bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastin- and Collagen-Rich Human Carotid Plaques Have Increased Levels of the Cysteine Protease Inhibitor Cystatin C
Authors: Gonçalves Isabel , Ares Mikko P.S. , Moberg Anna , Moses Jonatan , To Fong , Montan Jonathan , Pedro Luís M. , Dias Nuno , Fernandes e Fernandes José , Fredrikson Gunilla Nordin , Nilsson Jan , Jovinge Stefan , Bengtsson Eva
Published: March 2008

Background: Cystatin C is a major inhibitor of the elastin- and collagen-degrading cysteine proteases and may therefore have an important role in preserving atherosclerotic plaque stability. In this study we analyzed the associations between human carotid plaque cystatin C expression and the plaque content of collagen and elastin. Methods: Thirty-one plaques were removed by endarterectomy and homogenized. Cystatin C levels were analyzed by densitometry of Western blots and elastin and collagen levels were determined colorimetrically. Results: The plaque content of cystatin C correlated with total elastin (r = 0.58, p = 0.001) and collagen (r = 0.50, p = 0.004), as well as with cross-linked forms of elastin (r = 0.42, p = 0.022) and collagen (r = 0.52, p = 0.003). Immunohistochemical analysis demonstrated that cystatin C colocalized with elastin and collagen. No correlation was seen between cystatin C and the amount of degraded elastin or collagen in plaques. Conclusion: The positive correlation between cystatin C levels and collagen and elastin levels in plaques supports the notion that cystatin C plays an important role in maintaining atherosclerotic plaque stability.
Gelatinous Transformation of Bone Marrow in Chronic Myeloid Leukemia during Treatment with Imatinib Mesylate: A Disease or a Drug Effect?
Authors: Ram Ron , Gafter-Gvili Anat , Okon Elimelech , Pazgal Idit , Shpilberg Ofer , Raanani Pia
Published: March 2008

Gelatinous marrow transformation (GMT) is an unusual pathological manifestation of progressive malignant diseases and severe malnutrition states. GMT has been associated with various accelerated hematological malignancies, but has never been described in patients with chronic myelogenous leukemia (CML) treated with imatinib mesylate (IM), a novel tyrosine kinase inhibitor. Herein we report 2 patients with stable chronic phase CML who developed GMT during the course of treatment with IM. A comprehensive review of the relevant published data, several possible mechanisms and therapeutic alternatives are suggested.
Assessment of Treatment Practice Patterns for Severe Hemophilia A: A Global Nurse Perspective
Authors: Khair Kate , Lawrence Kingsley , Butler Regina , O’Shea Eadaoin , Christie Beverly A.
Published: March 2008

This paper reports findings from a global survey of practice patterns for severe hemophilia A. Nurses from 105 hemophilia treatment centers in the US, the UK, Canada and Sweden responded to a questionnaire and provided data for more than 10,100 children and adults. Forty-eight percent of the US patients and 38 and 37% of the British and Swedish patients, respectively, were reported to have severe hemophilia A. The survey found that 28% of US patients and 38% of UK patients with severe hemophilia A were on primary prophylaxis in 2005. These rates were significantly higher than those reported in a 2003 survey. Sweden continues to lead the world in prophylaxis utilization, with virtually 100% of patients aged 3–18 on primary prophylactic regimens. Bleeding history and target joint development were major reasons for initiating prophylaxis; poor adherence, inadequate family commitment and venous access problems were cited as the top causes for discontinuing treatment. Nurses in all 4 reporting countries agreed that prophylaxis is the optimal therapy for patients with severe hemophilia A because it prevents joint and muscle damage and improves quality of life. They cited patient/family education as the most appropriate strategy for overcoming the barriers to prophylaxis.
Impact of Preoperative Dental Plaque Culture for Predicting Postoperative Pneumonia in Esophageal Cancer Patients
Authors: Akutsu Yasunori , Matsubara Hisahiro , Okazumi Shinichi , Shimada Hideaki , Shuto Kiyohiko , Shiratori Toru , Ochiai Takenori
Published: March 2008

Background/Aims: In esophageal cancer patients, postoperative pneumonia frequently occurs. In the oral cavity, dental plaque is a major reservoir of bacteria, and it is possible that oral bacteria are aspirated into the upper respiratory tract after esophagectomy. We evaluated the interaction between preoperative dental plaque and postoperative pneumonia in patients undergoing esophagectomy. Patients and Methods: Thirty-nine patients with thoracic esophageal cancer who underwent esophagectomy were investigated. Preoperatively, dental plaque was collected and the bacterial flora investigated. If postoperative pneumonia occurred, the sputum was harvested and the pathogens were evaluated. Result: Postoperative pneumonia was observed in 14 patients (35.9%): 5 (71.4%) of 7 patients in the pathogen-positive group and 9 (28.1%) of 32 patients in the pathogen-negative group. In 2 (40.0%) of 5 patients with postoperative pneumonia, who had pathogenic bacteria in the preoperative dental plaque, the same pathogenic bacteria were also identified in the postoperative sputum. Conclusion: Pathogens in preoperative dental plaque are risk factors for postoperative pneumonia following thoracotomy in patients with thoracic esophageal cancer.
Multiple Repeat Metastasectomies for Recurrences of Colorectal Cancer
Authors: Ajisaka Hideyuki
Published: March 2008

Background/Aim: The disease-free interval after resection of the primary tumour was found to be an independent significant prognostic factor for single repeat metastasectomy for colorectal cancer. In the present study, the intervals from resection to relapse for multiple repeat metastasectomies were evaluated. Methods: Sixteen patients who underwent multiple repeat metastasectomies after the first curative resection were studied to determine whether their intervals from resection to relapse were associated with the prognosis. Results: The patients could be classified into three types by the intervals from resection to relapse: (1) the intervals of 4 patients between recurrences were constant and lasted a few years (long-term regular-type group); (2) those of 6 patients were almost constant between recurrences and lasted about 1 year (short-term regular-type group), and (3) the intervals of 6 patients became shorter with each recurrence (shortening-type group). 3 of the 4 patients in the long-term regular-type group, 2 of the 6 patients in the short-term regular-type group, and none of the 6 patients in the shortening-type group are currently alive without recurrence. The survival rate was significantly higher in the long-term regular-type group than in the shortening-type group. Conclusion: For patients with constant intervals of relapse, achieving curative resection is the most relevant prognostic factor for a favourable prognosis after repeat metastasectomies for recurrence of colorectal cancer.
Sentinel Node Mapping Guided by Indocyanine Green Fluorescence Imaging: A New Method for Sentinel Node Navigation Surgery in Gastrointestinal Cancer
Authors: Kusano Mitsuo , Tajima Yusuke , Yamazaki Kimiyasu , Kato Masanori , Watanabe Makoto , Miwa Mitsuharu
Published: March 2008

Background: Recently, gastrointestinal cancer has also been identified as a target for sentinel node navigation surgery (SNNS). This study is the first to determine the feasibility of sentinel node (SN) mapping guided by indocyanine green (ICG) fluorescence imaging in gastrointestinal cancer. Methods: Our series consisted of 22 patients with gastric cancer and 26 patients with colorectal cancer who had undergone standard surgical resection. ICG solution was injected intraoperatively into the subserosa around the tumor. Fluorescence imaging was obtained by a charge-coupled device (CCD) camera with a light-emitting diode with a wavelength of 760 nm as the light source and a cut filter to filter out light with wavelengths below 820 nm as the detector. Results: Immediately after the ICG injection, lymphatic vessels draining the tumor and round-shaped SNs were visualized by their bright fluorescence. Even SNs that were not green in color could be easily and clearly visualized by ICG fluorescence imaging. The SN detection rate and mean number of SNs were 90.9% and 3.6 ± 4.5 (mean ± SD), respectively, in patients with gastric cancer, and 88.5% and 2.6 ± 2.4, respectively, in patients with colorectal cancer. Among the patients with gastric cancer, the accuracy and false-negative rates were 88.9 and 33.3%, respectively, in patients with T1 stage cancer, and 70.0 and 60.0%, respectively, overall, in all the patients. Among the patients with colorectal cancer, the corresponding values were 100 and 0%, respectively, in patients with T1 stage cancer, and 82.6 and 66.7%, respectively, overall, in all the patients. Conclusions: Our preliminary results show that ICG fluorescence imaging allows easy, highly sensitive and real-time imaging-guided SN mapping in patients with gastric or colorectal cancer. SN mapping guided by ICG fluorescence imaging could be a promising tool deserving further clinical exploration.
Gastric Perforations from Abdominal Trauma
Authors: Rodríguez-Hermosa José Ignacio , Roig Josep , Sirvent Josep Maria , Codina-Cazador Antoni , Gironès Jordi , Puig Josep , Osorio Margarita
Published: March 2008

Background: Gastric rupture due to abdominal trauma is rare (0.02–1.7%); it is usually caused by traffic accidents. Delayed diagnosis, abdominal contamination and associated lesions cause morbidity and mortality. Patients and Methods: Retrospective review of 2,083 patients with abdominal traumatism treated at our center over 20 years. We reviewed recent ingestion of a meal, etiology, time to surgery, site, Stomach Injury Scale, abdominal contamination, treatment, associated injuries, complications and mortality. Results: Gastric perforation occurred in 25 patients (1.2%), median age 35 years. Stomachs were distended from recent meals in 16 (64%). The commonest causes were traffic accidents (n = 13) and blunt weapon injury (n = 7). The median time to surgery was 1 h. Gastric lesions occurred predominantly in the anterior wall (n = 12) followed by the greater curvature (n = 7). Type II lesions repaired with simple suturing were the most usual. Abdominal contamination occurred in all cases. Associated lesions were present in 22 patients; the most commonly affected intra-abdominal organ was the liver, and the lungs were the most affected extra-abdominal organ. The morbidity rate was 60% (n = 15) and the mortality rate 4% (n = 1). Conclusion: Early diagnosis and surgical treatment are important for reducing the morbidity and mortality in these patients.
Hilar Anatomical Variations in Living-Donor Liver Transplantation Using Right-Lobe Grafts
Authors: Ikegami Toru , Soejima Yuji , Taketomi Akinobu , Yoshizumi Tomoharu , Harada Noboru , Kayashima Hiroto , Itoh Shinji , Yamashita Yo-ichi , Maehara Yoshihiko
Published: March 2008

Background: Living-donor liver transplantation using a right-lobe graft has increased the frequency of hilar anatomical variations despite its advantage of a larger graft volume. Methods: Sixty-seven living-donor liver transplantations using right-lobe grafts are reviewed, regarding the surgical anatomy of hilar vascular and biliary systems. Results: The portal anatomy was classified into four types. The incidence of double portal vein was 6.0% (n = 4), and for such cases a unified orifice (n = 1) or a Y-graft (n = 3) was used for reconstruction. The arterial system was classified into five types. The incidence of arterial complications was 6.0% (n = 4), all of which occurred in cases where the graft artery was connected to the recipient’s right hepatic artery. The biliary system was classified into four types. The incidence of a double bile duct was 7.5% (n = 5), and that of a unified one was 29.8% (n = 20). Hepaticojejunostomy was more prone to biliary sepsis (25.0%) and bile leakage (18.8%) than duct-to-duct connection (0 and 2%, respectively). Conclusion: Hilar anatomical variations in right-lobe living-donor liver transplantation could be managed after preoperative detailed evaluation of the graft and intraoperative appropriate surgical decision and techniques.
Increased Prevalence of Significant Recurrent Headache in Preclinical Familial Alzheimer’s Disease Mutation Carriers
Authors: Ringman John M. , Romano Joseph D. , Medina Luis D. , Rodriguez-Agudelo Yaneth , Schaffer Barbara , Varpetian Arousiak , Ortiz Freddy , Fitten L. Jamie , Cummings Jeffrey L. , Baloh Robert W.
Published: March 2008

Background/Aims: A previous study found a high prevalence of headaches in persons with familial Alzheimer’s disease (FAD) due to a PSEN1 mutation. In our study we compared the prevalence of headaches between nondemented FAD mutation carriers (MCs) and non-mutation-carrying controls (NCs). Methods: A headache questionnaire that assessed the prevalence of significant headaches and diagnosis of migraine and aura by ICHD-2 criteria was administered to 27 individuals at risk for FAD. Frequency of significant headaches, migraine, and aura were compared between MCs and NCs by χ2 or Fisher’s exact tests. Results: Twenty-three subjects were at risk for PSEN1 mutations and 4 for an APP substitution. The majority of subjects were female (23/27). MCs were more likely to report significant recurrent headache than NCs (67 vs. 25%, p = 0.031). Forty percent of MCs had headaches that met criteria for migraine whereas 17% of NCs met such criteria. The tendency for a higher prevalence of headaches in MCs held for different PSEN1 and APP mutations but was not significant unless all families were combined. Conclusions: In this population, headache was more common in nondemented FAD MCs than NCs. Possible mechanisms for this include cerebral inflammation, aberrant processing of Notch3, or disrupted intracellular calcium regulation.
P2X Receptors: Epithelial Ion Channels and Regulators of Salt and Water Transport
Authors: Wildman Scott S.P. , King Brian F.
Published: March 2008

When the results from electrophysiological studies of renal epithelial cells are combined with data from in vivo tubule microperfusion experiments and immunohistochemical surveys of the nephron, the accumulated evidence suggests that ATP-gated ion channels, P2X receptors, play a specialized role in the regulation of ion and water movement across the renal tubule and are integral to electrolyte and fluid homeostasis. In this short review, we discuss the concept of P2X receptors as regulators of salt and water salvage pathways, as well as acknowledging their accepted role as ATP-gated ion channels.
HLA-DR Expression and Apoptosis: A Cross-Sectional Controlled Study in Hemodialysis and Peritoneal Dialysis Patients
Authors: de Cal Massimo , Cruz Dinna N. , Corradi Valentina , Nalesso Federico , Polanco Natalia , Lentini Paolo , Brendolan Alessandra , Tetta Ciro , Ronco Claudio
Published: March 2008

Background: Altered HLA-DR expression and apoptosis have been described to reflect a state of immunological dysfunction in uremia. Here, we performed a cross-sectional, controlled study to evaluate monocyte HLA-DR expression and apoptosis in dialyzed chronic kidney disease patients. Methods: Monocyte HLA-DR expression was determined in 81 hemodialysis (HD) and 51 peritoneal dialysis (PD) patients and 40 healthy controls. By triple-color flow cytometry, we analyzed the percentage of monocytes in whole blood, the percentage of HLA-DR+ monocytes and the mean fluorescence intensity. Using U937 cell line incubated with the patients’ plasma, we analyzed the percentage of apoptosis induced after 96 h. Results: Both HD and PD patients had lower, but statistically not significant, monocyte HLA-DR expression compared to controls (96.47 ± 3.83% and 96.64 ± 3.29% respectively, versus 98.42 ± 1.05%). However, mean fluorescence intensity of HLA-DR was significantly higher in PD (149.35 ± 80.96) than in HD (99.20 ± 40.46), and controls (73.25 ± 27.78, p < 0.001). Apoptosis was higher in both HD and PD (35.14 ± 6.77 and 14.37 ± 5.03%) compared to controls (11.30 ± 2.03%, p < 0.001), and significantly higher in HD compared to PD. Conclusion: A reduced inflammatory state and the continuous solute removal in PD may attenuate immune dysfunction in uremia. In HD but not in PD patients, there was a significant correlation between the percentage of HLA-DR+ monocytes with apoptosis (R = 0.230, p = 0.04).
Extract of Radix Curcumae Prevents Gastric Cancer in Rats
Authors: Lu Bin , Xu Lei , Yu Linfeng , Zhang Lu
Published: March 2008

Objective: Radix curcumae is a Chinese medicinal herb commonly used in the treatment of malignancy. This study was to investigate the chemopreventive effect of an extract solution from radix curcumae in a rat model of gastric cancer induced by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Methods: Eighty male Wistar rats were randomly allocated to 5 groups administered different agents for 40 weeks: group A, water and normal saline; group B, MNNG and normal saline; group C, MNNG and celecoxib; group D, MNNG and low-dose (1 g/ml) radix curcumae steam distillation extract solution; group E, MNNG and high-dose (2 g/ml) radix curcumae wet distillation extract solution. At the end of week 40, all rats alive were sacrificed. Gastric cancer and precancerous lesions in the stomach were evaluated by histology. Results: In total there were 35 deaths during the study period. The incidences of gastric cancer were 0.0% (0/16) in group A, 44.4% (7/16) in group B, 12.5% (2/16) in group C, 12.5% (2/16) in group D and 12.5% (2/16) in group E. Tumor incidence and tumor volume were significantly lower in groups C, D and E compared to those in group B (p < 0.05). There was no significant difference of tumor incidence and tumor volume among groups C, D and E (p = 1.000). Conclusion: Extract solution from radix curcumae obtained by the steam distillation procedure has a chemopreventive effect on gastric cancer induced by MNNG in rats.
Burden among Spousal and Child Caregivers of Patients with Mild Cognitive Impairment
Authors: Bruce Jared M. , McQuiggan Michael , Williams Vanessa , Westervelt Holly , Tremont Geoffrey
Published: March 2008

Background/Aims: Patients with mild cognitive impairment (MCI) experience cognitive declines and often report significant emotional/behavioral changes. Despite this, few studies have examined the impact of MCI on caregiver burden. The purpose of this study was to confirm the presence of caregiver burden in MCI and examine the relationship between burden and patients’ neuropsychological, behavioral and emotional functioning. Methods: The current study included 51 individuals who had been diagnosed as having MCI using Petersen’s criteria. The patients underwent a thorough neuropsychological evaluation and completed the Beck Depression Inventory and Cognitive Difficulties Scale. The caregivers completed the Zarit Burden Interview and the Revised Memory and Behavior Checklist. Results: More than 30% of the caregivers reported clinically significant burden. Increased caregiver burden was associated with a longer course of cognitive symptoms, patient reports of worse depression and greater cognitive difficulties, and informant reports of patients having more behavior, mood and memory problems. Caregiver burden was not significantly associated with patients’ neuropsychological test performance. Conclusion: The results highlight the importance of addressing patients’ behavioral and emotional difficulties, as well as caregiver burden, as part of the clinical exam in MCI.
Characterization of Pituitary Cell Populations in Rats with Induced Polycystic Ovaries
Authors: Francou Manuela , Durdos Mauro , Salvetti Natalia R. , Baravalle Celina , Rey Florencia , Ortega Hugo H.
Published: March 2008

Several hypotheses have been proposed about the pathogenesis of polycystic ovarian syndrome (PCOS), however, the fundamental physiological interactions that initiate the development of follicular cysts have not yet been elucidated. Hence, in this study the proliferation, density and population of gonadotrophs, mammotrophs, somatotrophs and corticotrophs of the pituitary glands of rats with induced follicular cysts have been investigated by 2 experimental models (continuous light exposition and estradiol valerate-treated rats). Specific immunoreactivity associated with follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone and adrenocorticotropic hormone was evaluated by immunohistochemistry with specific hormone antibodies and proliferation of secretory cells by their colocalization (double-labeling) with proliferating cell nuclear antigen. The results indicate a reduction in the density and proliferation of gonadotrophs in both experimental groups. A reduction in the average density, proliferation and population of lactotrophs and corticotrophs was also observed in estradiol valerate-treated animals. However, no significant differences were found in somatotrophs. The present study contributes to the information about alterations of some cell populations that occur in the pituitary gland of rats with polycystic ovaries, and will enhance our understanding of the pathogenesis of this disease.
Epoxycholesterol Impairs Cholesteryl Ester Hydrolysis in Macrophage Foam Cells, Resulting in Decreased Cholesterol Efflux
Authors: Ouimet Mireille , Wang Ming-Dong , Cadotte Natalie , Ho Kenneth , Marcel Yves L.
Published: March 2008

Objective—

Strategies to inhibit or reverse cholesterol accumulation in macrophages have been shown to be atheroprotective. Notably, the administration of LXR agonists upregulates key players in the reverse cholesterol transport pathway, including the ABCA1 and ABCG1 transporters. However, the effects of natural LXR activators, oxysterols, on lipid-laden macrophages remains elusive.

Methods and Results—

We assessed the ability of 2 oxysterols, 22(R)-hydroxycholesterol (22-OH) and 24(S),25-epoxycholesterol (epoxycholesterol), to promote cholesterol efflux to apoA-I from LDL- and modified LDL-labeled and loaded macrophages and thus rescue the phenotype associated with the accumulation of cellular cholesterol in these cells. In macrophages labeled with LDL-derived cholesterol, epoxycholesterol treatment enhances ABCA1-mediated cholesterol efflux. In contrast, in AcLDL-loaded macrophages, epoxycholesterol treatment decreases cholesterol efflux to apoA-I, despite a dramatic increase in the expression of ABCA1 in response to epoxycholesterol treatment. We show that the decreased efflux is attributable to impaired cholesterol mobilization from lipid droplets, resulting from decreased cholesteryl ester hydrolase activity.

Conclusion—

Epoxycholesterol impairs cholesteryl ester hydrolysis activity in macrophage foam cells, thus reducing the availability of cholesterol for efflux to cholesterol acceptors.
Human LDL Receptor Enhances Sequestration of ApoE4 and VLDL Remnants on the Surface of Hepatocytes but Not Their Internalization in Mice
Authors: Altenburg Michael , Arbones-Mainar Jose , Johnson Lance , Wilder Jennifer , Maeda Nobuyo
Published: March 2008

Objective—

In humans, apolipoprotein (apo) E4 is associated with elevated plasma cholesterol levels and a high risk of developing atherosclerosis, whereas apoE2 is protective. Here we investigate the mechanism by which mice expressing human apoE isoforms recapitulate this association when they also express high levels of human low-density lipoprotein receptor (LDLR).

Methods and Results—

Primary hepatocytes from apoE4 mice secreted less apoE into the medium than hepatocytes from apoE2 mice. Increased LDLR expression decreased this secretion and increased degradation of apoE4. An apoE4-GFP fusion protein expressed in the liver of apoE-deficient mice accumulated on the hepatocyte surface bordering the space of Disse in an LDLR-dependent manner. Fluorescence-labeled very low–density lipoprotein (VLDL) remnants accumulated on the hepatocyte surface in apoE4 mice with high LDLR, but they were internalized poorly. In contrast, apoE2-GFP did not accumulate on the hepatocyte surface even when the LDLR expression was high, but apoE2 mice with high LDLR internalized the remnants avidly without sequestering them on the hepatocyte surface.

Conclusions—

The high affinity of apoE4 to the LDLR enhances VLDL sequestration on the hepatocyte surface but delays their internalization. This delay likely increases VLDL conversion to cholesterol-enriched remnants in apoE4 mice with high LDLR, and probably to LDL in humans with apoE4.
Activation of Notch-Mediated Protective Signaling in the Myocardium
Authors: Gude Natalie A. , Emmanuel Gregory , Wu Weitao , Cottage Christopher T. , Fischer Kimberlee , Quijada Pearl , Muraski John A. , Alvarez Roberto , Rubio Marta , Schaefer Eric , Sussman Mark A.
Published: March 2008

The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades. The impact of HGF on Notch signaling was assessed following myocardial infarction as well as in cultured cardiomyocytes. Notch1 is activated in border zone cardiomyocytes coincident with nuclear c-Met following infarction. Intramyocardial injection of HGF enhances Notch1 and Akt activation in adult mouse myocardium. Corroborating evidence in cultured cardiomyocytes shows treatment with HGF or insulin increases levels of Notch effector Hes1 in immunoblots, whereas overexpression of activated Notch intracellular domain prompts a 3-fold increase in phosphorylated Akt. Infarcted hearts injected with adenoviral vector expressing Notch intracellular domain treatment exhibit improved hemodynamic function in comparison with control mice after 4 weeks, implicating Notch signaling in a cardioprotective role following cardiac injury. These results indicate Notch activation in cardiomyocytes is mediated through c-Met and Akt survival signaling pathways, and Notch1 signaling in turn enhances Akt activity. This mutually supportive crosstalk suggests a positive survival feedback mechanism between Notch and Akt signaling in adult myocardium following injury.
Proline and γ-Carboxylated Glutamate Residues in Matrix Gla Protein Are Critical for Binding of Bone Morphogenetic Protein-4
Authors: Yao Yucheng , Shahbazian Ani , Boström Kristina I.
Published: March 2008

Arterial calcification is ubiquitous in vascular disease and is, in part, prevented by matrix Gla protein (MGP). MGP binds calcium ions through γ-carboxylated glutamates (Gla residues) and inhibits bone morphogenetic protein (BMP)-2/-4. We hypothesized that a conserved proline (Pro)64 is essential for BMP inhibition. We further hypothesized that calcium binding by the Gla residues is a prerequisite for BMP inhibition. Site-directed mutagenesis was used to modify Pro64 and the Gla residues, and the effect on BMP-4 activity, and binding of BMP-4 and calcium was tested using luciferase reporter gene assays, coimmunoprecipitation, crosslinking, and calcium quantification. The results showed that Pro64 was critical for binding and inhibition of BMP-4 but not for calcium binding. The Gla residues were also required for BMP-4 binding but flexibility existed. As long as 1 Gla residue remained on each side of Pro64, the ability to bind and inhibit BMP-4 was preserved. Chelation of calcium ions by EDTA or warfarin treatment of cells led to loss of ability of MGP to bind BMP-4. Our results also showed that phenylalanine could replace Pro64 without loss of function and that zebrafish MGP, which lacks upstream Gla residues, did not function as a BMP inhibitor. The effect of MGP mutagenesis on vascular calcification was determined in calcifying vascular cells. Only MGP proteins with preserved ability to bind and inhibit BMP-4 prevented osteogenic differentiation and calcification. Together, our results suggest that BMP and calcium binding in MGP are independent but functionally intertwined processes and that the BMP binding is essential for prevention of vascular calcification.
Spatiotemporal Dynamics of β-Adrenergic cAMP Signals and L-Type Ca
2+
Channel Regulation in Adult Rat Ventricular Myocytes
Authors: Leroy Jérôme , Abi-Gerges Aniella , Nikolaev Viacheslav O. , Richter Wito , Lechêne Patrick , Mazet Jean-Luc , Conti Marco , Fischmeister Rodolphe , Vandecasteele Grégoire
Published: March 2008

Steady-state activation of cardiac β-adrenergic receptors leads to an intracellular compartmentation of cAMP resulting from localized cyclic nucleotide phosphodiesterase (PDE) activity. To evaluate the time course of the cAMP changes in the different compartments, brief (15 seconds) pulses of isoprenaline (100 nmol/L) were applied to adult rat ventricular myocytes (ARVMs) while monitoring cAMP changes beneath the membrane using engineered cyclic nucleotide-gated channels and within the cytosol with the fluorescence resonance energy transfer–based sensor, Epac2-camps. cAMP kinetics in the two compartments were compared to the time course of the L-type Ca
2+
channel current (
I
Ca,L
) amplitude. The onset and recovery of cAMP transients were, respectively, 30% and 50% faster at the plasma membrane than in the cytosol, in agreement with a rapid production and degradation of the second messenger at the plasma membrane and a restricted diffusion of cAMP to the cytosol.
I
Ca,L
amplitude increased twice slower than cAMP at the membrane, and the current remained elevated for ≈5 minutes after cAMP had already returned to basal level, indicating that cAMP changes are not rate-limiting in channel phosphorylation/dephosphorylation. Inhibition of PDE4 (with 10 μmol/L Ro 20-1724) increased the amplitude and dramatically slowed down the onset and recovery of cAMP signals, whereas PDE3 blockade (with 1 μmol/L cilostamide) had a minor effect only on subsarcolemmal cAMP. However, when both PDE3 and PDE4 were inhibited, or when all PDEs were blocked using 3-isobutyl-l-methylxanthine (300 μmol/L), cAMP signals and
I
Ca,L
declined with a time constant >10 minutes. cAMP-dependent protein kinase inhibition with protein kinase inhibitor produced a similar effect as a partial inhibition of PDE4 on the cytosolic cAMP transient. Consistently, cAMP-PDE assay on ARVMs briefly (15 seconds) exposed to isoprenaline showed a pronounced (up to ≈50%) dose-dependent increase in total PDE activity, which was mainly attributable to activation of PDE4. These results reveal temporally distinct β-adrenergic receptor cAMP compartments in ARVMs and shed new light on the intricate roles of PDE3 and PDE4.
The Influence of Psychiatric Morbidity on Return to Paid Work After Stroke in Younger Adults
Authors: Glozier Nick , Hackett Maree L. , Parag Varsha , Anderson Craig S.
Published: March 2008

Background and Purpose—

Few data exist on the determinants of return to paid work after stroke, yet participation in employment is vital to a person’s mental well-being and role in society. This study aimed to determine the frequency and determinants of return to work, in particular the effect of early psychiatric morbidity, in a population-based study of stroke survivors.

Methods—

The third Auckland Regional Community Stroke (ARCOS) study was a prospective, population-based, stroke incidence study undertaken in Auckland, New Zealand during 2002 to 2003. After a baseline assessment early after stroke, data were collected on all survivors at 1 and 6 months follow-up. Multiple variable logistic regression was used to determine predictors of return to paid work. Data are reported with odds ratios (OR) and 95% confidence intervals (CI).

Results—

Among 1423 patients registered with first-ever strokes, there were 210 previously in paid employment who survived to 6 months, of whom 155 (74%) completed the GHQ-28 and 112 (53%) had returned to paid work. Among those cognitively competent, psychiatric morbidity at 28 days was a strong independent predictor of not returning to work (Odds Ratio 0.39; 95% CI 0.22 to 0.80). Non–New Zealand European ethnicity (OR 0.40; 95% CI 0.17 to 0.91), prior part-time, as opposed to full-time, employment 0.36 (0.15 to 0.89), and not being functionally independent soon after the stroke 0.28 (0.13 to 0.59) were the other independent age- and gender-adjusted predictors of not successfully returning to paid work.

Conclusions—

About half of previously employed people return to paid employment after stroke, with psychiatric morbidity and physical disability being independent, yet potentially treatable, determinants of this outcome. Appropriate management of both emotional and physical sequelae would appear necessary for optimizing recovery and return to work in younger adults after stroke.
NXY-059 for the Treatment of Acute Stroke
Authors: Diener Hans-Christoph , Lees Kennedy R. , Lyden Patrick , Grotta Jim , Davalos Antoni , Davis Stephen M. , Shuaib Ashfaq , Ashwood Tim , Wasiewski Warren , Alderfer Vivian , Hårdemark Hans-Goran , Rodichok Larry
Published: March 2008

Background and Purpose—

In animal models of acute ischemic stroke (AIS), the free radical–trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS.

Methods—

Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome.

Results—

An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n=2438) compared with the placebo group (n=2456): odds ratio for limiting disability=1.02; 95% CI, 0.92 to 1.13 (
P
=0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome.

Conclusions—

NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.
Coffee and Tea Consumption and Risk of Stroke Subtypes in Male Smokers
Authors: Larsson Susanna C. , Männistö Satu , Virtanen Mikko J. , Kontto Jukka , Albanes Demetrius , Virtamo Jarmo
Published: March 2008

Background and Purpose—

Coffee and tea consumption could potentially reduce the risk of stroke because these beverages have antioxidant properties, and coffee may improve insulin sensitivity. We examined the associations of coffee and tea consumption with risk of stroke subtypes.

Methods—

We used prospective data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a cohort study of 26 556 male Finnish smokers aged 50 to 69 years without a history of stroke at baseline. Coffee and tea consumption was assessed at baseline using a validated food-frequency questionnaire. During a mean follow-up of 13.6 years, from 1985 through December 2004, 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were ascertained from national registries.

Results—

After adjustment for age and cardiovascular risk factors, both consumption of coffee and tea was statistically significantly inversely associated with the risk of cerebral infarction but not intracerebral or subarachnoid hemorrhage. The multivariate relative risk of cerebral infarction for men in the highest category of coffee consumption (≥8 cups/d) was 0.77 (95% CI, 0.66 to 0.90;
P
for trend <0.001) compared with those in the lowest category (<2 cups/d). The corresponding relative risk comparing men in the highest category of tea consumption (≥2 cups/d) with those in the lowest category (nondrinkers) was 0.79 (95% CI, 0.68 to 0.92;
P
for trend=0.002).

Conclusions—

These results suggest that high consumption of coffee and tea may reduce the risk of cerebral infarction among men, independent of known cardiovascular risk factors.
Factors Associated With a High Risk of Recurrence in Patients With Transient Ischemic Attack or Minor Stroke
Authors: Ois Angel , Gomis Meritxell , Rodríguez-Campello Ana , Cuadrado-Godia Elisa , Jiménez-Conde Jordi , Pont-Sunyer Claustre , Cuccurella Gracia , Roquer Jaume
Published: March 2008

Background and Purpose—

The aim of our study was to identify factors associated with stroke recurrence after an initial minor stroke or transient ischemic attack (TIA) in a prospective hospital-series.

Methods—

Included in the series were 689 patients with NIHSS lower than 4 at hospital admission. The end point was a new neurological event (worsening ≥4 points in the initial NIHSS was considered as recurrence) at 90 days (and additionally at 7 days). Factors based on two previous reported scores (ABCD and SPI-II) were analyzed in relation with stroke recurrence: age, duration of symptoms >1 hour, weakness, speech impairment, initial hypertension, hypertension, diabetes, coronary disease, minor stroke versus TIA, prior stroke, and heart failure. We also analyzed: gender, hyperlipidemia, severe alcohol intake (>60gr/d), current smoking habits, peripheral arterial disease, atrial fibrillation, acute lesion in initial head computed tomography, severe symptomatic extra or intracranial arterial disease (SSAD; arterial stenosis ≥70%), previous TIA, and vertebrobasilar event. Patients were also analyzed separately according to diagnosis of TIA or minor stroke.

Results—

90-day recurrence occurred in 111 patients (16.1%), whereas 62 patients had 7-day recurrence (9%). The independent variables associated with 90-day recurrence were: SSAD (OR=4.97), weakness (OR=3.25), speech impairment (OR=1.96), severe alcohol intake (OR=4.18), heart failure (OR=2.41), previous TIA (OR=4.62), and vertebrobasilar events (OR=2.87). SSAD was independently associated with 7-day recurrence (OR=7.73) and also for TIA (OR=3.45) and minor stroke (OR=5.15) patients.

Conclusions—

An arterial study to discard SSAD would be necessary, in combination with clinical factors, to improve the identification of patients with a higher risk of 90-day recurrence after an initial minor stroke or TIA.
Soluble Epoxide Hydrolase Gene Deletion Is Protective Against Experimental Cerebral Ischemia
Authors: Zhang Wenri , Otsuka Takashi , Sugo Nobuo , Ardeshiri Ardi , Alhadid Yazan K. , Iliff Jeffrey J. , DeBarber Andrea E. , Koop Dennis R. , Alkayed Nabil J.
Published: March 2008

Background and Purpose—

Cytochrome P450 epoxygenase metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs). EETs are produced in the brain and perform important biological functions, including vasodilation and neuroprotection. However, EETs are rapidly metabolized via soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We tested the hypothesis that sEH gene deletion is protective against focal cerebral ischemia through enhanced collateral blood flow.

Methods—

sEH knockout (sEHKO) mice with and without EETs antagonist 14, 15 epoxyeicosa-5(
Z
)-enoic acid (EEZE) were subjected to 2-hour middle cerebral artery occlusion (MCAO), and infarct size was measured at 24 hours of reperfusion and compared to wild-type (WT) mice. Local CBF rates were measured at the end of MCAO using iodoantipyrine (IAP) autoradiography, sEH protein was analyzed by Western blot and immunohistochemistry, and hydrolase activity and levels of EETs/DHETs were measured in brain and plasma using LC-MS/MS and ELISA, respectively.

Results—

sEH immunoreactivity was detected in WT, but not sEHKO mouse brain, and was localized to vascular and nonvascular cells. 14,15-DHET was abundantly present in WT, but virtually absent in sEHKO mouse plasma. However, hydrolase activity and free 14,15-EET in brain tissue were not different between WT and sEHKO mice. Infarct size was significantly smaller, whereas regional cerebral blood flow rates were significantly higher in sEHKO compared to WT mice. Infarct size reduction was recapitulated by 14,15-EET infusion. However, 14,15-EEZE did not alter infarct size in sEHKO mice.

Conclusions—

sEH gene deletion is protective against ischemic stroke by a vascular mechanism linked to reduced hydration of circulating EETs.
Urbanization Effects on Observed Surface Air Temperature Trends in North China
Authors: Ren Guoyu , Zhou Yaqing , Chu Ziying , Zhou Jiangxing , Zhang Aiying , Guo Jun , Liu Xuefeng
Published: March 2008

A dataset of 282 meteorological stations including all of the ordinary and national basic/reference surface stations of north China is used to analyze the urbanization effect on surface air temperature trends. These stations are classified into rural, small city, medium city, large city, and metropolis based on the updated information of total population and specific station locations. The significance of urban warming effects on regional average temperature trends is estimated using monthly mean temperature series of the station group datasets, which undergo inhomogeneity adjustment. The authors found that the largest effect of urbanization on annual mean surface air temperature trends occurs for the large-city station group, with the urban warming being 0.16°C (10 yr)−1, and the effect is the smallest for the small-city station group with urban warming being only 0.07°C (10 yr)−1. A similar assessment is made for the dataset of national basic/reference stations, which has been widely used in regional climate change analyses in China. The results indicate that the regional average annual mean temperature series, as calculated using the data from the national basic/reference stations, is significantly impacted by urban warming, and the trend of urban warming is estimated to be 0.11°C (10 yr)−1. The contribution of urban warming to total annual mean surface air temperature change as estimated with the national basic/reference station dataset reaches 37.9%. It is therefore obvious that, in the current regional average surface air temperature series in north China, or probably in the country as a whole, there still remain large effects from urban warming. The urban warming bias for the regional average temperature anomaly series is corrected. After that, the increasing rate of the regional annual mean temperature is brought down from 0.29°C (10 yr)−1 to 0.18°C (10 yr)−1, and the total change in temperature approaches 0.72°C for the period analyzed.
Calibrating and Evaluating Reanalysis Surface Temperature Error by Topographic Correction
Authors: Zhao Tianbao , Guo Weidong , Fu Congbin
Published: March 2008

Based on the observed daily surface air temperature data from 597 stations over continental China and two sets of reanalysis data [NCEP–NCAR and 40-yr ECMWF Re-Analysis (ERA-40)] during 1979–2001, the altitude effects in calibrating and evaluating reanalyzed surface temperature errors are studied. The results indicate that the accuracy of interpolated surface temperature from the reanalyzed gridpoint value or the station observations depends much on the altitudes of original data. Bias of interpolated temperature is usually in proportion to the increase of local elevation and topographical complexity. Notable improvements of interpolated surface temperature have been achieved through “topographic correction,” especially for ERA-40, which highlights the necessity of removal of “elevation-induced bias” when using and evaluating reanalyzed surface temperature.
Systematic Variation of Summertime Tropical Cyclone Activity in the Western North Pacific in Relation to the Madden–Julian Oscillation
Authors: Kim Joo-Hong , Ho Chang-Hoi , Kim Hyeong-Seog , Sui Chung-Hsiung , Park Seon Ki
Published: March 2008

The variability of observed tropical cyclone (TC) activity (i.e., genesis, track, and landfall) in the western North Pacific (WNP) is examined in relation to the various categories of the Madden–Julian oscillation (MJO) during summer (June–September) for the period 1979–2004. The MJO categories are defined based on the empirical orthogonal function analysis of outgoing longwave radiation data.

The number of TCs increases when the MJO-related convection center is located in the WNP. The axis of a preferable genesis region systematically shifts like a seesaw in response to changes in the large-scale environments associated with both the eastward and northward propagation of the MJO and the intraseasonal variability of the WNP subtropical high. Furthermore, the authors show that the density of TC tracks in each MJO category depends on the systematic shift in the main genesis regions at first order. Also, the shift is affected by the prevailing large-scale steering flows in each MJO category. When the MJO-related convection center is found in the equatorial Indian Ocean (the tropical WNP), a dense area of tracks migrates eastward (westward). The effects of extreme ENSO events and the variations occurring during ENSO neutral years are also examined.

A statistical analysis of TC landfalls by MJO category is applied in seven selected subareas: the Philippines, Vietnam, South China, Taiwan, East China, Korea, and Japan. While a robust and significant modulation in the number of TC landfalls is observed in south China, Korea, and Japan, the modulation is marginal in the remaining four subareas.
Sensitivity of an Ocean General Circulation Model to a Parameterization of Near-Surface Eddy Fluxes
Authors: Danabasoglu Gokhan , Ferrari Raffaele , McWilliams James C.
Published: March 2008

A simplified version of the near-boundary eddy flux parameterization developed recently by Ferrari et al. has been implemented in the NCAR Community Climate System Model (CCSM3) ocean component for the surface boundary only. This scheme includes the effects of diabatic mesoscale fluxes within the surface layer. The experiments with the new parameterization show significant improvements compared to a control integration that tapers the effects of the eddies as the surface is approached. Such surface tapering is typical of present implementations of eddy transport in some current ocean models. The comparison is also promising versus available observations and results from an eddy-resolving model. These improvements include the elimination of strong, near-surface, eddy-induced circulations and a better heat transport profile in the upper ocean. The experiments with the new scheme also show reduced abyssal cooling and diminished trends in the potential temperature drifts. Furthermore, the need for any ad hoc, near-surface taper functions is eliminated. The impact of the new parameterization is mostly associated with the modified eddy-induced velocity treatment near the surface. The new parameterization acts in the depth range exposed to enhanced turbulent mixing at the ocean surface. This depth range includes the actively turbulent boundary layer and a transition layer underneath, composed of waters intermittently exposed to mixing. The mixed layer, that is, the regions of weak stratification at the ocean surface, is found to be a good proxy for the sum of the boundary layer depth and transition layer thickness.