bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative shell buffering properties correlate with anoxia tolerance in freshwater turtles
Authors: Jackson Donald C. , Taylor Sarah E. , Asare Vivian S. , Villarnovo Dania , Gall Jonathan M. , Reese Scott A.
Published: September 2006

Freshwater turtles as a group are more resistant to anoxia than other vertebrates, but some species, such as painted turtles, for reasons not fully understood, can remain anoxic at winter temperatures far longer than others. Because buffering of lactic acid by the shell of the painted turtle is crucial to its long-term anoxic survival, we have tested the hypothesis that previously described differences in anoxia tolerance of five species of North American freshwater turtles may be explained at least in part by differences in their shell composition and buffering capacity. All species tested have large mineralized shells. Shell comparisons included 1) total shell CO2concentration, 2) volume of titrated acid required to hold incubating shell powder at pH 7.0 for 3 h (an indication of buffer release from shell), and 3) lactate concentration of shell samples incubated to equilibrium in a standard lactate solution. For each measurement, the more anoxia-tolerant species (painted turtle, Chrysemys picta; snapping turtle, Chelydra serpentina) had higher values than the less anoxia-tolerant species (musk turtle, Sternotherus odoratus; map turtle, Graptemys geographica; red-eared slider, Trachemys scripta). We suggest that greater concentrations of accessible CO2(as carbonate or bicarbonate) in the more tolerant species enable these species, when acidotic, to release more buffer into the extracellular fluid and to take up more lactic acid into their shells. We conclude that the interspecific differences in shell composition and buffering can contribute to, but cannot explain fully, the variations observed in anoxia tolerance among freshwater turtles.
Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance
Authors: Katakam Prasad V. G. , Jordan James E. , Snipes James A. , Tulbert Christina D. , Miller Allison W. , Busija David W.
Published: September 2006

Insulin resistance (IR) precedes the onset of Type 2 diabetes, but its impact on preconditioning against myocardial ischemia-reperfusion injury is unexplored. We examined the effects of diazoxide and ischemic preconditioning (IPC; 5-min ischemia and 5-min reperfusion) on ischemia (30 min)-reperfusion (240 min) injury in young IR Zucker obese (ZO) and lean (ZL) rats. ZO hearts developed larger infarcts than ZL hearts (infarct size: 57.3 ± 3% in ZO vs. 39.2 ± 3.2% in ZL; P < 0.05) and also failed to respond to cardioprotection by IPC or diazoxide (47.2 ± 4.3% and 52.5 ± 5.8%, respectively; P = not significant). In contrast, IPC and diazoxide treatment reduced the infarct size in ZL hearts (12.7 ± 2% and 16.3 ± 6.7%, respectively; P < 0.05). The mitochondrial ATP-activated potassium channel (KATP) antagonist 5-hydroxydecanoic acid inhibited IPC and diazoxide-induced preconditioning in ZL hearts, whereas it had no effect on ZO hearts. Diazoxide elicited reduced depolarization of isolated mitochondria from ZO hearts compared with ZL (73 ± 9% in ZL vs. 39 ± 9% in ZO; P < 0.05). Diazoxide also failed to enhance superoxide generation in isolated mitochondria from ZO compared with ZL hearts. Electron micrographs of ZO hearts revealed a decreased number of mitochondria accompanied by swelling, disorganized cristae, and vacuolation. Immunoblots of mitochondrial protein showed a modest increase in manganese superoxide dismutase in ZO hearts. Thus obesity accompanied by IR is associated with the inability to precondition against ischemic cardiac injury, which is mediated by enhanced mitochondrial oxidative stress and impaired activation of mitochondrial KATP.
Changes in mitochondrial electron transport chain activity during insect metamorphosis
Authors: Chamberlin M. E.
Published: September 2006

The midgut of the tobacco hornworm ( Manduca sexta) is a highly aerobic tissue that is destroyed by programmed cell death during larval-pupal metamorphosis. The death of the epithelium begins after commitment to pupation, and the oxygen consumption of isolated midgut mitochondria decreases soon after commitment. To assess the role of the electron transport chain in this decline in mitochondrial function, the maximal activities of complexes I–IV of the respiratory chain were measured in isolated midgut mitochondria. Whereas there were no developmental changes in the activity of complex I or III, activities of complexes II and IV [cytochrome c oxidase (COX)] were higher in mitochondria from precommitment than postcommitment larvae. This finding is consistent with a higher rate of succinate oxidation in mitochondria isolated from precommitment larvae and reveals that the metamorphic decline in mitochondrial respiration is due to the targeted destruction or inactivation of specific sites within the mitochondria, rather than the indiscriminate destruction of the organelles. The COX turnover number (e−·s−1·cytochrome aa3−1) was greater for the enzyme from precommitment than postcommitment larvae, indicating a change in the enzyme structure and/or its lipid environment during the early stages of metamorphosis. The turnover number of COX in the intact mitochondria (in organello COX) was also lower in postcommitment larvae. In addition to changes in the protein or membrane phospholipids, the metamorphic decline in this rate constant may be a result of the observed loss of endogenous cytochrome c.
Atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 are associated with uterine smooth muscle involution in the postpartum period
Authors: Bdolah Yuval , Segal Adam , Tanksale Preeti , Karumanchi S. Ananth , Lecker Stewart H.
Published: September 2006

The regulation of cell size depends on a delicate balance between protein synthesis and breakdown. Skeletal and cardiac muscle adapt to hormonal and neuronal stimuli and can rapidly hypertrophy and atrophy; however, the extent to which these processes occur in smooth muscle is less clear. Atrophy in striated muscle results from enhanced protein breakdown and is associated with a common transcriptional profile and activation of the ubiquitin-proteasome pathway, including induction of the muscle-specific ubiquitin protein ligases atrogin-1 and muscle ring-finger protein 1 (MuRF-1). Here we show that atrogin-1 is also expressed in smooth muscle, and that both atrogin-1 and MuRF-1 are upregulated in the uterus following delivery, as rapid involution occurs. While these two genes are similarly induced in all types of muscle during rapid loss of cell mass, other striated muscle atrophy-specific transcriptional changes are not observed during uterine involution, suggesting different underlying molecular mechanisms. These results raise the possibility that activation of atrogin-1 and MuRF-1 may be a common general adaptation in cells undergoing a rapid reduction in size.
Neuromechanical control of upper airway patency during sleep
Authors: Patil Susheel P. , Schneider Hartmut , Marx Jason J. , Gladmon Elizabeth , Schwartz Alan R. , Smith Philip L.
Published: September 2006

Obstructive sleep apnea is caused by pharyngeal occlusion due to alterations in upper airway mechanical properties and/or disturbances in neuromuscular control. The objective of the study was to determine the relative contribution of mechanical loads and dynamic neuromuscular responses to pharyngeal collapse during sleep. Sixteen obstructive sleep apnea patients and sixteen normal subjects were matched on age, sex, and body mass index. Pharyngeal collapsibility, defined by the critical pressure, was measured during sleep. The critical pressure was partitioned between its passive mechanical properties (passive critical pressure) and active dynamic responses to upper airway obstruction (active critical pressure). Compared with normal subjects, sleep apnea patients demonstrated elevated mechanical loads as demonstrated by higher passive critical pressures [−0.05 (SD 2.4) vs. −4.5 cmH2O (SD 3.0), P = 0.0003]. Dynamic responses were depressed in sleep apnea patients, as suggested by failure to lower their active critical pressures [−1.6 (SD 3.5) vs. −11.1 cmH2O (SD 5.3), P < 0.0001] in response to upper airway obstruction. Moreover, elevated mechanical loads placed some normal individuals at risk for sleep apnea. In this subset, dynamic responses to upper airway obstruction compensated for mechanical loads and maintained airway patency by lowering the active critical pressure. The present study suggests that increased mechanical loads and blunted neuromuscular responses are both required for the development of obstructive sleep apnea.
Cerebral blood flow autoregulation in early experimentalS. pneumoniaemeningitis
Authors: Pedersen Michael , Brandt Christian T. , Knudsen Gitte M. , Østergaard Christian , Skinhøj Peter , Frimodt-Møller Niels , Møller Kirsten
Published: September 2006

We studied cerebral blood flow (CBF) autoregulation and intracranial pressure (ICP) during normo- and hyperventilation in a rat model of Streptococcus pneumoniae meningitis. Meningitis was induced by intracisternal injection of S. pneumoniae. Mean arterial blood pressure (MAP), ICP, cerebral perfusion pressure (CPP, defined as MAP − ICP), and laser-Doppler CBF were measured in anesthetized infected rats ( n = 30) and saline-inoculated controls ( n = 30). CPP was either incrementally reduced by controlled hemorrhage or increased by intravenous norepinephrine infusion. Twelve hours postinoculation, rats were studied solely during normocapnia, whereas rats studied after 24 h were exposed to either normocapnia or to acute hypocapnia. In infected rats compared with control rats, ICP was unchanged at 12 h but increased at 24 h postinoculation (not significant and P < 0.01, respectively); hypocapnia did not lower ICP compared with normocapnia. Twelve hours postinoculation, CBF autoregulation was lost in all infected rats but preserved in all control rats ( P < 0.01). Twenty-four hours after inoculation, 10% of infected rats had preserved CBF autoregulation during normocapnia compared with 80% of control rats ( P < 0.01). In contrast, 60% of the infected rats and 100% of the control rats showed an intact CBF autoregulation during hypocapnia ( P < 0.05 for the comparison of infected rats at normocapnia vs. hypocapnia). In conclusion, CBF autoregulation is lost both at 12 and at 24 h after intracisternal inoculation of S. pneumoniae in rats. Impairment of CBF autoregulation precedes the increase in ICP, and acute hypocapnia may restore autoregulation without changing the ICP.
Effect of endurance exercise training on heart rate onset and heart rate recovery responses to submaximal exercise in animals susceptible to ventricular fibrillation
Authors: Billman George E. , Kukielka Monica
Published: September 2006

Both a large heart rate (HR) increase at exercise onset and a slow heart rate (HR) recovery following the termination of exercise have been linked to an increased risk for ventricular fibrillation (VF) in patients with coronary artery disease. Endurance exercise training can alter cardiac autonomic regulation. Therefore, it is possible that this intervention could restore a more normal HR regulation in high-risk individuals. To test this hypothesis, HR and HR variability (HRV, 0.24- to 1.04-Hz frequency component; an index of cardiac vagal activity) responses to submaximal exercise were measured 30, 60, and 120 s after exercise onset and 30, 60, and 120 s following the termination of exercise in dogs with healed myocardial infarctions known to be susceptible ( n = 19) to VF (induced by a 2-min coronary occlusion during the last minute of a submaximal exercise test). These studies were then repeated after either a 10-wk exercise program (treadmill running, n = 10) or an equivalent sedentary period ( n = 9). After 10 wk, the response to exercise was not altered in the sedentary animals. In contrast, endurance exercise increased indexes of cardiac vagal activity such that HR at exercise onset was reduced (30 s after exercise onset: HR pretraining 179 ± 8.4 vs. posttraining 151.4 ± 6.6 beats/min; HRV pretraining 4.0 ± 0.4 vs. posttraining 5.8 ± 0.4 ln ms2), whereas HR recovery 30 s after the termination of exercise increased (HR pretraining 186 ± 7.8 vs. posttraining 159.4 ± 7.7 beats/min; HRV pretraining 2.4 ± 0.3 vs. posttraining 4.0 ± 0.6 ln ms2). Thus endurance exercise training restored a more normal HR regulation in dogs susceptible to VF.
MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy
Authors: McCarthy John J. , Esser Karyn A.
Published: September 2006

MicroRNAs (miRNAs) are a class of highly conserved, noncoding RNAs involved in posttranscriptional gene regulation. A small number of muscle-specific miRNAs have been identified and shown to have a role in myoblast proliferation and differentiation as well as embryonic muscle growth. The primary objective of the present study was to determine the expression level of the muscle-specific miRNAs in the soleus and plantaris muscles and whether their expression in the plantaris was altered in response to functional overload. Of the miRNAs examined, only miRNA-206 was differentially expressed between soleus and plantaris muscles, as reflected by the sevenfold higher expression in the soleus for both the primary miRNA (pri-miRNA) and mature miRNA (miR). Following 7 days of functional overload, transcript levels for both pri-miRNA-1-2 and pri-miRNA-133a-2 increased by ∼2-fold, whereas pri-miRNA-206 levels were elevated 18.3-fold. In contrast, expression of miR-1 and miR-133a were downregulated by ∼50% following overload. The discrepancy between pri-miRNA and miR expression following overload was not explained by a change in the expression of components of the miRNA biogenesis pathway, since Drosha and Exportin-5 transcript levels were significantly increased by 50% in response to functional overload, whereas Dicer expression remained unchanged. These results are the first to report alterations in expression of muscle-specific miRNAs in adult skeletal muscle and suggest miRNAs may have a role in the adaptation to functional overload.
Non-Hodgkin Lymphoma and Pesticide Exposure: 25 Years of Research
Authors: Dreiher Jacob , Kordysh Ella
Published: September 2006

Over the past 40 years, a substantial rise in the incidence of non-Hodgkin lymphoma (NHL) has been observed. Epidemiologic studies aimed at understanding this rise have revealed some association with occupational exposure. NHL is common among farmers, where pesticides have been described as the culprit. The association between pesticides and NHL has been demonstrated mainly in case-control studies, while retrospective cohorts have been less convincing. Pesticides including chlorphenol and phenoxyacetic acid herbicides, organochlorines, and organophosphate insecticides, carbamates, and fungicides have been associated with NHL. Although the causality has not been clearly proven, both genotoxic and nongenotoxic mechanisms for lymphomagenesis have been proposed. The leveling-off of NHL incidence in certain countries may be the result of a favorable change in pesticide usage patterns. Future studies, such as the Agricultural Health Study, may clarify the uncertainties regarding this issue.
Ibandronate for the Treatment of Hypercalcemia or Nephrocalcinosis in Patients with Multiple Myeloma and Acute Renal Failure: Case Reports
Authors: Henrich Dirk , Hoffmann Martin , Uppenkamp Michael , Bergner Raoul
Published: September 2006

Multiple myeloma disrupts calcium homeostasis by a variety of mechanisms, including bone destruction and resorption. This causes hypercalcemia. When left untreated, hypercalcemia leads to nephrocalcinosis, impairment of kidney function, and eventually renal failure. Some degree of renal dysfunction is common in myeloma patients. Here, we report case studies showing the efficacy and renal safety of the single-nitrogen bisphosphonate, ibandronate, for the treatment of hypercalcemia and/or nephrocalcinosis in multiple myeloma patients hospitalized with acute renal failure. Patients (n = 7) received either one or two intravenous infusions of ibandronate (2–6 mg). Ibandronate was well tolerated in all patients and returned elevated blood calcium levels to normal. Renal function improved for all patients and normalized in 3/7 patients. We conclude that ibandronate is involved in rapidly improving or restoring acute renal function and calcium levels to within the normal range in this patient population. To clarify the exact value of ibandronate, further investigation is warranted in randomized prospective trials.
Flow Cytometry as a Diagnostic Tool for Hereditary Spherocytosis
Authors: Stoya Gudrun , Gruhn Bernd , Vogelsang Heinz , Baumann Eckehard , Linss Werner
Published: September 2006

Flow cytometric analysis of eosin-5′-maleimide-labeled red blood cells has been proposed as a new method of identifying hereditary spherocytosis (HS). The aim of the present study was to analyze sensitivity and specificity of this method. Red blood cells from patients with HS (n = 58) revealed significantly lower mean channel fluorescence values than red blood cells from normal subjects (n = 110), unaffected HS family members (n = 8), and patients with other anemias (n = 44). Taking a mean channel fluorescence of 400.0 units as the threshold value identified by logistic regression, sensitivity and specificity of the test for HS were 96.6 and 99.1%, respectively. Flow cytometric analysis is a valuable screening test for the diagnosis of HS.
Assessment of 8-Methoxypsoralen and Ultraviolet A Light Effects on Human Stroma Generation and Function
Authors: Legitimo Annalisa , Consolini Rita , Bencivelli Walter , Crimaldi Gaetano , Migliaccio Pasquale , Mosca Franco
Published: September 2006

Photopheresis or extracorporeal photochemotherapy (ECP) is a new immunomodulatory therapy in which a patient’s leukocytes are exposed extracorporeally to 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light. Although it is used for the treatment of cutaneous T cell lymphoma, graft-versus-host disease, and several autoimmune diseases, with efficacy and safety reported in almost all studies, the mechanisms by which ECP exerts its beneficial effects are still unclear. As cellular targets of this procedure are numerous, we investigated the effects of 8-MOP and UVA light on stromal precursors and mature stromal layers. Human bone marrow stromal cell layers were established in long-term bone marrow culture medium from normal marrow mononuclear cells. Normal marrow mononuclear cells were incubated with 8-MOP and/or exposed to UVA light (PUVA treatment) before culturing. A control without 8-MOP and UVA was also included in the study. Apoptosis induction was evaluated using annexin V following 7 days after PUVA. After 4–6 weeks of culture, stromal layers were examined under a phase-contrast microscope to identify structural differences between PUVA-treated and control stroma. To determine whether PUVA treatment affected stromal regulation of adherent hematopoietic cell survival, mature stromal layers, incubated with 8-MOP and exposed to UVA light, were cocultured with nonadherent mononuclear cells from normal marrow. After 24 h, the percentage of apoptotic hematopoietic cell precursors was quantified by flow cytometry. This study provides evidences that the in vitro exposure of human stromal cell precursors to UVA light, in the presence of 8-MOP, inhibits stromal layer generation by inducing apoptosis, as evidenced by annexin V staining following 7 days of culture. Here, we show an additional cell target for this psoralen following UVA irradiation. However, in a second set of experiments, PUVA treatment did not affect the stromal capacity to support hematopoiesis in culture. Our results can contribute to a better definition of ECP mechanisms of action for future development of experimental designs and clinical applications of this intriguing procedure.
Unusual Extramedullary Hematopoiesis in a Patient Receiving Granulocyte Colony-Stimulating Factor
Authors: Dagdas Simten , Ozet Gulsum , Alanoglu Guchan , Ayli Meltem , Gokmen Akoz Ayla , Erekul Selim
Published: September 2006

A 42-year-old woman was diagnosed with myelodysplastic syndrome with fibrosis that developed bilaterally, cervical lymphadenopathy and cutaneous infiltration by trilineage extramedullary hematopoiesis after granulocyte colony-stimulating factor therapy because of severe neutropenia. Hepatosplenomegaly was not observed during her follow-up. Extramedullary hematopoiesis disappeared after growth factor therapy was stopped. Although the neutropenia was alleviated by growth factor administration, the appearance of an unusual involvement of extramedullary hematopoiesis should be kept in mind.
Bortezomib-Induced Rhabdomyolysis in Multiple Myeloma
Authors: Cibeira M. Teresa , Mercadal Santiago , Arenillas Leonor , Muntañola Anna , Salamero Olga , Bladé Joan
Published: September 2006

Although multiple myeloma (MM) remains an incurable disease, its treatment has improved over the past decade. This improvement has been at least in part due to the introduction of novel antimyeloma agents with new mechanisms of action, including those that target both myeloma cells and the tumor microenvironment, with antiangiogenic and immunomodulatory properties. Among these drugs, bortezomib (Velcade®), a selective proteasome inhibitor, has been approved for the treatment of relapsed and refractory MM patients after one line of therapy. The toxicity profile of bortezomib includes gastrointestinal symptoms, fatigue, thrombocytopenia, peripheral neuropathy, postural hypotension, as well as some uncommon events. A patient with relapsed MM who developed recurrent bortezomib-induced rhabdomyolysis is reported. To our knowledge, this adverse event has not been previously described is this context.
Rapid Progression of Myelodysplastic Syndrome to Acute Myeloid Leukemia on Sequential Azathioprine, IFN-β and Copolymer-1 in a Patient with Multiple Sclerosis
Authors: Then Bergh Florian , Niklas Alexander , Strauss Angelika , von Ahsen Nicolas , Niederwieser Dietger , Schwarz Johannes , Wagner Armin , Al-Ali Haifa K.
Published: September 2006

A woman with relapsing-remitting multiple sclerosis (MS) was treated with oral azathioprine (AZA) for 4 years and subsequently switched to interferon-β1a. Five years later, leukopenia developed and resolved after interferon was discontinued; MS treatment was changed to copolymer-1. Recurrent pancytopenia subsequently led to diagnosis of myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 5 (MDS 5q–). Within several months, unusually rapid for this subtype, MDS progressed to secondary acute myeloid leukemia. While AZA is the probable cause for the chromosomal deletion and MDS, combined or sequential immunomodulatory therapies may permit clonal expansion of malignant hematopoietic progenitors.
Prevention and Treatment of Type 2 Diabetes in Youth
Authors: Libman Ingrid M. , Arslanian Silva A.
Published: September 2006

Parallel to the increase in obesity worldwide, there has been a rise in the prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents. The etiology of T2DM in youth, similar to adults, is multifactorial including genetic and environmental factors, among them obesity, sedentary lifestyle, family history of the disease, high-risk ethnicity and insulin resistance phenotype playing major roles. Treatment of T2DM should not have a glucocentric approach; it should rather target improving glycemia, dyslipidemia, hypertension, weight management and the prevention of short- and long-term complications. Prevention strategies, especially in high-risk groups, should focus on environmental change involving participation of families, schools, the food and entertainment industries and governmental agencies. Presently, limited pharmacotherapeutic options need to be expanded both for childhood T2DM and obesity. The coming decades will prove very challenging for healthcare providers battling socioeconomic waves conducive to obesity and T2DM. Evidence-based research and clinical experience in pediatrics, possibly modeled after adult trials, need to be developed if this public health threat is to be contained.
Changes in Lung Function and Respiratory Muscle Strength after Sternotomy vs. Laparotomy in Patients without Ventilatory Limitation
Authors: Chetta Alfredo , Bobbio Antonio , Aiello Marina , Del Donno Mario , Castagnaro Antonio , Comel Andrea , Malorgio Roberto , Carbognani Paolo , Rusca Michele , Olivieri Dario
Published: September 2006

A relevant ventilatory defect occurs after sternotomy, a very common thoracic surgical opening. The mechanism of the ventilatory impairment is unclear. Moreover, until now, the effect of sternotomy on pulmonary gas exchange has scarcely been investigated. We evaluated the time-course up to recovery and changes in spirometry, maximum static inspiratory (PImax) and expiratory (PEmax) mouth pressures and pulmonary gas exchange in 6 patients after sternotomy and in 8 patients after laparotomy. All patients were free of cardiopulmonary diseases and had normal preoperative lung function. Sternotomy and laparotomy decreased forced vital capacity (FVC) by 67 and 49%, respectively. Moreover, the percent decreases in PImax, PEmax and PaO2 after sternotomy vs. laparotomy were respectively 54 vs. 57%, 54 vs. 60%, and 22.6 vs. 7.5% (p < 0.05). Following sternotomy, the percent decreases in FVC correlated with the percent decreases in PImax (p < 0.05) and PEmax (p < 0.01). The return to baseline values occurred after approximately 2 weeks. The present study shows that sternotomy can induce greater respiratory effects than laparotomy and suggests a relevant involvement of respiratory muscle weakness after surgical opening of the thorax. The study also supports the view that the evaluation of patient’s lung function before sternotomy can be clinically relevant.
The RXR Agonist Bexarotene Improves Cholesterol Homeostasis and Inhibits Atherosclerosis Progression in a Mouse Model of Mixed Dyslipidemia
Authors: Lalloyer Fanny , Fiévet Catherine , Lestavel Sophie , Torpier Gérard , van der Veen Jelske , Touche Véronique , Bultel Stéphanie , Yous Saïd , Kuipers Folkert , Paumelle Réjane , Fruchart Jean-Charles , Staels Bart , Tailleux Anne
Published: September 2006

Objective—

The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions.

Methods and Results—

Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids.

Conclusion—

These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux.
Oxidized Low-Density Lipoprotein–Dependent Endothelial Arginase II Activation Contributes to Impaired Nitric Oxide Signaling
Authors: Ryoo Sungwoo , Lemmon Christopher A. , Soucy Kevin G. , Gupta Gaurav , White Anthony R. , Nyhan Daniel , Shoukas Artin , Romer Lewis H. , Berkowitz Dan E.
Published: September 2006

Oxidized low-density lipoprotein (OxLDL) impairs NO signaling and endothelial function, and contributes to the pathogenesis of atherosclerosis. Arginase reciprocally regulates NO levels in endothelial cells by competing with NO synthase for the substrate
l
-arginine. In human aortic endothelial cells, OxLDL stimulation increased arginase enzyme activity in a time- and dose-dependent manner. Arginase activity reached its maximum as early as 5 minutes, was maintained for a period of more than 48 hours, and was associated with a reciprocal decrease in NO metabolite (NOx [nitrite and nitrate]) production. Furthermore, OxLDL induced arginase II mRNA expression after 4 hours. Small interfering RNA targeted to arginase II decreased both the quantity and the activity of arginase from baseline, prevented OxLDL-dependent increases in arginase activity, and induced an increase in NOx production. Immunofluorescence analysis revealed an association of arginase II with the microtubule cytoskeleton. Microtubule disruption with nocodazole caused a dramatic redistribution of arginase II to a diffuse cytosolic pattern, increased arginase activity, and decreased NOx production, which was restored in the presence of the specific arginase inhibitor (
S
)-(2-boronoethyl)-
l
-cysteine (BEC). On the other hand, epothilone B prevented microtubule disruption and inhibited OxLDL-dependent increases in arginase activity and attenuated OxLDL-dependent decreases in NOx. Preincubation of rat aortic rings with OxLDL resulted in an increase in arginase activity and a decrease in NOx production. This was reversed by arginase inhibition with the BEC. Thus, OxLDLs increase arginase activity by a sequence of regulatory events that involve early activation through decreased association with microtubules and a later increase in transcription. Furthermore, increased arginase activity contributes to OxLDL-dependent impairment of NOx production. Arginase, therefore, represents a novel target for therapy in atherosclerosis.
Constitutive Endocytosis of CD163 Mediates Hemoglobin-Heme Uptake and Determines the Noninflammatory and Protective Transcriptional Response of Macrophages to Hemoglobin
Authors: Schaer Christian A. , Schoedon Gabriele , Imhof Alexander , Kurrer Michael O. , Schaer Dominik J.
Published: September 2006

Heme toxicity contributes to the pathogenesis of chronic inflammatory diseases, atherosclerosis, and hemolysis associated vasculopathy. Macrophage clearance of cell free hemoglobin (Hb) is thus an essential homeostatic function of these cells. We examined the transcriptional response of human PBMC derived macrophages to Hb by gene array analysis. The observed noninflammatory macrophage response was characterized by induction of an antioxidative and antiinflammatory gene expression pattern with most prominent induction of the inducible heme oxygenase (HO-1). The metabolically active Hb-CD163-HO-1 pathway resulted in synthesis of ferritin—1 of the antioxidative and antiinflammatory end products linked to heme breakdown by HO-1. This response was mediated by the Hb scavenger receptor CD163 and heme and was not related to Hb mediated depletion of reduced glutathione. In contrast to other cellular responses induced by CD163, there was no role of protein phosphorylation dependent CD163 signaling in the protective macrophage response to Hb. Instead, CD163 acted as an Hb transporter, which undergoes constitutive and ligand independent internalization and recycling between the cell surface and early endosomes. The expression of CD163 and HO-1 in macrophages of neovascularized atherosclerotic lesions suggests that the pathway described herein is active in vivo. Noninflammatory Hb clearance and intimately linked HO-1 expression may provide the long sought-after explanation for the antiinflammatory activity associated with CD163-positive macrophages.
Cardiac-Specific Ablation of G-Protein Receptor Kinase 2 Redefines Its Roles in Heart Development and β-Adrenergic Signaling
Authors: Matkovich Scot J. , Diwan Abhinav , Klanke Justin L. , Hammer Daniel J. , Marreez Yehia , Odley Amy M. , Brunskill Eric W. , Koch Walter J. , Schwartz Robert J. , Dorn Gerald W.
Published: September 2006

G-protein receptor kinase 2 (GRK2) is 1 of 7 mammalian GRKs that phosphorylate ligand-bound 7-transmembrane receptors, causing receptor uncoupling from G proteins and potentially activating non–G-protein signaling pathways. GRK2 is unique among members of the GRK family in that its genetic ablation causes embryonic lethality. Cardiac abnormalities in GRK2 null embryos implicated GRK2 in cardiac development but prevented studies of the knockout phenotype in adult hearts. Here, we created
GRK2-loxP
–targeted mice and used Cre recombination to generate germline and cardiac-specific
GRK2
knockouts.
GRK2
deletion in the preimplantation embryo with EIIa-Cre (germline null) resulted in developmental retardation and embryonic lethality between embryonic day 10.5 (E10.5) and E11.5. At E9.5, cardiac myocyte specification and cardiac looping were normal, but ventricular development was delayed. Cardiomyocyte-specific ablation of
GRK2
in the embryo with
Nkx2.5-
driven Cre (cardiac-specific GRK2 knockout) produced viable mice with normal heart structure, function, and cardiac gene expression. Cardiac-specific GRK2 knockout mice exhibited enhanced inotropic sensitivity to the β-adrenergic receptor agonist isoproterenol, with impairment of normal inotropic and lusitropic tachyphylaxis, and exhibited accelerated development of catecholamine toxicity with chronic isoproterenol treatment. These findings show that cardiomyocyte autonomous GRK2 is not essential for myocardial development after cardiac specification, suggesting that embryonic developmental abnormalities may be attributable to extracardiac effects of GRK2 ablation. In the adult heart, cardiac GRK2 is a major factor regulating inotropic and lusitropic tachyphylaxis to β-adrenergic agonist, which likely contributes to its protective effects in catecholamine cardiomyopathy.
Membrane Potential Fluctuations Resulting From Submembrane Ca
2+
Releases in Rabbit Sinoatrial Nodal Cells Impart an Exponential Phase to the Late Diastolic Depolarization That Controls Their Chronotropic State
Authors: Bogdanov Konstantin Y. , Maltsev Victor A. , Vinogradova Tatiana M. , Lyashkov Alexey E. , Spurgeon Harold A. , Stern Michael D. , Lakatta Edward G.
Published: September 2006

Stochastic but roughly periodic LCRs (
L
ocal subsarcolemmal ryanodine receptor–mediated
C
a
2+
R
eleases) during the late phase of diastolic depolarization (DD) in rabbit sinoatrial nodal pacemaker cells (SANCs) generate an inward current (
I
NCX
) via the Na
+
/Ca
2+
exchanger. Although LCR characteristics have been correlated with spontaneous beating, the specific link between LCR characteristics and SANC spontaneous beating rate, ie, impact of LCRs on the fine structure of the DD, have not been explicitly defined. Here we determined how LCRs and resultant
I
NCX
impact on the DD fine structure to control the spontaneous SANC firing rate. Membrane potential (
V
m
) recordings combined with confocal Ca
2+
measurements showed that LCRs impart a nonlinear, exponentially rising phase to the DD later part, which exhibited beat-to-beat
V
m
fluctuations with an amplitude of approximately 2 mV. Maneuvers that altered LCR timing or amplitude of the nonlinear DD (ryanodine, BAPTA, nifedipine or isoproterenol) produced corresponding changes in
V
m
fluctuations during the nonlinear DD component, and the
V
m
fluctuation response evoked by these maneuvers was tightly correlated with the concurrent changes in spontaneous beating rate induced by these perturbations. Numerical modeling, using measured LCR characteristics under these perturbations, predicted a family of local
I
NCX
that reproduced
V
m
fluctuations measured experimentally and determined the onset and amplitude of the nonlinear DD component and the beating rate. Thus, beat-to-beat
V
m
fluctuations during late DD phase reflect the underlying LCR/
I
NCX
events, and the ensemble of these events forms the nonlinear DD component that ultimately controls the SANC chronotropic state in tight cooperation with surface membrane ion channels.
Medium-Term Variability of Blood Pressure and Potential Underdiagnosis of Hypertension in Patients With Previous Transient Ischemic Attack or Minor Stroke
Authors: Cuffe Robert L. , Howard Sally C. , Algra Ale , Warlow Charles P. , Rothwell Peter M.
Published: September 2006

Background and Purpose—

Blood pressure (BP) is a major risk factor for stroke. However, the variability of systolic and diastolic BP (SBP and DBP) means that single measurements do not provide a reliable measure of usual BP. Although 24-hour ambulatory BP monitoring can correct for the effects of short-term variation, there is also important medium-term variability. The extent of medium-term variability in BP is most marked in patients with a previous transient ischemic attack (TIA) or stroke. We studied the potential impact of this variability on the likely recognition of hypertension.

Methods—

We analyzed multiple repeated measurements of BP in 3 large cohorts with a TIA or minor stroke: the UK-TIA trial (n=2098), the Dutch TIA trial (n=2953), and the European Carotid Surgery Trial (ECST; n=2646). Regression dilution ratios and coefficients of variation were calculated for SBP and DBP from baseline and repeated measurements during the subsequent 12 months. Categorization based on single baseline measurements was also compared with categorization based on the subsequent “usual” BP.

Results—

The correlation between measurements of BP at baseline and 3 to 5 months later was poor (
R
2
from 0.17 to 0.31 for SBP and from 0.10 to 0.20 for DBP). Categorization of patients by baseline values resulted in substantial misclassification in relation to usual BP. For example, of patients with an SBP <140 mm Hg at baseline, the percentage with a usual SBP ≥140 mm Hg was 31.6% in the UK-TIA trial, 48.2% in the Dutch TIA trial, and 57.7% in the ECST. At least 3 consecutive measurements of SBP <120 mm Hg were required to be >90% certain that subsequent usual SBP would not be ≥140 mm Hg.

Conclusions—

Given the greater medium-term variability of BP in patients with a previous TIA or stroke than in the general population, single measurements of “normal” or “low” BP will substantially underestimate the true prevalence of hypertension.
Sentinel Headache and the Risk of Rebleeding After Aneurysmal Subarachnoid Hemorrhage
Authors: Beck Jürgen , Raabe Andreas , Szelenyi Andrea , Berkefeld Joachim , Gerlach Rüdiger , Setzer Matthias , Seifert Volker
Published: September 2006

Background and Purpose—

The clinical significance of sentinel headaches in patients with subarachnoid hemorrhage (SAH) is still unknown. We investigated whether patients with a sentinel headache (SH) have a higher rate of rebleeding after SAH.

Methods—

An SH was defined as a sudden, severe, unknown headache lasting >1 hour with or without accompanying symptoms, not leading to a diagnosis of SAH in the 4 weeks before the index SAH. Age, sex, smoking status, clinical grade, computed tomography (CT) findings, angiographic findings, placement of an external ventricular drain, and time to aneurysm obliteration were prospectively recorded. All rebleeding events were confirmed by CT. Outcome was assessed at 6 months according to the modified Rankin Scale.

Results—

Of 237 consecutive patients with SAH, 41 (17.3%) had an SH. Rebleeding occurred in 23 (9.7%) of all patients. Patients with an SH had a 10-fold increased odds of rebleeding compared with patients without SH. Aneurysm size and the total number of aneurysms were also significantly associated with rebleeding. There were no differences in age, sex, smoking, CT or angiographic findings, external ventricular drain placement, or time to aneurysm obliteration between groups. Patients with rebeeding had a significantly worse outcome. Logistic regression revealed the presence of an SH as an independent risk factor for rebleeding.

Conclusions—

In our study, patients with SAH who had an SH constituted a special group of patients with a 10-fold odds for early rebleeding. The presence of an SH may select candidates for ultraearly aneurysm obliteration or drug treatment.
Progressive Decline in Stroke Mortality in Brazil From 1980 to 1982, 1990 to 1992, and 2000 to 2002
Authors: André Charles , Curioni Cíntia Chaves , Braga da Cunha Cynthia , Veras Renato
Published: September 2006

Background and Purpose—

We describe the trends in stroke mortality in Brazil during 3 decades and investigate their differences according to regional disparities, sex, and age distributions.

Methods—

Official data on mortality and population estimates were retrieved to calculate standardized mortality rates (with the 1980 Brazilian population as a reference) in 6 age strata and in the 5 political regions for the initial period (3 first years) of the 1980, 1990, and 2000 decades. Data were corrected for undefined causes of death. The Poisson model was used to estimate risk reduction during the 3 decades and to study the interaction between those rates and sex, age strata, and regions.

Results—

The stroke standardized mortality rate decreased consistently in the last 20 years, from 68.2 to 40.9 per 100 000 habitants. This reduction paralleled a decrease in total cardiovascular mortality rates in the same period, from 208.2 to 126.1 per 100 000 habitants. The reduction in stroke standardized mortality rate was detected in men and women and in all age strata. The reduction was evident in all geopolitical regions of the country, with the wealthiest regions’ exhibiting higher initial rates and more marked standardized mortality rate reductions. The risk of dying of stroke in the period 2000 to 2002 was 0.45 (95% CI, 0.44 to 0.45) of that found in the period 1980 to 1982.

Conclusions—

The risk of dying of stroke in Brazil declined dramatically between the initial period in the early 1980s and the early 2000s. The decline was especially marked in the most developed regions and may reflect an improvement in general health conditions during the study period.
Enriched Environment Attenuates Cell Genesis in Subventricular Zone After Focal Ischemia in Mice and Decreases Migration of Newborn Cells to the Striatum
Authors: Nygren Josefine , Wieloch Tadeusz , Pesic Jelena , Brundin Patrik , Deierborg Tomas
Published: September 2006

Background and Purpose—

Cells proliferate continuously in the adult mammalian brain, and in rodents, cell genesis is affected by housing conditions and brain injury. Increase in neurogenesis after brain ischemia has been postulated to be linked to functional recovery after stroke. Housing rodents in an enriched environment improves motor function after stroke injury. We have investigated whether changes in cell genesis can explain the beneficial effects of an enriched environment.

Methods—

Intact mice and mice subjected to transient occlusion of the middle cerebral artery were exposed to an enriched environment for 1 month. Bromodeoxyuridine was injected daily to label proliferating cells during the first postischemic week. Newborn cells were analyzed immunohistochemically after 4 weeks.

Results—

The enriched environment increased neurogenesis in the dentate gyrus in both intact and stroke-injured animals. An increased number of newborn cells was found in the subventricular zone of stroke-injured mice, but not in injured mice exposed to an enriched environment. Also, the number of newborn astrocytes (BrdU+/S-100β+ cells), neuroblasts (dcx+ cells), and reactive astrocytes (vimentin mRNA) in the striatum ipsilateral to the ischemic injury was markedly attenuated and new adult neurons (BrdU+/NeuN+) were not found. The enriched environment did not affect infarct size or mortality.

Conclusions—

An enriched environment after experimental stroke increased neurogenesis in the hippocampus, whereas there was a decreased cell genesis and migration of neuroblasts and newborn astrocytes in the striatum.
Tissue Oxygen Index
Authors: Al-Rawi Pippa G. , Kirkpatrick Peter J.
Published: September 2006

Background and Purpose—

To date, the clinical application of near infrared spectroscopy in the adult brain has been limited. The NIRO 300 (Hamamatsu Photonics) provides a continuous measurement of tissue oxygen index (TOI) using spatially resolved spectroscopy. Although TOI reflects cerebral oxygenation to a high degree of sensitivity and specificity, to become a useful clinical tool, thresholds for cerebral ischemia need to be defined. This study has attempted to identify a quantifiable TOI threshold for ischemia in the adult brain.

Methods—

One hundred sixty-seven patients undergoing carotid endarterectomy were studied. The NIRO 300 was incorporated into an established multimodal monitoring system enabling observations of cerebral hemodynamic changes under highly controlled conditions. Changes in TOI (%ΔTOI) on clamping the internal carotid artery were compared with intracranial blood flow (middle cerebral artery flow velocity) and cerebral function monitoring to identify and quantify periods of cerebral ischemia.

Results—

Significant correlation was seen between changes in middle cerebral artery flow velocity and ΔTOI on clamping (
r
=0.74,
P
=0.0001). Thirty-one patients showed cerebral ischemia on internal carotid artery clamping as defined by a sustained fall in cerebral function monitoring. A threshold for %ΔTOI of −13 was identified, above which no patients showed any evidence of ischemia on clamping. This threshold provided 100% sensitivity and 93.2% specificity for patients satisfying the preset criteria for cerebral ischemia.

Conclusions—

These data demonstrate the potential to identify TOI-quantified thresholds for cerebral ischemia in the adult brain and thus improve the clinical use of near infrared spectroscopy. Our observations have defined a drop in TOI (13%) that can be adopted as a threshold for severe cerebral ischemia with high sensitivity and specificity.
Conjugate Eye Deviation in Acute Stroke
Authors: Singer Oliver C. , Humpich Marek C. , Laufs Helmut , Lanfermann Heiner , Steinmetz Helmuth , Neumann-Haefelin Tobias
Published: September 2006

Background and Purpose—

The authors studied clinical features and lesion patterns associated with conjugate eye deviation (CED) in acute stroke.

Methods—

Consecutive patients with supratentorial stroke (<6 hours after symptom onset) were prospectively recruited. CED was classified according to the National Institute of Health Stroke Scale (NIHSS) item “gaze palsy” as being forced, partial, or absent. Lesion patterns on diffusion-weighted images (DWI) were analyzed in 46 patients using a normalization procedure for direct comparisons between patients. Perfusion data were analyzed for a subset of patients.

Results—

Partial CED was found in 7 (6%) and forced CED in 31 (26.7%) of 116 patients. Forced and partial CED were associated with higher initial NIHSS scores compared with patients without CED (16 and 10 versus 5;
P
<0.05). DWI lesion volume was larger in patients with CED (103.24±102.4 mL, mean±SD) as compared with patients without CED (17±34.98 mL,
P
<0.001). CED was more frequent in right hemispheric stroke (44.6% versus 23%,
P
<0.02). DWI pattern analysis in patients with CED with right hemispheric stroke revealed a network of affected regions, including basal ganglia and temporoparietal cortex. In left hemispheric CED, lesions were larger than in patients without CED, but no consistent pattern could be established. In a subset of selected patients with CED, a small temporoparietal perfusion deficit was sufficient to elicit CED.

Conclusions—

Selective dysfunction of cortical areas involved in spatial attention and control of eye movements is sufficient to cause CED in patients with acute stroke. However, in the majority of cases, CED is an indicator of large infarcts involving more than one area, including both cortical and subcortical structures.