bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrogen modulates the mechanical homeostasis of mouse arterial vessels through nitric oxide
Authors: Guo Xiaomei , Lu Xiao , Ren Huimin , Levin Ellis R. , Kassab Ghassan S.
Published: November 2005

We have recently shown that estrogen causes vessel dilation through receptor-mediated stimulation of nitric oxide (NO) production. Here, we hypothesize that estrogen modulates the mechanical homeostasis in the blood vessel wall through NO production. The mechanical properties of female ovariectomized (ovx) mice, female mice lacking the gene for endothelial NO synthase (eNOS−/−), and control female and male mice were studied to test the hypothesis. The femoral and carotid arteries and aorta were cannulated in situ and mechanically distended. The stress, strain, elastic modulus, and wall thickness of vessels in ovx and eNOS−/− mice, as well as intact female and male mice, were determined. Western blot and immunohistochemistry were used to assess eNOS protein expression in the aorta. Moreover, NO by-products of the femoral and carotid artery were determined by measuring the levels of nitrite and nitrate. Our results show that ovariectomy and eNOS−/− significantly decrease the strain in all arteries. Furthermore, the eNOS protein was significantly reduced in ovx mice. Finally, the NO metabolites were significantly decreased both in ovx and eNOS−/− mice. We found statistically significant correlations between the structural (wall thickness), mechanical (stress, strain, and elastic modulus), and biochemical parameters (NO by-products). These novel results connect NO to the structural and mechanical properties of the vessel wall. Hence, the effect of endogenous estrogen on the arterial mechanical properties is mediated by the regulation of NO derived from eNOS.
Do chronic primary insomniacs have impaired heat loss when attempting sleep?
Authors: Gradisar Michael , Lack Leon , Wright Helen , Harris Jodie , Brooks Amber
Published: November 2005

For good sleepers, distal skin temperatures (e.g., hands and feet) have been shown to increase when sleep is attempted. This process is said to reflect the body’s action to lose heat from the core via the periphery. However, little is known regarding whether the same process occurs for insomniacs. It would be expected that insomniacs would have restricted heat loss due to anxiety when attempting sleep. The present study compared the finger skin temperature changes when sleep was attempted for 11 chronic primary insomniacs [mean age = 40.0 years (SD 13.3)] and 8 good sleepers [mean age = 38.6 years (SD 13.2)] in a 26-h constant routine protocol with the inclusion of multiple-sleep latency tests. Contrary to predictions, insomniacs demonstrated increases in finger skin temperature when attempting sleep that were significantly greater than those in good sleepers ( P = 0.001), even though there was no significant differences in baseline finger temperature ( P = 0.25). These significant increases occurred despite insomniacs reporting significantly greater sleep anticipatory anxiety ( P < 0.0008). Interestingly, the core body temperature mesor of insomniacs (37.0 ± 0.2°C) was significantly higher than good sleepers (36.8 ± 0.2°C; P = 0.03). Whether insomniacs could have impaired heat loss that is masked by elevated heat production is discussed.
Baroreflex modulation by angiotensins at the rat rostral and caudal ventrolateral medulla
Authors: Alzamora Andréia C. , Santos Robson A. S. , Campagnole-Santos Maria J.
Published: November 2005

We determined the effect of microinjection of ANG-(1–7) and ANG II into two key regions of the medulla that control the circulation [rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively)] on baroreflex control of heart rate (HR) in anesthetized rats. Reflex bradycardia and tachycardia were induced by increases and decreases in mean arterial pressure produced by intravenous phenylephrine and sodium nitroprusside, respectively. The pressor effects of ANG-(1–7) and ANG II (25 pmol) after RVLM microinjection (11 ± 0.8 and 10 ± 2 mmHg, respectively) were not accompanied by consistent changes in HR. In addition, RVLM microinjection of these angiotensin peptides did not alter the bradycardic or tachycardic component of the baroreflex. CVLM microinjections of ANG-(1–7) and ANG II produced hypotension (−11 ± 1.5 and −11 ± 1.9 mmHg, respectively) that was similarly not accompanied by significant changes in HR. However, CVLM microinjections of angiotensins induced differential changes in the baroreflex control of HR. ANG-(1–7) attenuated the baroreflex bradycardia (0.26 ± 0.06 ms/mmHg vs. 0.42 ± 0.08 ms/mmHg before treatment) and facilitated the baroreflex tachycardia (0.86 ± 0.19 ms/mmHg vs. 0.42 ± 0.10 ms/mmHg before treatment); ANG II produced the opposite effect, attenuating baroreflex tachycardia (0.09 ± 0.06 ms/mmHg vs. 0.31 ± 0.07 ms/mmHg before treatment) and facilitating the baroreflex bradycardia (0.67 ± 0.16 ms/mmHg vs. 0.41 ± 0.05 ms/mmHg before treatment). The modulatory effect of ANG II and ANG-(1–7) on baroreflex sensitivity was completely abolished by peripheral administration of methylatropine. These results suggest that ANG II and ANG-(1–7) at the CVLM produce a differential modulation of the baroreflex control of HR, probably through distinct effects on the parasympathetic drive to the heart.
Cardiorespiratory responses to physical work during and following 17 days of bed rest and spaceflight
Authors: Trappe Todd , Trappe Scott , Lee Gary , Widrick Jeffrey , Fitts Robert , Costill David
Published: November 2005

To determine the influence of a 17-day exposure to real and simulated spaceflight (SF) on cardiorespiratory function during exercise, four male crewmembers of the STS-78 space shuttle flight and eight male volunteers were studied before, during, and after the 17-day mission and 17 days of −6° head-down-tilt bed rest (BR), respectively. Measurements of oxygen uptake, pulmonary ventilation, and heart rate were made during submaximal cycling 60, 30, and 15 days before the SF liftoff and 12 and 7 days before BR; on SF days 2, 8, and 13 and on BR days 2, 8, and 13; and on days 1, 4, 5, and 8 after return to Earth and on days 3 and 7 after BR. During 15 days before liftoff, day 4 after return, and day 8 after return and all BR testing, each subject completed a continuous exercise test to volitional exhaustion on a semirecumbent (SF) or supine (BR) cycle ergometer to determine the submaximal and maximal cardiorespiratory responses to exercise. The remaining days of the SF testing were limited to a workload corresponding to 85% of the peak pre-SF peak oxygen uptake (V̇o2 peak) workload. Exposure to and recovery from SF and BR induced similar responses to submaximal exercise at 150 W. V̇o2 peakdecreased by 10.4% from pre-SF (15 days before liftoff) to day 4 after return and 6.6% from pre-BR to day 3 after return, which was partially (SF: −5.2%) or fully (BR) restored within 1 wk of recovery. Workload corresponding to 85% of the peak pre-SF V̇o2 peakshowed a rapid and continued decline throughout the flight (SF day 2, −6.2%; SF day 8, −9.0%), reaching a nadir of −11.3% during testing on SF day 13. During BR, V̇o2 peakalso showed a decline from pre-BR (BR day 2, −7.3%; BR day 8, −7.1%; BR day 13, −9.0%). These results suggest that the onset of and recovery from real and simulated microgravity-induced cardiorespiratory deconditioning is relatively rapid, and head-down-tilt BR appears to be an appropriate model of this effect, both during and after SF.
Background Activity Regulates Excitability of Rat Hippocampal CA1 Pyramidal Neurons by Adaptation of a K+ Conductance
Authors: van Welie Ingrid , van Hooft Johannes A. , Wadman Wytse J.
Published: November 2005

In the in vivo brain background synaptic activity has a strong modulatory influence on neuronal excitability. Here we report that in rat hippocampal slices, blockade of endogenous in vitro background activity results in an increased excitability of CA1 pyramidal neurons within tens of minutes. The increase in excitability constitutes a leftward shift in the input–output relationship of pyramidal neurons, indicating a reduced threshold for the induction of action potentials. The increase in excitability results from an adaptive decrease in a sustained K+ conductance, as recorded from somatic cell–attached patches. After 20 min of blockade of background activity, the mean sustained K+ current amplitude in somatic patches was reduced to 46 ± 9% of that in time-matched control patches. Blockade of background activity did not affect fast Na+ conductance. Together, these results suggests that the reduction in K+ conductance serves as an adaptive mechanism to increase the excitability of CA1 pyramidal neurons in response to changes in background activity such that the dynamic range of the input–output relationship is effectively maintained.
Trial-by-Trial Discrimination of Three Enantiomer Pairs by Neural Ensembles in Mammalian Olfactory Bulb
Authors: Lehmkuhle M. J. , Normann R. A. , Maynard E. M.
Published: November 2005

Populations of output neurons in the mammalian olfactory bulb (OB) exhibit distinct, widespread spatial and temporal activation patterns when stimulated with odorants. However, questions remain as to how ensembles of mitral/tufted (M/T) neurons in the mammalian OB represent odorant information. In this report, the single-trial encoding limits of random ensembles of putative single- and multiunit M/T cells in the anesthetized rat OB during presentations of enantiomers of limonene, carvone, and 2-butanol are investigated using simultaneous multielectrode recording techniques. The results of these experiments are: the individual constituents of our recorded ensembles broadly represent information about the presented odorants, the ensemble single-trial response of small spatially distributed populations of M/T neurons can readily discriminate between six different odorants, and the most consistent odorant discrimination is attained when the ensemble consists of all available units and their responses are integrated over an entire breathing cycle. These results suggest that small differences in spike counts among the ensemble members become significant when taken within the context of the entire ensemble. This may explain how ensembles of broadly tuned OB neurons contribute to olfactory perception and may explain how small numbers of individual units receiving input from distinct olfactory receptor neurons can be combined to form a robust representation of odorants.
Effects of Fasting and Refeeding on Serum Leptin, Adiponectin and Free Fatty Acid Concentrations in Young and Old Male Rats
Authors: Kmiec Zbigniew , Pokrywka Leszek , Kotlarz Grazyna , Kubasik Jolanta , Szutowicz Andrzej , Mysliwski Andrzej
Published: November 2005

Background: Regulatory mechanisms of metabolic homeostasis undergo important alterations during ageing. The age-related changes become often evident only during stimulation of basic functions that occurs, e.g. during fasting and refeeding which represent natural challenge to energy metabolism. Objective: To determine the effect of short-term fasting and subsequent refeeding on serum levels of key hormones and metabolites in young adult 5- and 24-month-old male Wistar rats. Methods: Control rats were fed ad libitum. Animals were fasted for 48 h or fasted and refed for 24 h. Metabolite serum concentrations were measured by standard methods. Leptin and insulin were determined by rat-specific RIA, and adiponectin serum levels by mouse/rat–specific ELISA. Results: (1) Control serum levels of key metabolites and hormones were similar in both age groups except for increased triglycerides (TG) in old fed rats. (2) Fasting caused a significant decrease of leptin, insulin, glucose, and TG serum levels in both age groups, and an increase of free fatty acids (FFA) concentration, however, only in young animals. (3) Upon refeeding serum glucose, TG and insulin reversed to control levels in both age groups, however, FFA concentration decreased to control values only in young rats. (4) In contrast to young animals, refeeding of old rats did not increase serum leptin concentration to control level. (5) Neither fasting nor refeeding changed adiponectin serum levels in both age groups. Conclusion: Aging suppresses leptin secretion and metabolism of FFA during refeeding that follows short-term starvation. In old rats serum levels of FFA are refractive to the alterations induced by fasting/refeeding in young ones.
Cell Proliferation in the Dentate Gyrus of Rat Hippocampus Is Inhibited by Soft Diet Feeding
Authors: Aoki Hiromichi , Kimoto Katsuhiko , Hori Norio , Toyoda Minoru
Published: November 2005

Background: Recently it has become well accepted that neurogenesis occurs in the dentate gyrus of the hippocampus, a region important to memory and learning function in rodents and humans. Reports show that neurogenesis in the hippocampus is regulated by certain factors, such as exposure to an enriched environment, physical activity, aging and stress. The relationship between the change in the task of chewing as one oral environmental factor, and the mechanisms of hippocampal neuron generation are unclear. Objective: We examined whether cell proliferation varies by chewing tasks with different food textures in the dentate gyrus of the rat hippocampus. Methods: Wistar rats were divided into two groups, one was fed a solid diet, known as the hard-diet feeding group, and the soft-diet feeding group, which was fed a powder diet containing the same components as the solid one for 3, 7, 16 and 24 weeks. Thymidine analog 5-bromo-2′-deoxyuridine (BrdU) was used as a marker of cell proliferation within the dentate gyrus of the hippocampus and olfactory bulb. Results: The results of this study indicated that the total number of BrdU-positive cells in the hippocampal dentate gyrus significantly decreased with aging and were significantly fewer in the soft-diet feeding group than in hard-diet feeding group in 7-, 16- and 24-week-old rats after the BrdU injection. The change of BrdU-positive cell expression between soft and hard diets in 3- and 24-week-old rats was not observed in the olfactory bulb. Conclusion: It has been suggested that cell proliferation in the dentate gyrus of the rat hippocampus is characteristically suppressed by soft diet feeding.
The Preference and Importance of Bathing, Toileting and Mouth Care Habits in Older Persons
Authors: Cohen-Mansfield Jiska , Jensen Barbara
Published: November 2005

Purpose: The goal of this study was to describe bathing, toileting, and mouth care habits and preferences of older persons, as well as the importance of such habits. Design and Methods: Fifty-eight community-dwelling older persons were administered the Self-maintenance Habits And Preferences in Elderly questionnaire (SHAPE) during a one-on-one interview with a research assistant. Preferences were described by frequency distributions and mean importance for each item was calculated. Gender differences in preferences were examined using χ2 analyses, t tests were used to compare importance levels. Results: Women reported spending a longer time bathing, they were more likely to have privacy while bathing, to use a washcloth, a regular size towel, and less likely to use a large towel than were men. One-third of the women reported using some type of absorbent undergarment, while no men did so. Mouth care was the category that received the highest importance ratings. Although order of importance of items was similar across genders, women assigned higher levels of importance to these items than did men. Importance ratings given to atypical habits, such as unusually long or more than 1 bath/day, were higher than those attributed to more usual habits. Implications: Knowledge of the range and importance of such self-care practices can provide information useful in the development of programs and for individualized care.
Benign Paroxysmal Positional Vertigo among Elderly Patients in Primary Health Care
Authors: Ekvall Hansson Eva , Månsson Nils-Ove , Håkansson Anders
Published: November 2005

Background:Dizziness influences well-being in old age, and benign paroxysmal positional vertigo (BPPV) is a common cause. The condition is diagnosed using the Hallpike maneuver and treated by the particle-repositioning maneuver or habituation exercises. Objective:To identify patients with BPPV among a variety of diagnoses represented by the ICD-10 diagnosis R42 in people 65 aged years and older who visited primary health care because of vertigo and dizziness. Methods:Searches were performed in the computerized medical records of 6 different health care centers over the period of 1 year for the ICD-10 diagnosis R42 and the age group 65 years and older. Letters were sent to the patients identified with an invitation for assessment and physical examination by a physiotherapist. Thirty-eight patients responded to the letter and were included in the study. All patients were assessed by physical examination including the Hallpike maneuver. Results: The study group included 13 men and 25 women, 65–94 (median 83) years of age. After physical examination, 15 patients were found to have BPPV (confidence interval 24–55%). Conclusion:In this study, 2 of 5 of the patients with ICD-10 diagnosis R42 (dizziness and giddiness) had BPPV. BPPV is probably an underestimated cause of dizziness/vertigo among elderly patients in primary health care.
Physiological and Psychological Predictors of Walking Speed in Older Community-Dwelling People
Authors: Tiedemann Anne , Sherrington Catherine , Lord Stephen R.
Published: November 2005

Background: Six-metre walking speed (SMWS) is a commonly used test for measuring functional performance in older people. However, apart from lower limb strength, few studies have examined the range of physiological and psychological factors that influence performance in this test. Objective: To investigate the relative contributions of a range of sensorimotor, balance and psychological factors to SMWS in a large sample of older people. Methods: 668 community-dwelling people aged 75–98 years (mean age 80.1, SD = 4.4) underwent the SMWS test as well as quantitative tests of vision, peripheral sensation, strength, reaction time, balance, fear of falling, pain and vitality. Results: Many physiological and psychological factors were significantly associated with SMWS in univariate analyses. Stepwise multiple regression analyses revealed that a composite lower limb strength measure (sum of knee extension, knee flexion and ankle dorsiflexion muscle strength scores), postural sway, leaning balance as assessed with the coordinated stability test, reaction time, edge contrast sensitivity, SF12 body pain and vitality scores and age were significant and independent predictors of SMWS. Of these measures, the combined lower limb strength measure had the highest beta weight indicating it was the most important variable in explaining the variance in SMWS. However, the other sensorimotor, balance and psychological measures each provided important independent information. The combined set of variables explained 40% of the variance in SMWS (multiple r = 0.63). Conclusions: The findings indicate that in community-dwelling older people, self-selected walking speed is influenced not only by lower limb strength but also by balance, reaction time, vision, pain and emotional well-being.
Small Bowel Bacterial Overgrowth in Symptomatic Older People: Can It Be Diagnosed Earlier?
Authors: Elphick D.A. , Chew T.S. , Higham S.E. , Bird N. , Ahmad A. , Sanders D.S.
Published: November 2005

Background/Objectives: In older people, small bowel bacterial overgrowth syndrome may be a common, but under-diagnosed, cause of diarrhoea and nutrient malabsorption. We aim to determine which clinical features and baseline laboratory investigations indicate a high likelihood of small bowel bacterial overgrowth as defined by a positive glucose breath test. Methods: A retrospective analysis of records for all patients referred for glucose breath test over a 6-year period to a teaching hospital. Results: Out of 197 referrals, 168 patient records were located and analysed (62 male, 106 female; median age 65). Patient characteristics predictive of a positive glucose breath test were: increasing age (p < 0.01), low serum vitamin B12 (p = 0.02), low serum albumin (p = 0.03), previous partial gastrectomy (p < 0.01), previous right hemi-colectomy (p < 0.01), presence of small bowel diverticulae (p = 0.01) and concurrent use of a proton pump inhibitor (p < 0.01). 52.5% (n = 21/40) of patients studied who were over 75 years old versus 21.8% (n = 28/128) of those under 75 years old had a positive glucose breath test (p < 0.01). The median time to diagnosis, from first hospital visit to positive glucose breath test, was 39 weeks. Conclusions: There is often a significant delay in diagnosis of small bowel bacterial overgrowth. We suggest that this diagnosis should be considered earlier in the investigative algorithm in older patients with indicative symptoms and a predisposing factor (including previous partial gastrectomy, previous right hemi-colectomy, small bowel diverticulae or use of a proton pump inhibitor) or concurring laboratory indices (low vitamin B12 or albumin).
Social Determinants of Frailty
Authors: Woo J. , Goggins W. , Sham A. , Ho S.C.
Published: November 2005

Background: Frailty represents a body-wide set of a linked deterioration that occurs with ageing, but is susceptible to active intervention and is reversible. The concept of frailty should include broader environmental factors. A quantitative measure of frailty, the frailty index (FI), developed for elderly Canadians and shown to be valid for an elderly Chinese population, was examined for its association with socioeconomic, lifestyle, and social support network factors in an elderly Chinese cohort. Objective: 2,032 people aged 70 years and over recruited by stratified random sampling of the population were surveyed in 1990–1991, and information obtained regarding physical and functional health, psychological factors, lifestyle, socioeconomic and social support factors. The FI was constructed from 62 variables covering cognitive, psychological and physical health, and tested for association with socioeconomic, lifestyle and social support factors using ANOVA and t test. Results: The mean FI for women was higher than for men (0.16 ± 0.08, n = 1,033 vs. 0.13 ± 0.08, n = 999, p < 0.001, t test). For men, increasing frailty was observed with non-white collar occupations, inadequate expenses, no or little exercise, abstinence from alcohol, few relatives or neighbours and no or infrequent participation in helping others. For women, little contact with relatives (rather than number of relatives), and absence of participation in community/religious activities were additional factors. Conclusion: FI is influenced by social and environmental factors in keeping with the concept of frailty being multi-dimensional. Such a quantitative measure may be a useful indicator of the health of elderly populations as well as for public health measures to combat frailty.
Association between β2-Adrenergic Receptor Genetic Polymorphisms and Nocturnal Asthmatic Patients of Chinese Han Nationality
Authors: Yin Kaisheng , Zhang Xilong , Qiu Yuying
Published: November 2005

Background: As a result of the finding that the mutation of Arg into Gly at β2-adrenergic receptor (β2-AR)16 loci could promote the downregulation effect triggered by the β2-agonist, it was supposed that Gly16 might be associated with the downregulation of β2-AR in patients with nocturnal asthma. Objective: It was the aim of this study to analyze the association between β2-AR genetic polymorphisms and nocturnal asthmatic patients of Chinese Han nationality. Methods: A polymerase chain reaction allele-specific oligonucleotide hybridization assay was used to determine 16 and 27 loci alleles of β2-AR genetic polymorphisms in 25 nocturnal asthmatic patients (nocturnal asthma group), 22 non-nocturnal asthmatic patients (non-nocturnal asthma group), and 72 healthy people (control group). All people investigated were of Chinese Han nationality. Results: The distribution frequency of genotype Arg/Arg, Arg/Gly, and Gly/Gly at β2-AR 16 loci was 12, 16 and 72% in the nocturnal asthma group; and 27, 41 and 32% in the non-nocturnal asthma group. There was a significant increase in the frequency of genotype Gly/Gly and allele Gly in the nocturnal asthma group compared with the non-nocturnal asthma group (p < 0.01). However, there was no significant difference in the frequency of genotype Gly/Gly and allele Gly in the non-nocturnal asthma group, compared with the control group. There was no significance in the frequency of the genotypes and alleles of β2-AR 27 loci among the three groups (p > 0.05). Conclusion: The Gly16 polymorphism of β2-AR was overrepresented in nocturnal asthmatic patients, correlated with nocturnal asthma, and therefore appeared to be an important genetic factor in the expression of this asthmatic phenotype.
Elevated Plasma Membrane Cholesterol Content Alters Macrophage Signaling and Function
Authors: Qin Chunbo , Nagao Tomokazu , Grosheva Inna , Maxfield Frederick R. , Pierini Lynda M.
Published: November 2005

Objective—During atherogenesis, macrophages migrate into the subendothelial space where they ingest deposited lipoproteins, accumulate lipids, and transform into foam cells. It is unclear why these macrophages do not remove their lipid loads from the region. This study was aimed at testing the hypothesis that macrophage behavior is altered when membrane cholesterol levels are elevated, as might be the case for cells in contact with lipoproteins within atherosclerotic lesions.

Methods and Results—We examined the effects of elevating membrane cholesterol on macrophage behavior. J774 macrophages were treated with either acetylated low-density lipoprotein (ac-LDL) and ACAT inhibitor or cholesterol-chelated methyl-β-cyclodextrin (chol-MβCD) to increase membrane cholesterol levels. Our results show that elevating the membrane cholesterol of J774 macrophages induced dramatic ruffling, stimulated cell spreading, and affected F-actin organization. Cellular adhesion was required for these effects, and Rac-mediated signaling pathways were involved. Additionally, 3-dimensional transwell chemotaxis assays showed that migration of J774 macrophages was significantly inhibited when membrane cholesterol levels were raised.

Conclusions—These findings indicate that increased membrane cholesterol causes dramatic effects on macrophage cellular functions related to the actin cytoskeleton. They should provide new insights into the early steps of atherogenesis.
Hypoxia Inducible Factor-1 Activation by Prolyl 4-Hydroxylase-2 Gene Silencing Attenuates Myocardial Ischemia Reperfusion Injury
Authors: Natarajan Ramesh , Salloum Fadi N. , Fisher Bernard J. , Kukreja Rakesh C. , Fowler Alpha A.
Published: November 2005

Hypoxia inducible factor-1 (HIF-1) regulates changes in transcription of key genes such as inducible NO synthase (iNOS) in hypoxic/ischemic environments. In normoxia, HIF-1 activation is controlled by HIF-1α-prolyl 4-hydroxylases, which target HIF-1α for ubiquitination and proteasomal degradation. We hypothesized that normoxic HIF-1 preservation could attenuate cardiac ischemia/reperfusion injury via a preconditioning effect. HIF-1 preservation was achieved by using small interfering RNA (siRNA) to silence murine HIF-1α-prolyl-4 hydroxylase-2 (PHD2). PHD2 siRNA reduced PHD2 mRNA expression 89±1.5% (
P
<0.001) in a time- and concentration-dependent manner in normoxic murine microvascular endothelial cells (EC). PHD2 silencing in normoxic EC stabilized HIF-1α protein levels while significantly increasing HIF-1 transcriptional activity and iNOS mRNA expression. Wild-type mice infused with PHD2 siRNA (1.5 μg/g body weight) showed a 61±2.4% (
P
<0.05) reduction in cardiac PHD2 mRNA within 24 hours. In addition HIF-1α protein levels and HIF-1-dependent iNOS mRNA levels were increased. PHD2 siRNA-transfected hearts from wild-type mice (n=6) subjected to 30 minutes ischemia followed by 60 minutes reperfusion exhibited reduced infarct size when compared with saline-treated controls (9.7±1.9% versus 31.6±1.8%, respectively,
P
<0.0001, n=6) and to control mice transfected with a nontargeting siRNA control (28.4±3.0%,
P
<0.0001, n=6). Hearts from iNOS knockout mice receiving PHD2 siRNA by identical injection protocol (n=6) exhibited infarct size indistinguishable from saline controls (28.7±1.3%). These results show that in vitro and in vivo, PHD2 silencing using a siRNA strategy produces transcriptionally active HIF-1. Normoxic activation of HIF-1 in hearts following in vivo PHD2 siRNA administration attenuates reperfusion injury via an iNOS-dependent pathway.
Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Ca
v
1.2
Authors: Moosmang Sven , Haider Nicole , Brüderl Birgit , Welling Andrea , Hofmann Franz
Published: November 2005

The role of T-type Ca
2+
channels for cardiovascular physiology, in particular blood pressure regulation, is controversial. Selective blockade of T-type Ca
2+
channels in resistance arteries has been proposed to explain the effect of the antihypertensive drug mibefradil. In the present study, we used a third generation, time- and tissue-specific conditional knockout model of the L-type Ca
2+
channel Ca
v
1.2 (Ca
v
1.2
SMAKO
mice) to genetically dissect the effects of mibefradil on T- and L-type Ca
2+
channels. Myogenic tone and phenylephrine-induced contraction in hindlimb perfusion experiments were sensitive to mibefradil in control mice, whereas the drug showed no effect in Ca
v
1.2-deficient animals. Mean arterial blood pressure in awake, freely moving control mice was reduced by 38±2.5 mm Hg at a dose of 1.25 mg/kg bodyweight mibefradil, but not changed in Ca
v
1.2
SMAKO
mice. These results demonstrate that the effect of the putative T-type Ca
2+
channel-selective blocker mibefradil on blood pressure and small vessel myogenic tone is mediated by the Ca
v
1.2 L-type Ca
2+
channel.
Fluoxetine Treatment in Poststroke Depression, Emotional Incontinence, and Anger Proneness
Authors: Choi-Kwon Smi , Han Sung W. , Kwon Sun U. , Kang Dong-Wha , Choi Ji M. , Kim Jong S.
Published: November 2005

Background and Purpose—

The efficacy and safety of the selective serotonin reuptake inhibitor fluoxetine have rarely been studied in the treatment of poststroke emotional disturbances.

Methods—

Stroke patients (152) who had poststroke depression (PSD), emotional incontinence (PSEI), or anger proneness (PSAP) were studied. PSD was evaluated by Beck Depression Inventory and
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
, PSEI by Kim’s criteria, and PSAP was assessed by Spielberger Trait Anger Scale. Subjects were randomly given either fluoxetine 20 mg/day (n=76) or placebo (n=76) for 3 months. Follow-up evaluations were done 1, 3, and 6 months after the beginning of the treatment. The primary outcome measurement was the scores of emotional disturbances at each follow-up assessment. The secondary outcome measurements were the percentage changes of the scores and the subjective responses of the patients.

Results—

Although patients in the fluoxetine group more often dropped out because of adverse effects, fluoxetine administration was generally safe. Fluoxetine significantly improved PSEI and PSAP, whereas no definitive improvement of PSD was found. Improvement of PSAP was noted even at 3 months after the discontinuation of the treatment.

Conclusions—

Fluoxetine is efficacious in the treatment of PSEI and PSAP. Its effect on PSD is not solidly confirmed.
Subtype Hypertension and Risk of Stroke in Middle-Aged and Older Chinese
Authors: Fang Xiang-Hua , Zhang Xin-Hua , Yang Qi-Dong , Dai Xiu-Ying , Su Fang-Zhong , Rao Ming-Li , Wu Sheng-Ping , Du Xiao-Li , Wang Wen-Zhi , Li Shi-Chuo
Published: November 2005

Background and Purpose—

Hypertension is the most important indicator of stroke. We aim to compare the long-term effects of the subtypes of hypertension on the risk of stroke in a Chinese cohort.

Methods—

A total of 26 587 subjects ≥35 years of age and free of stroke were recruited in 5 cities in 1987. The subtypes of hypertension were defined as isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), systolic and diastolic hypertension (SDH), as well as managed hypertension (MHT), according to the criteria of systolic blood pressure ≥140 or diastolic blood pressure >90 mm Hg or under antihypertensive treatment. The relative risks of stroke with the subtypes of hypertension, compared with normotensives, were estimated using the Cox model after adjustments for age, sex, and other confounders.

Results—

The prevalence of hypertension was: ISH 7.1%, SDH 18.4%, IDH 6.7%, and MHT 3.9%. During a total of 233 437 person years of follow-up, 1107 subjects developed stroke (614 ischemic and 451 hemorrhagic events and 42 unclassified). SDH patients were at the highest risk of stroke among all the hypertensives. The hazard ratio and 95% CI was 2.96 (2.49 to 3.52) for all stroke, 4.05 (3.10 to 5.30) for hemorrhagic, and 2.33 (1.84 to 2.95) for ischemic stroke. Although the incidence of stroke was higher in the older population, the effect of hypertension, especially SDH, on hemorrhagic stroke is stronger in the middle-aged population.

Conclusion—

ISH and IDH are similarly prevalent in the population; both are independent predictors of stroke. Patients with SDH are at the highest risk of stroke and should be treated more aggressively.
Antiplatelet Drugs In the Secondary Prevention After Stroke
Authors: Ariesen Marie-José , Algra Ale , Kappelle L. Jaap
Published: November 2005

Background and Purpose—

Arterial disease resulting in cerebral ischemia can be classified into large vessel disease (LVD) and small vessel disease (SVD). We assessed whether antiplatelet drugs were more efficacious in large than in small vessel cerebrovascular disease.

Methods—

Individual patient data of the second European Stroke Prevention Study (n=6602), in which patients with a previous transient ischemic attack or ischemic stroke were randomized to aspirin, dipyridamole, their combination, or placebo, were reanalyzed. Type of vessel disease was classified according to clinical symptoms or physical examination. Presence of a lacunar syndrome was considered typical for SVD and evidence of cortical dysfunction for LVD. Vascular events (nonfatal stroke, nonfatal myocardial infarction, nonfatal other vascular event, or vascular death) were taken as outcome. Cox regression analyses were performed.

Results—

A total of 419 first vascular events occurred in 2600 patients with SVD and 367 in 1816 patients with LVD (mean follow-up 1.7 years). For aspirin versus placebo, the hazard ratio (HR) was 0.86 (95% CI, 0.66 to 1.11) in patients with SVD and 0.80 (95% CI, 0.61 to 1.06) in those with LVD (
P
interaction
=0.74). For dipyridamole versus placebo, the HR was 0.86 (95% CI, 0.67 to 1.12) in patients with SVD and 0.90 (95% CI, 0.68 to 1.19) in patients with LVD (
P
interaction
=0.84). Similar observations were made for the outcome stroke only.

Conclusions—

Our findings do not concur with the hypothesis that aspirin, dipyridamole, or the combination may be especially effective in preventing vascular events in patients with previous cerebral ischemia that was caused by LVD compared with SVD.
Timing of Fresh Frozen Plasma Administration and Rapid Correction of Coagulopathy in Warfarin-Related Intracerebral Hemorrhage
Authors: Goldstein Joshua N. , Thomas Stephen H. , Frontiero Virginia , Joseph Annelise , Engel Chana , Snider Ryan , Smith Eric E. , Greenberg Stephen M. , Rosand Jonathan
Published: November 2005

Background and Purpose—

Anticoagulation-related intracerebral hemorrhage (ICH) is often fatal, and rapid reversal of anticoagulation is the most appealing strategy currently available for treatment. We sought to determine whether particular emergency department (ED) interventions are effective in reversing coagulopathy and improving outcome.

Methods—

Consecutive patients with warfarin-related ICH presenting to an urban tertiary care hospital from 1998 to 2004 were prospectively captured in a database. ED records were retrospectively reviewed for dose and timing of fresh-frozen plasma (FFP) and vitamin K, as well as serial coagulation measures. After excluding patients with incomplete ED records, do-not-resuscitate orders established in the ED, initial international normalized ratio (INR) ≤1.4, and for whom no repeat INR was performed, 69 patients were available for analysis. The primary outcome was a documented INR ≤1.4 within 24 hours of ED presentation.

Results—

Patients whose INR was successfully reversed within 24 hours had a shorter median time from diagnosis to first dose of FFP (90 minutes versus 210 minutes;
P
=0.02). In multivariable analysis, shorter time to vitamin K, as well as FFP, predicted INR correction. Every 30 minutes of delay in the first dose of FFP was associated with a 20% decreased odds of INR reversal within 24 hours (odds ratio, 0.8; 95% CI, 0.63 to 0.99). Dosing of FFP and vitamin K had no effect. No ED intervention was associated with improved clinical outcome.

Conclusions—

Time to treatment is the most important determinant of 24-hour anticoagulation reversal. Although additional study is required to determine the clinical benefit of rapid reversal of anticoagulation, minimizing delays in FFP administration is a prudent first step in emergency management of warfarin-related ICH.
Moderate Alcohol Consumption Reduces Risk of Ischemic Stroke
Authors: Elkind Mitchell S.V. , Sciacca Robert , Boden-Albala Bernadette , Rundek Tanja , Paik Myunghee C. , Sacco Ralph L.
Published: November 2005

Background and Purpose—

Moderate alcohol consumption is protective against coronary disease, but its relationship to ischemic stroke (IS) is controversial.

Methods—

Stroke-free participants ≥40 years of age identified by random-digit dialing were enrolled in a prospective cohort study between 1993 and 2001. Alcohol consumption was assessed through in-person interview and categorized as none in the past year, ≥1 drink in past month to ≤2 per day (moderate drinkers), and >2 drinks daily. Lifetime drinking was also assessed. Cox proportional hazard regression modeling was used to assess hazard ratios and their 95% CIs for the association of drinking with risk of stroke and vascular events.

Results—

Mean age among participants (n=3176) was 69.1±10.3 years; 62.8% were women, 20.8% were non-Hispanic white, 24.5% non-Hispanic black, and 52.4% were Hispanic. No alcohol in the previous year was present in 62.3%, and 32.5% drank moderately. After adjusting for other risk factors compared with those who did not drink in the past year, moderate drinkers had a reduced risk of IS (0.67; 95% CI, 0.46 to 0.99) and IS, myocardial infarction, or vascular death (0.74; 95% CI, 0.59 to 0.94). Results were similar when never-drinkers were used as referent group. Reduction in risk was seen for nonatherosclerotic IS subtypes, and results stratified by age, sex, and race–ethnicity were similar.

Conclusion—

Moderate alcohol consumption is associated with decreased risk of IS in a multiethnic population. This effect is independent of other risk factors and holds for nonatherosclerotic stroke subtypes.
Retinal Microvascular Abnormalities and MRI-Defined Subclinical Cerebral Infarction
Authors: Cooper Lawton S. , Wong Tien Y. , Klein Ronald , Sharrett A. Richey , Bryan R. Nick , Hubbard Larry D. , Couper David J. , Heiss Gerardo , Sorlie Paul D.
Published: November 2005

Background and Purpose—

Retinal microvascular abnormalities reflect cumulative small vessel damage from elevated blood pressure and may reflect subclinical cerebral microvascular changes. We examined their associations with MRI-defined cerebral infarcts.

Methods—

Population-based, cross-sectional study of 1684 persons 55 to 74 years of age without a history of clinical stroke, sampled from 2 US southeastern communities. Retinal photographs were obtained and graded for presence of retinal microvascular abnormalities, including arteriovenous nicking, focal arteriolar narrowing, retinal hemorrhages, soft exudates and microaneurysms. Photographs were also digitized, and retinal vessel diameters were measured and summarized as the arteriole-to-venule ratio (AVR). Cerebral MRI scans were graded for presence of cerebral infarct, defined as a lesion ≥3 mm diameter in a vascular distribution with typical imaging characteristics.

Results—

There were a total of 183 MRI cerebral infarcts. After adjustment for age, gender, race, 6-year mean arterial blood pressure, diabetes, and other stroke risk factors, cerebral infarcts were associated with retinal microvascular abnormalities, with odds ratios 1.90 (95% CI, 1.25 to 2.88) for arteriovenous nicking, 1.89 (95% CI, 1.22 to 2.92) for focal arteriolar narrowing, 2.95 (95% CI, 1.30 to 6.71) for blot hemorrhages, 2.08 (95% CI, 0.69, 6.31) for soft exudates, 3.17 (95% CI, 1.05 to 9.64) for microaneurysms, and 1.74 (95% CI, 0.95 to 3.21) for smallest compared with largest AVR. In stratified analyses, these associations were only present in persons with hypertension.

Conclusions—

Retinal microvascular abnormalities are associated with MRI-defined subclinical cerebral infarcts independent of stroke risk factors. These data suggest that retinal photography may be useful for studying subclinical cerebrovascular disease in population-based studies.
Prophylaxis of Thrombotic and Embolic Events in Acute Ischemic Stroke With the Low-Molecular-Weight Heparin Certoparin
Authors: Diener Hans-Christoph , Ringelstein Erich B. , von Kummer Rüdiger , Landgraf Helmut , Koppenhagen Klaus , Harenberg Job , Rektor Ivan , Csányi Attila , Schneider Dietmar , Klingelhöfer Jürgen , Brom Joachim , Weidinger Gottfried
Published: November 2005

Background and Purpose—

Patients with stroke are at substantial risk of thromboembolic complications and therefore require antithrombotic prophylaxis. To show the noninferiority of the low-molecular-weight heparin certoparin to unfractionated heparin (UFH) for the prevention of thromboembolic complications, we performed a randomized, double-blind, active-controlled multicenter trial in patients with acute ischemic stroke.

Methods—

Overall, 545 patients were randomized within 24 hours of stroke onset to treatment with certoparin (3000 U anti-Xa OD; n=272) or UFH (5000 U TID; n=273) for 12 to 16 days. Patients with paresis of a leg and an National Institutes of Health Stroke Scale score of 4 to 30 points were included. The primary end point was a composite outcome of proximal deep vein thrombosis, pulmonary embolism, or death related to venous thromboembolism during treatment. Computed tomography was performed at trial entry, after 7 days, and when clinical deterioration occurred.

Results—

The per-protocol analysis revealed 17 (7.0%) primary events in the certoparin group compared with 24 (9.7%) in the UFH group, thereby demonstrating noninferiority (
P
=0.0011), confirmed by intention-to-treat analysis (6.6% versus 8.8%;
P
=0.008). Major bleeding occurred during treatment in 3 patients allocated to certoparin (1.1%) and 5 patients allocated to UFH (1.8%).

Conclusions—

Certoparin (3000 U anti-Xa OD) is at least as effective and safe as UFH (TID) for the prevention of thromboembolic complications in patients with acute ischemic stroke.
Cardiac Magnetic Resonance Imaging After Stage I Norwood Operation for Hypoplastic Left Heart Syndrome
Authors: Muthurangu Vivek , Taylor Andrew M. , Hegde Sanjeet R. , Johnson Robert , Tulloh Robert , Simpson John M. , Qureshi Shakeel , Rosenthal Eric , Baker Edward , Anderson David , Razavi Reza
Published: November 2005

Background—

After the Norwood operation, a patient’s suitability for proceeding to a bidirectional cavopulmonary connection (BCPC) is assessed by a combination of echocardiography and diagnostic cardiac catheterization. In this study, we describe the results of 37 patients who underwent cardiovascular magnetic resonance (MR) assessment before BCPC.

Methods and Results—

Cardiovascular MR and echocardiography were performed in 37 infants with hypoplastic left heart syndrome before BCPC, and the findings were compared with surgical findings. MR assessment of ventricular function and valvar regurgitation were compared with echocardiography. MR exhibited high sensitivity and specificity for identification of neoaortic (sensitivity 86%, specificity 97%) and left pulmonary artery (sensitivity 100%, specificity 94%) obstruction. Echocardiography exhibited poor sensitivity for identification of vascular stenosis. The mean right ventricular ejection fraction calculated from the MR data was 50±10%. There was general agreement between MR and echocardiographic measures of ventricular function, although patients with good function on echocardiography demonstrated a wide range of ejection fractions. There was good agreement between MR and echocardiography for identification of valvar regurgitation.

Conclusions—

Cardiovascular MR can be used to define ventricular and valvar function and vascular anatomy in infants with hypoplastic left heart syndrome after the Norwood operation. We have shown how this information can be used to plan the BCPC and identify any revisions or additional valvar surgery.
Metabolic Modulation With Perhexiline in Chronic Heart Failure
Authors: Lee Leong , Campbell Ross , Scheuermann-Freestone Michaela , Taylor Rachel , Gunaruwan Prasad , Williams Lynne , Ashrafian Houman , Horowitz John , Fraser Alan G. , Clarke Kieran , Frenneaux Michael
Published: November 2005

Background—

Chronic heart failure (CHF) is a major cause of morbidity and mortality that requires a novel approach to therapy. Perhexiline is an antianginal drug that augments glucose metabolism by blocking muscle mitochondrial free fatty acid uptake, thereby increasing metabolic efficiency. We assessed the effects of perhexiline treatment in CHF patients.

Methods and Results—

In a double-blind fashion, we randomly assigned patients with optimally medicated CHF to either perhexiline (n=28) or placebo (n=28). The primary end point was peak exercise oxygen consumption (V̇
o
2
max), an important prognostic marker. In addition, the effect of perhexiline on myocardial function and quality of life was assessed. Quantitative stress echocardiography with tissue Doppler measurements was used to assess regional myocardial function in patients with ischemic CHF.
31
P magnetic resonance spectroscopy was used to assess the effect of perhexiline on skeletal muscle energetics in patients with nonischemic CHF. Treatment with perhexiline led to significant improvements in V̇
o
2
max (16.1±0.6 to 18.8±1.1 mL · kg
−1
· min
−1
;
P
<0.001), quality of life (Minnesota score reduction from 45±5 to 34±5;
P
=0.04), and left ventricular ejection fraction (24±1% to 34±2%;
P
<0.001). Perhexiline treatment also increased resting and peak dobutamine stress regional myocardial function (by 15% and 24%, respectively) and normalized skeletal muscle phosphocreatine recovery after exercise. There were no adverse effects during the treatment period.

Conclusions—

In patients with CHF, metabolic modulation with perhexiline improved V̇
o
2
max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Perhexiline may therefore represent a novel treatment for CHF with a good safety profile, provided that the dosage is adjusted according to plasma levels.