive disorders, age-related macular degeneration and open-angle glaucoma. Conclusions: These data of a large prospective study of PVD confirm some of the findings of previous smaller and retrospective studies. They also provide new information which may be helpful for the understanding of the pathophysiology of PVD and the role of PVD in the pathogenesis of various retinal and optic disc lesions.
Review of the Ischemia Hypothesis for Ocular Hypertension Other than Congenital Glaucoma and Closed-Angle Glaucoma
Authors: Nakabayashi Masao
Published: August 2004

Experimentally induced ischemia of the endothelial cells surrounding the aqueous drainage sites led to a rise in intraocular pressure (IOP) in monkey and pigeon eyes. Clinical conditions associated with a rise in IOP in human eyes, e.g. peripheral retinal detachments, subluxated lenses, and occlusion of the internal carotid artery, can result in ischemia of the endothelial cells lining Schlemm’s canal. These findings led to the hypothesis that ischemia of the endothelial cells of Schlemm’s canal induces hypertension in human eyes. Thus, the ischemia hypothesis should be considered in discussions of the etiology of age-related open-angle glaucoma.
Diagnostic Utility of a Low-Dose Gonadotropin-Releasing Hormone Test in the Context of Puberty Disorders
Authors: Zevenhuijzen H. , Kelnar C.J.H. , Crofton P.M.
Published: August 2004

Objectives: The 10-µg gonadotropin-releasing hormone (GnRH) test assesses pituitary gonadotroph responsiveness, whereas the 100-µg dose assesses maximal secretory capacity. Our aims were to establish normative data for the low-dose test in children and to evaluate the test in diagnosing common pubertal disorders. Methods: We retrospectively classified 107 children who underwent 10-µg GnRH tests into normal prepubertal (20 boys, 10 girls), normal early pubertal (10 boys, 16 girls), constitutional delay of puberty (CDP, 13 prepubertal boys >12 years), hypogonadotropic hypogonadism (HH, 5 prepubertal boys >12 years), central precocious puberty (CPP, 19 girls) or premature thelarche/variant (13 girls). Results: Peak LH response was higher in prepubertal boys >12 years compared with younger boys (p < 0.01) but showed no further change in early puberty. CDP boys had LH responses similar to prepubertal boys >12 years. HH boys showed an absent LH response which diagnosed HH with 100% sensitivity and 96% specificity. Thelarche girls had LH:FSH peak ratios lower than normal prepubertal (p = 0.001), pubertal (p < 0.05) or CPP (p = 0.001) girls. Conclusions: We have established normative values for the low-dose GnRH test in children. The test successfully differentiated HH from CDP in boys, and contributed to the differential diagnosis of CPP and premature thelarche in girls.
Perceived Family Difficulties and Prediction of 23-Year Stroke Mortality among Middle-Aged Men
Authors: Tanne David , Goldbourt Uri , Medalie Jack H.
Published: August 2004

Background/Objective: To examine the association of indicators of family problems, support and coping style and prediction of stroke mortality among a large cohort of middle-aged men. Methods: A cohort of 10,059 men aged ≧40 years at study inclusion that were tenured civil servants or municipal employees were followed for mortality over 23 years, for a total of about 200,000 person-years of follow-up. Mortality attributed to stroke and to CHD as underlying causes was determined. Subjects underwent a structured psychosocial questionnaire at baseline by trained interviewers, and associations between each indicator of perceived family difficulties, support and coping (9 indicators in total) and mortality from stroke and from CHD were estimated using the proportional hazard model by Cox. Results: During the 23-year follow-up period, 364 men died of stroke, and 1,098 men died of CHD.Among the indicators, perceived serious family difficulties at baseline, adjusted for traditional risk factors, were associated with higher risk of dying from stroke (HR 1.34, 95% CI 1.04–1.72), as were wife and children not tending to listen (HR 1.29, 95% CI 1.00–1.65), and person tending to keep feelings to oneself when conflict with wife (HR 1.27, 95% CI 1.03–1.37), while other indicators had associated HRs nearer unity. None of the variables assessed predicted mortality from CHD over a long-term follow-up. Conclusion: Several indicators of perceived family problems, family support and coping style are related to risk of dying from stroke over a long-term follow-up among middle-aged men.
Incidence and Etiologies of Stroke during Pregnancy and Puerperium as Evidenced in Taiwanese Women
Authors: Jeng Jiann-Shing , Tang Sung-Chun , Yip Ping-Keung
Published: August 2004

Background: Pregnancy is a known risk factor for stroke, but relatively few studies have been conducted in Asian populations to document the risk. This study aimed to analyze the incidence and etiologies of stroke occurring during pregnancy and puerperium in Taiwanese women. Methods: From 1984 to 2002, female patients 15 through 40 years of age with first-ever stroke during pregnancy or within 6 weeks of delivery were recruited. Stroke was classified as ischemic stroke (IS), cerebral venous thrombosis (CVT), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). The incidence, time of stroke onset (1st through 3rd trimester or puerperium), and etiologies of different stroke subtypes were analyzed. Results: Of 402 young female stroke patients, 49 had stroke during pregnancy and puerperium, including 16 with IS, 11 with CVT, 19 with ICH and 3 with SAH. After excluding referral patients, the incidences of pregnancy-related stroke were 46.2 (95% CI 30.7–69.5) per 100,000 pregnancies. 67% developed stroke in the 3rd trimester and puerperium, and 73% of CVT occurred in the puerperium period. Etiologies were well defined in 78% of patients. Eclampsia (37%) and arteriovenous malformation (26%) were the most important etiologies of ICH. For IS and CVT, rheumatic heart disease (44%) and coagulopathy (64%) were the major etiologies respectively. Conclusions: The incidence of stroke occurrence during pregnancy and puerperium in Taiwanese women is higher than that of Caucasian populations; the majority of strokes occurred in the 3rd trimester and puerperium, particularly CVT.
Relevance of Transient Ischemic Attack to Early Neurological Recovery after Nonlacunar Ischemic Stroke
Authors: Arboix A. , Cabeza N. , García-Eroles L. , Massons J. , Oliveres M. , Targa C. , Balcells M.
Published: August 2004

Background: We hypothesized that previous transient ischemic attack (TIA) had a favorable effect on early outcome after acute nonlacunar ischemic stroke. Methods: Data of 1,753 consecutive patients with ischemic stroke collected from a prospective hospital-based stroke registry were studied. A comparison was made of the groups with and without previous TIA. Favorable outcome included spontaneous neurological recovery or grades 0–2 of the modified Rankin scale at hospital discharge. Results: Previous TIA occurred in 55 (11.5%) of 484 patients with lacunar stroke and in 166 (13.1%) of 1,269 patients with nonlacunar stroke. The percentage of nonlacunar ischemic stroke patients with favorable outcome was 21.7% in those with a history of TIA compared to 15% without TIA (p < 0.03). In the lacunar stroke group, differences were not significant. In the multivariate analysis, TIA was an independent predictor of spontaneous in-hospital recovery. Conclusions: Prior TIA was associated with a favorable outcome in nonlacunar ischemic stroke, suggesting a neuroprotective effect of TIA possibly by inducing a phenomenon of ischemic tolerance allowing better recovery from a subsequent ischemic stroke.
Plasma Concentrations of Orexins in Children
Authors: Tomasik Przemyslaw J. , Spodaryk Mikolaj , Sztefko Krystyna
Published: August 2004

Background: According to experiments done on animals and adult humans, orexins are involved in homeostasis of energy balance, feeding and arousal. The purpose of this study was to evaluate plasma orexins concentrations in children in relation to body mass index (BMI), energy demand and duration of sleep. Material and Methods: Studied children were grouped as follows: newborns (n = 7), infants (n = 15), prepubertal children (2–9 years, n = 12), pubertal children (10–15 years, n = 8) and postpubertal adolescents (16–18 years, n = 8). Plasma orexins concentrations were determined by EIA after extraction of samples on Sep-Pak columns. Results: The plasma concentration of orexin A was higher than the concentration of orexin B in all children studied. The concentrations of these two peptides were correlated (r = 0.45, p < 0.03). The highest mean plasma levels of orexin A and B were found in neonates and in children during puberty (orexin A: 1.02 ± 0.17 ng/ml and 1.01 ± 0.12 ng/ml, orexin B: 0.67 ± 0.18 and 0.65 ± 0.09 ng/ml, respectively) while in other groups the results were significantly lower. A significant negative correlation was found between BMI and the concentrations of orexin A (r = –0.51, p < 0.01) and orexin B (r = –0.45, p < 0.03). A positive correlation was found between the concentrations of both orexins and caloric demand (orexin A: r = 0.43, p < 0.05, orexin B: r = 0.48, p < 0.02). No correlation was found between the concentrations of orexins and the duration of sleep. Conclusion: Orexins play a significant role in children’s growth as a long-term satiety factor and may coordinate energy homeostasis with sexual maturation.
Accumulation of Selected Carotenoids, α-Tocopherol and Retinol in Human Ovarian Carcinoma Ascitic Fluid
Authors: Schweigert Florian J. , Raila Jens , Sehouli Jalid , Buscher Ulrich
Published: August 2004

Background: Patients with severe forms of cancer are reported to have reduced concentrations of micronutrients in plasma due to the chronic reduction of food intake and an increased metabolism of these components. The purpose of this study was to evaluate if an accumulation of carotenoids, α-tocopherol and retinol in malignant ascitic fluid in women with ovarian cancer might contribute to a loss of these components from plasma. Methods: Blood and ascitic fluid samples obtained from 21 women with ovarian carcinomas and 17 healthy controls were analyzed for retinol, retinol-binding protein (RBP), α-tocopherol and carotenoids. Results: Plasma concentrations of all micronutrients were lower in cancer patients compared to controls. Ascitic fluid concentration of all investigated components was comparable (73–110%) to plasma. While the mean concentration of retinol in malignant ascites represented 73% of that in plasma, the concentration of RBP was less than 10% resulting in an increased mean molar ratio of retinol to RBP from 1.18 to 10.5. Conclusions: The results suggest that lower plasma concentrations of micronutrients in women suffering from ovarian carcinoma are not only caused by a cachexia-induced decrease of food intake and a higher rate of metabolic utilization, but also by a substantial yet not considered transfer from plasma into ascitic fluid possibly associated with plasma lipoproteins. This raises questions with regard to the protective function of these plasma components in ascitic fluid, the consequences of paracentesis on an additional supplementation and finally the possibility to use one or a combination of these components as an additional marker to discriminate between benign and malignant ascites.
Effects of Undernutrition on Glycine Metabolism in the Cerebellum of Rats
Authors: de Souza Karine B. , Feoli Ana Maria , Krüger Adriane H. , de Souza Marcelo R. , Perry Carolina T. , Rotta Liane N. , Souza Diogo O. , Perry Marcos L.S.
Published: August 2004

Undernutrition is a worldwide problem affecting millions of unborn and young children during the most vulnerable stages of brain development. Total restriction of protein during the perinatal period of life can alter the development of the mammalian fetus and have marked repercussions on development of the central nervous system (CNS). The brain is vulnerable to undernutrition with altered morphologic and biochemical maturation, leading to impaired functions. The focus of this study is to investigate [U-14C]glycine metabolism in undernourished rats submitted to pre- and postnatal protein deprivation (diet: 8% protein with and without addition of L-methionine; control group: 25% protein). Although undernutrition produced a reduction in cerebellar weight and alterations in the DNA concentration, the present study shows that glycine metabolism in this structure is partially protected because the undernourished group with L-methionine did not show modifications in glycine metabolism at all ages studied. However, L-methionine deficiency alters glycine metabolism at 7 and 21 days, but in the adult age both undernourished groups presented no differences in oxidation to CO2, conversion to lipids and incorporation into protein from glycine, compared to the control group.
The Construction of a New Evaluative GERD Questionnaire – Methods and State of the Art
Authors: Armstrong David , Mönnikes Hubert , Bardhan Karna Dev , Stanghellini Vincenzo
Published: August 2004

Gastroesophageal reflux disease (GERD) is one of the most prevalent diseases worldwide, and it is becoming increasingly important to monitor the effect of various interventions on GERD symptoms. There can be rapid temporal changes in the severity and frequency of patients’ symptoms as well as their health status and well-being, all of which could, theoretically, be monitored using diaries or questionnaires. However, current GERD monitoring instruments are not appropriate because they do not assess symptoms daily, they are not sufficiently responsive to short-term changes in health status or they are not adequately validated. To address these problems, the conceptual and psychometric requirements for a GERD symptom assessment questionnaire were identified. A dimension-based scale was designed to reduce the number of symptoms monitored on a daily basis, and the validation process was defined to produce parallel long and short forms of a scale for patients’ self-assessment of their GERD symptom response to therapy. These basic principles which underlie the successful development of a new, self-assessed symptomatic reflux questionnaire (ReQuestTM) are also applicable to the development of validated questionnaires for daily symptom self-assessment in other disease areas.
Bone Marrow–Derived Monocyte Chemoattractant Protein-1 Receptor CCR2 Is Critical in Angiotensin II–Induced Acceleration of Atherosclerosis and Aneurysm Formation in Hypercholesterolemic Mice
Authors: Ishibashi Minako , Egashira Kensuke , Zhao Qingwei , Hiasa Ken-ichi , Ohtani Kisho , Ihara Yoshiko , Charo Israel F. , Kura Shinobu , Tsuzuki Teruhisa , Takeshita Akira , Sunagawa Kenji
Published: August 2004

Angiotensin II (Ang II) is implicated in atherogenesis by activating inflammatory responses in arterial wall cells. Ang II accelerates the atherosclerotic process in hyperlipidemic apoE−/− mice by recruiting and activating monocytes. Monocyte chemoattractant protein-1 (MCP-1) controls monocyte-mediated inflammation through its receptor, CCR2. The roles of leukocyte-derived CCR2 in the Ang II-induced acceleration of the atherosclerotic process, however, are not known. We hypothesized that deficiency of leukocyte-derived CCR2 suppresses Ang II-induced atherosclerosis.

Methods and Results—A bone marrow transplantation technique (BMT) was used to develop apoE−/− mice with and without deficiency of CCR2 in leukocytes (BMT-apoE−/−CCR2+/+ and BMT-apoE−/−CCR2−/− mice). Compared with BMT-apoE−/−CCR2+/+ mice, Ang II-induced increases in atherosclerosis plaque size and abdominal aortic aneurysm formation were suppressed in BMT-apoE−/−CCR2−/− mice. This suppression was associated with a marked decrease in monocyte-mediated inflammation and inflammatory cytokine expression.

Conclusion—Leukocyte-derived CCR2 is critical in Ang II-induced atherosclerosis and abdominal aneurysm formation. The present data suggest that vascular inflammation mediated by CCR2 in leukocytes is a reasonable target of therapy for treatment of atherosclerosis.
Hypercholesterolemia Impairs Transduction of Vasodilator Signals Derived From Ischemic Myocardium
Authors: Sato Kouichi , Komaru Tatsuya , Shioiri Hiroki , Takeda Satoru , Takahashi Katsuaki , Kanatsuka Hiroshi , Nakayama Masaharu , Shirato Kunio
Published: August 2004

Objective—

Coronary microvessels are functionally coupled to the myocardial metabolic state. In hypercholesterolemia, the coronary vascular dysfunction extends to microvascular levels. We hypothesized that the vasodilator signal transduction from ischemic heart is impaired in the coronary microvascular wall of hypercholesterolemia.

Methods and Results—

Rabbits were fed with normal chow (control group) or 2% high-cholesterol diet (hypercholesterolemia group) for 8 weeks. Coronary microvessels isolated from rabbit hearts were pressurized and gently placed on a beating canine heart. Myocardial ischemia was produced in the beating heart and the diameter of the isolated microvessel was observed using an intravital microscope with a floating objective. In control group, the isolated microvessels significantly dilated 2 minutes after the onset of ischemia, and a plateau was observed at 10 minutes. In contrast, the microvessels from hypercholesterolemia group did not dilate during ischemia. Dihydroethidium fluorescence microscopy revealed an elevated superoxide level in the microvessels of hypercholesterolemia group. The application of tiron (free radical scavenger) significantly dilated the isolated microvessels only from hypercholesterolemic animals.

Conclusions—

We conclude that the transduction of vasodilator signals derived from ischemic myocardium is impaired in the coronary microvascular wall of hypercholesterolemia. Enhanced oxidative stress in hypercholesterolemia may alter the microvascular function.
Inhibition of Cholesteryl Ester Transfer Protein Activity by JTT-705 Increases Apolipoprotein E–Containing High-Density Lipoprotein and Favorably Affects the Function and Enzyme Composition of High-Density Lipoprotein in Rabbits
Authors: Zhang Bo , Fan Ping , Shimoji Eiso , Xu Huali , Takeuchi Kazuma , Bian Cheng , Saku Keijiro
Published: August 2004

Background—

Inhibition of cholesteryl ester transfer protein (CETP) is an efficient way to increase high-density lipoprotein (HDL) levels in humans. We investigated the effects of the inhibition of CETP activity by a CETP inhibitor, JTT-705, on the function and composition of HDL particles.

Methods and Results—

Japanese white rabbits were fed either normal rabbit chow LRC-4 (n=10) or a food admixture of LRC-4 and 0.75% JTT-705 (n=10) for 7 months. JTT-705 significantly inhibited CETP activities, increased HDL cholesterol (HDL-C) levels and the ratio of HDL
2
-C/HDL
3
-C, and decreased the fractional esterification rate of cholesterol in HDL, indicating preferentially increased large HDL particles. Treatment with JTT-705 increased all of the 3 charge-based HDL subfractions as determined by capillary isotachophoresis: fast-migrating, intermediate-migrating, and slow-migrating HDL. The percentage of slow HDL, ie, apolipoprotein E (apoE)-containing HDL and levels of apoE in HDL fraction, was also increased. JTT-705 treatment increased serum paraoxonase activity and HDL-associated platelet-activating factor acetylhydrolase activity, but decreased the plasma lysophosphatidylcholine concentration.

Conclusion—

Inhibition of CETP activity by JTT-705 not only increased the quantity of HDL, including HDL-C levels and charge-based HDL subfractions, but also favorably affected the size distribution of HDL subpopulations and the apolipoprotein and enzyme composition of HDL in rabbits.
Function of Interstitial Cells of Cajal in the Rabbit Portal Vein
Authors: Harhun Maksym I. , Gordienko Dmitri V. , Povstyan Oleksandr V. , Moss Ray F. , Bolton Thomas B.
Published: August 2004

Interstitial cells of Cajal (ICCs) were identified in the intact fixed media of the rabbit portal vein (RPV) using
c-kit
staining. The following experiments were performed using single cell preparations of the enzyme-dispersed vessel. Surviving contacts between the processes of single ICCs and the bodies of smooth muscle cells (SMCs) were observed in electron micrographs and by confocal microscopy. Spontaneous rhythmical [Ca
2+
]
i
oscillations were observed in ICCs after loading with the calcium indicator fluo-3 and were associated with depolarizations of the ICCs recorded by tight-seal patch pipette. To investigate signal transmission from ICCs to SMCs in dispersed cell pairs, or within small surviving fragments of the ICC network, an ICC was stimulated under voltage-clamp, while changes in [Ca
2+
]
i
in the stimulated cell as well as in a closely adjacent SMC or ICCs were monitored using fast
x
-
y
confocal imaging of fluo-3 fluorescence. After stimulation of single voltage-clamped ICC by a depolarizing step similar in duration to depolarizations associated with spontaneous [Ca
2+
]
i
oscillations, a depolarization and transient elevation of [Ca
2+
]
i
was observed in a closely adjacent SMCs after a delay of up to 4 seconds. In contrast, signal transmission from ICC to ICC was much faster, the delay being less than 200 ms. These results suggest that the an ICC may, in addition to generating an electrical signal (such as a slow wave) and thereby acting as a pacemaker for vascular SMCs of RPV, also release some unknown diffusible substance, which depolarizes the SMCs.
Genome-Wide Linkage in a Large Dutch Consanguineous Family Maps a Locus for Intracranial Aneurysms to Chromosome 2p13
Authors: Roos Y.B.W.E.M. , Pals G. , Struycken P.M. , Rinkel G.J.E. , Limburg M. , Pronk J.C. , van den Berg J.S.P. , Luijten J.A.F.M. , Pearson P.L. , Vermeulen M. , Westerveld A.
Published: August 2004

Background and Purpose—

Familial occurrence of intracranial aneurysms suggests a genetic factor in the development of these aneurysms. In this study, we present the identification of a susceptibility locus for the development of intracranial aneurysms detected by a genome-wide linkage approach in a large consanguineous pedigree.

Methods—

Patients with clinical signs and symptoms of intracranial aneurysms, confirmed by radiological, surgical, or postmortem investigations, were included in the study. Magnetic resonance angiography was used to detect asymptomatic aneurysms in relatives.

Results—

Seven out of 20 siblings had an intracranial aneurysm. Genome-wide multipoint linkage analysis showed a significant logarithm of the odds score of 3.55.

Conclusion—

In a large consanguineous pedigree intracranial aneurysms are linked to chromosome 2p13 in a region between markers D2S2206 and D2S2977.
Prediction of Stroke by Self-Measurement of Blood Pressure at Home Versus Casual Screening Blood Pressure Measurement in Relation to the Joint National Committee 7 Classification
Authors: Asayama Kei , Ohkubo Takayoshi , Kikuya Masahiro , Metoki Hirohito , Hoshi Haruhisa , Hashimoto Junichiro , Totsune Kazuhito , Satoh Hiroshi , Imai Yutaka
Published: August 2004

Background and Purpose—

To compare the predictive power of self-measured home blood pressure (HBP) and casual blood pressure (CBP) for stroke risk in relation to the Joint National Committee 7 (JNC-7) classification.

Methods—

HBP and CBP measurements were taken in 1702 subjects (≥40 years) without a history of stroke, who were followed up for an average of 11 years. Subjects were classified into 4 groups on the basis of either HBP or CBP, according to the JNC-7 criteria: group 1 (HBP <115/75 mm Hg; CBP <120/80 mm Hg); group 2 (115/75≤HBP<135/85 mm Hg; 120/80≤CBP<140/90 mm Hg); group 3 (135/85≤HBP<150/95 mm Hg; 140/90≤CBP<160/100 mm Hg); and group 4 (HBP≥150/95 mm Hg; CBP ≥160/100 mm Hg). Groups 2, 3, and 4 were further divided into 2 subgroups (a and b): those without and with cardiovascular disease risks, respectively. The risk of the first stroke in these groups was examined by the Cox hazards model adjusted for age and sex.

Results—

The stroke risk in groups 3b and 4b (defined by HBP and CBP) was 2 to 5× higher than that in group 1 with significant differences. The risk in groups 2a, 3a, and even 4a was not significantly different from that in group 1 by the CBP-based classification, but the risk in group 4a was significantly higher than that in group 1 by the HBP-based classification, which also showed a stepwise increase in risk from groups 2a to 4a.

Conclusions—

The JNC-7 classification had a stronger predictive power using HBP-based classification compared with CBP-based classification, suggesting the usefulness of HBP in the management of hypertension.