bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms
Authors: Loutzenhiser Rodger , Griffin Karen , Williamson Geoffrey , Bidani Anil
Published: April 2006

When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature.
Remodeling of astrocytes, a prerequisite for synapse turnover in the adult brain? Insights from the oxytocin system of the hypothalamus
Authors: Theodosis Dionysia T. , Trailin Andrei , Poulain Dominique A.
Published: April 2006

Neurons, including their synapses, are generally ensheathed by fine processes of astrocytes, but this glial coverage can be altered under different physiological conditions that modify neuronal activity. Changes in synaptic connectivity accompany astrocytic transformations so that an increased number of synapses are associated with reduced astrocytic coverage of postsynaptic elements, whereas synaptic numbers are reduced on reestablishment of glial coverage. A system that exemplifies activity-dependent structural synaptic plasticity in the adult brain is the hypothalamo-neurohypophysial system, and in particular, its oxytocin component. Under strong, prolonged activation (parturition, lactation, chronic dehydration), extensive portions of somatic and dendritic surfaces of magnocellular oxytocin neurons are freed of intervening astrocytic processes and become directly juxtaposed. Concurrently, they are contacted by an increased number of inhibitory and excitatory synapses. Once stimulation is over, astrocytic processes again cover oxytocinergic surfaces and synaptic numbers return to baseline levels. Such observations indicate that glial ensheathment of neurons is of consequence to neuronal function, not only directly, for example by modifying synaptic transmission, but indirectly as well, by preparing neuronal surfaces for synapse turnover.
Contribution of adenosine A2A and A2B receptors and heme oxygenase to AMPA-induced dilation of pial arterioles in rats
Authors: Ohata Hiroto , Cao Suyi , Koehler Raymond C.
Published: April 2006

Nitric oxide (NO) has been implicated in mediation of cerebral vasodilation during neuronal activation and, specifically, in pharmacological activation of N-methyl-d-aspartate (NMDA) and kainate receptors. Possible mediators of cerebral vasodilation to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) have not been well studied in mature brain, although heme oxygenase (HO) activity has been implicated in newborn pigs. In anesthetized rats, 5 min of topical superfusion of 30 and 100 μM AMPA on the cortical surface through a closed cranial window resulted in increases in pial arteriolar diameter. The dilatory response to AMPA was not inhibited by superfusion of an NO synthase inhibitor, a cyclooxygenase-2 inhibitor, or a cytochrome P-450 epoxygenase inhibitor, all of which have been shown to inhibit the cortical blood flow response to sensory activation. However, the 48 ± 13% dilation to 100 μM AMPA was attenuated 56–71% by superfusion of the adenosine A2A receptor antagonist ZM-241385, the A2B receptor antagonist alloxazine, and the HO inhibitor chromium mesoporphyrin. Combination of the latter three inhibitors did not attenuate the dilator response more than the individual inhibitors, whereas an AMPA receptor antagonist fully blocked the vasodilation to AMPA. These results indicate that cortical pial arteriolar dilation to AMPA does not require activation of NO synthase, cyclooxygenase-2, or cytochrome P-450 epoxygenase but does depend on activation of adenosine A2A and A2B receptors. In addition, CO derived from HO appears to play a role in the vascular response to AMPA receptor activation in mature brain by a mechanism that is not additive with that of adenosine receptor activation.
NMDA receptor antagonism disrupts the development of morphine analgesic tolerance in male, but not female C57BL/6J mice
Authors: Bryant Camron D. , Eitan Shoshana , Sinchak Kevin , Fanselow Michael S. , Evans Christopher J.
Published: April 2006

Multiple studies demonstrate that coadministration of N-methyl-d-aspartate (NMDA) receptor antagonists with the opioid agonist morphine attenuates the development of analgesic tolerance. Sex differences in the effects of noncompetitive, but not competitive NMDA receptor antagonists on acute morphine analgesia, have been reported in mice, yet the role of sex in modulation of morphine tolerance by NMDA receptor antagonists has yet to be addressed. Therefore, we tested whether there is a sex difference in the effect of NMDA receptor antagonists on the development of morphine analgesic tolerance in C57BL/6J mice. Acutely, at a dose required to affect morphine tolerance in male mice, the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) prolonged morphine analgesia similarly in both sexes in the hot plate and tail withdrawal assays. In the hot plate assay, coadministration of MK-801 or the competitive antagonist 3-(2-carboxpiperazin-4-yl)propyl-1-phosphanoic acid (CPP) with morphine attenuated the development of tolerance in male mice, while having no effect in females. Like normal and sham females, ovariectomized mice were similarly insensitive to the attenuation of morphine tolerance by MK-801 in the hot plate assay. Surprisingly, in the tail withdrawal assay, MK-801 facilitated the development of morphine-induced hyperalgesia and tolerance in males but not females. The results demonstrate that male mice are more sensitive to modulation of nociception and morphine analgesia after repeated coadministration of NMDA receptor antagonists. Furthermore, the underlying mechanisms are likely to be different from those mediating the sex difference in the modulation of acute morphine analgesia that has previously been reported.
Comparison between two rat sympathetic pathways activated in cold defense
Authors: Ootsuka Youichirou , McAllen Robin M.
Published: April 2006

In cold defense and fever, activity increases in sympathetic nerves supplying both tail vessels and interscapular brown adipose tissue (iBAT). These mediate cutaneous vasoconstrictor and thermogenic responses, respectively, and both depend upon neurons in the rostral medullary raphé. To examine the commonality of brain circuits driving these two outflows, sympathetic nerve activity (SNA) was recorded simultaneously from sympathetic fibers in the ventral tail artery (tail SNA) and the nerve to iBAT (iBAT SNA) in urethane-anesthetized rats. From a warm baseline, cold-defense responses were evoked by intermittently circulating cold water through a water jacket around the animal's shaved trunk. Repeated episodes of trunk skin cooling decreased core (rectal) temperature. The threshold skin temperature to activate iBAT SNA was 37.3 ± 0.5°C ( n = 7), significantly lower than that to activate tail SNA (40.1 ± 0.4°C; P < 0.01, n = 7). A fall in core temperature always strongly activated tail SNA (threshold 38.3 ± 0.2°C, n = 7), but its effect on iBAT SNA was absent (2 of 7 rats) or weak (threshold 36.9 ± 0.1°C, n = 5). The relative sensitivity to core vs. skin cooling (K-ratio) was significantly greater for tail SNA than for iBAT SNA. Spectral analysis of paired recordings showed significant coherence between tail SNA and iBAT SNA only at 1.0 ± 0.1 Hz. The coherence was due entirely to the modulation of both signals by the ventilatory cycle because it disappeared when the coherence spectrum was partialized with respect to airway pressure. These findings indicate that independent central pathways drive cutaneous vasoconstrictor and thermogenic sympathetic pathways during cold defense.
Sex differences in the effects of amiloride on formalin test nociception in mice
Authors: Chanda Mona Lisa , Mogil Jeffrey S.
Published: April 2006

Amiloride is a nonspecific blocker of acid-sensing ion channels (ASICs) that have been recently implicated in the mediation of mechanical and chemical/inflammatory nociception. Preliminary data using a transgenic model are suggestive of sex differences in the role of ASICs. We report here that systemic administration of amiloride (10–70 mg/kg ip) produces a robust, dose-dependent blockade of late/tonic phase nociceptive behavior on the mouse formalin test (5%; 20 μl) in female but not male mice, completely abolishing the known sex difference in formalin test response. Adult gonadectomy produced a “switching” of sex differences in amiloride efficacy, with castrated males displaying an amiloride blockade and ovariectomized females rendered less sensitive to amiloride. Gonadectomized mice could be switched back to their intact status using chronic estrogen benzoate or testosterone propionate replacement via osmotic minipump (6 μg/day or 250 μg/day, respectively). It is unclear whether this striking sex difference is due to sex-specific involvement of ASICs in pain processing, but the present data represent one of the first demonstrations of pain-related sex differences with no obvious opioid involvement.
Maximal oxygen consumption in relation to subordinate traits in lines of house mice selectively bred for high voluntary wheel running
Authors: Rezende Enrico L. , Gomes Fernando R. , Malisch Jessica L. , Chappell Mark A. , Garland Theodore
Published: April 2006

We studied relations between maximal O2consumption (V̇o2 max) during forced exercise and subordinate traits associated with blood O2transport and cellular respiration in four lines of mice selectively bred for high voluntary wheel running (S lines) and their four nonselected control (C) lines. Previously, we reported V̇o2 maxof 59 females at three Po2(hypoxia = 14% O2, normoxia = 21%, hyperoxia = 30%). Here, we test the hypothesis that variation in V̇o2 maxcan be explained, in part, by hemoglobin concentration and Po2necessary to obtain 50% O2saturation of Hb (an estimate of Hb affinity for O2) of the blood as well as citrate synthase activity and myoglobin concentration of ventricles and gastrocnemius muscle. Statistical analyses controlled for body mass, compared S and C lines, and also considered effects of the mini-muscle phenotype (present only in S lines and resulting from a Mendelian recessive allele), which reduces hindlimb muscle mass while increasing muscle mass-specific aerobic capacity. Although S lines had higher V̇o2 maxthan C, subordinate traits showed no statistical differences when the presence of the mini-muscle phenotype was controlled. However, subordinate traits did account for some of the individual variation in V̇o2 max. Ventricle size was a positive predictor of V̇o2 maxat all three Po2. Blood Hb concentration was a positive predictor of V̇o2 maxin S lines but a negative predictor in C lines, indicating that the physiological underpinnings of V̇o2 maxhave been altered by selective breeding. Mice with the mini-muscle phenotype had enlarged ventricles, with higher mass-specific citrate synthase activity and myoglobin concentration, which may account for their higher V̇o2 maxin hypoxia.
Reflexes from the lungs and airways: historical perspective
Authors: Widdicombe John
Published: April 2006

Historical aspects of respiratory reflexes from the lungs and airways are reviewed, up until about 10 yr ago. For most of the 19th century, the possible reflex inputs into the “respiratory center,” the position of which had been identified, were very speculative. There was little concept of reflex control of the pattern of breathing. Then, in 1868, Breuer published his paper on “The self-steering of respiration via the Nervus Vagus.” For the first time this established the role of vagal inflation and deflation reflexes in determining the pattern of breathing. Head later extended Breuer’s work, and Kratschmer laid a similar basis for reflexes from the nose and larynx. Then, 50–60 yr later, the development of the thermionic valve and the oscilloscope allowed recording action potentials from single nerve fibers in the vagus. In 1933, Adrian showed that slowly adapting pulmonary stretch receptors were responsible for the inflation reflex. Later, Knowlton and Larrabee described rapidly adapting receptors and showed that they mediated deep augmented breaths and the deflation reflex. Still later, it was established that rapidly adapting receptors were, at least in part, responsible for cough. In 1954, Paintal began his study of C-fiber receptors (J receptors), work greatly extended by the Coleridges. Since ∼10 yr ago, when the field of this review stops, there has been an explosion of research on lung and airway receptors, many aspects of which are dealt with in other papers in this series.
Active hyperemia and vascular conductance differ between men and women for an isometric fatiguing contraction
Authors: Hunter Sandra K. , Schletty Jennie M. , Schlachter Kristine M. , Griffith Erin E. , Polichnowski Aaron J. , Ng Alexander V.
Published: April 2006

To understand the role of muscle perfusion in the sex differences of muscle fatigue, we compared the time to task failure, postcontraction (active) hyperemia, and vascular conductance for an isometric fatiguing contraction performed by young men and women with the handgrip muscles at 20% of maximal voluntary contraction (MVC) force. In study 1, the men ( n = 16) were stronger than the women ( n = 18), and study 2, the men ( n = 7) and women ( n = 7) were matched for strength. Isometric contractions were sustained during two sessions: 1) until the target force could no longer be achieved or 2) for 4 min. For both studies, blood flow and vascular conductance were similar for the men and women at rest and after 10 min of occlusion, and at task failure for the fatiguing contraction estimated using forearm venous occlusion plethysmography. In study 1, the time to task failure was longer for the women (11.4 ± 2.8 min) than for the men (8.4 ± 2.4 min; P = 0.003). However, at the end of the 4-min contraction, active hyperemia and vascular conductance were greater for the men than the women (99 vs. 70% peak blood flow; P < 0.001). In study 2, the men and women had similar strength and a similar time to failure (8.4 ± 1.6 vs. 8.6 ± 2.3 min). Active hyperemia was greater for the men than the women (86 vs. 64% peak flow; P = 0.038) after the 4-min contraction, as was vascular conductance (80 vs. 57% peak conductance; P = 0.02). Thus the briefer time to failure of men than women for an isometric fatiguing contraction is a function of the greater strength of men but is not dependent on differences in the active hyperemia and vascular conductance.
Activin Receptor-Like Kinase 7 Induces Apoptosis through Up-Regulation of Bax and Down-Regulation of Xiap in Normal and Malignant Ovarian Epithelial Cell Lines
Authors: Xu Guoxiong , Zhou Hong , Wang Qinghua , Auersperg Nelly , Peng Chun
Published: April 2006

Transforming growth factor-β superfamily has been implicated in tumorigenesis. We have recently shown that Nodal, a member of transforming growth factor-β superfamily, and its receptor, activin receptor-like kinase 7 (ALK7), inhibit proliferation and induce apoptosis in human epithelial ovarian cancer cell lines. In this study, we further investigated the cellular mechanisms underlying the apoptotic action of ALK7 using an immortalized ovarian surface epithelial cell line, IOSE397, and an epithelial ovarian cancer cell line, OV2008. Infection of these cells with an adenoviral construct carrying constitutively active ALK7 (Ad-ALK7-ca) potently induced cell death; all cells died after 3 and 5 days of Ad-ALK7-ca infection in IOSE397 and OV2008 cells, respectively. ALK7-ca induced the expression of proapoptotic factor Bax but suppressed the expression of antiapoptotic factors Bcl-2, Bcl-XL, and Xiap. Silencing of Bax by small interfering RNA in IOSE397 cells significantly reduced ALK7-ca-induced apoptosis as measured by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay but partially blocked ALK7-ca-induced caspase-3 activation and did not affect the down-regulation of Xiap by ALK7-ca. Dominant-negative Smad2, Smad3, and Smad4 blocked ALK7-ca-regulated Xiap and Bax expression and caspase-3 activation. Thus, ALK7-induced apoptosis is at least in part through two Smad-dependent pathways, Bax/Bcl-2 and Xiap. (Mol Cancer Res 2006;4(4):235–46)
Analysis of Co-Aggregation of Cancer Based on Registry Data
Authors: Matthews Abigail G. , Betensky Rebecca A. , Anton-Culver Hoda , Bowen Deborah , Griffin Constance , Isaacs Claudine , Kasten Carol , Mineau Geraldine , Nayfield Susan , Schildkraut Joellen , Strong Louise , Weber Barbara , Finkelstein Dianne M.
Published: April 2006

Objective: An exploratory analysis of co-aggregation of cancers using registry-based data. Methods: We utilized sibships from over 18,000 families who had been recruited to the NCI-sponsored multi-institutional Cancer Genetics Network. The analysis assesses co-aggregation at the individual and family level and adjusts for ascertainment. Results: We found statistically significant familial co-aggregation of lung cancer with pancreatic (adjusted p < 0.001), prostate (adjusted p < 0.003), and colorectal cancers (adjusted p = 0.004). In addition, we found significant familial co-aggregation of pancreatic and colorectal cancers (adjusted p = 0.018), and co-aggregation of hematopoietic and (non-ovarian) gynecologic cancers (adjusted p = 0.01). Conclusion: This analysis identified familial aggregation of cancers for which a genetic component has yet to be established.
Fourteen-Year Experience of Prenatal Diagnosis of Thalassemia in Iran
Authors: Najmabadi Hossein , Ghamari Alireza , Sahebjam Farhad , Kariminejad Roxana , Hadavi Valeh , Khatibi Talayeh , Samavat Ashraf , Mehdipour Elaheh , Modell Bernadette , Kariminejad Mohammand Hassan
Published: April 2006

For 14 years, Iranian scientists have worked to develop a national thalassemia prevention program. Although historically abortion was considered unacceptable in Iran, intensive consultations led to the clerical approval of induced abortion in cases with β-thalassemia major in 1997, and a nationwide prevention program with screening, counseling and prenatal diagnosis (PND) networks has been developed. This paper reports the experience from one of the two national PND reference laboratories. As one of the oldest reference laboratories, we performed a total of 906 PND in 360 couples at risk for thalassemia from 1990 to 2003. Direct and indirect mutation detection methods were applied for all cases. In total, 22 mutations were tested routinely, and an additional 30 rare mutations were identified. 208 fetuses were found to be normal, 215 fetuses had β-thalassemia major, and 435 fetuses were carriers of the trait. In 40 cases, we only defined one allele. In 8 cases, we were unable to provide any diagnosis, corresponding to 0.9%. Our data support the functionality of the Iranian β-thalassemia prevention program. The success of this system in Iran, a multiethnic and Islamic-based country, would mean that it might be applied as an adaptive system for neighboring and other Islamic countries.
Increased Aortic Intima-Media Thickness Is Related to Lipid Profile in Newborns with Intrauterine Growth Restriction
Authors: Koklu Esad , Kurtoglu Selim , Akcakus Mustafa , Koklu Selmin , Buyukkayhan Derya , Gumus Hakan , Yikilmaz Ali
Published: April 2006

Background and Aim: Low birth-weight is known to be associated with an increase in cardiovascular risk similar to that seen with major environmental risk factors, such as cigarette smoking or hypertension. Much epidemiological evidence has linked low birth-weight with hypertriglyceridaemia. Method: We measured aortic wall thickness by ultrasonography and lipid profile in 40 newborn babies with intrauterine growth restriction and 40 controls. Results: Maximum and mean aortic intima-media thickness were significantly higher in the babies with intrauterine growth retardation (0.58 ± 0.06, 0.52 ± 0.03 mm, respectively) than in controls (0.44 ± 0.05, 0.40 ± 0.03 mm, p < 0.0001, p < 0.0001, respectively), more so after adjustment for birth-weight (maximum intima-media thickness: 0.23 ± 0.03 mm/kg vs. 0.12 ± 0.02 mm/kg, p < 0.0001; mean intima-media thickness: 0.21 ± 0.02 mm/kg vs. 0.11 ± 0.01 mm/kg, p < 0·0001). Serum triglyceride levels were significantly higher in the intrauterine growth retardation group (48.9 ± 14.8 mg/dl) compared with the control group (32.5 ± 9.8 mg/dl, p < 0.0001). The mean body mass index, prepregnancy weight, weight gain during pregnancy, maternal LDL cholesterol level and, height of the mothers were significantly lower in the intrauterine growth retardation group compared with the control group. For maximum aIMT, significant associations included the ponderal index (p = <0.01), length (p = 0.01) and serum triglyceride levels of infants (p = 0.02). Conclusion: Newborn babies with growth restriction have significant maximum aortic thickening with hypertriglyceridaemia, suggesting that prenatal events might predispose to later cardiovascular risk.
Distinct Pattern of Commensal Gut Microbiota in Toddlers with Eczema
Authors: Mah K.W. , Björkstén B. , Lee B.W. , van Bever H.P. , Shek L.P. , Tan T.N. , Lee Y.K. , Chua K.Y.
Published: April 2006

Background: Recent studies have demonstrated differences in the composition of gut microbiota in infants with and without allergic diseases, particularly eczema. Methods: A case-control study involving 21 toddlers (age 3.0 ± 0.5 years) with and 28 age-matched toddlers without eczema was conducted. Four groups of aerobic gut microbiota were identified and quantitated in stool samples grown on selective media. Three groups of anaerobes were enumerated by fluorescent in situ hybridization followed by quantitative flow cytometry. We also performed molecular typing of lactic-acid-producing bacteria (LAB) and enterococcal isolates to facilitate detailed analysis at species level by bacterial 16S rDNA sequencing. Results: Toddlers with eczema harbored significantly lower counts of Bifidobacterium [(median 0.14 (25th and 75th percentile: 0.04 and 0.47) vs. 0.71% (0.16, 1.79) of cells acquired, p = 0.003)] and Clostridium [(0.28 (0.09, 0.78) vs. 0.83% (0.35, 1.82) of cells acquired, p = 0.012)] but significantly higher counts of total LAB [7.3 (6.1, 8.5) vs. 5.7 (4.4, 7.3) log CFU/g, p = 0.006] in particular enterococci [6.3 (4.8, 7.4) vs. 5.0 (3.4, 6.4) log CFU/g, p = 0.018]. There was no significant correlation between eczema severity score and bifidobacterial counts. Conclusion: The results further confirm previous reports that the gut microecosystem differs between children with and without eczema and extend them beyond infancy.
Envelope Following Responses to Natural Vowels
Authors: Aiken Steven J. , Picton Terence W.
Published: April 2006

Envelope following responses to natural vowels were recorded in 10 normal hearing people. Responses were recorded to individual vowels (/ɑ/, /i/, /u/) with a relatively steady pitch, to /∧/ with a variable and steady pitch, and to a multivowel stimulus (/∧ui/) with a steady pitch. Responses were analyzed using a Fourier analyzer, so that recorded responses could follow the changes in the pitch. Significant responses were detected for all subjects to /ɑ/, /i/ and /u/ with the time required to detect a significant response ranging from 6 to 66 s (average time: 19 s). Responses to /∧/ and /∧ui/ were detected in all subjects, but took longer to demonstrate (average time: 73 s). These results support the use of a Fourier analyzer to measure envelope following responses to natural speech.
Clinical Features and Outcome of Patients with Apical Hypertrophic Cardiomyopathy in Taiwan
Authors: Lee Cheng-Han , Liu Ping-Yen , Lin Li-Jen , Chen Jyh-Hong , Tsai Liang-Miin
Published: April 2006

Objectives: The aim of this study was to analyze clinical characteristics and the outcome of patients with apical hypertrophic cardiomyopathy (ApHCM) followed in a Taiwan tertiary referral medical center. Background: ApHCM is regarded as a subgroup of nonobstructive HCM that occurs largely in Japanese patients. The clinical features, gender differences and prognosis of the disease in Taiwan are poorly understood. Methods: A retrospective cohort study with 40 patients was performed. Diagnosis was based on the demonstration of left ventricular hypertrophy by echocardiography. Clinical features, cardiovascular morbidity and mortality were analyzed. Multiple logistic regression was used to adjust for potential confounding factors. Results: Among 40 patients, males predominated with a percentage of 75%. The female patients obviously had later onset of presentation (mean age ± SD, 62.2 ± 5.7 vs. 54.1 ± 11.4 years; p = 0.038). During a mean follow-up of 72.2 ± 60.1 months, there was no mortality. However, 13 patients (32.5%) had one or more major cardiovascular morbidities, the most frequent being syncope or near syncope (15%) and ischemic stroke-associated atrial fibrillation (10%). In a multivariate analysis, left atrial enlargement (odds ratio 5.85, 95% CI 1.15–29.40; p = 0.034) was the only predictor of cardiovascular morbidity. Conclusions: Patients with ApHCM in Taiwan have a benign clinical course without association with sudden death and cardiovascular mortality. Left atrial enlargement was the only identified predictor of cardiovascular morbidity
Effects of Phytoestrogen Extracts Isolated from Rye, Green and Yellow Pea Seeds on Hormone Production and Proliferation of Trophoblast Tumor Cells Jeg3
Authors: Matscheski A. , Richter D.-U. , Hartmann A.-M. , Effmert U. , Jeschke U. , Kupka M.S. , Abarzua S. , Briese V. , Ruth W. , Kragl U. , Piechulla B.
Published: April 2006

Background: Phytoestrogens are a diverse group of non-steroidal plant compounds. Because they have chemical structures similar to estrogens they are able to bind on estrogen receptors in humans. Objectives: In this study, we tested the effects of crude phytoestrogen extracts from rye (Secale cereale), green pea (Pisum sativum) and yellow pea seeds (Pisum sativum cv.) on cell proliferation and the production of progesterone in trophoblast tumor cells of the cell line Jeg3. Methods: Isoflavone extracts from green and yellow pea seeds and lignan extracts from rye seeds were obtained, using different extraction methods. Isolated extracts were incubated in different concentrations with trophoblast tumor cells. Untreated cells were used as controls. At designated times, aliquots were removed and tested for estradiol and progesterone production. In addition, we tested the effects of the phytoestrogen extracts on cell proliferation. Results: Cell proliferation is significantly inhibited by potential phytoestrogens isolated from rye, green and yellow pea seeds in trophoblast tumor cells of the cell line Jeg3. We found a correlation between the effects of proliferation and production of estradiol in isoflavone extracts from green and yellow pea seeds in Jeg3 cells. In addition, higher concentrations of isoflavones isolated from green pea seeds and lignans from rye showed also a inhibition of progesterone production whereas higher concentrations of rye lignans elevated estradiol production in Jeg3 cells. Conclusion: A useful indicator test system for potential phytoestrogens could be established. Based on the obtained results it is proposed that green and yellow pea seeds contain measurable concentrations of isoflavones and rye seeds contain lignans which can be isolated and used for special human diet programs.
Pamidronate: Treatment for Severe Hypercalcemia in Neonatal Subcutaneous Fat Necrosis
Authors: Alos Nathalie , Eugène Dardye , Fillion Marc , Powell Julie , Kokta Victor , Chabot Gilles
Published: April 2006

Background: Subcutaneous fat necrosis (SCFN) of the newborn is an uncommon disorder that occurs in the first weeks of life after foetal distress. It can be complicated by potentially life-threatening hypercalcemia. Treatments of hypercalcemia have included hydration, furosemide and corticosteroids. Only one report has described the use of intravenous bisphosphonates for this condition. We propose that pamidronate could be the first line therapy for severe hypercalcemia in SCFN. Patients and Results: Four newborns presented between 2001 and 2004 with SCFN complicated by severe hypercalcemia. At diagnosis, ionized calcium levels were higher than 1.4 mmol/l and were associated with high urinary calcium/creatinine ratios and high 1,25-dihydroxyvitamin D levels. Despite treatment with IV fluids, low calcium diet and furosemide, calcium levels remained high. The patients were given 3–4 doses (0.25–0.50 mg/kg/dose) of pamidronate. Urinary calcium/creatinine ratios and calcium levels decreased within 48–96 h. 1,25-dihydroxyvitamin D levels normalized with resolution of the skin lesions. No persistent nephrocalcinosis was observed. Conclusion: Pamidronate is effective, well-tolerated in the short-term and obviates the need for prolonged treatment with furosemide and corticosteroids. To prevent nephrocalcinosis, pamidronate might be considered as first line treatment for severe hypercalcemia in SCFN.
Reduced Serum Acylated Ghrelin Levels in Patients with Hyperthyroidism
Authors: Altınova Alev E. , Törüner Füsun B. , Aktürk Müjde , Elbeğ Şehri , Yetkin İlhan , Çakır Nuri , Arslan Metin
Published: April 2006

Background and Objective: Recent studies have revealed that circulating ghrelin levels seem to play a role in energy homeostasis. The effect of hyperthyroidism on ghrelin levels is not fully known. Methods: Serum levels of ghrelin and its relationship with insulin resistance were evaluated in 48 patients with hyperthyroidism and 43 euthyroid healthy controls. Thyroid hormones, insulin, glucose, ghrelin levels and lipid parameters were measured in all subjects. Insulin sensitivity was determined using the homeostasis model assessment. Results: Serum ghrelin levels were significantly decreased in hyperthyroid patients than in controls (32.5 ± 23.3 vs. 54.1 ± 35.5 pg/ml, p < 0.001). Circulating ghrelin levels significantly correlated with age (r = –0.26, p = 0.01), fasting glucose (r = –0.21, p = 0.01), free triiodothyronine (r = –0.18, p = 0.04), free thyroxine (r = –0.23, p = 0.02) and thyroid stimulating hormone (r = 0.21, p = 0.04), but not with blood pressure, body mass index, lipid parameters, insulin and homeostasis model assessment (p > 0.05). Multiple regression analysis revealed glucose level to be the most important predictor of circulating ghrelin level. Conclusion: These results indicate that hyperthyroidism has effect on serum ghrelin levels. Further studies are needed for the exact mechanism.
Screening for the Formation of Reactive Oxygen Species and of NO in Muscle Tissue and Remote Organs upon Mechanical Trauma to the Mouse Hind Limb
Authors: Kerkweg Uta , Schmitz Daniel , de Groot Herbert
Published: April 2006

Background: Until now, no systematic surveys exist in the literature on the early local and systemic generation of reactive oxygen species and of nitric oxide in response to muscle crush injury. Therefore, this study aims to evaluate the formation of reactive oxygen species and nitric oxide in different tissues (injured and contralateral muscle, liver, kidney, spleen and blood) that is induced by closed muscle trauma. Methods: 5, 45 and 180 min after induction of blunt trauma to the mouse gastrocnemius muscle, animals were sacrificed, tissues harvested and homogenized, and analyzed for their content of glutathione, nitrate and thiobarbituric acid-reactive substances. Results: The local formation of reactive oxygen species in the injured muscle started immediately upon induction of the mechanical trauma as indicated by changes in the glutathione redox balance. Liver and kidney did not show any response to trauma; however, a marked and immediate increase in the splenic nitrate content was detected, thus suggesting a specific nitric oxide-dependent response of splenic cells to injury. Conclusion: We conclude that immediately after the induction of trauma a formation of reactive oxygen species takes place at the site of crush injury. This might constitute the basis of further damage to the injured tissue by free radical-dependent mechanisms. The immediate formation of nitric oxide within the spleen upon muscle crush appears to represent a specific signalling mechanism of the body in response to distant organ injury.
Biologically Active CD40 Ligand Is Elevated in Sickle Cell Anemia
Authors: Lee Sheritha P. , Ataga Kenneth I. , Orringer Eugene P. , Phillips David R. , Parise Leslie V.
Published: April 2006

Objective—

After activation, platelets expose CD40 ligand (CD40L) on their surface, then subsequently release the inflammatory mediator as a soluble fragment (sCD40L). Because sickle cell anemia (SCA) is noted for both platelet activation and chronic inflammation, we asked whether platelet-released CD40L potentially plays a role in SCA.

Methods and Results—

ELISAs demonstrate that SCA patient plasma contains 30-fold more sCD40L than control plasma. Correspondingly, platelets from these patients contain less than half the CD40L found in control platelets. Platelets from patients in painful crises are further depleted of CD40L, with even higher plasma levels, suggesting a correlation to the patient’s clinical state. In addition, elevated sCD40L correlates with increased tissue factor in SCA plasma. Blockage of the CD40L receptor CD40 reduces SCA plasma-induced production of tissue factor and endothelial intercellular adhesion molecule-1 (ICAM-1). Finally, sCD40L activity in SCA plasma is confirmed by its induction of B-cell proliferation.

Conclusions—

Platelet-derived sCD40L is elevated in SCA, further elevated in crises, and biologically active. The participation of sCD40L in SCA plasma-induced production of B cells, tissue factor, and ICAM-1 suggests that CD40L may contribute to the chronic inflammation and increased thrombotic activity known to occur in SCA.
Transforming Growth Factor-β–Induced Expression of the Apolipoprotein E Gene Requires c-Jun N-Terminal Kinase, p38 Kinase, and Casein Kinase 2
Authors: Singh Nishi N. , Ramji Dipak P.
Published: April 2006

Objective—The cytokine transforming growth factor-β (TGF-β) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF-β have not been characterized and were therefore investigated.

Methods and Results—Using THP-1 cell line as a model system, with key findings confirmed in primary cultures, we show that TGF-β induces the expression of apoE, and this is prevented by pharmacological inhibitors of c-Jun N-terminal kinase (JNK), p38 kinase, and casein kinase 2 (CK2). In support for an important role for these pathways, TGF-β activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF-β also increases the phosphorylation and expression of c-Jun, a downstream target for JNK action and a component of activator protein-1 (AP-1), and DN c-Jun inhibits the induction of apoE expression in response to the cytokine. AP-1 DNA binding was also induced by TGF-β, and the action of p38 kinase, JNK, and CK2 converged on the activation of c-Jun/AP-1.

Conclusions—These studies reveal a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the TGF-β–induced expression of apoE.
Endoplasmic Reticulum Stress Gene Induction and Protection From Ischemia/Reperfusion Injury in the Hearts of Transgenic Mice With a Tamoxifen-Regulated Form of ATF6
Authors: Martindale Joshua J. , Fernandez Rayne , Thuerauf Donna , Whittaker Ross , Gude Natalie , Sussman Mark A. , Glembotski Christopher C.
Published: April 2006

Ischemia/reperfusion (I/R) affects the integrity of the endoplasmic reticulum (ER), the site of synthesis and folding of numerous proteins. Therefore, I/R may activate the unfolded protein response (UPR), resulting in the induction of a collection of ER stress proteins, many of which are protective and function to resolve the ER stress. In this study, we showed that when mouse hearts were subjected to ex vivo I/R, the levels of 2 ER stress-inducible markers of the UPR, the ER-targeted cytoprotective chaperones glucose-regulated proteins 78 and 94 (GRP78 and GRP94), were increased, consistent with I/R-mediated UPR activation in the heart. The UPR-mediated activation of ATF6 (
A
ctivation of
T
ranscription
F
actor
6
) induces cytoprotective ER stress proteins, including GRP78 and GRP94. To examine whether ATF6 protects the myocardium from I/R injury in the heart, we generated transgenic (TG) mice featuring cardiac-restricted expression of a novel tamoxifen-activated form of ATF6, ATF6-MER. When NTG and ATF6-MER TG mice were treated with or without tamoxifen for 5 days, only the hearts from the tamoxifen-treated TG mice exhibited increased levels of many ER stress–inducible mRNAs and proteins; for example, GRP78 and GRP94 transcript levels were increased by 8- and 15-fold, respectively. The tamoxifen-treated TG mouse hearts also exhibited better functional recovery from ex vivo I/R, as well as significantly reduced necrosis and apoptosis. These results suggest that the UPR is activated in the heart during I/R and that, as a result, the ATF6 branch of the UPR may induce expression of proteins that can function to reduce I/R injury.
Why Does Acute Hyperglycemia Worsen the Outcome of Transient Focal Cerebral Ischemia?
Authors: Martín Abraham , Rojas Santiago , Chamorro Ángel , Falcón Carles , Bargalló Núria , Planas Anna M.
Published: April 2006

Background and Purpose—

Hyperglycemia adversely affects the outcome of stroke. Global ischemia data support that the harmful effect of hyperglycemia is mediated by glucose-induced elevated plasma glucocorticoids. Here we sought to evaluate the negative effects of hyperglycemia on transient focal ischemia in the rat, and to test whether these could be prevented by inhibition of either corticosteroid production or neutrophil infiltration.

Methods—

Sprague-Dawley rats (n=217) were used. Ischemia was induced by 1 hour middle cerebral artery occlusion (n=196). Acute hyperglycemia was induced by IP injection of dextrose 30 minutes before ischemia. Neutrophil infiltration was blocked by neutropenia with vinblastine. Corticosterone synthesis was inhibited by chemical adrenalectomy with metyrapone. We measured MRI lesion and tissue infarct volumes, evaluated the neurological function, brain myeloperoxidase and matrix metalloproteinase-9 activities, and protein O-glycosylation.

Results—

Hyperglycemia significantly enhanced MRI diffusion-weighted imaging alterations, increased cortical, but not subcortical, infarct volume, worsened neurological score, and enhanced brain myeloperoxidase and matrix metalloproteinase-9 activities. Metyrapone did not prevent hyperglycemic brain damage despite successful reduction of plasma corticosterone. Yet, metyrapone tended to reduce cortical infarction and apparent diffusion coefficient lesion volume, indicating some negative contribution of corticosterone. Blocking neutrophil infiltration was also ineffective to prevent the harmful effect of hyperglycemia. A new finding was that O-linked glycosylation of cerebral proteins was increased under hyperglycemia.

Conclusions—

In transient middle cerebral artery occlusion, the hyperglycemia-exacerbated brain damage cannot be fully explained by the negative effects of plasma corticosteroids or neutrophil infiltration. The contribution of other intrinsic effects of high glucose, such as brain protein O-glycosylation, deserves further investigation.
Effect of a New Inhibitor of the Synthesis of 20-HETE on Cerebral Ischemia Reperfusion Injury
Authors: Omura Tomohiro , Tanaka Yu , Miyata Noriyuki , Koizumi Chie , Sakurai Takanobu , Fukasawa Misako , Hachiuma Kenji , Minagawa Toshiya , Susumu Teruo , Yoshida Shigeru , Nakaike Shiro , Okuyama Shigeru , Harder David R. , Roman Richard J.
Published: April 2006

Background and Purpose—

Arachidonic acid that is released following cerebral ischemia can be metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys.

Methods—

Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery.

Results—

Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys.

Conclusion—

These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.
Outcome of Carotid Stenting Versus Endarterectomy
Authors: Cao Piergiorgio , De Rango Paola , Verzini Fabio , Maselli Agostino , Norgiolini Lucia , Giordano Giuseppe
Published: April 2006

Background and Purpose—

To compare perioperative and midterm results of carotid artery stenting (CAS) versus carotid endarterectomy (CEA) in similar cohorts of patients, a retrospectively matched case-control study was performed.

Methods—

Three hundred and one case subjects undergoing CAS with cerebral protection and 301 concurrent matched-controls undergoing CEA were examined. Matching was by sex, age (±2 years), symptoms and coronary disease.

Results—

The 30-day disabling stroke/death rate was 2.6% in the CAS group versus 1.3% in the CEA group (odds ratio [OR] 2; 95% CI, 0.54 to 9.35;
P
=0.4). CAS patients had a significantly higher risk of periprocedural stroke (7.9% versus 2.3%; OR, 5.2; 95% CI, 1.7 to 18;
P
=0.001) than CEA patients. However, there was a decreasing trend in 30-day neurological event rates for the last 201 CAS matched cases: 5.4% versus 1.9% (OR 2.8; 95% CI, 0.8 to 10.2;
P
=0.1). Fifty percent of CAS disabling strokes occurred during cannulation of epiaortic vessels before placement of cerebral protection. Conditional multivariate analysis revealed CAS as a predictor of 30-day stroke (hazard ratios [HR] 3.9; 95% CI, 1.6 to 9.4;
P
=0.002) but not of 30-day disabling stroke/death (HR 3.6; 95% CI, 0.93 to 13.9;
P
=0.06). Restenosis free intervals at 36 months were 93.6% versus 92.1% for CAS and CEA, respectively, (
P
=0.6).

Conclusions—

When comparing CAS with CEA, the risk of any neurological events is still higher, particularly during catheterism and ballooning. The effect of the learning curve related to technical expertise and patient selection may influence the outcome of CAS versus CEA. In the midterm the restenosis rate of CAS compares favorably to CEA.
Alcohol Intake, Carotid Plaque, and Cognition
Authors: Wright Clinton B. , Elkind Mitchell S.V. , Rundek Tatjana , Boden-Albala Bernadette , Paik Myunghee C. , Sacco Ralph L.
Published: April 2006

Background and Purpose—

Moderate alcohol intake has been associated with better cognitive performance, implicating vascular and neurodegenerative processes. Few studies to clarify the importance of vascular disease have included direct measures of atherosclerosis or minority populations at higher risk of vascular disease and dementia.

Methods—

The Northern Manhattan Study includes stroke-free community based Hispanic (54%), black (25%), and white (22%) participants. We performed a cross-sectional study of alcohol intake and performance on the Mini-Mental State Examination (MMSE) in subjects with sonographic measurement of maximal carotid plaque thickness and adjusted for sociodemographic and vascular risk factors.

Results—

The median MMSE score was 27 (interquartile range 24 to 29; n=2215). Reported alcohol intake was divided into 5 groups: never (n=509), past (n=494), <1 drink/week (n=300), 1/week to ≤2 drinks/day (n=796), and >2 drinks/day (n=116). Drinking 1 drink weekly up to 2 daily was associated with better performance on the MMSE (odds ratio=1.19; 95% CI, 1.10 to 1.26) compared with nondrinkers in women (
P
≤0.0001) but not in men, adjusting for sociodemographic and vascular risk factors. Maximal carotid plaque thickness (mean 1.1 mm; SD 1.2 mm) was not associated with alcohol intake and did not mediate the relationship between alcohol and cognition.

Conclusions—

Moderate alcohol consumption was independently associated with better cognitive performance in women from this multiethnic sample. Carotid plaque was not a mediator of this association suggesting alcohol may impact cognition through a separate vascular or degenerative pathway.