bluuebunny/crossref_metadata_2025 huggingface dataset:
A Simple and Safe Method for Gastrojejunostomy in Laparoscopic Distal Gastrectomy Using the Hemidouble-Stapling Technique: Efficient Purse-String Stapling Technique
Authors: Omori Takeshi , Oyama Tsukasa , Akamatsu Hiroki , Tori Masayuki , Ueshima Shigeyuki , Nakahara Masaaki , Toshirou Nishida
Published: January 2010

Aim: To describe a simple technique for intracorporeal circular-stapled gastrojejunostomy in laparoscopic distal gastrectomy with Roux-en-Y reconstruction. Methods: After the stomach and duodenum were mobilized, gastrotomy was established in the anterior gastric wall. An anvil, which was secured with a suture needle, was inserted completely through the gastrotomy. The needle was advanced to the greater curvature of the gastric wall to enable penetration of the central rod into the gastric wall. Subsequently, the stomach was cut using a linear stapler to secure the anvil on the stomach and was sequentially transected using another linear stapler to achieve distal gastrectomy. Circular-stapled gastrojejunostomy was then performed intracorporeally using the hemidouble-stapling technique, while handling the shaft of the instrument via the umbilical incision. The jejunal stump was closed using a linear stapler. Results: Gastrojejunostomies were successfully performed in 20 gastric cancer patients using this technique. None of the patients showed anastomotic leakage and/or stenosis. There were no mortalities in this series. Conclusions: Gastrojejunostomy performed using the above-mentioned technique was safe and simple. The most important feature of the technique was the elimination of the need for purse-string suture placement, as well as the achievement of better cosmesis using the transumbilical approach.
Totally Laparoscopic Low Anterior Resection for Lower Rectal Cancer: Combination of a New Technique for Intracorporeal Anastomosis with Prolapsing Technique
Authors: Akamatsu Hiroki , Omori Takeshi , Oyama Tsukasa , Tori Masayuki , Ueshima Shigeyuki , Nishida Toshirou , Nakahara Masaaki , Abe Takashi
Published: January 2010

Background: Laparoscopically assisted low anterior resection is difficult even for experienced surgeons because of difficulties in selecting the appropriate transection line and completing anastomosis in the narrow pelvic space. The prolapsing technique resolves these problems. We combined our new technique for intracorporeal anastomosis with this prolapsing technique and achieved a totally laparoscopic low anterior resection. Methods: After the total mesorectal excision, a semi-circumferential colotomy is made at the anterior colonic wall just proximal to the proximal transection site. The anvil of a circular stapling device, secured with a Prolene suture, is introduced via the colotomy. The suture is advanced anteriorly so that the center rod of the anvil penetrates the colonic wall. The colon is staple-transected at this point to secure the anvil on the proximal colon. The distal rectum is everted and pulled transanally outside the body using a grasping forceps inserted from the anus. Staple-closure and transection of the distal rectum is performed under direct vision. Anastomosis is established using the double-stapling technique. Results: Totally laparoscopic low anterior resections using this technique were performed for 7 patients with rectal cancer. There was no anastomotic leakage/stenosis. Conclusions: Our procedure can be performed easily, which enables surgeons to achieve minimal invasiveness compared with hybrid NOTES.
The Therapeutic Potential of Erythropoiesis-Stimulating Agents for Tissue Protection: A Tale of Two Receptors
Authors: Brines Michael
Published: January 2010

Erythropoietin (EPO) is a well-known therapeutic protein employed widely in the treatment of anemia. Over the past decade, abundant evidence has shown that in addition to its systemic role in the regulation of plasma pO2 by modulating erythrocyte numbers, EPO is also a cytoprotective molecule made locally in response to injury or metabolic stress. Many studies have shown beneficial effects of EPO administration in reducing damage caused by ischemia-reperfusion, trauma, cytotoxicity, infection and inflammation in a variety of organs and tissues. Notably, the receptor mediating the nonerythropoietic effects of EPO differs from the one responsible for hematopoiesis. The tissue-protective receptor exhibits a lower affinity for EPO and is a heteromer consisting of EPO receptor monomers in association with the common receptor that is also employed by granulocyte macrophage colony-stimulating factor, interleukin 3, and interleukin 5. This heteromeric receptor is expressed immediately following injury, whereas EPO production is delayed. Thus, early administration of EPO can dramatically reduce the deleterious components of the local inflammatory cascade. However, a high dose of EPO is required and this also stimulates the bone marrow to produce highly reactive platelets and activates the vascular endothelium into a prothrombotic state. To circumvent these undesirable effects, the EPO molecule has been successfully altered to selectively eliminate erythropoietic and prothrombotic potencies, while preserving tissue-protective activities. Very recently, small peptide mimetics have been developed that recapitulate the tissue-protective activities of EPO. Nonerythropoietic tissue-protective molecules hold high promise in a wide variety of acute and chronic diseases.
Special Considerations for Antihypertensive Agents in Dialysis Patients
Authors: Redon Josep , Martinez Fernando , Cheung Alfred K.
Published: January 2010

Hypertension is present in most patients with end-stage renal disease and likely contributes to the premature cardiovascular disease in dialysis patients. Previous practice guidelines have recommended that, in patients on chronic dialysis, blood pressure (BP) should be reduced below 130/80 mm Hg. This is based on opinions but not strong evidence, since no concrete information exists about which BP values should be the parameter to follow and which should be the target BP values. The majority of the antihypertensive agents can be used in this population, but the pharmacokinetics altered by the impaired kidney function and dialyzability influence the appropriate dosage as well as the time and frequency of administration. Combination therapy using multiple agents is often necessary. Because of the prevalence of overactivity of the renin-angiotensin-aldosterone system and sympathetic tone as well as the high calcium influx in vascular smooth muscle cells in dialysis patients, drugs acting in these three specific systems may potentially have additional cardioprotective benefits beyond their BP-lowering effect. Thus, antihypertensive regimens should preferably be based on these classes of drugs, alone or in combination. Other antihypertensive drug classes can play a complementary role.
Haemodialysis-Induced Myocardial Stunning in Chronic Kidney Disease – A New Aspect of Cardiovascular Disease
Authors: McIntyre Chris W.
Published: January 2010

Chronic haemodialysis (HD) patients are already primed by a large number of structural and functional peripheral vascular and cardiac abnormalities to experience demand myocardial ischaemia. Transient myocardial ischaemia may lead to left ventricular (LV) dysfunction that can persist after the return of normal perfusion. This prolonged dysfunction is known as myocardial stunning. Repetitive episodes of ischaemia can be cumulative and have been shown to lead to prolonged LV dysfunction (in patients with ischaemic heart disease). Conventional HD itself is a sufficient cardiovascular functional stressor to precipitate such recurrent ischaemic insults, leading to myocardial functional and structural changes, eventually resulting in fixed systolic dysfunction and heart failure (conferring a dismal prognosis for patients undergoing dialysis). Furthermore these same haemodynamic insults may also adversely affect other vascular beds in other vulnerable organ systems, driving an even wider range of pathophysiological processes. A variety of therapeutic manoeuvres aimed at improving the haemodynamic tolerability of treatment have been shown to reduce acute dialysis-induced myocardial ischaemia. This article aims to give an appreciation of the possibility that modification of the dialysis treatment to improve tolerability of therapy may have the potential to provide us with additional therapeutic targets, to reduce currently excessive rates of cardiovascular morbidity and mortality.
Immune Mechanisms Involved in Cardiovascular Complications of Chronic Kidney Disease
Authors: Stinghen Andréa E.M. , Bucharles Sergio , Riella Miguel C. , Pecoits-Filho R.
Published: January 2010

A sustained status of chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular degeneration, myocardial fibrosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. These consequences of a chronically activated immune system impact on the acceleration of atherosclerosis, vascular calcification and development of heart dysfunction. Recent evidence suggests that these immune-mediated consequences of uremic toxicity are not only important to stratify the risk and understand the mechanisms of disease, but also represent an important area for intervention. Thus, the aim of this brief review is to discuss the immune mechanisms behind atherosclerosis and myocardiopathy in CKD. We also display the emerging evidence that strategies focusing on modulating the immune response or reducing the generation of triggers of inflammation may represent an important tool to reduce mortality in this group of patients. Ongoing studies may generate the evidence that will translate these strategies to definitive changes in clinical practice.
Ethnicity and Renal Replacement Therapy
Authors: Feehally John
Published: January 2010

There are significant ethnic variations in the incidence of kidney disease. White European populations appear to be uniquely protected compared to increased incidences of end-stage renal disease in indigenous and migrant ethnic minority populations. This increase is partly explained by a high prevalence of diabetic nephropathy, but there is also an increased susceptibility to a range of other renal diseases. The relative contributions of genetic, environmental and fetal environmental factors to this susceptibility are not yet well understood. Strategies for early detection and management of chronic kidney disease to delay progression are particularly critical in countries where access to renal replacement therapy (RRT) is restricted. In developed countries with wide availability of RRT, resources to provide dialysis will need to be increased in regions with substantial minority populations. There is apparently counterintuitive evidence that survival on dialysis is increased in many minority populations. Access to renal transplantation, both from deceased and living donors, is also restricted in many minority populations, and graft survival is often inferior. Analysis of the explanations for these differences is complex because of the many confounding factors (for example cultural, social and economic) which typically cosegregate with ethnicity. Nevertheless, reduction of the varied and substantial inequities faced by ethnic minority populations with kidney disease is an important responsibility for the renal community.
Phosphate Elimination in Modalities of Hemodialysis and Peritoneal Dialysis
Authors: Kuhlmann Martin K.
Published: January 2010

Hyperphosphatemia is highly prevalent in hemodialysis (HD) and peritoneal dialysis (PD) patients and is a major risk factor for cardiovascular mortality. Elimination of inorganic phosphate by dialysis is a cornerstone of the management of hyperphosphatemia. Phosphate clearance during HD is affected by various factors of dialysis prescription, such as blood and dialysate flow rate, dialyzer membrane surface area and ultrafiltration volume. Phosphate mass removal can be improved by hemodiafiltration, increased dialysis frequencies and extended treatment times. Short daily or extended daily or 3 times weekly nocturnal HD allow higher phosphate mass removal and potentially complete discontinuation of phosphate binder medication. In PD, phosphate mass removal appears to be correlated with peritoneal creatinine but not urea clearance. In hyperphosphatemic PD patients, the decision on the optimal PD modality should be based on peritoneal creatinine and ideally also on peritoneal phosphate transport characteristics.
Endothelial Progenitor Cells and Endothelial Vesicles – What Is the Significance for Patients with Chronic Kidney Disease?
Authors: Mohandas Rajesh , Segal Mark S.
Published: January 2010

Endothelial progenitor cells are cells derived from the bone marrow that circulate in the bloodstream and can exhibit phenotypic characteristics of endothelial cells. They are thought to be involved in postnatal vasculogenesis and to potentially help repair injured endothelium. Circulating endothelial cells are mature endothelial cells in the circulation, and endothelial vesicles or microparticles are thought to be derived from the membranes of endothelial cells as a result of injury or activation. Recent research has focused on using these markers of endothelial injury and repair to assess the state of endothelial health. These efforts have been hampered by lack of uniformity in methodology and terminology. Recent developments in flow cytometry techniques have allowed better characterization and definition of these cells. We review the common techniques used to identify and isolate these cells, clinical studies in patients with chronic kidney disease (CKD) where they serve as markers of endothelial health and predictors of outcome, and possible mechanisms of progenitor cell dysfunction in CKD.
A Selective Cytopheretic Inhibitory Device to Treat the Immunological Dysregulation of Acute and Chronic Renal Failure
Authors: Humes H. David , Sobota Joseph T. , Ding Feng , Song Joon Ho
Published: January 2010

Background: The poor outcomes in patients with acute kidney injury (AKI) and end-stage renal disease (ESRD) on chronic dialysis are due to immune dysregulation associated with these disorders. Evolving evidence suggests that the kidney, and specifically renal epithelial cells, plays an important role in the immunological response of leukocytes under disease states. Method: In this regard, the development of two therapeutic approaches utilizing renal epithelial cells and ‘smart’ immunomodulatory membranes has been tested in preclinical animal models and clinical trials. Results: These two approaches have been demonstrated in phase II human trials to improve the survival of intensive care unit patients with AKI and multiorgan failure. The use of a ‘smart’ immunomodulatory membrane is also being evaluated in a small exploratory clinical trial to assess its effects on immunoregulation in ESRD patients requiring chronic hemodialysis. Conclusions: The use of renal progenitor/stem cell therapy and/or cytopheretic membranes may result in effective treatments to alter the dysregulated immunological state of acute or chronic renal failure and improve the outcomes of these diseases.
Citrate Anticoagulation for Continuous Renal Replacement Therapy in the Critically Ill
Authors: Oudemans-van Straaten Heleen M.
Published: January 2010

Background: Heparins are used for circuit anticoagulation during continuous renal replacement therapy (CRRT). Because heparins cause systemic anticoagulation, they increase the risk of bleeding. Citrate provides regional anticoagulation. Since citrate is a buffer as well, its use has metabolic consequences. The preferential use of citrate therefore remains controversial. Methods: A synthesis was performed of published studies comparing citrate to heparin for anticoagulation in CRRT with specific regard to feasibility, efficacy and safety. Search of the literature was made to explain the reported superiority of citrate. Results: Citrate provides good metabolic control if and when a well-designed protocol is strictly followed. Randomized studies report similar or longer circuit survival with citrate compared to heparin and less bleeding. The largest randomized trial up to now found that citrate was better tolerated than heparin and improved patient and kidney survival, especially in patients after surgery, with sepsis, a high degree of organ failure or younger age. Both citrate and heparin interfere with inflammation. Conclusion: During critical illness, regional anticoagulation with citrate for CRRT seems superior to heparin anticoagulation concerning tolerance and safety, mainly due to less bleeding. Whether circuit survival is better depends on the modality. In addition, citrate seems to improve patient and kidney survival. This finding needs to be confirmed. Citrate seems to confer a specific benefit in severe organ failure and sepsis. To what extent citrate protects or heparin does harm in the setting of multiple organ failure needs to be unraveled.
A Mathematical Model of Regional Citrate Anticoagulation in Hemodialysis
Authors: Thijssen Stephan , Kruse Anja , Raimann Jochen , Bhalani Viraj , Levin Nathan W. , Kotanko Peter
Published: January 2010

Background/Aims: Regional citrate anticoagulation (RCA) during hemodialysis (HD) has several advantages over heparin anticoagulation, but calcium (Ca) derangements are a major concern necessitating repeated monitoring of systemic ionized Ca (Ca2+). We developed a mathematical model of Ca and citrate (Ci) kinetics during RCA. Methods: Using patient- and treatment-related parameters, including pre-HD serum Ca and protein concentrations, hematocrit, blood and dialysate flow rates, dialysate composition and access recirculation, the model computes all relevant aspects of RCA based on physicochemical, biochemical and physiological principles such as chemical Ca and Ci equilibria, transmembrane solute fluxes and Ci metabolic rate. The model was validated in 17 treatments using arterial Ci infusion, Citrasate® dialysate, and no postdialyzer Ca substitution. Results: Measured and predicted systemic Ca2+ before HD was 1.08 ± 0.06 and 1.05 ± 0.05 mmol/l, respectively (difference –0.03 ± 0.046, 95% confidence interval, CI, –0.055 to –0.007), and at 15 min into the treatment 1.01 ± 0.05 and 1.02 ± 0.05 mmol/l, respectively (difference 0.012 ± 0.054, 95% CI –0.015 to 0.04). At 15 min, the measured and predicted predialyzer Ca2+ was 0.33 ± 0.06 and 0.39 ± 0.05 mmol/l, respectively (difference 0.06 ± 0.03; 95% CI 0.044–0.077), and the measured and predicted postdialyzer Ca2+ was 0.7 ± 0.05 and 0.61 ± 0.05 mmol/l, respectively (difference –0.09 ± 0.04; 95% CI –0.11 to –0.07). Bland-Altman analysis showed no systematic bias in these predictions. Conclusion: This novel model of RCA shows excellent accuracy in predicting systemic, pre- and postdialyzer Ca2+ concentrations and may prove valuable in both research and clinical applications of RCA.
Modeling Hepatitis C Virus Therapies Combining Drugs and Lectin Affinity Plasmapheresis
Authors: Tullis Richard H. , Duffin R. Paul , Ichim Thomas E. , Joyce James A. , Levin Nathan W.
Published: January 2010

Hepatitis C virus (HCV) infection can be cured by standard pegylated interferon (IFN) + ribavirin drug therapy in 30–50% of treatment-naïve genotype 1 HCV patients. Cure rate is defined as a sustained viral response measured 6 months after the end of treatment. Recently, Fujiwara et al. [Hepatol Res 2007;37:701–710], using a double-filtration plasmapheresis (DFPP) technique, showed that simple physical reduction in circulating HCV using a 1-week pretreatment increased the cure rate for treatment-naïve type 1 HCV patients from 50 (controls) to 78% (treated). For previous nonresponders, the cure rate increased from 30 to 71%. This effect occurs even though the DFPP per treatment HCV viral load reduction averaged 26%. In clinical studies discussed here, a lectin affinity plasmapheresis (LAP) device caused an estimated 41% decrease in viral load as previously reported. A more detailed analysis using normalized data to correct for any variations in initial viral load gave an average 29% per treatment viral load reduction in 5 HCV-positive dialysis patients. The latter data indicate that continuous application of LAP could bring HCV viral load to undetectable levels in 4.1 days. Compared to DFPP, the LAP approach has the advantage that no plasma losses are incurred. In addition hemopurification can be carried out for extended periods of time analogous to continuous renal replacement therapy for the treatment of acute kidney failure, making the process much more effective. Calculations based on these data predict that continuous hemopurification would substantially increase the rate of viral load reduction (approx. 14-fold) and therefore increase the cure rate for HCV standard-of-care drug therapies without adding additional drugs and their associated side effects.
Cross-Linked Hyaluronic Acid Films to Reduce Intra-Abdominal Postsurgical Adhesions in an Experimental Model
Authors: Falabella Christine A. , Chen Weiliam
Published: January 2010

Background/Aims: Intra-abdominal adhesions typically occur after surgically damaged tissues are situated in apposition, leading to fibrotic connections. The goal of this study was to demonstrate the in vivo efficacy of a cross-linked and insoluble hyaluronic acid (HA) film to reduce postsurgical adhesion in a rat model. Methods: To measure in vitro adhesion resistance, porcine monocytes were deposited on the surface of films and their attachment was monitored by scanning electron microscopy. A rat cecum abrasion and abdominal insult model was utilized to demonstrate in vivo efficacy. Briefly, an HA film was deployed as a barrier between the damaged cecal and abdominal tissue surfaces for 21 days; control animals did not receive treatment. At the study conclusion, the rats were sacrificed and the degree of adhesion was determined using a scale from 0 to 3, where 0 = no adhesion and 3 = severe fibrosis. Results: HA films resisted monocyte adhesion in vitro. The in vivo study results demonstrated a significantly lower mean adhesion score (0.625 ± 0.517) with HA film treatment compared to the controls (2.09 ± 1.22). Conclusion: Placement of HA films between injured tissues significantly decreases the severity of abdominal adhesions. Furthermore, the HA film’s resistance to monocyte adhesion could be contributory to lowering in vivo adhesion scores.
Neutrophil Gelatinase-Associated Lipocalin in Dialyzed Patients Is Related to Residual Renal Function, Type of Renal Replacement Therapy and Inflammation
Authors: Malyszko Jolanta , Malyszko Jacek S. , Koc-Zorawska Ewa , Kozminski Piotr , Mysliwiec Michal
Published: January 2010

Neutrophil gelatinase-associated lipocalin (NGAL) has recently been proved useful in the quantitation of chronic kidney disease. A cross-sectional study was performed to assess NGAL in serum, urine and ultrafiltrate in relation to the type of renal replacement therapy and NGAL correlations with renal function and markers of inflammation. Methods: NGAL, hsCRP, TNFα, and IL-6 were measured using commercially available kits in 200 patients on hemodialysis (HD), 17 on hemodiafiltration (HDF). Results: Patients on HDF had lower serum NGAL than those on HD. In hemodialyzed patients with residual renal function, serum NGAL was significantly lower than in anuric patients. NGAL was significantly higher in patients dialyzed on modified cellulose dialyzers versus polysulphone dialyzers. NGAL correlated with age, residual renal function, hsCRP, IL-6, TNF-α, time on HD, ferritin, TSAT, creatinine, urea, urea reduction ratio, and Kt/V in hemodialyzed patients. In multiple regression analysis, residual renal function and hsCRP were predictors of NGAL in hemodialyzed patients. NGAL correlated with hsCRP and creatinine in HDF patients. Conclusions: Residual renal function seems to play a pivotal role in NGAL levels in dialyzed patients. Low-grade inflammation, more pronounced in anuric patients may also contribute to elevated NGAL. Removal of NGAL with ultrafiltrate may also partially explain its lower concentration after dialysis.
Protease Imaging of Human Atheromata Captures Molecular Information of Atherosclerosis, Complementing Anatomic Imaging
Authors: Kim Dong-Eog , Kim Jeong-Yeon , Schellingerhout Dawid , Kim Eo-Jin , Kim Hyang Kyoung , Lee Seulki , Kim Kwangmeyung , Kwon Ick Chan , Shon Soo-Min , Jeong Sang-Wuk , Im So-Hyang , Lee Dong Kun , Lee Myoung Mook , Kim Geun-Eun
Published: January 2010

Objective—

There is hope that molecular imaging can identify vulnerable atherosclerotic plaques. However, there is a paucity of clinical translational data to guide the future development of this field. Here, we cross-correlate cathepsin-B or matrix metalloproteinase-2/-9 molecular optical imaging data of human atheromata or emboli with conventional imaging data, clinical data, and histopathologic data.

Methods and Results—

Fifty-two patients undergoing carotid endarterectomy (41 atheromata) or carotid stenting (15 captured emboli) were studied with protease-activatable imaging probes. We show that protease-related fluorescent signal in carotid atheromata or in emboli closely reflects the pathophysiologic alterations of plaque inflammation and statin-mediated therapeutic effects on plaque inflammation. Inflammation-related fluorescent signal was observed in the carotid bifurcation area and around ulcero-hemorrhagic lesions. Pathologically proven unstable plaques had high cathepsin-B–related fluorescent signal. The distribution patterns of the mean cathepsin-B imaging signals showed a difference between the symptomatic vs asymptomatic plaque groups. However, the degree of carotid stenosis or ultrasonographic echodensity was weakly correlated with the inflammatory proteolytic enzyme-related signal, suggesting that molecular imaging yields complimentary new information not available to conventional imaging.

Conclusion—

These results could justify and facilitate clinical trials to evaluate the use of protease-sensing molecular optical imaging in human atherosclerosis patients.
c-Jun N-Terminal Kinase Primes Endothelial Cells at Atheroprone Sites for Apoptosis
Authors: Chaudhury Hera , Zakkar Mustafa , Boyle Joseph , Cuhlmann Simon , van der Heiden Kim , Luong Le Anh , Davis Jeremy , Platt Adam , Mason Justin C. , Krams Rob , Haskard Dorian O. , Clark Andrew R. , Evans Paul C.
Published: January 2010

Objective—

Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree. Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites.

Methods and Results—

We identified transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays. This approach and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1
−/−
, and MKP-1
−/−
mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1.

Conclusion—

Spatial variation of JNK1 activity delineates the spatial distribution of apoptosis and turnover of EC in arteries.
Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response
Authors: Li Xuehua , Syrovets Tatiana , Genze Felicitas , Pitterle Kai , Oberhuber Alexander , Orend Karl-Heinz , Simmet Thomas
Published: January 2010

Objective—

Dendritic cells (DC) accumulate in atherosclerotic arteries where they can modulate atherogenesis. We investigated whether plasmin might alter the function of human DC.

Methods and Results—

Stimulation of monocyte-derived DC with plasmin elicited a time-dependent actin polymerization and chemotaxis comparable to that triggered by the standard chemoattractant formyl-methionyl-leucyl-phenylalanine. Plasmin triggered rapid activation of Akt and mitogen-activated protein kinases, followed by phosphorylation of the regulatory myosin light chain and chemotaxis. For the chemotactic DC migration, the activation of Akt and p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases were indispensable, as shown by pharmacological inhibitors. DC express Akt1 and Akt2, but not Akt3. However, in DC, plasmin activates exclusively Akt2 via a p38 mitogen-activated protein kinase-dependent pathway. Accordingly, knockdown of Akt2 with short-hairpin RNA, but not of Akt1, blocked the plasmin-induced extracellular signal-regulated kinase 1/2 activation and the chemotactic response. Moreover, plasmin-stimulated DC induced polarization of CD4
+
T cells toward the interferon-γ–producing, proinflammatory Th1 phenotype. Consistent with a role for DC and adaptive immune response in atherogenesis, we demonstrate DC in human atherosclerotic vessels and show that plasmin is abundant in human atherosclerotic lesions, where it colocalizes with DC.

Conclusion—

Plasmin generation in the atherosclerotic vessel wall might contribute to accumulation of DC, activation of the adaptive immune response, and aggravation of atherosclerosis.
CaMKII-Dependent Diastolic SR Ca
2+
Leak and Elevated Diastolic Ca
2+
Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation
Authors: Neef Stefan , Dybkova Nataliya , Sossalla Samuel , Ort Katharina R. , Fluschnik Nina , Neumann Kay , Seipelt Ralf , Schöndube Friedrich A. , Hasenfuss Gerd , Maier Lars S.
Published: January 2010

Rationale
:

Although research suggests that diastolic Ca
2+
levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca
2+
leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca
2+
levels and play a role in triggering or maintaining AF by transient inward currents through Na
+
/Ca
2+
exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca
2+
/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca
2+
leak.

Objective
:

We tested the hypothesis that CaMKII-dependent diastolic SR Ca
2+
leak and elevated diastolic Ca
2+
levels occurs in atrial myocardium of patients with AF.

Methods and Results
:

We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40±14% (
P
<0.05), as well as CaMKII phosphorylation by 33±12% (
P
<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110±53%. Furthermore, cytosolic Ca
2+
levels were elevated during diastole (229±20 versus 164±8 nmol/L,
P
<0.05). Most likely, this resulted from an increased SR Ca
2+
leak in AF (
P
<0.05), which was not attributable to higher SR Ca
2+
load. Tetracaine experiments confirmed that SR Ca
2+
leak through RyR2 leads to the elevated diastolic Ca
2+
level. CaMKII inhibition normalized SR Ca
2+
leak and cytosolic Ca
2+
levels without changes in L-type Ca
2+
current.

Conclusion
:

Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca
2+
leak in human AF, causing elevated cytosolic Ca
2+
levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.
Involvement of Phosphoinositide 3-Kinase γ in Angiogenesis and Healing of Experimental Myocardial Infarction in Mice
Authors: Siragusa Mauro , Katare Rajesh , Meloni Marco , Damilano Federico , Hirsch Emilio , Emanueli Costanza , Madeddu Paolo
Published: January 2010

Rationale
:

Phosphoinositide 3-kinase (PI3K)γ is expressed in hematopoietic cells, endothelial cells (ECs), and cardiomyocytes and regulates different cellular functions relevant to inflammation, tissue remodeling and cicatrization. Recently, PI3Kγ inhibitors have been indicated for the treatment of chronic inflammatory/autoimmune diseases and atherosclerosis.

Objective
:

We aimed to determine PI3Kγ contribution to the angiogenic capacity of ECs and the effect of PI3Kγ inhibition on healing of myocardial infarction (MI).

Methods and Results
:

Human umbilical ECs were treated with a selective PI3Kγ inhibitor, AS605240, or a pan-phosphoinositide 3-kinases inhibitor, LY294002. Both inhibitory treatments and small interfering RNA–mediated PI3Kγ knockdown strongly impaired ECs angiogenic capacity, because of suppression of the PI3K/Akt and mitogen-activated protein kinase pathways. Constitutive activation of Akt rescued the angiogenic defect. Reparative angiogenesis was studied in vivo in a model of MI. AS605240 did not affect MI-induced PI3Kγ upregulation, whereas it suppressed Akt activation and downstream signaling. AS605240 strongly reduced inflammation, enhanced cardiomyocyte apoptosis, and impaired survival and proliferation of ECs in peri-infarct zone, which resulted in defective reparative neovascularization. As a consequence, AS605240-treated MI hearts showed increased infarct size and impaired recovery of left ventricular function. Similarly,
PI3K
γ-deficient mice showed impaired reparative neovascularization, enhanced cardiomyocyte apoptosis and marked deterioration of cardiac function following MI. Mice expressing catalytically inactive
PI3K
γ also failed to mount a proper neovascularization, although cardiac dysfunction was similar to wild-type controls.

Conclusions
:

PI3Kγ expression and catalytic activity are involved at different levels in reparative neovascularization and healing of MI.
Angiotensin II Inhibits Neuronal Nitric Oxide Synthase Activation Through the ERK1/2-RSK Signaling Pathway to Modulate Central Control of Blood Pressure
Authors: Cheng Wen-Han , Lu Pei-Jung , Ho Wen-Yu , Tung Che-Se , Cheng Pei-Wen , Hsiao Michael , Tseng Ching-Jiunn
Published: January 2010

Rationale:Angiotensin (Ang) II exerts diverse physiological actions in both the peripheral and central neural systems. It was reported that the activity of Ang II is higher in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and that angiotensin type-1 receptors are colocalized with NAD(P)H oxidase in the neurons of the NTS, resulting in the induction of local reactive oxygen species production by Ang II. However, the signaling mechanisms of Ang II that induce hypertension remain unclear.

Objective:The aim of this study was to investigate the possible signaling pathways involved in Ang II–mediated blood pressure regulation in the NTS.

Methods and Results:Male SHRs were treated with losartan or tempol for 2 weeks, after which systolic blood pressure was observed to decrease significantly. Dihydroethidium staining showed many cells with high reactive oxygen species in the NTS of SHRs. The addition of losartan or tempol decreased the numbers of reactive oxygen species–positive cells in the NTS. The systemic administration of losartan or tempol reduced the systolic blood pressure and increased NO production. Immunoblotting and immunohistochemical analysis further showed that inhibition of Ang II activity by losartan or tempol significantly increased the expression extracellular signal-regulated kinase (ERK)1/2, ribosomal protein S6 kinase (RSK), and also increased neuronal NO synthase (nNOS) phosphorylation. RSK was also found to bind directly to nNOS and induce phosphorylation at the Ser1416 position.

Conclusions:Taken together, these results suggest that the ERK1/2-RSK-nNOS signaling pathway may play a significant role in Ang II–mediated central blood pressure regulation.
Comparison of Bone Marrow Stromal Cells Derived From Stroke and Normal Rats for Stroke Treatment
Authors: Zacharek Alex , Shehadah Amjad , Chen Jieli , Cui Xu , Roberts Cynthia , Lu Mei , Chopp Michael
Published: January 2010

Background and Purpose—

We compared the effect of treatment of stroke with bone marrow stromal cells from stroke rats (Isch-BMSC) and normal rats (Nor-BMSC) on functional outcome.

Methods—

Isch-BMSCs and Nor-BMSCs were intravenously injected into rats 24 hours after middle cerebral artery occlusion. To test the mechanism of Isch-BMSC-enhanced neurorestoration, Isch-BMSC and Nor-BMSC cultures were used.

Results—

Isch-BMSC significantly promoted functional outcome and enhanced angiogenesis, arterial density, and axonal regeneration compared with Nor-BMSC treatment animals. Isch-BMSCs exhibited increased Angiopoietin-1, Tie2, basic fibroblast growth factor, glial cell-derived neurotrophic factor, vascular endothelial growth factor, and Flk1 gene expression compared with Nor-BMSC. Using transwell coculture of BMSCs with brain-derived endothelial cells, Isch-BMSCs increased phosphorylated-Tie2 activity in brain-derived endothelial cells and enhanced brain-derived endothelial cells capillary tube formation compared with Nor-BMSCs. Inhibition of Tie2 gene expression in brain-derived endothelial cells using siRNA significantly attenuated BMSC-induced capillary tube formation.

Conclusions—

These data suggest that Isch-BMSCs are superior to Nor-BMSCs for the neurorestorative treatment of stroke, which may be mediated by the enhanced trophic factor and angiogenic characteristics of Isch-BMSCs.
Decentralized local governance in fragile states: learning from Iraq
Authors: Brinkerhoff Derick W. , Johnson Ronald W.
Published: January 2010

This article examines the role that local governance plays in creating an effective state and in building constructive state—society relations. Reconstruction efforts in fragile, post-conflict states have focused largely on central government, yet decentralized local authorities offer a number of positive features. Looking at the governance reconstruction experience in Iraq, the analysis explores the extent to which these positive features have characterized Iraqi sub-national government. The article draws lessons for governance reconstruction more generally, addressing decentralization choices, capacity-building, and political factors.

Points for practitioners

In fragile, post-conflict states, good governance reconstruction agendas often aim too high. Targeting good enough governance solutions is more realistic. Decentralized local governance can be integral to such solutions, and offers several advantages to counter problems that central governments face: weak roots beyond the center, poor distribution of services, and weak national integration. Experience shows that local governments can increase speed of service delivery, address ethnic/regional inequities, build democratic and conflict management capacities, mitigate political conflict, experiment to find creative solutions, and enhance legitimacy. We examine governance reconstruction in Iraq in terms of how efforts to build local governance have resulted in these positive outcomes. The Iraq case offers some support for our argument that in fragile, post-conflict states, decentralized local governance is an important feature of good enough governance.
Public administration and governance: a sector-level analysis of World Bank aid
Authors: Moloney Kim
Published: January 2010

This article turns the question about socioeconomic development away from its usual goal of economic growth and argues that governance is another appropriate measure of economic development. Instead of econometric analyses of country-level data, this article shows how aggregating project-level data to a sector-based approach is a new methodological tool for determining whether project and policy objectives translate into improved governance. Using the World Bank’s public administration, law and justice projects and panel-corrected time series, this article finds that the World Bank’s public administration, law and justice projects inconsistently improve governance. failures. Policy prescriptions removed from implementation considerations may limit public sector management project effectiveness.

Points for practitioners (1) Foreign aid evaluation is assisted by sector-specific analyses. This is comple- mentary to traditional foreign aid evaluations’ focus on countries in general. (2) The World Bank’s Public Sector Management projects inconsistently improve a client country’s governance environment. (3) The World Bank’s ‘efficiency’ assumptions and partial understanding of public administration’s models may contribute to uneven project performances. (4) Certain public sector management projects neg- atively impact rule of law and the control of corruption. (5) Foreign aid researchers should re-engage their understanding of project outcomes and implementation
What Do Transnational Terrorists Target? Has It Changed? Are We Safer?
Authors: Brandt Patrick T. , Sandler Todd
Published: January 2010

This article utilizes Bayesian Poisson changepoint regression models to demonstrate how transnational terrorists adjusted their target choices in response to target hardening. In addition, changes in the collective tastes of terrorists and their sponsorship have played a role in target selection over time. For each of four target types— officials, military, business, and private parties—the authors identify the number of regimes and the probable predictors of the events. Regime changes are tied to the rise of modern transnational terrorism, the deployment of technological barriers, the start of state sponsorship, and the dominance of the fundamentalists. The authors also include two sets of covariates—logistical outcome and victim’s nature—to better explain the dynamics. As other targets have been fortified and terrorists have sought greater carnage, private parties have become the preferred target type. In recent years, terrorists have increasingly favored people over property for all target types. Moreover, authorities have been more successful at stopping attacks against officials and the military, thereby motivating terrorists to attack business targets and private parties.
Foreign Aid Versus Military Intervention in the War on Terror
Authors: Azam Jean-Paul , Thelen Véronique
Published: January 2010

This article presents a theoretical framework and some empirical results showing that the level of foreign aid received reduces the supply of terrorist attacks from recipient countries, while U.S. military interventions are liable to increase this supply. Due account is taken of endogeneity problems in producing these results. They suggest that Western democracies, which are the main targets of terrorist attacks, should invest more funds in foreign aid, with a special emphasis on supporting education, and use military interventions more sparingly.
Legislative Constraints: A Path to Peace?
Authors: Choi Seung-Whan
Published: January 2010

Tsebelis’ veto players theory predicts that legislative veto players constrain the executive’s political decisions because their approval is needed to implement policy change. This study extends the veto players argument into international conflict literature, specifically in regard to legislative constraints emanating from the number of legislative veto players, their policy preferences, and their internal cohesion. A cross-sectional, time-series dyadic data analysis shows that, in general, an increase of legislative constraints notably reduces the likelihood of the onset of militarized interstate disputes. However, while legislative constraints in democratic and mixed dyads are likely to discourage democratic executives’ use of force, those in autocratic dyads do not produce effective pacifying effects.
Trajectories of Offending and Their Relation to Life Failure in Late Middle Age: Findings from the Cambridge Study in Delinquent Development
Authors: Piquero Alex R. , Farrington David P. , Nagin Daniel S. , Moffitt Terrie E.
Published: January 2010

Researchers have hypothesized that over the life course, criminal offending varies with problems in other domains, including life failure and physical and mental health.To examine this issue, the authors use data from the Cambridge Study in Delinquent Development, a prospective longitudinal survey of 411 South London males first studied at age 8 in 1961. Developmental trajectories of criminal activity were defined on the basis of conviction records through age 40, and these were used to predict self-report measures of life failure at age 48 obtained during personal interviews. Results indicate that offending in the first 40 years of life relates to life failure, that childhood risk factors are also implicated in adult life outcomes, and that differences emerge in how offender trajectories predict life failure after controlling for individual and environmental risk factors. This is the first longitudinal investigation to show that chronic offending is associated with life failure into the late 40s, an age period not previously reported, and it also shows that different offending trajectories have different outcomes in late middle age.
Vacationers and eWOM: Who Posts, and Why, Where, and What?
Authors: Bronner Fred , de Hoog Robert
Published: January 2010

Vacationers not only read and use information from the Internet during their choice process, but also post information on the Internet. This posted information is described as eWOM (electronic word of mouth). The central questions are, which type of vacationers do post, with which motivations do they post reviews, on which type of site, and what are the message characteristics? These questions are approached in a way that differs from the usual site-centered approach. It is topic-centered and independent of a specific review site, and it focuses on motivations for all vacation sites. The conclusion is that why a vacationer makes a contribution influences the choice of a site to which he or she contributes and what he or she contributes. The main discriminating motivational factor is the one that sets vacationers with a primarily self-directed motivation apart from those with a more other-directed help motivation. Implications for tourism research and vacation marketing are discussed.
Analyzing Tourist Consumption: A Dynamic System-of-Equations Approach
Authors: Chenguang Wu Doris , Gang Li  , Haiyan Song
Published: January 2010

The dynamic system-of-equations approach has been used to analyze the demand for outbound tourism among a number of destinations. However, this approach has not been applied to the context of the tourist consumption of different products in a given destination. Given the importance of understanding tourists’ consumption behavior to destination management, this study seeks to gain new insights into Hong Kong inbound tourist expenditure patterns using a dynamic system-of-equations approach: the almost ideal demand system model. Based on the estimation of a complete demand system, this study investigates the interactions among the demand for different tourism products (i.e., shopping, hotel accommodation, meals outside hotels, and other) and the impacts of price changes on demand. Tourists from different source markets are examined separately, and the results show that their consumption behavior differs significantly.