bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of stretching in tendon injuries
Authors: Witvrouw E , Mahieu N , Roosen P , McNair P
Published: February 2007

The function of tendons can be classified into two categories: tensile force transmission, and storage and release of elastic energy during locomotion. The action of tendons in storing and releasing energy is mainly seen in sports activities with stretch-shortening cycles (SSCs). The more intense the SSC movements are (jumping-like activities), the more frequently tendon problems are observed. High SSC movements impose high loads on tendons. Consequently, tendons that frequently deal with high SSC motion require a high energy-absorbing capacity to store and release this large amount of elastic energy. As the elasticity of tendon structures is a leading factor in the amount of stored energy, prevention and rehabilitation programmes for tendon injuries should focus on increasing this tendon elasticity in athletes performing high SSC movements. Recently, it has been shown that ballistic stretching can significantly increase tendon elasticity. These findings have important clinical implications for treatment and prevention of tendon injuries.
Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme
Authors: Zeng Weifen F , Navaratne Kapila , Prayson Richard A , Weil Robert J
Published: February 2007

Chromosomal abnormalities and genomic instability are common features of, and possible driving forces in, tumorigenesis. Recently, several mitotic proteins that are critical to proper chromosome segregation have been identified. Members of the Aurora kinase family have been identified as having important roles in mitosis; overexpression induces multicellularity and fosters polyploidy. As aneuploidy is a common feature of malignant gliomas, particularly glioblastomas (GBMs), we examined 25 prospectively collected GBMs to assess the role that overexpression of one member of this family, Aurora B, might have in the clinical behaviour of GBMs. Aurora B expression levels were markedly correlated with a shortened survival. Aurora B expression was not directly related to age, tumour proliferation status or to several common molecular changes found in GBMs. These results suggest that Aurora B may be a prognostic feature of impaired survival and a novel therapeutic target in some patients.
Female genital mutilation: the ethical impact of the new Italian law
Authors: Turillazzi E , Fineschi V
Published: February 2007

Despite global and local attempts to end female genital mutilation (FGM), the practice persists in some parts of the world and has spread to non-traditional countries through immigration. FGM is of varying degrees of invasiveness, but all forms raise health-related concerns that can be of considerable physical or psychological severity. FGM is becoming increasingly prohibited by law, both in countries where it is traditionally practised and in countries of immigration. Medical practice prohibits FGM. The Italian parliament passed a law prohibiting FGM, which has put in place a set of measures to prevent, to oppose and to suppress the practice of FGM as a violation of a person’s fundamental rights to physical and mental integrity and to the health of women and girls. The Italian law not only treats new offences but also wants to deal with the problem in its entirety, providing important intervention in all the sectors. Different kinds of interventions are considered, starting with the development of informative campaigns, training of health workers, institution of a tollfree number, international cooperation programmes and the responsibility of the institution where the crime is committed. Particularly, the law recognises that doctors have a role in eliminating FGM by educating patients and communities.
Effect of Acupuncture Treatment on the Immune Function Impairment Found in Anxious Women
Authors: Arranz Lorena , Guayerbas Noelia , Siboni León , De la Fuente Mónica
Published: February 2007

It is presently accepted that emotional disturbances lead to immune system impairment, and that therefore their treatment could restore the immune response. Thus, the aim of the present work was to study the effect of an acupuncture treatment, designed specifically to relieve the emotional symptoms stemming from anxiety, on several functions (adherence, chemotaxis, phagocytosis, basal and stimulated superoxide anion levels, lymphocyte proliferation in response to phytohemagglutinin A (PHA) and natural killer (NK) activity) of leukocytes (neutrophils and lymphocytes) from anxious women. The acupuncture protocol consisted of manual needle stimulation of 19 acupoints, with each session lasting 30 min. It was performed on 34 female 30–60 year old patients, suffering from anxiety, as determined by the Beck Anxiety Inventory (BAI). Before and 72 hours after receiving the first acupuncture session, peripheral blood samples were drawn. In 12 patients, samples were also collected immediately after the first single acupuncture session and one month after the end of the whole acupuncture treatment, which consisted of 10 sessions during a year, until the complete remission of anxiety. Twenty healthy non-anxious women in the same age range were used as controls. The results showed that the most favorable effects of acupuncture on the immune functions appear 72 hours after the single session and persist one month after the end of the complete treatment. Impaired immune functions in anxious women (chemotaxis, phagocytosis, lymphoproliferation and NK activity) were significantly improved by acupuncture, and augmented immune parameters (superoxide anion levels and lymphoproliferation of the patient subgroup whose values had been too high) were significantly diminished. Acupuncture brought the above mentioned parameters to values closer to those of healthy controls, exerting a modulatory effect on the immune system.
Antioxidant and Hepatoprotective Effects of Orthosiphon stamineus Benth.
Authors: Yam Mun Fei , Basir Rusliza , Asmawi Mohd. Zaini , Ismail Zhari
Published: February 2007

Orthosiphon stamineus (OS), Benth. (Lamiaceae) is widely used in Malaysia for treatments of various kidney and liver ailments. In the experiment, DPPH• radicals scavenging, Fe 3+-induced lipid peroxidation inhibiting activities and trolox equivalent antioxidant capacity (TEAC) of methanol/water extract of Orthosiphon stamineus (SEOS) were determined. The results indicated that SEOS exhibited antioxidant, lipid peroxidation inhibition and free radical scavenging activities. The hepatoprotective activity of the SEOS was studied using CCl 4-induced liver toxicity in rats. The activity was assessed by monitoring liver function tests through the measurement of alanine transaminase (ALT) and aspartate transaminase (AST). Furthermore, hepatic tissues were also subjected to histopathological studies. Pretreatment of SEOS (125, 250, 500 and 1000 mg/kg p.o.) dose-dependently reduced the necrotic changes in rat liver and inhibited the increase of serum ALT and AST activities. The results of the present study indicated that the hepatoprotective effect of Orthosiphon stamineus might be ascribable to its antioxidant and free radical scavenging property.
ANALYSIS ON q-DEFORMED QUANTUM SPACES
Authors: WACHTER HARTMUT
Published: February 2007

A q-deformed version of classical analysis is given to quantum spaces of physical importance, i.e. Manin plane, q-deformed Euclidean space in three or four dimensions, and q-deformed Minkowski space. The subject is presented in a rather complete and self-contained way. All relevant notions are introduced and explained in detail. The different possibilities to realize the objects of q-deformed analysis are discussed and their elementary properties are studied. In this manner attention is focused on star products, q-deformed tensor products, q-deformed translations, q-deformed partial derivatives, dual pairings, q-deformed exponentials, and q-deformed integration. The main concern of this work is to show that these objects fit together in a consistent framework, which is suitable to formulate physical theories on quantum spaces.
JORDAN CELLS IN LOGARITHMIC LIMITS OF CONFORMAL FIELD THEORY
Authors: RASMUSSEN JØRGEN
Published: February 2007

It is discussed how a limiting procedure of conformal field theories may result in logarithmic conformal field theories with Jordan cells of arbitrary rank. This extends our work on rank-two Jordan cells. We also consider the limits of certain three-point functions and find that they are compatible with known results. The general construction is illustrated by logarithmic limits of minimal models in conformal field theory. Characters of quasirational representations are found to emerge as the limits of the associated irreducible Virasoro characters.
Global Environmental Standards for Industry
Authors: Angel David P. , Hamilton Trina , Huber Matthew T.
Published: February 2007

Global environmental standards are emerging as an increasingly important influence on the environmental performance of industry. In this chapter, we develop a new definition and a categorization of global environmental standards that reflect the different agents involved in their development and the particular network architecture through which environmental standards achieve global reach. We examine new forms of global environmental standards, such as firm-based standards and standards initiated by third-party organizations, such as nongovernmental organizations (NGOs) and industry associations. The growing interest in global environmental standards is shown to arise from processes of economic globalization as well as from increasing external pressure on firms and industries with respect to environmental concerns. The chapter reviews what is known about the prevalence of different types of global environmental standards and the efficacy of these standards in influencing the environmental performance of firms and industries.
Shared Waters: Conflict and Cooperation
Authors: Wolf Aaron T.
Published: February 2007

This review examines the state of conflict and cooperation over transboundary water resources from an environmental, political, and human development perspective. Although the potential for outright war between countries over water is low, cooperation is often missing in disputes over transboundary resources. This background chapter will

▪ Provide a brief overview of the nature of conflict and experiences of cooperation over transboundary resources.

▪ Provide a conceptual basis for understanding cooperation and the costs of noncooperation over water.

▪ Indicate the possible triggers for conflict over water sharing and the implications on the livelihoods of ordinary communities.

▪ Offer evidence on the potential costs of noncooperation or even conflict over water resources.

▪ Analyze power asymmetries between riparian states and how they affect the outcomes of negotiations.

▪ Analyze different examples of cases that countries have used to manage the competition for water resources.

▪ Propose general principles and conclusions on conflict and cooperation.
Population and Environment
Authors: Sherbinin Alex de , Carr David , Cassels Susan , Jiang Leiwen
Published: February 2007

The interactions between human population dynamics and the environment have often been viewed mechanistically. This review elucidates the complexities and contextual specificities of population-environment relationships in a number of domains. It explores the ways in which demographers and other social scientists have sought to understand the relationships among a full range of population dynamics (e.g., population size, growth, density, age and sex composition, migration, urbanization, vital rates) and environmental changes. The chapter briefly reviews a number of the theories for understanding population and the environment and then proceeds to provide a state-of-the-art review of studies that have examined population dynamics and their relationship to five environmental issue areas. The review concludes by relating population-environment research to emerging work on human-environment systems.
Women, Water, and Development
Authors: Ray Isha
Published: February 2007

That women play a central role in the provision, management, and safeguarding of water is one of the four internationally accepted principles of water management. This principle is especially important for the developing world where millions of women lack access to water for their basic needs. The objectives of this chapter are to summarize what is known about women with respect to water and about water with respect to women as well as to provide a sense of the current debates around these themes. A review of the literature suggests that the lack of gender-disaggregated data on the impacts of water policies, and underlying disagreements on how gender and development should be theorized, makes it difficult to reach robust conclusions on which policies can best assure poor women reliable access to water for their lives and livelihoods.
Physical activity of adult female rhesus monkeys (Macaca mulatta) across the menstrual cycle
Authors: Hunnell Nathan A. , Rockcastle Nathan J. , McCormick Kristen N. , Sinko Laurel K. , Sullivan Elinor L. , Cameron Judy L.
Published: February 2007

Physical activity is an important physiological variable impacting on a number of systems in the body. In rodents and several species of domestic animals, levels of physical activity have been reported to vary across the estrous cycle; however, it is unclear whether such changes in activity occur in women and other primates across the menstrual cycle. To determine whether significant changes in activity occur over the menstrual cycle, we continuously measured physical activity in seven adult female rhesus monkeys by accelerometry over the course of one menstrual cycle. Monkeys were checked daily for menses, and daily blood samples were collected for measurement of reproductive hormones. All monkeys displayed ovulatory menstrual cycles, ranging from 23 to 31 days in length. There was a significant increase in estradiol from the early follicular phase to the day of ovulation (F1.005,5.023 = 40.060, P = 0.001). However, there was no significant change in physical activity across the menstrual cycle (F2,12 = 0.225, P = 0.802), with activity levels being similar in the early follicular phase, on the day of the preovulatory rise in estradiol and during the midluteal phase. Moreover, the physical activity of these monkeys was not outside the range of physical activity that we measured in 15 ovariectomized monkeys. We conclude that, in primates, physical activity does not change across the menstrual cycle and is not influenced by physiological changes in circulating estradiol. This finding will allow investigators to record physical activity in female primates without the concern of controlling for the phase of the menstrual cycle.
Furosemide increases water content in renal tissue
Authors: Pedersen Michael , Vajda Zsolt , Stødkilde-Jørgensen Hans , Nielsen Søren , Frøkiær Jørgen
Published: February 2007

The present study was designed to evaluate the short-term effects of intravenous administration of furosemide on key functions in the kidney cortex and the outer and inner medulla of rats by using magnetic resonance imaging (MRI). Renal tissue water content, renal tissue oxygenation (in relation to the magnetic resonance spin-spin relaxation rate), the apparent diffusion coefficient (ADC) of water, and volume of renal blood flow were measured. Furosemide administration resulted in an increased water content in all regions of the kidney. In parallel with this, we found a significant reduction in ADC in the cortex (2.7 ± 0.1 × 10−3to 2.3 ± 0.1 × 10−3mm2/s; P < 0.01) and in the outer medulla (2.3 ± 0.1 × 10−3to 2.0 ± 0.1 × 10−3mm2/s; P < 0.01), indicating that the intra- to extracellular volume fraction of water increased in response to furosemide administration. Furosemide also decreased the blood oxygenation in the cortex (49.1 ± 2.9 to 40.9 ± 2.0 s−1; P < 0.01), outer medulla (41.9 ± 2.8 to 33.2 ± 1.6 s−1; P < 0.01) and in the inner medulla (37.1 ± 2.9 to 26.7 ± 1.8 s−1; P < 0.01), indicating an increased amount of oxygenated Hb in the renal tissue. Moreover, renal blood flow decreased in response to furosemide (6.9 ± 0.2 to 4.4 ± 0.2 ml/min; P < 0.001). In conclusion, furosemide administration was associated with increased renal water content, an increase in the intra- to extracellular volume fraction of water, an increased oxygen tension, and a decrease in the renal blood flow. Thus MRI provides an integrated evaluation of changes in renal function, leading to decreased renal water and solute reabsorption in response to furosemide, and, in addition, MRI provides an alternative tool to monitor noninvasively changes at the cellular level.
Role of 20-HETE in D1/D2 dopamine receptor synergism resulting in the inhibition of Na+-K+-ATPase activity in the proximal tubule
Authors: Kirchheimer Carolina , Mendez Carlos F. , Acquier Andrea , Nowicki Susana
Published: February 2007

Previous studies propose 20-hydroxyeicosatetraenoic acid (20-HETE), a major arachidonic acid metabolite of cytochrome P-450 (CYP), as a possible mediator of Na+-K+-ATPase inhibition by dopamine (DA). The aim of this study was to investigate the intracellular mechanisms involved in this effect and to elucidate the DA receptor associated with the 20-HETE pathway in the rat kidney. DA (10−5M) inhibited Na+-K+-ATPase activity in microdissected tubular segments to 59.4 ± 3.8% of control activity. This response was suppressed by the CYP4A inhibitor 17-octadecynoic acid (10−6M), which had no effect per se, thus confirming the participation of CYP arachidonic acid metabolites in DA-induced Na+-K+-ATPase inhibition. We next examined whether 20-HETE is involved in the signaling pathways triggered by either D1or D2receptors. Neither fenoldopam nor quinpirole (D1and D2agonists, respectively, both 10−5M) modified Na+-K+-ATPase activity when tried alone. However, coincubation of a threshold concentration of 20-HETE (10−9M) with fenoldopam resulted in a synergistic inhibition of Na+-K+-ATPase activity (66 ± 2% of control activity), while 20-HETE plus quinpirole had no effect. Furthermore, 20-HETE (10−9M) synergized with forskolin (10−5M) and with the diacylglycerol analog 1-oleoyl-2-acetoyl- sn-glycerol (OAG; 10−11M; 62.0 ± 5.3 and 69.9 ± 2.0% of control activity, respectively), indicating a cooperative role of 20-HETE with the D1-triggered pathways. In line with these results, no additive effect was observed when OAG and 20-HETE were combined at concentrations which per se produced maximal inhibition (10−6M). These results demonstrate that the inhibition of Na+-K+-ATPase activity by DA in the proximal tubule may be the result of the synergism between 20-HETE and the D1signaling pathway.
Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: evidence for a role of P2X4
Authors: Solini Anna , Santini Eleonora , Chimenti Daniele , Chiozzi Paola , Pratesi Federico , Cuccato Sabina , Falzoni Simonetta , Lupi Roberto , Ferrannini Ele , Pugliese Giuseppe , Virgilio Francesco Di
Published: February 2007

Apoptosis, a normal event in renal tissue homeostasis, has been considered as a major mechanism for either resolution of glomerular hypercellularity in glomerulonephritis or loss of cellularity and progression to glomerulosclerosis in chronic renal disease. This study was aimed at investigating the role of extracellular ATP (eATP) in mediating apoptosis in human mesangial cells (HMC) and identifying the subtype(s) of purinergic receptors involved. eATP, but not uridin-5′-triphosphate (UTP), caused dose-dependent modifications of cellular morphology, as assessed by contrast-phase microscopy, and late apoptosis, as measured by Annexin V/propidium iodide-based flow cytometry and caspase-3 activation. Both phenomena were prevented by the P2X antagonist oxidized-ATP. 2′, 3′-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP) was less effective than ATP, whereas 1[N,O-bis (5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl] -4-phenylpiperazine (KN62), a selective inhibitor of human P2X7, prevented morphological changes but potentiated apoptosis induced by BzATP. P2X7was barely expressed in HMC and showed a relatively scarce functional activity, as assessed by monitoring nucleotide-induced intracellular calcium surge and plasma membrane depolarization by Fura-2/AM and bis[1,3-diethylthiobarbiturate]trimethineoxonal uptake, respectively. These data indicated a negligible role of P2X7in eATP-mediated apoptosis and pointed to the involvement of other P2X receptor(s). Molecular and inhibitor studies suggested a main role for P2X4receptor in nucleotide-induced apoptosis in HMC, indicating a relevant role for purinergic signaling in regulating death rate in these cells.
Presynaptic Efficacy Directs Normalization of Synaptic Strength in Layer 2/3 Rat Neocortex After Paired Activity
Authors: Hardingham Neil R. , Hardingham Giles E. , Fox Kevin D. , Jack Julian J. B.
Published: February 2007

Paired neuronal activity is known to induce changes in synaptic strength that result in the synapse in question having different properties to unmodified synapses. Here we show that in layer 2/3 excitatory connections in young adult rat cortex paired activity acts to normalize the strength and quantal parameters of connections. Paired action potential firing produces long-term potentiation in only a third of connections, whereas a third remain with their amplitude unchanged and a third exhibit long-term depression. Furthermore, the direction of plasticity can be predicted by the initial strength of the connection: weak connections potentiate and strong connections depress. A quantal analysis reveals that changes in synaptic efficacy were predominantly presynaptic in locus and that the key determinant of the direction and magnitude of synaptic modification was the initial release probability ( Pr) of the synapse, which correlated inversely with change in Pr after pairing. Furthermore, distal synapses also exhibited larger potentiations including postsynaptic increases in efficacy, whereas more proximal inputs did not. This may represent a means by which distal synapses preferentially increase their efficacy to achieve equal weighting at the soma. Paired activity thus acts to normalize synaptic strength, by both pre- and postsynaptic mechanisms.
Survey of Physician’s Attitudes and Practices toward Lipid-Lowering Management Strategies
Authors: Goldberg Robert J. , Rosen Jonathan , Roselli Anthony , Lewis Barbara
Published: February 2007

Background: The purpose of the present study was to examine physician’s attitudes and practices toward the use of different lipid-lowering management strategies in patients at increased risk for coronary heart disease (CHD). Aims/Methods: An internet-based questionnaire was completed by 78 general internists and family practitioners (mean age = 49 years; 80% male) affiliated with a large primary care health delivery system in Connecticut. Questions were asked about physician knowledge and use of current national guidelines for lipid-lowering therapy and their treatment practices for patients at varying risk for CHD. Results: Most physicians reported they were very knowledgeable about different interventions to lower serum lipids. Most (92%) indicated that they were aware of and followed national guidelines for the treatment of patients with hyperlipidemia the majority of the time. Physicians were likely to initiate lipid-lowering therapy at lower levels of serum LDL cholesterol in patients at high, as compared to those at moderate, risk for coronary disease. Targeted treatment levels were also reported to be considerably lower for patients at higher risk, than for those at moderate risk, for the development of coronary disease. Diabetes, cigarette smoking, and elevated LDL cholesterol levels were reported to be the three most important risk factors for CHD by the physician sample. Gaps in the recommendation of lifestyle changes to patients with hyperlipidemia were observed. Conclusions: Despite adequate physician knowledge, achieving desirable serum lipid levels in primary care patients remains elusive. Provider education is needed to optimize the care of patients with elevated serum lipids treated in the primary care setting.
Different Migration of Vascular Smooth Muscle Cells from Human Coronary Artery Bypass Vessels
Authors: Weiss Sabine , Frischknecht Karin , Greutert Helen , Payeli Sravan , Steffel Jan , Lüscher Thomas F. , Carrel Thierry P. , Tanner Felix C.
Published: February 2007

Background: We examined whether vascular smooth muscle (VSMC) or endothelial cell (EC) migration from internal mammary artery (MA) differed from VSMC or EC migration from saphenous vein (SV). Methods and Results: Migration to PDGF-BB (1–10 ng/ml) was lower in VSMC from MA than SV; however, attachment, movement without chemokine, and chemokinesis were identical. Unlike VSMC, migration of EC was similar in response to several mediators. Expression of PDGF receptor-β was lower in VSMC from MA than SV, while α-receptor expression was higher. PDGF-BB-induced RhoA activity was lower in MA than SV, while basal activity was identical. Rosuvastatin and hydroxyfasudil impaired PDGF-BB-induced migration of VSMC from MA and SV. Mevalonate and geranylgeranylpyrophosphate rescued inhibition by rosuvastatin. PDGF-BB induced less stress fiber formation in VSMC from MA than SV. A dominant negative RhoA mutant inhibited stress fiber formation to PDGF-BB, while a constitutively active mutant resulted in maximal stress fiber formation in MA and SV. Rosuvastatin and hydroxyfasudil impaired PDGF-BB-induced stress fiber formation in MA and SV. Conclusions: VSMC migration to PDGF-BB is lower in MA than SV, which is at least in part related to lower activity of the Rho/ROCK pathway.
Dehydration among Long-Term Care Elderly Patients with Oropharyngeal Dysphagia
Authors: Leibovitz A. , Baumoehl Y. , Lubart E. , Yaina A. , Platinovitz N. , Segal R.
Published: February 2007

Introduction: Long-term care (LTC) residents, especially the orally fed with dysphagia, are prone to dehydration. The clinical consequences of dehydration are critical. The validity of the common laboratory parameters of hydration status is far from being absolute, especially so in the elderly. However, combinations of these indices are more reliable. Objective: Assessment of hydration status among elderly LTC residents with oropharyngeal dysphagia. Methods: A total of 28 orally fed patients with grade-2 feeding difficulties on the functional outcome swallowing scale (FOSS) and 67 naso-gastric tube (NGT)-fed LTC residents entered the study. The common laboratory, serum and urinary tests were used as indices of hydration status. The results were considered as indicative of dehydration and used as ‘markers of dehydration’, if they were above the accepted normal values. Results: The mean number of dehydration markers was significantly higher in the FOSS-2 group (3.8 ± 1.3 vs. 2 ± 1.4, p = 0.000). About 75% of these FOSS-2 patients had ≧4 dehydration markers versus 18% of the NGT-fed group (p = 0.000). A low urine output (<800 ml/day) was significantly more common in the FOSS-2 group (39 vs. 12%, p = 0.002). Above normal values of blood urea nitrogen (BUN), BUN/serum creatinine ratio (BUN/SCr), urine/serum osmolality ratio (U/SOsm), and urine osmolality UOsm, were significantly more frequent in the dehydration-prone FOSS-2 group. This combination of 4 indices was present in 65% of low urine output patients. In contrast, it was present in only 36% of the higher urine output patients (p = 0.01). Patients with a ‘normal’ daily urine output (>800 ml/day) also had a significant number (2 ± 1.5) of positive indices of dehydration. Conclusions: Dehydration was found to be common among orally fed FOSS-2 LTC patients. Surprisingly, probable dehydration, although of a mild degree, was not a rarity among NGT-fed patients either. The combination of 4 parameters, BUN, BUN/SCr , U/SOsm and UOsm, offers reasonable reliability to be used as an indication of dehydration status in daily clinical practice.
Effect of Estrogen Therapy on Insulin Resistance and Plasminogen Activator Inhibitor Type 1 Concentrations in Postmenopausal Women
Authors: Saucedo Renata , Basurto Lourdes , Zarate Arturo , Martínez Carlos , Hernandez Marcelino , Galván Rosa
Published: February 2007

Background/Aims: An elevated thrombotic risk due to abnormal fibrinolysis might be associated with insulin resistance in postmenopause. The aim of this study was to investigate the association of insulin resistance with a biochemical marker of fibrinolysis as well as the effect of transdermal estrogen treatment (ET) on this association. Methods: Thirty postmenopausal hysterectomized women received transdermal estradiol during 3 months. 17β-Estradiol, FSH, LH, plasminogen activator inhibitor type 1 (PAI-1), insulin and glucose were measured in blood samples before and after ET. Insulin resistance was calculated by the use of the homeostasis model assessment for insulin resistance (HOMA-IR).Results:ET induced a significant decrement in both PAI-1 levels and HOMA-IR values. The study also showed that HOMA-IR was a significant predictor for PAI-1 concentrations. Conclusion: Short-term ET improved HOMA-IR values in parallel with a decrease in PAI-1 levels.
Computer-Assisted Fiberoptic Pharyngoscopy in Obstructive Sleep Apnea Syndrome
Authors: Ye Jingying , Han Demin , Wang Jun , Yang Qingwen , Lin Yuhua , Wang Jiangyong , Li Yanru
Published: February 2007

Objective: To investigate the upper airway (UA) characteristics of patients with obstructive sleep apnea syndrome (OSAS) using computer-assisted fiberoptic pharyngoscopy with Müller’s maneuver (CFPMM). Methods: The pharyngeal cavity were measured and calculated by CFPMM in 30 OSAS patients and 30 controls. The correlation between UA anatomy and polysomnography data was analyzed. Results: CFPMM can measure the cross-section area of UA accurately. All OSAS patients had minimal cross-section areas of pharyngeal apertures below 40 mm2 during Müller’s maneuver and 60% of cases had complete occlusion. Obstruction sites at the velopharynx were observed in all cases and 40% had multiple obstruction sites. Diminished pharyngeal apertures and increased collapsibility were associated with increased rates of apnea and hypopnea index (p < 0.05). Conclusion: CFPMM is able to evaluate UA’s characteristics and help determine the site of obstruction. Complete occlusion of UA during Müller’s maneuver is the criterion to determine the obstruction site in OSAS patients.
Coordinated Upregulation of COX-2 and NF-κB Is a Steady Feature of Laryngeal Carcinogenesis
Authors: Kourelis Konstantinos , Sotiropoulou-Bonikou Georgia , Vandoros Gerasimos , Repanti Maria , Varakis Ioannis , Goumas Panagiotis
Published: February 2007

Background/Aims: Laryngeal cancer is the endpoint of a multistage process involving hyperplastic and dysplastic lesions, not adequately defined in their molecular aspect. Our objective was to evaluate the expression of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) and the chief transcription factor nuclear factor-ĸB (NF-ĸB) in laryngeal carcinomas and their precursors, as well as to explore any association between the two molecules. Methods: We performed paraffin section immunohistochemistry for COX-2 and the p65 subunit of NF-ĸB, in tissues from 129 patients with tumors or premalignancies. p65 cytoplasmic and nuclear immunostaining were listed individually. Results: COX-2 was positively correlated with histopathological grading from normal mucosa to carcinomas (Spearman’s coefficient rs = 0.286, p < 0.001). No association was revealed between COX-2 expression and tumor grade. p65 immunoreactivity, both of cytoplasmic and nuclear origin, increased along the carcinogenesis course, manifesting highest expression in invasive cancer (rs = 0.419, p < 0.001 and rs = 0.241, p < 0.001, respectively). Again, tumor grade had no influence on expression. COX-2 and p65 cytoplasmic, but no nuclear, expression showed a positive correlation (rs = 0.352, p < 0.001). Conclusions: This study demonstrates that lesional advance in the larynx towards cancer is marked by ongoing upregulation of COX-2 and NF-ĸB. Synchronism between individual expressions may denote a regulatory role of the latter in COX-2 transactivation.
Maternal Endothelial Nitric Oxide Synthase Genotype Influences Offspring Blood Pressure and Activity in Mice
Authors: Van Vliet Bruce N. , Chafe Linda L.
Published: February 2007

Deficiencies in maternal endothelial NO synthase (eNOS) have been associated with pregnancy complications, intrauterine growth retardation, and altered vascular function in offspring. In the present study, we investigated the influence of the maternal eNOS genotype on offspring’s blood pressure, heart rate, and locomotor activity. The effect of maternal eNOS genotype was made by comparing telemetered blood pressure and activity between 2 groups of 13- to 16-week–old male heterozygous eNOS knockout mice, 1 produced by a cross of eNOS knockout (eNOS
−/−
) mothers and wild-type (eNOS
+/+
) fathers (eNOS
+/−MAT
offspring, N=11), the other by a cross of eNOS
+/+
mothers and eNOS
−/−
fathers (eNOS
+/−PAT
offspring, N=10). Data were also collected for homozygous eNOS
−/−
and eNOS
+/+
mice (N=15 each). Heterozygous eNOS knockout mice exhibited blood pressures that were intermediate to the eNOS
+/+
and eNOS
−/−
groups. Relative to eNOS
+/−PAT
mice, eNOS
+/−MAT
mice exhibited significant increases in nocturnal diastolic arterial pressure and diurnal variations (dark–light difference) in systolic, mean, and diastolic arterial pressure. In addition, indices of spontaneous nocturnal locomotor activity, including both the proportion of time spent active and the intensity of activity when active, were also significantly increased. Heart rate did not differ between the groups. Our results suggest that the maternal eNOS genotype influences both blood pressure and behavior of offspring, possibly as a consequence of developmental programming associated with intrauterine growth retardation.
FK506 Binding Protein 12/12.6 Depletion Increases Endothelial Nitric Oxide Synthase Threonine 495 Phosphorylation and Blood Pressure
Authors: Long Cheng , Cook Leslie G. , Hamilton Susan L. , Wu Gang-Yi , Mitchell Brett M.
Published: February 2007

Chronic treatment with the immunosuppressive drug rapamycin leads to hypertension; however, the mechanisms are unknown. Rapamycin binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and displaces them from intracellular Ca2+release channels (ryanodine receptors) eliciting a Ca2+leak from the endoplasmic/sarcoplasmic reticulum. We tested whether this Ca2+leak promotes conventional protein kinase C–mediated endothelial NO synthase phosphorylation at Thr495, which reduces production of the vasodilator NO. Rapamycin treatment of control mice for 7 days, as well as genetic deletion of FKBP12.6, increased systolic arterial pressure significantly compared with controls. Untreated aortas from FKBP12.6−/−mice and in vitro rapamycin-treated control aortas had similarly decreased endothelium-dependent relaxation responses and NO production and increased endothelial NO synthase Thr495 phosphorylation and protein kinase C activity. Inhibition of either conventional protein kinase C or ryanodine receptor restored endothelial NO synthase Thr495 phosphorylation and endothelial function to control levels. Rapamycin induced a small increase in basal intracellular Ca2+levels in isolated endothelial cells, and rapamycin or FKBP12.6 gene deletion decreased acetylcholine-induced intracellular Ca2+release, all of which were reversed by ryanodine. These data demonstrate that displacement of FKBP12/12.6 from ryanodine receptors induces an endothelial intracellular Ca2+leak and increases conventional protein kinase C–mediated endothelial NO synthase Thr495 phosphorylation leading to decreased NO production and endothelial dysfunction. This molecular mechanism may, in part, explain rapamycin-induced hypertension.
Genomic Profiles of Stroke in Blood
Authors: Sharp Frank R. , Xu Huichun , Lit Lisa , Walker Wynn , Pinter Joseph , Apperson Michelle , Verro Piero
Published: February 2007

These studies show that gene expression changes in most patients by 2 to 3 hours after ischemic stroke, and in all patients studied by 24 hours.
Left Atrial Appendage Exclusion for Stroke Prevention in Patients With Nonrheumatic Atrial Fibrillation
Authors: Onalan Orhan , Crystal Eugene
Published: February 2007

The efficacy of oral anticoagulation (OAC) for stroke prevention in patients with nonrheumatic atrial fibrillation (AF) has clearly been established. However, a substantial number of patients with AF who are at high risk for thromboembolic events are not candidates for long-term OAC. The left atrial appendix (LAA) is the most common place of thrombosis in patients with AF, and it can easily be excluded from the systemic circulation at the time of cardiac surgery by excision, ligation, suturing, or stapling. Currently, removal of the LAA at the time of mitral valve surgery is recommended to reduce future stroke risk. The ongoing LAA Occlusion Study (LAAOS) is evaluating the efficacy of the routine LAA occlusion in patients undergoing elective coronary artery bypass graft surgery. Recently, two devices specifically designed for percutaneous transcatheter LAA occlusion have been introduced: the Percutaneous LAA Transcatheter Occlusion (PLAATO; Appriva Medical Inc) and WATCHMAN LAA system (Atritech, Inc). More than 200 PLAATO devices were implanted worldwide in patients with nonrheumatic AF who were at high risk for ischemic stroke and not candidates for long-term OAC. In a follow-up time of 258 patient-years, an estimated 61% reduction in stroke risk was achieved with PLAATO procedure. The WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation (PROTECT AF) study was designed to demonstrate the safety and efficacy of the WATCHMAN device in patients with nonvalvular AF who are eligible for long-term OAC. The trial is assessing whether the treatment arm (WATCHMAN device) is noninferior to the control arm (warfarin). Although present results suggest that LAA occlusion may reduce the long-term stroke risk, available data are still very limited. At present, percutaneous LAA occlusion may be an acceptable option in selected high-risk patients with AF who are not candidates for OAC. The current understanding of LAA exclusion for the prevention of stroke in patients with nonrheumatic AF is the major focus of this review.
Stroke-Induced Immunodepression
Authors: Dirnagl Ulrich , Klehmet Juliane , Braun Johann S. , Harms Hendrik , Meisel Christian , Ziemssen Tjalf , Prass Konstantin , Meisel Andreas
Published: February 2007

Stroke affects the normally well-balanced interplay of the 2 supersystems: the nervous and the immune system. Recent research elucidated some of the involved signals and mechanisms and, importantly, was able to demonstrate that brain-immune interactions are highly relevant for functional outcome after stroke. Immunodepression after stroke increases the susceptibility to infection, the most relevant complication in stroke patients. However, immunodepression after stroke may also have beneficial effects, for example, by suppressing autoaggressive responses during lesion-induced exposure of central nervous system-specific antigens to the immune system. Thus, before immunomodulatory therapy can be applied to stroke patients, we need to understand better the interaction of brain and immune system after focal cerebral ischemia. Until then, anticipating an important consequence of stroke-induced immunodepression, bacterial infection, preventive antibiotic strategies have been proposed. In mouse experiments, preventive antibiotic treatment dramatically improves mortality and outcome. Results of clinical studies on this issue are contradictory at present, and larger trials are needed to settle the question whether (and which) stroke patients should be preventively treated. Nevertheless, clinical evidence is emerging demonstrating that stroke-induced immunodepression in humans not only exists, but has very similar features to those characterized in rodent experiments.
Clinical Trials of Neuroprotective Therapies
Authors: Zivin Justin A.
Published: February 2007

There have been numerous failures in the field of acute stroke therapy over many years, but the first large clinical trial showing preliminary indications of efficacy and safety of a neuroprotective drug, NXY-059, has now been fully reported. If confirmed, it will mean that a second therapy for acute stroke has been identified and neuroprotective drug development as a class can proceed. Additionally, a new class of drugs, HMG CoA-reductase inhibitors (statins), specifically high-dose atorvastatin, has been shown to be safe and effective for secondary stroke prevention. This drug should now become a regular part of stroke patient care.
Nonconventional Clinical Trial Designs
Authors: Howard George
Published: February 2007

Statistical sciences have recently made advancements that allow improved precision or reduced sample size in clinical research studies. Herein, we review 4 of the more promising: (1) improvements in approaches for dose selection trials, (2) approaches for sample size adjustment, (3) selection of study end point and associated statistical methods, and (4) frequentist versus Bayesian statistical methods. Whereas each of these holds the opportunity for more efficient trials, each are associated with the need for more stringent assumptions or increased complexity in the interpretation of results. The opportunities for these promising approaches, and their associated “costs,” are reviewed.
Neurovascular Proteases in Brain Injury, Hemorrhage and Remodeling After Stroke
Authors: Zhao Bing-Qiao , Tejima Emiri , Lo Eng H.
Published: February 2007

Matrix metalloproteinases (MMPs) mediate tissue injury during acute stroke. Clinical data show that elevated MMPs in plasma of stroke patients may correlate with outcomes, suggesting its use as a biomarker. MMP-9 signal has also been detected in clinical stroke brain tissue samples. Because tissue plasminogen activator can upregulate MMPs via lipoprotein receptor signaling, these neurovascular proteolytic events may underlie some of the complications of edema and hemorrhage that plague thrombolytic therapy. However, in contrast to its deleterious actions in acute stroke, MMPs and other neurovascular proteases may play beneficial roles during stroke recovery. MMPs are increased in the subventricular zone weeks after focal stroke, and inhibition of MMPs suppress neurogenic migration from subventricular zone into damaged tissue. In peri-infarct cortex, MMPs may mediate neurovascular remodeling. Delayed inhibition of MMPs decrease markers of remodeling, and these phenomena may be related to reductions in bioavailable growth factors. Acute versus chronic protease profiles within the neurovascular unit are likely to underlie critical responses to stroke, therapy, and recovery.
Microglial Activation and Matrix Protease Generation During Focal Cerebral Ischemia
Authors: del Zoppo Gregory J. , Milner Richard , Mabuchi Takuma , Hung Stephanie , Wang Xiaoyun , Berg Greta I. , Koziol James A.
Published: February 2007

Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro–MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors.
Modeling Intracerebal Hemorrhage
Authors: Wagner Kenneth R.
Published: February 2007

A significant amount of new information has been generated in animal models of intracerebral hemorrhage during the past several years. These include findings on the pathophysiological, biochemical and molecular processes that underlie the development of brain tissue injury after intracerebral hemorrhage as well as potential new treatments. We review these various findings that include glutamate receptor activation, oxidative stress development, intracellular signaling through the transcription factor, nuclear factor-κB, and markedly upregulated cytokine gene expression. We also briefly review the surgical treatment for intracerebral hemorrhage and list the pharmacological treatment studies that have recently appeared.
Screening Potential Therapies
Authors: Tilley Barbara C. , Galpern Wendy R.
Published: February 2007

In Parkinson Disease (PD) as well as in stroke research there is an urgent need to both optimize the use of resources (number of patients, costs, and time) and select potential effective neuroprotective agents. The processes used to identify and study new therapies for PD may be applicable to the search for new therapies in stroke. The National Institute of Neurological Disorders and Stroke (NINDS) organized the Committee to Identify Neuroprotective Agents for Parkinson’s (CINAPS). CINAPS broadly solicited suggestions for agents and evaluated these agents using rigorous criteria. NINDS also created the NIH Exploratory Trials in PD program (NET-PD), a clinical network where CINAPS recommendations could be tested. Given multiple recommended agents, NET-PD investigators used Phase II futility designs with calibration controls, tested against an historical standard, to screen agents for testing in Phase III trials. Investigators also used the Phase II trial to assess ancillary outcome measures for use in Phase III. The observed value for the calibration controls in the first NET-PD Phase II trial was outside the 95% CI for the historical standard. Using bootstrap methodology it appeared unlikely this outcome happened by chance. The historical standard was updated using more contemporaneous data than were available at the start of the futility trials and a re-evaluation using the new threshold was conducted. Assessment of ancillary outcome measures led to a reduced set of outcome measures for use in Phase III. The CINAPS process, and lessons learned from NET-PD futility studies, particularly with respect to calibration controls and assessment of outcome measures, could enhance the choice and testing of new agents for stroke treatment.